Left posterior inferior frontal gyrus is causally involved in complex sentence comprehension

INTRODUCTION Storage and reordering of words are two core processes required for successful sentence comprehension. Storage is necessary whenever the verb and its arguments (i.e., subject and object) are separated over a long distance, while reordering is necessary whenever the argument order is atypical (e.g., object-first order in German, where subject-first order is typical). Previous neuroimaging work (Meyer et al., 2012) has associated storage with the left planum temporale (PT), and reordering with the left posterior inferior frontal gyrus (pIFG). However, it is unclear whether left PT and pIFG are indeed causally relevant for storage and reordering, respectively. Here, we tested the necessity of the PT and pIFG for storage and reordering using repetitive transcranial magnetic stimulation (rTMS). METHODS We applied either effective online rTMS (5 pulses at 10 Hz) over PT or pIFG, or sham rTMS, while subjects listened to sentences that independently manipulated storage demands (short vs. long argument–verb distance) and reordering demands (subject– vs. object-first argument order). We employed behavioral modeling, using a drift diffusion model, to assess rTMS-induced disruption of sentence comprehension. RESULTS We found that rTMS over pIFG, but not PT, selectively impaired reordering during the processing of sentences with a long argument–verb distance. Specifically, relative to sham rTMS, rTMS over pIFG significantly increased the performance decline for object– vs. subject-first long-distance sentences (t23 = 2.86; p = 0.009). This effect was anatomically specific as the same comparison for PT stimulation was far from significant (t23 = −0.11; p = 0.9), and a direct across-sites comparison showed that the pIFG effect was significantly stronger (t23 = −2.62; p = 0.015). CONCLUSION Our results provide the first causal evidence that the left pIFG supports the reordering of arguments in long-distance sentences. We thereby substantially extend previous neuroimaging studies that showed a correlation between pIFG activation and reordering demands. Together with previous evidence (Lauro et al., 2010), our findings indicate that the left pIFG crucially supports the comprehension of syntactically complex sentences. These results might extend to other domains, such as music (Maess et al., 2001) and action (Clerget et al., 2009), indicating a domain-general role of left pIFG in the processing of hierarchically-structured sequences

The role of the angular gyrus in semantic cognition: A synthesis of five functional neuroimaging studies

Semantic knowledge is central to human cognition. The angular gyrus (AG) is widely considered a key brain region for semantic cognition. However, the role of the AG in semantic processing is controversial. Key controversies concern response polarity (activation vs. deactivation) and its relation to task difficulty, lateralization (left vs. right AG), and functional-anatomical subdivision (PGa vs. PGp subregions). Here, we combined the fMRI data of five studies on semantic processing (n = 172) and analyzed the response profiles from the same anatomical regions-of-interest for left and right PGa and PGp. We found that the AG was consistently deactivated during non-semantic conditions, whereas response polarity during semantic conditions was inconsistent. However, the AG consistently showed relative response differences between semantic and non-semantic conditions, and between different semantic conditions. A combined analysis across all studies revealed that AG responses could be best explained by separable effects of task difficulty and semantic processing demand. Task difficulty effects were stronger in PGa than PGp, regardless of hemisphere. Semantic effects were stronger in left than right AG, regardless of subregion. These results suggest that the AG is engaged in both domain-general task-difficulty-related processes and domain-specific semantic processes. In semantic processing, we propose that left AG acts as a "multimodal convergence zone" that binds different semantic features associated with the same concept, enabling efficient access to task-relevant features

B-cell populations discriminate between pediatric- and adult-onset multiple sclerosis

Objective: To comparatively assess the B-cell composition in blood and CSF of patients with pediatric-onset multiple sclerosis (pedMS) and adult-onset multiple sclerosis (adMS). / Methods: In this cross-sectional study, we obtained blood and CSF samples from 25 patients with pedMS (8–18 years) and 40 patients with adMS (23–65 years) and blood specimens from 66 controls (1–55 years). By using multicolor flow cytometry, we identified naive, transitional, isotype class-switched memory, nonswitched memory, and double-negative memory B-cell subsets as well as plasmablasts (PB) and terminally differentiated plasma cells (PC). Flow cytometric data were compared to concentrations of B-cell-specific cytokines in serum and CSF as determined by ELISA. / Results: Frequencies of circulating naive B-cells decreased with higher age in controls but not in patients with multiple sclerosis (MS). B-cell patterns in CSF differed between pedMS and adMS with an acute relapse: in pedMS-derived CSF samples, high frequencies of nonswitched memory B cells and PB were present, whereas class-switched memory B cells and PC dominated in the CSF of patients with adMS. In pedMS, PB were also elevated in the periphery. Accumulation of PB in the CSF correlated with high intrathecal CXCL-13 levels and augmented intrathecal synthesis of immunoglobulin G and immunoglobulin M. / Conclusions: We demonstrate distinct changes in intrathecal B-cell homeostasis in patients with pedMS during active disease, which differ from those in adults by an expansion of plasmablasts in blood and CSF and similarly occur in prototypic autoantibody-driven autoimmune disorders. This emphasizes the particular importance of activated B-lymphocyte subsets for disease progression in the earliest clinical stages of MS

Structure and function of the bacterial heterodimeric ABC transporter CydDC: stimulation of ATPase activity by thiol and heme compounds.

In Escherichia coli, the biogenesis of both cytochrome bd-type quinol oxidases and periplasmic cytochromes requires the ATP-binding cassette-type cysteine/GSH transporter, CydDC. Recombinant CydDC was purified as a heterodimer and found to be an active ATPase both in soluble form with detergent and when reconstituted into a lipid environment. Two-dimensional crystals of CydDC were analyzed by electron cryomicroscopy, and the protein was shown to be made up of two non-identical domains corresponding to the putative CydD and CydC subunits, with dimensions characteristic of other ATP-binding cassette transporters. CydDC binds heme b. Detergent-solubilized CydDC appears to adopt at least two structural states, each associated with a characteristic level of bound heme. The purified protein in detergent showed a weak basal ATPase activity (approximately 100 nmol Pi/min/mg) that was stimulated ∼3-fold by various thiol compounds, suggesting that CydDC could act as a thiol transporter. The presence of heme (either intrinsic or added in the form of hemin) led to a further enhancement of thiol-stimulated ATPase activity, although a large excess of heme inhibited activity. Similar responses of the ATPase activity were observed with CydDC reconstituted into E. coli lipids. These results suggest that heme may have a regulatory role in CydDC-mediated transmembrane thiol transport

Gold chain formation via local lifting of surface reconstruction by hot electron injection on H_2(D_2)/Au(111)

The hexagonal close packed surface of gold shows a 22 x root 3 "herringbone" surface reconstruction which makes it unique among the (111) surfaces of all metals. This long-range energetically favored dislocation pattern appears in response to the strong tensile stress that would be present on the unreconstructed surface. Adsorption of molecular and atomic species can be used to tune this surface stress and lift the herringbone reconstruction. Here we show that herringbone reconstruction can be controllably lifted in ultrahigh vacuum at cryogenic temperatures by precise hot electron injection in the presence of hydrogen molecules. We use the sharp tip of a scanning tunneling microscope (STM) for charge carrier injection and characterization of the resulting chain nanostructures. By comparing STM images, rotational spectromicroscopy and ab initio calculations, we show that formation of gold atomic chains is associated with release of gold atoms from the surface, lifting of the reconstruction, dissociation of H_2 molecules, and formation of surface hydrides. Gold hydrides grow in a zipper-like mechanism forming chains along the [1 (1) over bar0] directions of the Au(111) surface and can be manipulated by further electron injection. Finally, we demonstrate that Au(111) terraces can be transformed with nearly perfect terrace selectivity over distances of hundreds of nanometers

Structures and functions of mitochondrial ABC transporters

A small number of physiologically important ATP-binding cassette (ABC) transporters are found in mitochondria. Most are half transporters of the B group forming homodimers and their topology suggests they function as exporters. The results of mutant studies point towards involvement in iron cofactor biosynthesis. In particular, ABC subfamily B member 7 (ABCB7) and its homologues in yeast and plants are required for iron-sulfur (Fe-S) cluster biosynthesis outside of the mitochondria, whereas ABCB10 is involved in haem biosynthesis. They also play a role in preventing oxidative stress. Mutations in ABCB6 and ABCB7 have been linked to human disease. Recent crystal structures of yeast Atm1 and human ABCB10 have been key to identifying substrate-binding sites and transport mechanisms. Combined with in vitro and in vivo studies, progress is being made to find the physiological substrates of the different mitochondrial ABC transporters

Coupled Contagion Dynamics of Fear and Disease: Mathematical and Computational Explorations

Background: In classical mathematical epidemiology, individuals do not adapt their contact behavior during epidemics. They do not endogenously engage, for example, in social distancing based on fear. Yet, adaptive behavior is welldocumented in true epidemics. We explore the effect of including such behavior in models of epidemic dynamics. Methodology/Principal Findings: Using both nonlinear dynamical systems and agent-based computation, we model two interacting contagion processes: one of disease and one of fear of the disease. Individuals can ‘‘contract’ ’ fear through contact with individuals who are infected with the disease (the sick), infected with fear only (the scared), and infected with both fear and disease (the sick and scared). Scared individuals–whether sick or not–may remove themselves from circulation with some probability, which affects the contact dynamic, and thus the disease epidemic proper. If we allow individuals to recover from fear and return to circulation, the coupled dynamics become quite rich, and can include multiple waves of infection. We also study flight as a behavioral response. Conclusions/Significance: In a spatially extended setting, even relatively small levels of fear-inspired flight can have a dramatic impact on spatio-temporal epidemic dynamics. Self-isolation and spatial flight are only two of many possible actions that fear-infected individuals may take. Our main point is that behavioral adaptation of some sort must b

MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 1: Frequency, syndrome specificity, influence of disease activity, long-term course, association with AQP4-IgG, and origin

BACKGROUND: Antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) have been suggested to play a role in a subset of patients with neuromyelitis optica and related disorders. OBJECTIVE: To assess (i) the frequency of MOG-IgG in a large and predominantly Caucasian cohort of patients with optic neuritis (ON) and/or myelitis; (ii) the frequency of MOG-IgG among AQP4-IgG-positive patients and vice versa; (iii) the origin and frequency of MOG-IgG in the cerebrospinal fluid (CSF); (iv) the presence of MOG-IgG at disease onset; and (v) the influence of disease activity and treatment status on MOG-IgG titers. METHODS: 614 serum samples from patients with ON and/or myelitis and from controls, including 92 follow-up samples from 55 subjects, and 18 CSF samples were tested for MOG-IgG using a live cell-based assay (CBA) employing full-length human MOG-transfected HEK293A cells. RESULTS: MOG-IgG was detected in 95 sera from 50 patients with ON and/or myelitis, including 22/54 (40.7 %) patients with a history of both ON and myelitis, 22/103 (21.4 %) with a history of ON but no myelitis and 6/45 (13.3 %) with a history of longitudinally extensive transverse myelitis but no ON, and in 1 control patient with encephalitis and a connective tissue disorder, all of whom were negative for AQP4-IgG. MOG-IgG was absent in 221 further controls, including 83 patients with AQP4-IgG-seropositive neuromyelitis optica spectrum disorders and 85 with multiple sclerosis (MS). MOG-IgG was found in 12/18 (67 %) CSF samples from MOG-IgG-seropositive patients; the MOG-IgG-specific antibody index was negative in all cases, indicating a predominantly peripheral origin of CSF MOG-IgG. Serum and CSF MOG-IgG belonged to the complement-activating IgG1 subclass. MOG-IgG was present already at disease onset. The antibodies remained detectable in 40/45 (89 %) follow-up samples obtained over a median period of 16.5 months (range 0-123). Serum titers were higher during attacks than during remission (p < 0.0001), highest during attacks of simultaneous myelitis and ON, lowest during acute isolated ON, and declined following treatment. CONCLUSIONS: To date, this is the largest cohort studied for IgG to human full-length MOG by means of an up-to-date CBA. MOG-IgG is present in a substantial subset of patients with ON and/or myelitis, but not in classical MS. Co-existence of MOG-IgG and AQP4-IgG is highly uncommon. CSF MOG-IgG is of extrathecal origin. Serum MOG-IgG is present already at disease onset and remains detectable in the long-term course. Serum titers depend on disease activity and treatment status

Structure and magnetism of atomically thin Fe layers on flat and vicinal Pt surfaces

Ultrathin Fe films on Pt substrates have been investigated under ultrahigh vacuum conditions by scanning tunneling microscopy, low energy electron diffraction, magneto-optical Kerr effect, x-ray magnetic circular dichroism measurements, and Kerr microscopy. We present a comparison between Fe films on flat Pt(111) and stepped Pt(997), with particular focus on the magnetic anisotropy in the submonolayer thickness range below 0.2 monolayer coverage, and above the spin reorientation transition at 3 monolayer thickness. The comparison of structure and magnetism suggests that the perpendicular easy axis found for films thinner than three monolayers is due to dominating contributions from both film interfaces to the anisotropy energy. The Fe-Pt interface contribution has its origin in the hybridization of the Fe 3d with the Pt 5d band. The in-plane magnetic anisotropy above 3 atomic layers film thickness can be correlated directly with peculiarities of the film structure