A Synaptic Basis for Auditory-Vocal Integration in the Songbird

Songbirds learn to sing by memorizing a tutor song that they then vocally mimic using auditory feedback. This developmental sequence suggests that brain areas that encode auditory memories communicate with brain areas for learned vocal control. In the songbird, the secondary auditory telencephalic region caudal mesopallium (CM) contains neurons that encode aspects of auditory experience. We investigated whether CM is an important source of auditory input to two sensorimotor structures implicated in singing, the telencephalic song nucleus interface (NIf) and HVC. We used reversible inactivation methods to show that activity in CM is necessary for much of the auditory-evoked activity that can be detected in NIf and HVC of anesthetized adult male zebra finches. Furthermore, extracellular and intracellular recordings along with spike-triggered averaging methods indicate that auditory selectivity for the bird’s own song is enhanced between CM and NIf. We used lentiviral-mediated tracing methods to confirm that CM neurons directly innervate NIf. To our surprise, these tracing studies also revealed a direct projection from CM to HVC. We combined irreversible lesions of NIf with reversible inactivation of CM to establish that CM supplies a direct source of auditory drive to HVC. Finally, using chronic recording methods, we found that CM neurons are active in response to song playback and during singing, indicating their potential importance to song perception and processing of auditory feedback. These results establish the functional synaptic linkage between sites of auditory and vocal learning and may identify an important substrate for learned vocal communication

Oral Sciences PhD Program Enrollment, Graduates, and Placement: 1994 to 2016

For decades, dental schools in the United States have endured a significant faculty shortage. Studies have determined that the top 2 sources of dental faculty are advanced education programs and private practice. Those who have completed both DDS and PhD training are considered prime candidates for dental faculty positions. However, there is no national database to track those trainees and no evidence to indicate that they entered academia upon graduation. The objective of this study was to assess outcomes of dental school–affiliated oral sciences PhD program enrollment, graduates, and placement between 1994 and 2016. Using the American Dental Association annual survey of advanced dental education programs not accredited by the Commission on Dental Accreditation and data obtained from 22 oral sciences PhD programs, we assessed student demographics, enrollment, graduation, and placement. Based on the data provided by program directors, the average new enrollment was 33, and graduation was 26 per year. A total of 605 graduated; 39 did not complete; and 168 were still in training. Among those 605 graduates, 211 were faculty in U.S. academic institutions, and 77 were faculty in foreign institutions. Given that vacant budgeted full-time faculty positions averaged 257 per year during this period, graduates from those oral sciences PhD programs who entered academia in the United States would have filled 9 (3.6%) vacant faculty positions per year. Therefore, PhD programs have consistently generated only a small pipeline of dental school faculty. Better mentoring to retain talent in academia is necessary. Stronger support and creative funding plans are essential to sustain the PhD program. Furthermore, the oral sciences PhD program database should be established and maintained by dental professional organizations to allow assessments of training models, trends of enrollment, graduation, and placement outcomes

Managing resources in NHS dentistry: using health economics to inform commissioning decisions

Background: The aim of this study is to develop, apply and evaluate an economics-based framework to assist commissioners in their management of finite resources for local dental services. In April 2006, Primary Care Trusts in England were charged with managing finite dental budgets for the first time, yet several independent reports have since criticised the variability in commissioning skills within these organisations. The study will explore the views of stakeholders (dentists, patients and commissioners) regarding priority setting and the criteria used for decision-making and resource allocation. Two inter-related case studies will explore the dental commissioning and resource allocation processes through the application of a pragmatic economics-based framework known as Programme Budgeting and Marginal Analysis. Methods/Design: The study will adopt an action research approach. Qualitative methods including semi-structured interviews, focus groups, field notes and document analysis will record the views of participants and their involvement in the research process. The first case study will be based within a Primary Care Trust where mixed methods will record the views of dentists, patients and dental commissioners on issues, priorities and processes associated with managing local dental services. A Programme Budgeting and Marginal Analysis framework will be applied to determine the potential value of economic principles to the decision-making process. A further case study will be conducted in a secondary care dental teaching hospital using the same approach. Qualitative data will be analysed using thematic analysis and managed using a framework approach. Discussion: The recent announcement by government regarding the proposed abolition of Primary Care Trusts may pose challenges for the research team regarding their engagement with the research study. However, whichever commissioning organisations are responsible for resource allocation for dental services in the future; resource scarcity is highly likely to remain an issue. Wider understanding of the complexities of priority setting and resource allocation at local levels are important considerations in the development of dental commissioning processes, national oral health policy and the future new dental contract which is expected to be implemented in April 2014

Endocrine therapy resistant ESR1 variants revealed by genomic characterization of breast cancer derived xenografts

To characterize patient-derived xenografts (PDXs) for functional studies, we made whole-genome comparisons with originating breast cancers representative of the major intrinsic subtypes. Structural and copy number aberrations were found to be retained with high fidelity. However, at the single-nucleotide level, variable numbers of PDX-specific somatic events were documented, although they were only rarely functionally significant. Variant allele frequencies were often preserved in the PDXs, demonstrating that clonal representation can be transplantable. Estrogen-receptor-positive PDXs were associated with ESR1 ligand-binding-domain mutations, gene amplification, or an ESR1/YAP1 translocation. These events produced different endocrine-therapy-response phenotypes in human, cell line, and PDX endocrine-response studies. Hence, deeply sequenced PDX models are an important resource for the search for genome-forward treatment options and capture endocrine-drug-resistance etiologies that are not observed in standard cell lines. The originating tumor genome provides a benchmark for assessing genetic drift and clonal representation after transplantation

Newborn Sequencing in Genomic Medicine and Public Health

The rapid development of genomic sequencing technologies has decreased the cost of genetic analysis to the extent that it seems plausible that genome-scale sequencing could have widespread availability in pediatric care. Genomic sequencing provides a powerful diagnostic modality for patients who manifest symptoms of monogenic disease and an opportunity to detect health conditions before their development. However, many technical, clinical, ethical, and societal challenges should be addressed before such technology is widely deployed in pediatric practice. This article provides an overview of the Newborn Sequencing in Genomic Medicine and Public Health Consortium, which is investigating the application of genome-scale sequencing in newborns for both diagnosis and screening

Genome modeling system: A knowledge management platform for genomics

In this work, we present the Genome Modeling System (GMS), an analysis information management system capable of executing automated genome analysis pipelines at a massive scale. The GMS framework provides detailed tracking of samples and data coupled with reliable and repeatable analysis pipelines. The GMS also serves as a platform for bioinformatics development, allowing a large team to collaborate on data analysis, or an individual researcher to leverage the work of others effectively within its data management system. Rather than separating ad-hoc analysis from rigorous, reproducible pipelines, the GMS promotes systematic integration between the two. As a demonstration of the GMS, we performed an integrated analysis of whole genome, exome and transcriptome sequencing data from a breast cancer cell line (HCC1395) and matched lymphoblastoid line (HCC1395BL). These data are available for users to test the software, complete tutorials and develop novel GMS pipeline configurations. The GMS is available at https://github.com/genome/gms

An Efficient Coding Hypothesis Links Sparsity and Selectivity of Neural Responses

To what extent are sensory responses in the brain compatible with first-order principles? The efficient coding hypothesis projects that neurons use as few spikes as possible to faithfully represent natural stimuli. However, many sparsely firing neurons in higher brain areas seem to violate this hypothesis in that they respond more to familiar stimuli than to nonfamiliar stimuli. We reconcile this discrepancy by showing that efficient sensory responses give rise to stimulus selectivity that depends on the stimulus-independent firing threshold and the balance between excitatory and inhibitory inputs. We construct a cost function that enforces minimal firing rates in model neurons by linearly punishing suprathreshold synaptic currents. By contrast, subthreshold currents are punished quadratically, which allows us to optimally reconstruct sensory inputs from elicited responses. We train synaptic currents on many renditions of a particular bird's own song (BOS) and few renditions of conspecific birds' songs (CONs). During training, model neurons develop a response selectivity with complex dependence on the firing threshold. At low thresholds, they fire densely and prefer CON and the reverse BOS (REV) over BOS. However, at high thresholds or when hyperpolarized, they fire sparsely and prefer BOS over REV and over CON. Based on this selectivity reversal, our model suggests that preference for a highly familiar stimulus corresponds to a high-threshold or strong-inhibition regime of an efficient coding strategy. Our findings apply to songbird mirror neurons, and in general, they suggest that the brain may be endowed with simple mechanisms to rapidly change selectivity of neural responses to focus sensory processing on either familiar or nonfamiliar stimuli. In summary, we find support for the efficient coding hypothesis and provide new insights into the interplay between the sparsity and selectivity of neural responses