Origins of choice-related activity in mouse somatosensory cortex.

During perceptual decisions about faint or ambiguous sensory stimuli, even identical stimuli can produce different choices. Spike trains from sensory cortex neurons can predict trial-to-trial variability in choice. Choice-related spiking is widely studied as a way to link cortical activity to perception, but its origins remain unclear. Using imaging and electrophysiology, we found that mouse primary somatosensory cortex neurons showed robust choice-related activity during a tactile detection task. Spike trains from primary mechanoreceptive neurons did not predict choices about identical stimuli. Spike trains from thalamic relay neurons showed highly transient, weak choice-related activity. Intracellular recordings in cortex revealed a prolonged choice-related depolarization in most neurons that was not accounted for by feed-forward thalamic input. Top-down axons projecting from secondary to primary somatosensory cortex signaled choice. An intracellular measure of stimulus sensitivity determined which neurons converted choice-related depolarization into spiking. Our results reveal how choice-related spiking emerges across neural circuits and within single neurons

Isotope effect for associative detachment: H(D)−+H(D)→H2(D2)+e

We report experimental and theoretical results for associative detachment (AD) of D−+D→D2+e−. We compare these data to our previously published results for H−+H→H2+e−. The measurements show no significant isotope effect in the total cross section. This is to be contrasted with previously published experimental and theoretical work which has found a significant isotope effect in diatomic systems for partial AD cross sections, i.e., as a function of the rotational and vibrational levels of the final molecule formed. Our work implies that though the rovibrational distribution of flux is different for AD of H− + H and D− + D, the total flux for these two systems is essentially the same when summed over all possible final channels

Improving the efficiency of genomic loci capture using oligonucleotide arrays for high throughput resequencing

<p>Abstract</p> <p>Background</p> <p>The emergence of next-generation sequencing technology presents tremendous opportunities to accelerate the discovery of rare variants or mutations that underlie human genetic disorders. Although the complete sequencing of the affected individuals' genomes would be the most powerful approach to finding such variants, the cost of such efforts make it impractical for routine use in disease gene research. In cases where candidate genes or loci can be defined by linkage, association, or phenotypic studies, the practical sequencing target can be made much smaller than the whole genome, and it becomes critical to have capture methods that can be used to purify the desired portion of the genome for shotgun short-read sequencing without biasing allelic representation or coverage. One major approach is array-based capture which relies on the ability to create a custom in-situ synthesized oligonucleotide microarray for use as a collection of hybridization capture probes. This approach is being used by our group and others routinely and we are continuing to improve its performance.</p> <p>Results</p> <p>Here, we provide a complete protocol optimized for large aggregate sequence intervals and demonstrate its utility with the capture of all predicted amino acid coding sequence from 3,038 human genes using 241,700 60-mer oligonucleotides. Further, we demonstrate two techniques by which the efficiency of the capture can be increased: by introducing a step to block cross hybridization mediated by common adapter sequences used in sequencing library construction, and by repeating the hybridization capture step. These improvements can boost the targeting efficiency to the point where over 85% of the mapped sequence reads fall within 100 bases of the targeted regions.</p> <p>Conclusions</p> <p>The complete protocol introduced in this paper enables researchers to perform practical capture experiments, and includes two novel methods for increasing the targeting efficiency. Coupled with the new massively parallel sequencing technologies, this provides a powerful approach to identifying disease-causing genetic variants that can be localized within the genome by traditional methods.</p

Evolution of Hominin Polyunsaturated Fatty Acid Metabolism: From Africa to the New World

The metabolic conversion of dietary omega-3 and omega-6 18 carbon (18C) to long chain (>20 carbon) polyunsaturated fatty acids (LC-PUFAs) is vital for human life. The rate-limiting steps of this process are catalyzed by fatty acid desaturase (FADS) 1 and 2. Therefore, understanding the evolutionary history of the FADS genes is essential to our understanding of hominin evolution. The FADS genes have two haplogroups, ancestral and derived, with the derived haplogroup being associated with more efficient LC-PUFA biosynthesis than the ancestral haplogroup. In addition, there is a complex global distribution of these haplogroups that is suggestive of Neanderthal introgression. We confirm that Native American ancestry is nearly fixed for the ancestral haplogroup, and replicate a positive selection signal in Native Americans. This positive selection potentially continued after the founding of the Americas, although simulations suggest that the timing is dependent on the allele frequency of the ancestral Beringian population. We also find that the Neanderthal FADS haplotype is more closely related to the derived haplogroup and the Denisovan clusters closer to the ancestral haplogroup. Furthermore, the derived haplogroup has a time to the most recent common ancestor of 688,474years before present. These results support an ancient polymorphism, as opposed to Neanderthal introgression, forming in the FADS region during the Pleistocene with possibly differential selection pressures on both haplogroups. The near fixation of the ancestral haplogroup in Native American ancestry calls for future studies to explore the potential health risk of associated low LC-PUFA levels in these populations.Center for Health Related Informatics and Biomaging at the University of Maryland School of Medicine; National Institutes of Health/National Heart, Lung, and Blood Institute [U01 HL72518, HL087698, HL112064]; National Institutes of Health [R01-AT008621]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Differences in IV alcohol-induced dopamine release in the ventral striatum of social drinkers and nontreatment-seeking alcoholics

Background Striatal dopamine (DA) has been implicated in alcohol use disorders, but it is still unclear whether or not alcohol can induce dopamine release in social drinkers. Furthermore, no data exist on dopamine responses to alcohol in dependent drinkers. We sought to characterize the DA responses to alcohol intoxication in moderately large samples of social drinkers (SD) and nontreatment-seeking alcoholics (NTS). Methods Twenty-four SD and twenty-one NTS received two [11C]raclopride (RAC) PET scans; one at rest, and one during an intravenous alcohol infusion, with a prescribed ascent to a target breath alcohol concentration (BrAC), at which it was then “clamped.” The alcohol clamp was started 5 min after scan start, with a linear increase in BrAC over 15 min to the target of 80 mg%, the legal threshold for intoxication. Target BrAC was maintained for 30 min. Voxel-wise binding potential (BPND) was estimated with MRTM2. Results IV EtOH induced significant increases in DA in the right ventral striatum in NTS, but not SD. No decreases in DA were observed in either group. Conclusions Alcohol intoxication results in distinct anatomic profiles of DA responses in SD and NTS, suggesting that in NTS, the striatal DA system may process effects of alcohol intoxication differently than in SD

Identification of Subject-Specific Immunoglobulin Alleles From Expressed Repertoire Sequencing Data

The adaptive immune receptor repertoire (AIRR) contains information on an individuals' immune past, present and potential in the form of the evolving sequences that encode the B cell receptor (BCR) repertoire. AIRR sequencing (AIRR-seq) studies rely on databases of known BCR germline variable (V), diversity (D), and joining (J) genes to detect somatic mutations in AIRR-seq data via comparison to the best-aligning database alleles. However, it has been shown that these databases are far from complete, leading to systematic misidentification of mutated positions in subsets of sample sequences. We previously presented TIgGER, a computational method to identify subject-specific V gene genotypes, including the presence of novel V gene alleles, directly from AIRR-seq data. However, the original algorithm was unable to detect alleles that differed by more than 5 single nucleotide polymorphisms (SNPs) from a database allele. Here we present and apply an improved version of the TIgGER algorithm which can detect alleles that differ by any number of SNPs from the nearest database allele, and can construct subject-specific genotypes with minimal prior information. TIgGER predictions are validated both computationally (using a leave-one-out strategy) and experimentally (using genomic sequencing), resulting in the addition of three new immunoglobulin heavy chain V (IGHV) gene alleles to the IMGT repertoire. Finally, we develop a Bayesian strategy to provide a confidence estimate associated with genotype calls. All together, these methods allow for much higher accuracy in germline allele assignment, an essential step in AIRR-seq studies

Miscarriage and stillbirth following maternal Zika virus infection in nonhuman primates.

Zika virus (ZIKV) infection is associated with congenital defects and pregnancy loss. Here, we found that 26% of nonhuman primates infected with Asian/American ZIKV in early gestation experienced fetal demise later in pregnancy despite showing few clinical signs of infection. Pregnancy loss due to asymptomatic ZIKV infection may therefore be a common but under-recognized adverse outcome related to maternal ZIKV infection

The study protocol of a cluster-randomised controlled trial of family-mediated personalised activities for nursing home residents with dementia

<p>Abstract</p> <p>Background</p> <p>Following admission to a nursing home, the feelings of depression and burden that family carers may experience do not necessarily diminish. Additionally, they may experience feelings of guilt and grief for the loss of a previously close relationship. At the same time, individuals with dementia may develop symptoms of depression and agitation (BPSD) that may be related to changes in family relationships, social interaction and stimulation. Until now, interventions to alleviate carer stress and BPSD have treated carers and relatives separately rather than focusing on maintaining or enhancing their relationships. One-to-one structured activities have been shown to reduce BPSD and also improve the caring experience, but barriers such as a lack of resources impede the implementation of activities in aged care facilities. The current study will investigate the effect of individualised activities based on the Montessori methodology administered by family carers in residential care.</p> <p>Methods/Design</p> <p>We will conduct a cluster-randomised trial to train family carers in conducting personalised one-to-one activities based on the Montessori methodology with their relatives. Montessori activities derive from the principles espoused by Maria Montessori and subsequent educational theorists to promote engagement in learning, namely task breakdown, guided repetition, progression in difficulty from simple to complex, and the careful matching of demands to levels of competence. Persons with dementia living in aged care facilities and frequently visiting family carers will be included in the study. Consented, willing participants will be randomly assigned by facility to a treatment condition using the Montessori approach or a control waiting list condition. We hypothesise that family carers conducting Montessori-based activities will experience improvements in quality of visits and overall relationship with the resident as well as higher self-rated mastery, fewer depressive symptoms, and a better quality of life than carers in the waiting list condition.</p> <p>Discussion</p> <p>We hypothesise that training family carers to deliver personalised activities to their relatives in a residential setting will make visits more satisfying and may consequently improve the quality of life for carers and their relatives. These beneficial effects might also reduce nursing staff burden and thus impact positively on residential facilities.</p> <p>Trial Registration</p> <p>Australian New Zealand Clinical Trials Registry - <a href="http://www.anzctr.org.au/ACTRN12611000998943.aspx">ACTRN12611000998943</a></p