Multishot versus Single-Shot Pulse Sequences in Very High Field fMRI: A Comparison Using Retinotopic Mapping

High-resolution functional MRI is a leading application for very high field (7 Tesla) human MR imaging. Though higher field strengths promise improvements in signal-to-noise ratios (SNR) and BOLD contrast relative to fMRI at 3 Tesla, these benefits may be partially offset by accompanying increases in geometric distortion and other off-resonance effects. Such effects may be especially pronounced with the single-shot EPI pulse sequences typically used for fMRI at standard field strengths. As an alternative, one might consider multishot pulse sequences, which may lead to somewhat lower temporal SNR than standard EPI, but which are also often substantially less susceptible to off-resonance effects. Here we consider retinotopic mapping of human visual cortex as a practical test case by which to compare examples of these sequence types for high-resolution fMRI at 7 Tesla. We performed polar angle retinotopic mapping at each of 3 isotropic resolutions (2.0, 1.7, and 1.1 mm) using both accelerated single-shot 2D EPI and accelerated multishot 3D gradient-echo pulse sequences. We found that single-shot EPI indeed led to greater temporal SNR and contrast-to-noise ratios (CNR) than the multishot sequences. However, additional distortion correction in postprocessing was required in order to fully realize these advantages, particularly at higher resolutions. The retinotopic maps produced by both sequence types were qualitatively comparable, and showed equivalent test/retest reliability. Thus, when surface-based analyses are planned, or in other circumstances where geometric distortion is of particular concern, multishot pulse sequences could provide a viable alternative to single-shot EPI

Neural protection by naturopathic compounds—an example of tetramethylpyrazine from retina to brain

Given the advantages of being stable in the ambient environment, being permeable to the blood–brain and/or blood–eye barriers and being convenient for administration, naturopathic compounds have growingly become promising therapeutic candidates for neural protection. Extracted from one of the most common Chinese herbal medicines, tetramethylpyrazine (TMP), also designated as ligustrazine, has been suggested to be neuroprotective in the central nervous system as well as the peripheral nerve network. Although the detailed molecular mechanisms of its efficacy for neural protection are understood limitedly, accumulating evidence suggests that antioxidative stress, antagonism for calcium, and suppression of pro-inflammatory factors contribute significantly to its neuroprotection. In animal studies, systemic administration of TMP (subcutaneous injection, 50 mg/kg) significantly blocked neuronal degeneration in hippocampus as well as the other vulnerable regions in brains of Sprague–Dawley rats following kainate-induced prolonged seizures. Results from us and others also demonstrated potent neuroprotective efficacy of TMP for retinal cells and robust benefits for brain in Alzheimer’s disease or other brain injury. These results suggest a promising prospect for TMP to be used as a treatment of specific neurodegenerative diseases. Given the assessment of the distribution, metabolism, excretion, and toxicity information that is already available on most neuroprotective naturopathic compounds such as TMP, it would not take much preclinical data to justify bringing such therapeutic compounds to clinical trials in humans

Plasmids and Rickettsial Evolution: Insight from Rickettsia felis

BACKGROUND: The genome sequence of Rickettsia felis revealed a number of rickettsial genetic anomalies that likely contribute not only to a large genome size relative to other rickettsiae, but also to phenotypic oddities that have confounded the categorization of R. felis as either typhus group (TG) or spotted fever group (SFG) rickettsiae. Most intriguing was the first report from rickettsiae of a conjugative plasmid (pRF) that contains 68 putative open reading frames, several of which are predicted to encode proteins with high similarity to conjugative machinery in other plasmid-containing bacteria. METHODOLOGY/PRINCIPAL FINDINGS: Using phylogeny estimation, we determined the mode of inheritance of pRF genes relative to conserved rickettsial chromosomal genes. Phylogenies of chromosomal genes were in agreement with other published rickettsial trees. However, phylogenies including pRF genes yielded different topologies and suggest a close relationship between pRF and ancestral group (AG) rickettsiae, including the recently completed genome of R. bellii str. RML369-C. This relatedness is further supported by the distribution of pRF genes across other rickettsiae, as 10 pRF genes (or inactive derivatives) also occur in AG (but not SFG) rickettsiae, with five of these genes characteristic of typical plasmids. Detailed characterization of pRF genes resulted in two novel findings: the identification of oriV and replication termination regions, and the likelihood that a second proposed plasmid, pRFδ, is an artifact of the original genome assembly. CONCLUSION/SIGNIFICANCE: Altogether, we propose a new rickettsial classification scheme with the addition of a fourth lineage, transitional group (TRG) rickettsiae, that is unique from TG and SFG rickettsiae and harbors genes from possible exchanges with AG rickettsiae via conjugation. We offer insight into the evolution of a plastic plasmid system in rickettsiae, including the role plasmids may have played in the acquirement of virulence traits in pathogenic strains, and the likely origin of plasmids within the rickettsial tree

Alexithymia may explain the relationship between autistic traits and eating disorder psychopathology

Background: Autistic people are disproportionately vulnerable to anorexia nervosa and other eating disorders (ED), and within the general population, autistic traits correlate with ED psychopathology. A putative mechanism which may underpin this heightened risk is alexithymia, a difficulty identifying and describing emotional states which is observed in both autism and ED. In two experiments with independent non-clinical samples, we explored whether alexithymia might mediate the heightened risk of eating psychopathology in individuals high in autistic traits. Methods: Our first experiment used the PROCESS macro for SPSS to examine relationships between alexithymia (measured by the Toronto Alexithymia Scale (TAS-20)), autistic traits (autism quotient (AQ)), and eating psychopathology (Eating Attitudes Test (EAT-26)) in 121 participants. Our second experiment (n = 300) replicated and furthered this analysis by examining moderating effects of sex and controlling for anxiety and depression as covariates. We also included an additional performance-based measure of alexithymia, the Levels of Emotional Awareness Scale (LEAS). Results: Study 1 suggested that TAS-20 scores mediated the relationship between heightened autistic traits and eating psychopathology. Replication and further scrutiny of this finding, in study 2, revealed that this mediation effect was partial and specific to the female participants in this sample. The mediation effect appeared to be carried by the difficulty identifying feelings subscale of the TAS-20, even when depression and anxiety were controlled for. LEAS scores, however, were not significantly related to autistic traits or eating psychopathology. Limitations: Cross-sectional data prevents any conclusions around the direction and causality of relationships between alexithymia, autistic traits, and eating psychopathology (alongside depression and anxiety), necessitating longitudinal research. Our non-clinical sample was predominantly Caucasian undergraduate students, so it remains to be seen if these results would extrapolate to clinical and/or autistic samples. Divergence between the TAS-20 and LEAS raises crucial questions regarding the construct validity of these measures. Conclusions: Our findings with respect to autistic traits suggest that alexithymia could partially explain the prevalence of ED in autistic people and may as such be an important consideration in the pathogenesis and treatment of ED in autistic and non-autistic people alike. Further research with clinical samples is critical to explore these ideas. Differences between men and women, furthermore, emphasize the importance of looking for sexspecific as well as generic risk factors in autistic and non-autistic men and women

Higher CO₂ concentrations increase extreme event risk in a 1.5 °c world

The Paris Agreement1 aims to ‘pursue efforts to limit the temperature increase to 1.5°C above pre-industrial levels.’ However, it has been suggested that temperature targets alone are unable to limit the risks associated with anthropogenic emissions2, 3. Here, using an ensemble of model simulations, we show that atmospheric CO2 increase - a more predictable consequence of emissions compared to global temperature increase - has a significant impact on Northern Hemisphere summer temperature, heat stress, and tropical precipitation extremes. Hence in an iterative climate mitigation regime aiming solely for a specific temperature goal, an unexpectedly low climate response may have corresponding ‘dangerous’ changes in extreme events. The direct impact of higher CO2 concentrations on climate extremes therefore substantially reduces the upper bound of the carbon budget, and highlights the need to explicitly limit atmospheric CO2 concentration when formulating allowable emissions. Thus, complementing global mean temperature goals with explicit limits on atmospheric CO2 concentrations in future climate policy would reduce the adverse effects of high-impact weather extremes

An Anomalous Type IV Secretion System in Rickettsia Is Evolutionarily Conserved

Bacterial type IV secretion systems (T4SSs) comprise a diverse transporter family functioning in conjugation, competence, and effector molecule (DNA and/or protein) translocation. Thirteen genome sequences from Rickettsia, obligate intracellular symbionts/pathogens of a wide range of eukaryotes, have revealed a reduced T4SS relative to the Agrobacterium tumefaciens archetype (vir). However, the Rickettsia T4SS has not been functionally characterized for its role in symbiosis/virulence, and none of its substrates are known.Superimposition of T4SS structural/functional information over previously identified Rickettsia components implicate a functional Rickettsia T4SS. virB4, virB8 and virB9 are duplicated, yet only one copy of each has the conserved features of similar genes in other T4SSs. An extraordinarily duplicated VirB6 gene encodes five hydrophobic proteins conserved only in a short region known to be involved in DNA transfer in A. tumefaciens. virB1, virB2 and virB7 are newly identified, revealing a Rickettsia T4SS lacking only virB5 relative to the vir archetype. Phylogeny estimation suggests vertical inheritance of all components, despite gene rearrangements into an archipelago of five islets. Similarities of Rickettsia VirB7/VirB9 to ComB7/ComB9 proteins of epsilon-proteobacteria, as well as phylogenetic affinities to the Legionella lvh T4SS, imply the Rickettsiales ancestor acquired a vir-like locus from distantly related bacteria, perhaps while residing in a protozoan host. Modern modifications of these systems likely reflect diversification with various eukaryotic host cells.We present the rvh (Rickettsiales vir homolog) T4SS, an evolutionary conserved transporter with an unknown role in rickettsial biology. This work lays the foundation for future laboratory characterization of this system, and also identifies the Legionella lvh T4SS as a suitable genetic model

The Concise Guide to PHARMACOLOGY 2013/14: overview.

The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties from the IUPHAR database. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full. This compilation of the major pharmacological targets is divided into seven areas of focus: G protein-coupled receptors, ligand-gated ion channels, ion channels, catalytic receptors, nuclear hormone receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets. It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors & Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates

Long-Baseline Neutrino Facility (LBNF) and Deep Underground Neutrino Experiment (DUNE) Conceptual Design Report Volume 1: The LBNF and DUNE Projects

This document presents the Conceptual Design Report (CDR) put forward by an international neutrino community to pursue the Deep Underground Neutrino Experiment at the Long-Baseline Neutrino Facility (LBNF/DUNE), a groundbreaking science experiment for long-baseline neutrino oscillation studies and for neutrino astrophysics and nucleon decay searches. The DUNE far detector will be a very large modular liquid argon time-projection chamber (LArTPC) located deep underground, coupled to the LBNF multi-megawatt wide-band neutrino beam. DUNE will also have a high-resolution and high-precision near detector

Long-Baseline Neutrino Facility (LBNF) and Deep Underground Neutrino Experiment (DUNE) Conceptual Design Report, Volume 4 The DUNE Detectors at LBNF

A description of the proposed detector(s) for DUNE at LBN