You took the words right out of my mouth:Dual-fMRI reveals intra- and inter-personal neural processes supporting verbal interaction.

Verbal communication relies heavily upon mutual understanding, or common ground. Inferring the intentional states of our interaction partners is crucial in achieving this, and social neuroscience has begun elucidating the intra- and inter-personal neural processes supporting such inferences. Typically, however, neuroscientific paradigms lack the reciprocal to-and-fro characteristic of social communication, offering little insight into the way these processes operate online during real-world interaction. In the present study, we overcame this by developing a “hyperscanning” paradigm in which pairs of interactants could communicate verbally with one another in a joint-action task whilst both undergoing functional magnetic resonance imaging simultaneously. Successful performance on this task required both interlocutors to predict their partner's upcoming utterance in order to converge on the same word as each other over recursive exchanges, based only on one another's prior verbal expressions. By applying various levels of analysis to behavioural and neuroimaging data acquired from 20 dyads, three principal findings emerged: First, interlocutors converged frequently within the same semantic space, suggesting that mutual understanding had been established. Second, assessing the brain responses of each interlocutor as they planned their upcoming utterances on the basis of their co-player's previous word revealed the engagement of the temporo-parietal junctional (TPJ), precuneus and dorso-lateral pre-frontal cortex. Moreover, responses in the precuneus were modulated positively by the degree of semantic convergence achieved on each round. Second, effective connectivity among these regions indicates the crucial role of the right TPJ in this process, consistent with the Nexus model. Third, neural signals within certain nodes of this network became aligned between interacting interlocutors. We suggest this reflects an interpersonal neural process through which interactants infer and align to one another's intentional states whilst they establish a common ground

Adult patient preferences for long-acting ADHD treatments: A discrete choice experiment

Background and Objective: Treatment for attention deficit hyperactivity disorder (ADHD) requires a multifaceted approach including psychosocial interventions and pharmacological treatment. This study evaluates preferences for specific attributes associated with different long-acting stimulant treatment among US adults with ADHD. Methods: Patients completed an online, cross-sectional survey, incorporating a discrete choice experiment to assess preferences for attributes. Results: Analyses included 200 adults with ADHD (mean age 33.0 years; 60% self-reporting moderate severity); the mean (SD) Adult ADHD Self-Report Scale-v1.1 score was 45.9 (12.4). Overall, patients valued speed of onset most and risk of rebound least. Three population groups with distinct preferences were identified: side effect-driven (n=69, 35%), quick onset-driven (n=47, 24%) and quick onset and long duration-driven (n=84, 42%). Conclusion: This study shows differences in how adults with ADHD value and assess benefit-risk trade-offs when considering the desired attributes of stimulant treatments, highlighting the importance of patient-physician shared decision-making to optimize the desired benefits of individualized treatment

Nature of orchestral noise

Professional orchestral musicians are at risk of exposure to excessive noise when at work. This is an industry-wide problem that threatens not only the hearing of orchestral musicians but also the way orchestras operate. The research described in this paper recorded noise levels within a professional orchestra over three years in order to provide greater insight to the orchestral noise environment; to guide future research into orchestral noise management and hearing conservation strategies; and to provide a basis for the future education of musicians and their managers. Every rehearsal, performance, and recording from May 2004 to May 2007 was monitored, with the woodwind, brass, and percussion sections monitored in greatest detail. The study recorded dBALEQ and dBC peak data, which are presented in graphical form with accompanying summarized data tables. The findings indicate that the principal trumpet, first and third horns, and principal trombone are at greatest risk of exposure to excessive sustained noise levels and that the percussion and timpani are at greatest risk of exposure to excessive peak noise levels. However, the findings also strongly support the notion that the true nature of orchestral noise is a great deal more complex than this simple statement would imply

The Statistics of Bulk Segregant Analysis Using Next Generation Sequencing

We describe a statistical framework for QTL mapping using bulk segregant analysis (BSA) based on high throughput, short-read sequencing. Our proposed approach is based on a smoothed version of the standard statistic, and takes into account variation in allele frequency estimates due to sampling of segregants to form bulks as well as variation introduced during the sequencing of bulks. Using simulation, we explore the impact of key experimental variables such as bulk size and sequencing coverage on the ability to detect QTLs. Counterintuitively, we find that relatively large bulks maximize the power to detect QTLs even though this implies weaker selection and less extreme allele frequency differences. Our simulation studies suggest that with large bulks and sufficient sequencing depth, the methods we propose can be used to detect even weak effect QTLs and we demonstrate the utility of this framework by application to a BSA experiment in the budding yeast Saccharomyces cerevisiae

Huntingtin mediates dendritic transport of β-actin mRNA in rat neurons

Transport of mRNAs to diverse neuronal locations via RNA granules serves an important function in regulating protein synthesis within restricted sub-cellular domains. We recently detected the Huntington's disease protein huntingtin (Htt) in dendritic RNA granules; however, the functional significance of this localization is not known. Here we report that Htt and the huntingtin-associated protein 1 (HAP1) are co-localized with the microtubule motor proteins, the KIF5A kinesin and dynein, during dendritic transport of β-actin mRNA. Live cell imaging demonstrated that β-actin mRNA is associated with Htt, HAP1, and dynein intermediate chain in cultured neurons. Reduction in the levels of Htt, HAP1, KIF5A, and dynein heavy chain by lentiviral-based shRNAs resulted in a reduction in the transport of β-actin mRNA. These findings support a role for Htt in participating in the mRNA transport machinery that also contains HAP1, KIF5A, and dynein

Hepatic profile analyses of tipranavir in Phase II and III clinical trials

<p>Abstract</p> <p>Background</p> <p>The risk and course of serum transaminase elevations (TEs) and clinical hepatic serious adverse event (SAE) development in ritonavir-boosted tipranavir (TPV/r) 500/200 mg BID recipients, who also received additional combination antiretroviral treatment agents in clinical trials (TPV/r-based cART), was determined.</p> <p>Methods</p> <p>Aggregated transaminase and hepatic SAE data through 96 weeks of TPV/r-based cART from five Phase IIb/III trials were analyzed. Patients were categorized by the presence or absence of underlying liver disease (+LD or -LD). Kaplan-Meier (K-M) probability estimates for time-to-first US National Institutes of Health, Division of AIDS (DAIDS) Grade 3/4 TE and clinical hepatic SAE were determined and clinical actions/outcomes evaluated. Risk factors for DAIDS Grade 3/4 TE were identified through multivariate Cox regression statistical modeling.</p> <p>Results</p> <p>Grade 3/4 TEs occurred in 144/1299 (11.1%) patients; 123/144 (85%) of these were asymptomatic; 84% of these patients only temporarily interrupted treatment or continued, with transaminase levels returning to Grade ≤ 2. At 96 weeks of study treatment, the incidence of Grade 3/4 TEs was higher among the +LD (16.8%) than among the -LD (10.1%) patients. K-M analysis revealed an incremental risk for developing DAIDS Grade 3/4 TEs; risk was greatest through 24 weeks (6.1%), and decreasing thereafter (>24-48 weeks: 3.4%, >48 weeks-72 weeks: 2.0%, >72-96 weeks: 2.2%), and higher in +LD than -LD patients at each 24-week interval. Treatment with TPV/r, co-infection with hepatitis B and/or C, DAIDS grade >1 TE and CD4⁺> 200 cells/mm³at baseline were found to be independent risk factors for development of DAIDS Grade 3/4 TE; the hazard ratios (HR) were 2.8, 2.0, 2.1 and 1.5, respectively. Four of the 144 (2.7%) patients with Grade 3/4 TEs developed hepatic SAEs; overall, 14/1299 (1.1%) patients had hepatic SAEs including six with hepatic failure (0.5%). The K-M risk of developing hepatic SAEs through 96 weeks was 1.4%; highest risk was observed during the first 24 weeks and decreased thereafter; the risk was similar between +LD and -LD patients for the first 24 weeks (0.6% and 0.5%, respectively) and was higher for +LD patients, thereafter.</p> <p>Conclusion</p> <p>Through 96 weeks of TPV/r-based cART, DAIDS Grade 3/4 TEs and hepatic SAEs occurred in approximately 11% and 1% of TPV/r patients, respectively; most (84%) had no significant clinical implications and were managed without permanent treatment discontinuation. Among the 14 patients with hepatic SAE, 6 experienced hepatic failure (0.5%); these patients had profound immunosuppression and the rate appears higher among hepatitis co-infected patients. The overall probability of experiencing a hepatic SAE in this patient cohort was 1.4% through 96 weeks of treatment. Independent risk factors for DAIDS Grade 3/4 TEs include TPV/r treatment, co-infection with hepatitis B and/or C, DAIDS grade >1 TE and CD4⁺> 200 cells/mm³at baseline.</p> <p>Trial registration</p> <p>US-NIH Trial registration number: NCT00144170</p

Cortico-cerebellar functional connectivity and sequencing of movements in schizophrenia

<p>Abstract</p> <p>Background</p> <p>Abnormal execution of several movements in a sequence is a frequent finding in schizophrenia. Successful performance of such motor acts requires correct integration of cortico-subcortical processes, particularly those related to cerebellar functions. Abnormal connectivity between cortical and cerebellar regions with resulting cognitive dysmetria has been proposed as the core dysfunction behind many signs and symptoms of schizophrenia. The aim of the present study was to assess if these proposed abnormalities in connectivity are a unifying feature of schizophrenia, or, rather, reflect a specific symptom domain of a heterogeneous disease. We predicted that abnormal functional connectivity between the motor cortex and cerebellum would be linked with abnormal performance of movement sequencing.</p> <p>Methods</p> <p>We examined 24 schizophrenia patients (SCH) and 24 age-, sex-, and handedness-matched healthy controls (HC) using fMRI during a modified finger-tapping task. The ability to perform movement sequencing was tested using the Neurological Evaluation Scale (NES). The subjects were categorized into two groups, with (SQ+) and without (SQ-) movement sequencing abnormalities, according to the NES-SQ score. The effects of diagnosis and movement sequencing abnormalities on the functional connectivity parameters between the motor cortex and cerebellum (MC-CRBL) and the supplementary motor cortex and cerebellum (SMA-CRBL) activated during the motor task were analyzed.</p> <p>Results</p> <p>We found no effect of diagnosis on the functional connectivity measures. There was, however, a significant effect on the SQ group: SQ + patients showed a lower level of MC-CRBL connectivity than SQ- patients and healthy controls. Moreover, the level of MC-CRBL and SMA-CRBL negatively correlated with the magnitude of NES-SQ abnormalities, but with no other NES domain.</p> <p>Conclusions</p> <p>Abnormal cortico-cerebellar functional connectivity during the execution of a motor task is linked with movement sequencing abnormalities in schizophrenia, but not with the diagnosis of schizophrenia per se. It seems that specific patterns of inter-regional connectivity are linked with corresponding signs and symptoms of clinically heterogeneous conditions such as schizophrenia.</p

Two Genetic Determinants Acquired Late in Mus Evolution Regulate the Inclusion of Exon 5, which Alters Mouse APOBEC3 Translation Efficiency

Mouse apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like editing complex 3 (mA3), an intracellular antiviral factor, has 2 allelic variations that are linked with different susceptibilities to beta- and gammaretrovirus infections among various mouse strains. In virus-resistant C57BL/6 (B6) mice, mA3 transcripts are more abundant than those in susceptible BALB/c mice both in the spleen and bone marrow. These strains of mice also express mA3 transcripts with different splicing patterns: B6 mice preferentially express exon 5-deficient (Δ5) mA3 mRNA, while BALB/c mice produce exon 5-containing full-length mA3 mRNA as the major transcript. Although the protein product of the Δ5 mRNA exerts stronger antiretroviral activities than the full-length protein, how exon 5 affects mA3 antiviral activity, as well as the genetic mechanisms regulating exon 5 inclusion into the mA3 transcripts, remains largely uncharacterized. Here we show that mA3 exon 5 is indeed a functional element that influences protein synthesis at a post-transcriptional level. We further employed in vitro splicing assays using genomic DNA clones to identify two critical polymorphisms affecting the inclusion of exon 5 into mA3 transcripts: the number of TCCT repeats upstream of exon 5 and the single nucleotide polymorphism within exon 5 located 12 bases upstream of the exon 5/intron 5 boundary. Distribution of the above polymorphisms among different Mus species indicates that the inclusion of exon 5 into mA3 mRNA is a relatively recent event in the evolution of mice. The widespread geographic distribution of this exon 5-including genetic variant suggests that in some Mus populations the cost of maintaining an effective but mutagenic enzyme may outweigh its antiviral function