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Understanding the meaning of others' actions involves mentally simulating those actions by oneself. Embodied theories of language espouse a prominent role for motor simulation in reading comprehension, especially when words, sentences, or narratives portray everyday actions. Inherent in these actions is the level of agency of the actor. Motor cortex activity in response to processing action verbs has been relatively well-established. What has been less explored, however, are: (1) the neural bases of determining whether an action is intentional or accidental (agency); and (2) whether agency influences level of motor simulation. This functional MRI study investigated how language and motor areas of the brain respond to sentences depicting intentional versus accidental action. 25 healthy adults read a series of sentences in the MRI scanner and determined whether the actions described were accidental or intentional. The main results include: (1) left hemisphere language areas (left inferior frontal gyrus, LIFG; left superior temporal gyrus, LSTG), premotor cortex (PM), and presupplementary motor area (pSMA) were strongly activated by both sentence types; (2) processing accidental action, relative to intentional action, elicited greater activity in LIFG, medial prefrontal cortex (MPFC), and left amygdala; no statistically significant activity was found in the opposite contrast; and (3) greater percent signal change was observed in LIFG while processing accidental action and in right precentral gyrus for intentional action. The results of this study support language and motor region involvement in action sentence comprehension in accordance with embodiment theories. Additionally, it provides new insight into the linguistic, integrative, and emotional demands of comprehending accidental action, its underlying neural circuitry, and its relationship to intentionality bias: the predisposition to ascribe purpose to action., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

In 2006, the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network (NINDS-CSN) Vascular Cognitive Impairment Harmonization Standards recommended a 5-Minute Protocol as a brief screening instrument for vascular cognitive impairment (VCI). We report demographically adjusted norms for the 5-Minute Protocol and its relation to other measures of cognitive function and cerebrovascular risk factors. We performed a cross-sectional analysis of 7199 stroke-free adults in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study on the NINDS-CSN 5-Minute Protocol score. Total scores on the 5-Minute Protocol were inversely correlated with age and positively correlated with years of education, and performance on the Six-Item Screener, Word List Learning, and Animal Fluency (all p-values <.001). Higher cerebrovascular risk on the Framingham Stroke Risk Profile (FSRP) was associated with lower total 5-Minute Protocol scores (p <.001). The 5-Minute Protocol also differentiated between participants with and without confirmed stroke and with and without stroke symptom histories (p <.001). The NINDS-CSN 5-Minute Protocol is a brief, easily administered screening measure that is sensitive to cerebrovascular risk and offers a valid method of screening for cognitive impairment in populations at risk for VCI.

Background: Statin use and type have been variably associated with impaired or improved cognitive performance., Hypothesis: To assess the association of statin use and type (lipophilic vs hydrophilic) and cognitive impairment., Methods: Cross-sectional analysis of 24 595 participants (7191 statin users and 17 404 nonusers) age > or = 45 years, from a population-based national cohort study (Reasons for Geographic And Racial Differences in Stroke) enrolled between January 2003 and October 2008, with oversampling from the southeastern Stroke Belt and African Americans. Statin use and type were documented in participants' homes by a trained health professional. Cognitive performance was assessed with a prior validated instrument of global cognitive status (Six-Item Screener). Cognitive impairment was defined as a score of < 4., Results: Overall, an association of cognitive impairment and statin use was observed (8.6% of users vs 7.7% of nonusers had cognitive impairment, P = 0.014); but, after adjusting for variables known to be associated with cognition (age, gender, race, income, education level, and cardiovascular disease), the association was attenuated (odds ratio [OR]: 0.98, confidence interval [CI]: 0.87-1.10). No association was observed between statin type (lipophilic vs hydrophilic) and cognition (OR: 1.03, CI: 0.86-1.24), and there were no regional differences in cognitive impairment in statin users (8% in the Stroke Belt and 7.9% in other regions, P = 0.63)., Conclusions: Statin use and type were marginally associated with cognitive impairment. After adjusting for known variables that affect cognition, no association was observed. No regional differences were observed. This large study found no evidence to support an association between statins and cognitive performance., (Copyright 2010 Wiley Periodicals, Inc.)

Mycobacterium tuberculosis possesses a diversity of potential virulence factors including complex branched lipids such as the phenolic glycolipid PGL-tb. PGL-tb expression by the clinical M. tuberculosis isolate HN878 has been associated with a less efficient Th1 response and increased virulence in mice and rabbits. It has been suggested that the W-Beijing family is the only group of M. tuberculosis strains with an intact pks1-15 gene, required for the synthesis of PGL-tb and capable of producing PGL-tb. We have found that some strains with an intact pks1-15 do not produce PGL-tb while others may produce a variant of PGL-tb. We examined the early host cytokine response to infection with these strains in vitro to better understand the effect of PGL-tb synthesis on immune responses. In addition, we generated a PGL-tb-producing H37Rv in order to determine the effect of PGL-tb production on the host immune response during infection by a strain normally devoid of PGL-tb synthesis. We observed that PGL-tb production by clinical M. tuberculosis isolates affected cytokine production differently depending on the background of the strain. Importantly, while ectopic PGL-tb production by H37Rv suppressed the induction of several pro- and anti-inflammatory cytokines in vitro in human monocytes, it did not lead to increased virulence in infected mice and rabbits. Collectively, our data indicate that, while PGL-tb may play a role in the immunogenicity and/or virulence of M. tuberculosis, it probably acts in concert with other bacterial factors which seem to be dependent on the background of the strain.

The cydAB genes from Mycobacterium smegmatis have been cloned and characterized. The cydA and cydB genes encode the two subunits of a cytochrome bd oxidase belonging to the widely distributed family of quinol oxidases found in prokaryotes. The cydD and cydC genes located immediately downstream of cydB encode a putative ATP-binding cassette-type transporter. At room temperature, reduced minus oxidized difference spectra of membranes purified from wild-type M. smegmatis displayed spectral features that are characteristic of the gamma-proteobacterial type cytochrome bd oxidase. Inactivation of cydA or cydB by insertion of a kanamycin resistance marker resulted in loss of d-heme absorbance at 631 nm. The d-heme could be restored by transformation of the M. smegmatis cyd mutants with a replicating plasmid carrying the highly homologous cydABDC gene cluster from Mycobacterium tuberculosis. Inactivation of cydA had no effect on the ability of M. smegmatis to exit from stationary phase at 37 or 42 degrees C. The growth rate of the cydA mutant was tested under oxystatic conditions. Although no discernible growth defect was observed under moderately aerobic conditions (9.2 to 37.5 x 10(2) Pa of pO(2) or 5 to 21% air saturation), the mutant displayed a significant growth disadvantage when cocultured with the wild type under extreme microaerophilia (0.8 to 1.7 x 10(2) Pa of pO(2) or 0.5 to 1% air saturation). These observations were in accordance with the two- to threefold increase in cydAB gene expression observed upon reduction of the pO(2) of the growth medium from 21 to 0.5% air saturation and with the concomitant increase in d-heme absorbance in spectra of membranes isolated from wild-type M. smegmatis cultured at 1% air saturation. Finally, the cydA mutant displayed a competitive growth disadvantage in the presence of the terminal oxidase inhibitor, cyanide, when cocultured with wild type at 21% air saturation in an oxystat. In conjunction with these findings, our results suggest that cytochrome bd is an important terminal oxidase in M. smegmatis.

Murine stress-inducible protein 1 (mSTI1) is a co-chaperone homologous with the human heat shock cognate protein 70 (hsc70)/heat shock protein 90 (hsp90)-organizing protein (Hop). The concomitant interaction of mSTI1 with hsp70 and hsp90 at its N- and C-termini respectively is mediated by the tetratricopeptide repeat (TPR) motifs in these regions. With the use of co-precipitation assays, we show here that the N-terminal TPR domain of mSTI1 without extensive flanking regions is both necessary and sufficient to mediate a specific interaction with hsc70. In contrast, other TPR-containing co-chaperones require TPR flanking regions for target substrate recognition, suggesting different mechanisms of TPR-mediated chaperone-co-chaperone interactions. Furthermore, the interaction between mSTI1 and hsc70 was analysed to ascertain the effect of replacing or deleting conserved amino acid residues and sequences within the three TPR motifs constituting the N-terminal TPR domain of full-length mSTI1. Replacement of a bulky hydrophobic residue in TPR1 disrupted the interaction of mSTI1 with hsc70. A highly conserved sequence in TPR2 was altered by deletion or single amino acid replacement. These derivatives retained a specific interaction with hsc70. These results are consistent with a model in which conserved residues within the N-terminal TPR region of mSTI1 contribute differentially to the interaction with hsc70, and in which TPR1 has a significant role in targeting mSTI1 to hsc70. The contribution of the TPR domain mutations and deletions are discussed with respect to their effect on target substrate interactions.

A review of fossil mammalian faunas from the Middle Awash indicates they span most of the later Neogene and document evolutionary change in several mammalian groups, especially Primates, Proboscidea and Artiodactyla. Oldowan artefacts first appear in the late Pliocene, while Acheulian and later industries and apparent occupation sites occur in Pleistocene beds.