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Functional MRI of young adults has implicated the striatum in the processing of rewarding and punishing events. To date, only two published experiments (Samanez-Larkin et al., 2007; Schott et al., 2007) have explored similar phenomena in older adults, with both studies emphasizing the anticipation of monetary outcomes. To better understand older participants’ striatal responses to delivered outcomes, we engaged 20 older adults and 13 younger adults in a card-guessing task that rewarded correct guesses with monetary gain and punished incorrect guesses with monetary loss. Overall, the older adults retained most of the typical features of the striatal response, so that activity in the caudate head showed reliable differentiation between rewards and punishments during the 6- to 9-sec postoutcome window. Comparison of the older and younger adults also pointed to some potential aging effects on outcome activity, including reductions in the magnitude and extent of striatal activation, and a trend for the older adults to show a decreased early punishment response. In sum, our data suggest that the signaling of outcome valence remains relatively stable into late adulthood, although more research is needed to understand some subtle changes that might occur across the life span.

Oscillations figure prominently as neurological disease hallmarks and neuromodulation targets. To detect oscillations in a neuron's spiking, one might attempt to seek peaks in the spike train's power spectral density (PSD) which exceed a flat baseline. Yet for a non-oscillating neuron, the PSD is not flat: The recovery period (\"RP\", the post-spike drop in spike probability, starting with the refractory period) introduces global spectral distortion. An established \"shuffling\" procedure corrects for RP distortion by removing the spectral component explained by the inter-spike interval (ISI) distribution. However, this procedure sacrifices oscillation-related information present in the ISIs, and therefore in the PSD. We asked whether point process models (PPMs) might achieve more selective RP distortion removal, thereby enabling improved oscillation detection. In a novel \"residuals\" method, we first estimate the RP duration ( ) from the ISI distribution. We then fit the spike train with a PPM that predicts spike likelihood based on the time elapsed since the most recent of any spikes falling within the preceding milliseconds. Finally, we compute the PSD of the model's residuals. We compared the residuals and shuffling methods' ability to enable accurate oscillation detection with flat baseline-assuming tests. Over synthetic data, the residuals method generally outperformed the shuffling method in classification of true- versus false-positive oscillatory power, principally due to enhanced sensitivity in sparse spike trains. In single-unit data from the internal globus pallidus (GPi) and ventrolateral anterior thalamus (VLa) of a parkinsonian monkey -- in which alpha-beta oscillations (8-30 Hz) were anticipated -- the residuals method reported the greatest incidence of significant alpha-beta power, with low firing rates predicting residuals-selective oscillation detection. These results encourage continued development of the residuals approach, to support more accurate oscillation detection. Improved identification of oscillations could promote improved disease models and therapeutic technologies.

How the brain organizes discrete actions into fluid sequences is a central problem in motor neuroscience. Competing models of basal ganglia (BG) function propose that BG neurons either signal sequence boundaries or encode movements across ordinal positions. Prior studies have largely examined fixed sequences with end-of-sequence rewards, leaving open whether such findings generalize to more naturalistic conditions. We trained four rhesus macaques to perform a visuomotor sequence task requiring four or five out-and-back joystick movements to peripheral targets. Sequences were completed under two conditions: a random condition, in which target order varied across trials, and a fixed condition, in which order was predictable and consistent. Rewards were delivered after each movement, dissociating reward timing from sequence completion. We recorded single-unit activity in arm-related regions of the globus pallidus (GP; n = 458) and primary motor cortex (M1; n = 306). Regression analyses revealed that many neurons in both GP and M1 encoded ordinal position within a sequence. Order effects were more frequent in the fixed condition, but were also present during random sequences. We found no evidence for preferential encoding of sequence initiation or termination in overlearned sequences, in contrast to prior studies reporting start/stop signals in basal ganglia. Weak effects appeared under the random condition in one animal pair, but these did not generalize across animals or conditions. Instead, neurons exhibited heterogeneous order-related responses spanning the full sequence. These results demonstrate that GP neurons, like those in M1, encode ordinal position throughout a sequence rather than acting solely as sequence initiators or terminators. This challenges boundary-specific models of BG function and highlights the BG's broader role in representing serial order during motor sequence production.

Although the basal ganglia (BG) plays a central role in the motor symptoms of Parkinson's disease, few studies have investigated the influence of parkinsonism on movement-related activity in the BG. Here, we studied the perimovement activity of neurons in globus pallidus internus (GPi) of non-human primates during performance of a choice reaction time reaching task before and after the induction of parkinsonism by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Neuronal responses, including increases or decreases in firing rate, were equally common in the parkinsonian brain as seen prior to MPTP and the distribution of different response types was largely unchanged. The slowing of behavioral reaction times and movement durations following the induction of parkinsonism was accompanied by a prolongation of the time interval between neuronal response onset and movement initiation. Neuronal responses were also reduced in magnitude and prolonged in duration after the induction of parkinsonism. Importantly, those two effects were more pronounced among decrease-type responses, and they persisted after controlling for MPTP-induced changes in the between-trial variability in response timing. Following MPTP the trial-to-trial timing of neuronal responses also became uncoupled from the time of movement onset and more variable in general. Overall, the effects of MPTP on temporal features of GPi responses were related to the severity of parkinsonian motor impairments whereas changes in response magnitude and duration did not reflect symptom severity consistently. These findings point to a previously underappreciated potential role for abnormalities in the timing of GPi task-related activity in the generation of parkinsonian motor signs.

High-density analysis methods for localization microscopy increase acquisition speed but produce artifacts. We demonstrate that these artifacts can be eliminated by the combination of Haar wavelet kernel (HAWK) analysis with standard single-frame fitting. We tested the performance of this method on synthetic, fixed-cell, and live-cell data, and found that HAWK preprocessing yielded reconstructions that reflected the structure of the sample, thus enabling high-speed, artifact-free super-resolution imaging of live cells.

Vaccines and other alternative products can help minimize the need for antibiotics by preventing and controlling infectious diseases in animal populations, and are central to the future success of animal agriculture. To assess scientific advancements related to alternatives to antibiotics and provide actionable strategies to support their development, the United States Department of Agriculture, with support from the World Organisation for Animal Health, organized the second International Symposium on Alternatives to Antibiotics. It focused on six key areas: vaccines; microbial-derived products; non-nutritive phytochemicals; immune-related products; chemicals, enzymes, and innovative drugs; and regulatory pathways to enable the development and licensure of alternatives to antibiotics. This article, part of a two-part series, synthesizes and expands on the expert panel discussions regarding opportunities, challenges and needs for the development of vaccines that may reduce the need for use of antibiotics in animals; new approaches and potential solutions will be discussed in part 2 of this series. Vaccines are widely used to prevent infections in food animals. Various studies have demonstrated that their animal agricultural use can lead to significant reductions in antibiotic consumption, making them promising alternatives to antibiotics. To be widely used in food producing animals, vaccines have to be safe, effective, easy to use, and cost-effective. Many current vaccines fall short in one or more of these respects. Scientific advancements may allow many of these limitations to be overcome, but progress is funding-dependent. Research will have to be prioritized to ensure scarce public resources are dedicated to areas of potentially greatest impact first, and private investments into vaccine development constantly compete with other investment opportunities. Although vaccines have the potential to improve animal health, safeguard agricultural productivity, and reduce antibiotic consumption and resulting resistance risks, targeted research and development investments and concerted efforts by all affected are needed to realize that potential.

Purpose: Although there is a long history of use of semi-occluded vocal tract gestures in voice therapy, including phonation through thin tubes or straws, the efficacy of phonation through tubes has not been established. This study compares results from a therapy program on the basis of phonation through a flow-resistant tube (FRT) with Vocal Function Exercises (VFE), an established set of exercises that utilize oral semi-occlusions. Method: Twenty subjects (16 women, 4 men) with dysphonia and/or vocal fatigue were randomly assigned to 1 of 4 treatment conditions: (a) immediate FRT therapy, (b) immediate VFE therapy, (c) delayed FRT therapy, or (d) delayed VFE therapy. Subjects receiving delayed therapy served as a no-treatment control group. Results: Voice Handicap Index (Jacobson et al., 1997) scores showed significant improvement for both treatment groups relative to the no-treatment group. Comparison of the effect sizes suggests FRT therapy is noninferior to VFE in terms of reduction in Voice Handicap Index scores. Significant reductions in Roughness on the Consensus Auditory-Perceptual Evaluation of Voice (Kempster, Gerratt, Verdolini Abbott, Barkmeier-Kraemer, & Hillman, 2009) were found for the FRT subjects, with no other significant voice quality findings. Conclusions: VFE and FRT therapy may improve voice quality of life in some individuals with dysphonia. FRT therapy was noninferior to VFE in improving voice quality of life in this study.

Introduction The MYH7 c.5135G > A p.(Arg1712Gln) variant has been identified in several patients worldwide and is classified as pathogenic in the ClinVar database. We aimed to delineate its associated phenotype and evaluate a potential founder effect. Methods We retrospectively collected clinical and genetic data of 22 probands and 74 family members from an international cohort. Results In total, 53 individuals carried the MYH7 p.(Arg1712Gln) variant, of whom 38 (72%) were diagnosed with hypertrophic cardiomyopathy (HCM). Mean age at HCM diagnosis was 48.8 years (standard deviation: 18.1; range: 8–74). The clinical presentation ranged from asymptomatic HCM to arrhythmias (atrial fibrillation and malignant ventricular arrhythmias). Aborted sudden cardiac death (SCD) leading to the diagnosis of HCM occurred in one proband at the age of 68 years, and a family history of SCD was reported by 39% (5/13) probands. Neither heart failure deaths nor heart transplants were reported. Women had a generally later-onset disease, with 14% of female carriers diagnosed with HCM at age 50 years compared with 54% of male carriers. In both sexes, the disease was fully penetrant by age 75 years. Haplotypes were reconstructed for 35 patients and showed a founder effect in a subset of patients. Conclusion MYH7 p .(Arg1712Gln) is a pathogenic founder variant with a consistent HCM phenotype that may present with delayed penetrance. This suggested that clinical follow-up should be pursued after the seventh decade in healthy carriers and that longer intervals between screening may be justified in healthy women < 30 years.

Background The influence of genetics on variation in DNA methylation (DNAme) is well documented. Yet confounding from population stratification is often unaccounted for in DNAme association studies. Existing approaches to address confounding by population stratification using DNAme data may not generalize to populations or tissues outside those in which they were developed. To aid future placental DNAme studies in assessing population stratification, we developed an ethnicity classifier, PlaNET (Placental DNAme Elastic Net Ethnicity Tool), using five cohorts with Infinium Human Methylation 450k BeadChip array (HM450k) data from placental samples that is also compatible with the newer EPIC platform. Results Data from 509 placental samples were used to develop PlaNET and show that it accurately predicts (accuracy = 0.938, kappa = 0.823) major classes of self-reported ethnicity/race (African: n  = 58, Asian: n  = 53, Caucasian: n  = 389), and produces ethnicity probabilities that are highly correlated with genetic ancestry inferred from genome-wide SNP arrays (> 2.5 million SNP) and ancestry informative markers ( n  = 50 SNPs). PlaNET’s ethnicity classification relies on 1860 HM450K microarray sites, and over half of these were linked to nearby genetic polymorphisms ( n  = 955). Our placental-optimized method outperforms existing approaches in assessing population stratification in placental samples from individuals of Asian, African, and Caucasian ethnicities. Conclusion PlaNET provides an improved approach to address population stratification in placental DNAme association studies. The method can be applied to predict ethnicity as a discrete or continuous variable and will be especially useful when self-reported ethnicity information is missing and genotyping markers are unavailable.

Vaccines and other alternative products are central to the future success of animal agriculture because they can help minimize the need for antibiotics by preventing and controlling infectious diseases in animal populations. To assess scientific advancements related to alternatives to antibiotics and provide actionable strategies to support their development, the United States Department of Agriculture, with support from the World Organisation for Animal Health, organized the second International Symposium on Alternatives to Antibiotics. It focused on six key areas: vaccines; microbial-derived products; non-nutritive phytochemicals; immune-related products; chemicals, enzymes, and innovative drugs; and regulatory pathways to enable the development and licensure of alternatives to antibiotics. This article, the second part in a two-part series, highlights new approaches and potential solutions for the development of vaccines as alternatives to antibiotics in food producing animals; opportunities, challenges and needs for the development of such vaccines are discussed in the first part of this series. As discussed in part 1 of this manuscript, many current vaccines fall short of ideal vaccines in one or more respects. Promising breakthroughs to overcome these limitations include new biotechnology techniques, new oral vaccine approaches, novel adjuvants, new delivery strategies based on bacterial spores, and live recombinant vectors; they also include new vaccination strategies in-ovo, and strategies that simultaneously protect against multiple pathogens. However, translating this research into commercial vaccines that effectively reduce the need for antibiotics will require close collaboration among stakeholders, for instance through public–private partnerships. Targeted research and development investments and concerted efforts by all affected are needed to realize the potential of vaccines to improve animal health, safeguard agricultural productivity, and reduce antibiotic consumption and resulting resistance risks.