Cellular resolution anatomical and molecular atlases for prenatal human brains.

Increasing interest in studies of prenatal human brain development, particularly using new single-cell genomics and anatomical technologies to create cell atlases, creates a strong need for accurate and detailed anatomical reference atlases. In this study, we present two cellular-resolution digital anatomical atlases for prenatal human brain at postconceptional weeks (PCW) 15 and 21. Both atlases were annotated on sequential Nissl-stained sections covering brain-wide structures on the basis of combined analysis of cytoarchitecture, acetylcholinesterase staining, and an extensive marker gene expression dataset. This high information content dataset allowed reliable and accurate demarcation of developing cortical and subcortical structures and their subdivisions. Furthermore, using the anatomical atlases as a guide, spatial expression of 37 and 5 genes from the brains, respectively, at PCW 15 and 21 was annotated, illustrating reliable marker genes for many developing brain structures. Finally, the present study uncovered several novel developmental features, such as the lack of an outer subventricular zone in the hippocampal formation and entorhinal cortex, and the apparent extension of both cortical (excitatory) and subcortical (inhibitory) progenitors into the prenatal olfactory bulb. These comprehensive atlases provide useful tools for visualization, segmentation, targeting, imaging, and interpretation of brain structures of prenatal human brain, and for guiding and interpreting the next generation of cell census and connectome studies.

Bisphosphonates in dentistry: Historical perspectives, adverse effects, and novel applications.

Studies of the potential role of bisphosphonates in dentistry date back to physical chemical research in the 1960s, and the genesis of the discovery of bisphosphonate pharmacology in part can be linked to some of this work. Since that time, parallel research on the effects of bisphosphonates on bone metabolism continued, while efforts in the dental field included studies of bisphosphonate effects on dental calculus, caries, and alveolar bone loss. While some utility of this drug class in the dental field was identified, leading to their experimental use in various dentrifice formulations and in some dental applications clinically, adverse effects of bisphosphonates in the jaws have also received attention. Most recently, certain bisphosphonates, particularly those with strong bone targeting properties, but limited biochemical effects (low potency bisphosphonates), are being studied as a local remedy for the concerns of adverse effects associated with other more potent members of this drug class. Additionally, low potency bisphosphonate analogs are under study as vectors to target active drugs to the mineral surfaces of the jawbones. These latter efforts have been devised for the prevention and treatment of oral problems, such as infections associated with oral surgery and implants. Advances in the utility and mechanistic understanding of the bisphosphonate class may enable additional oral therapeutic options for the management of multiple aspects of dental health.

Referrals to Urgent Dental Centres During the COVID-19 Pandemic: A Multi-Site Analysis Research Project.

INTRODUCTION: The COVID-19 pandemic enforced the cessation of routine dentistry and the creation of local urgent dental care systems in the UK. General dental practices are obligated by NHS guidance to remain open and provide remote consultation and referral where appropriate to patients having pain or problems. AIMS: To compare two urgent dental centres with different triage and referral systems with regard to quality and appropriateness of referrals, and patient management outcomes. METHODS: 110 consecutive referrals received by a primary care urgent dental centre and a secondary care urgent dental centre were assessed. It was considered whether the patients referred had access to remote primary care dental services, fulfilled the criteria required to be deemed a dental emergency as mandated by NHS guidance, and what the outcomes of referrals were. RESULTS: At the primary care centre, 100% of patients were referred by general dental practitioners and had access to remote primary care dental services. 95.5% of referrals were deemed appropriate and were seen for treatment. At the secondary care site, 94.5% of referrals were direct from the patient by contacting NHS 111. 40% had received triaging to include 'advice, analgesia and antimicrobial' from a general dental practitioner, and 25.5% were deemed appropriate and resulted in treatment. CONCLUSION: Urgent dental centres face many issues, and it would seem that easy access to primary care services, collaboration between primary care clinicians and urgent dental centres, and training of triaging staff are important in operating a successful system.

Integrated personalized diabetes management goes Europe: A multi-disciplinary approach to innovating type 2 diabetes care in Europe.

Type 2 diabetes mellitus represents a multi-dimensional challenge for European and global societies alike. Building on an iterative six-step disease management process that leverages feedback loops and utilizes commodity digital tools, the PDM-ProValue study program demonstrated that integrated personalized diabetes management, or iPDM, can improve the standard of care for persons living with diabetes in a sustainable way. The novel "iPDM Goes Europe" consortium strives to advance iPDM adoption by (1) implementing the concept in a value-based healthcare setting for the treatment of persons living with type 2 diabetes, (2) providing tools to assess the patient's physical and mental health status, and (3) exploring new avenues to take advantage of emerging big data resources.

Palatal rugae morphology is associated with variation in tooth number.

This observational study compared palatal rugae morphology in adolescent subjects with normal tooth number and tooth agenesis. Maxillary dental study casts were used to compare rugae number, length and shape. Each study group contained 60 subjects (30 females and 30 males) mean age 13.4 (SD, 1.55) in control and 13.56 (SD, 1.54) years in tooth agenesis groups (p = 0.576). Mean number of missing tooth units in the tooth agenesis group was 2.1. Mean number of primary rugae in the whole sample was 4.35 (SD, 0.98) on the right and 4.33 (SD, 0.92) on the left with no significant differences (p = 0.236 and p = 0.404, respectively). However, the number of secondary rugae on the left (p = 0.006) and fragmentary rugae on the right (p = 0.004) was significantly increased in the tooth agenesis group. The shape of left primary rugae 2 and 3 also differed between groups, tending towards a wavy pattern in the control group and curved in the tooth agenesis group (p = 0.012 and p = 0.004, respectively). In addition, primary rugae 3 was more convergent (p = 0.008) whilst left primary rugae 3 and 5 were orientated in an antero-posterior direction (p = 0.04 for both rugae) in the tooth agenesis group. Subgroup analysis also identified significant associations between patterns of tooth agenesis and rugae number, in addition to shape of primary rugae. The identification of significant differences in rugae pattern between subjects with normal tooth number and agenesis suggests potential commonality in signal pathway disruption during establishment of these structures.

A comparison of conventional vs automated digital Peer Assessment Rating scoring using the Carestream 3600 scanner and CS Model+ software system: A randomized controlled trial.

INTRODUCTION: A prospective randomized study was undertaken to compare conventional study model-based manual Peer Assessment Rating (PAR) scoring with computer-based automated scoring using scanned study models or intraoral scanning. METHODS: The sample consisted of 67 patients, mean age 15.03 (range 11-37) years. Sixty-seven patients underwent alginate impression-taking and intraoral scanning (CS 3600; Carestream Dental, Stuttgart, Germany) at a single appointment in a randomized order. For each patient, a weighted PAR score was calculated manually by a calibrated examiner using study models and a PAR ruler (conventional group), and automatically using Carestream Dental CS Model+ software and data from scanned study models (indirect digital group) or intraoral scans (direct digital group). All procedures were timed, and each patient completed a binary questionnaire relating to their experience. RESULTS: There were no significant differences between methods for calculated mean weighted PAR score (P = 0.68). Mean (standard deviation) chairside time for impression-taking was 5.35 (± 1.16) minutes and for intraoral scanning, 7.76 (± 2.76) minutes (P <0.05). Mean (standard deviation) times taken to calculate weighted PAR scores were 2.86 (± 0.96), 5.58 (± 2.33), and 4.58 (± 2.18) minutes for conventional, indirect digital, and direct digital groups, respectively (P >0.05). A total of 61 patients (91%) preferred intraoral scanning to impression-taking. CONCLUSIONS: Automated PAR scoring using cast study models or intraoral scanning is valid, though both methods take longer than conventional scoring. Patients prefer intraoral scanning to impression-taking. REGISTRATION: ClinicalTrials.gov (NCT03405961). PROTOCOL: The protocol was not published before study commencement.

An expanded rating curve model to estimate river discharge during tidal influences across the progressive-mixed-standing wave systems.

Empirically quantifying tidally-influenced river discharge is typically laborious, expensive, and subject to more uncertainty than estimation of upstream river discharge. The tidal stage-discharge relationship is not monotonic nor necessarily single-valued, so conventional stage-based river rating curves fail in the tidal zone. Herein, we propose an expanded rating curve method incorporating stage-rate-of-change to estimate river discharge under tidal influences across progressive, mixed, and standing waves. This simple and inexpensive method requires (1) stage from a pressure transducer, (2) flow direction from a tilt current meter, and (3) a series of ADP surveys at different flow rates for model calibration. The method was validated using excerpts from 12 tidal USGS gauging stations during baseflow conditions. USGS gauging stations model discharge using a different more complex and expensive method. Comparison of new and previous models resulted in good R2 correlations (min 0.62, mean 0.87 with S.D. 0.10, max 0.97). The method for modeling tidally-influenced discharge during baseflow conditions was applied de novo to eight intertidal stations in the Mission and Aransas Rivers, Texas, USA. In these same rivers, the model was further expanded to identify and estimate tidally-influenced stormflow discharges. The Mission and Aransas examples illustrated the potential scientific and management utility of the applied tidal rating curve method for isolating transient tidal influences and quantifying baseflow and storm discharges to sensitive coastal waters.

Hierarchical organization of cortical and thalamic connectivity.

The mammalian cortex is a laminar structure containing many areas and cell types that are densely interconnected in complex ways, and for which generalizable principles of organization remain mostly unknown. Here we describe a major expansion of the Allen Mouse Brain Connectivity Atlas resource1, involving around a thousand new tracer experiments in the cortex and its main satellite structure, the thalamus. We used Cre driver lines (mice expressing Cre recombinase) to comprehensively and selectively label brain-wide connections by layer and class of projection neuron. Through observations of axon termination patterns, we have derived a set of generalized anatomical rules to describe corticocortical, thalamocortical and corticothalamic projections. We have built a model to assign connection patterns between areas as either feedforward or feedback, and generated testable predictions of hierarchical positions for individual cortical and thalamic areas and for cortical network modules. Our results show that cell-class-specific connections are organized in a shallow hierarchy within the mouse corticothalamic network.

Shared and distinct transcriptomic cell types across neocortical areas.

The neocortex contains a multitude of cell types that are segregated into layers and functionally distinct areas. To investigate the diversity of cell types across the mouse neocortex, here we analysed 23,822 cells from two areas at distant poles of the mouse neocortex: the primary visual cortex and the anterior lateral motor cortex. We define 133 transcriptomic cell types by deep, single-cell RNA sequencing. Nearly all types of GABA (γ-aminobutyric acid)-containing neurons are shared across both areas, whereas most types of glutamatergic neurons were found in one of the two areas. By combining single-cell RNA sequencing and retrograde labelling, we match transcriptomic types of glutamatergic neurons to their long-range projection specificity. Our study establishes a combined transcriptomic and projectional taxonomy of cortical cell types from functionally distinct areas of the adult mouse cortex.

Advancing 'real-world' trials that take account of social context and human volition.

BACKGROUND: The recent paper in Trials by Porter and colleagues highlights the utility of applying a critical realism approach in randomised trials, an approach central to the Medical Research Council's (MRC) Framework for the Development and Evaluation of Complex Healthcare Interventions. The MRC framework offers a pragmatic step towards a more open systems approach that bridges randomised evaluation with social context and human agency in an effort to improve the generalisability of trial outcomes. MAIN BODY: The MRC framework has contributed to the proliferation of a more open systems approach in health research; however, the broader acceptance of the realist approach to health research does not seem to be emulated by norms in research fund allocation, which largely prioritises laboratory-based research. CONCLUSION: This commentary is simply a plea, to those who make the strategic decisions regarding allocation of research funding, to support all phases of health intervention research in complex systems that contribute to the development of effective, translational and sustainable interventions in the promotion of health.

Does systemic administration of casein phosphopeptides affect orthodontic movement and root resorption in rats?

OBJECTIVES: To assess the potential effects of casein phosphopeptides (CPPs) on orthodontically induced iatrogenic root resorption (OIIRR) and orthodontic teeth movement. MATERIALS AND METHODS: Forty Wistar rats (aged 11 weeks) were randomly divided into experimental group (EG; n = 20) that received a diet supplemented with CPP and control group (CG; n = 20) devoid of diet supplement. A 150 g force was applied using nickel titanium (NiTi) coil that was bonded on maxillary incisors and extended unilaterally to a maxillary first molar. At Day 28, animals in both groups were euthanized. Volumetric assessment of root resorption craters and linear measurement of maxillary first molars movement were blindly examined using a micro-computed tomography scan. RESULTS: Nine rats were excluded from the experiment due to loss during general anesthesia or appliances' failure. Intra-operator reproducibility was high in both volumetric and linear measurements, 92.8 per cent and 98.5-97.6 per cent, respectively. The results reveal that dietary CPP has statistically insignificant effect on the overall OIIRR and orthodontic movement. CONCLUSIONS: CPP seems to have statistically insignificant effect on the volume of OIIRR and orthodontic movement in rats. A long-term study with larger sample size using a different concentration of CPP is required to clarify the dentoalveolar effect of CPP.

The State of Systems Genetics in 2017.

Cell Systems invited 16 experts to share their views on the field of systems genetics. In questions repeated in the headings, we asked them to define systems genetics, highlight its relevance to researchers outside the field, discuss what makes a strong systems genetics paper, and paint a picture of where the field is heading in the coming years. Their responses, ordered by the journal but otherwise unedited, make it clear that deciphering genotype to phenotype relationships is a central challenge of systems genetics and will require understanding how networks and higher-order properties of biological systems underlie complex traits. In addition, our experts illuminate the applications and relevance of systems genetics to human disease, the gut microbiome, development of tools that connect the global research community, sustainability, drug discovery, patient-specific disease and network models, and personalized treatments. Finally, a table of suggested reading provides a sample of influential work in the field.

Recent advances in molecular biomarkers for diabetes mellitus: a systematic review.

CONTEXT: Diabetes is a growing global metabolic epidemic. Current research is focussing on exploring how the biological processes and clinical outcomes of diabetes are related and developing novel biomarkers to measure these relationships, as this can subsequently improve diagnostic, therapeutic and management capacity. OBJECTIVE: The objective of this study is to identify the most recent advances in molecular biomarkers of diabetes and directions that warrant further research. METHODS: Using a systematic search strategy, the MEDLINE, CINAHL and OVID MEDLINE databases were canvassed for articles that investigated molecular biomarkers for diabetes. Initial selections were made based on article title, whilst final inclusion was informed by a critical appraisal of the full text of each article. RESULTS: The systematic search returned 246 records, of which 113 were unique. Following screening, 29 records were included in the final review. Three main research strategies (the development of novel technologies, broad biomarker panels, and targeted approaches) identified a number of potential biomarkers for diabetes including miR-126, C-reactive protein, 2-aminoadipic acid and betatrophin. CONCLUSION: The most promising research avenue identified is the detection and quantification of micro RNA. Further, the utilisation of functionalised electrodes as a means to detect biomarker compounds also warrants attention.

Control of diabetic hyperglycaemia and insulin resistance through TSC22D4.

Obesity-related insulin resistance represents the core component of the metabolic syndrome, promoting glucose intolerance, pancreatic beta cell failure and type 2 diabetes. Efficient and safe insulin sensitization and glucose control remain critical therapeutic aims to prevent diabetic late complications Here, we identify transforming growth factor beta-like stimulated clone (TSC) 22 D4 as a molecular determinant of insulin signalling and glucose handling. Hepatic TSC22D4 inhibition both prevents and reverses hyperglycaemia, glucose intolerance and insulin resistance in diabetes mouse models. TSC22D4 exerts its effects on systemic glucose homeostasis-at least in part-through the direct transcriptional regulation of the small secretory protein lipocalin 13 (LCN13). Human diabetic patients display elevated hepatic TSC22D4 expression, which correlates with decreased insulin sensitivity, hyperglycaemia and LCN13 serum levels. Our results establish TSC22D4 as a checkpoint in systemic glucose metabolism in both mice and humans, and propose TSC22D4 inhibition as an insulin sensitizing option in diabetes therapy.

Big Science, Team Science, and Open Science for Neuroscience.

The Allen Institute for Brain Science is a non-profit private institution dedicated to basic brain science with an internal organization more commonly found in large physics projects-large teams generating complete, accurate and permanent resources for the mouse and human brain. It can also be viewed as an experiment in the sociology of neuroscience. We here describe some of the singular differences to more academic, PI-focused institutions.

Comprehensive cellular-resolution atlas of the adult human brain.

Detailed anatomical understanding of the human brain is essential for unraveling its functional architecture, yet current reference atlases have major limitations such as lack of whole-brain coverage, relatively low image resolution, and sparse structural annotation. We present the first digital human brain atlas to incorporate neuroimaging, high-resolution histology, and chemoarchitecture across a complete adult female brain, consisting of magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), and 1,356 large-format cellular resolution (1 µm/pixel) Nissl and immunohistochemistry anatomical plates. The atlas is comprehensively annotated for 862 structures, including 117 white matter tracts and several novel cyto- and chemoarchitecturally defined structures, and these annotations were transferred onto the matching MRI dataset. Neocortical delineations were done for sulci, gyri, and modified Brodmann areas to link macroscopic anatomical and microscopic cytoarchitectural parcellations. Correlated neuroimaging and histological structural delineation allowed fine feature identification in MRI data and subsequent structural identification in MRI data from other brains. This interactive online digital atlas is integrated with existing Allen Institute for Brain Science gene expression atlases and is publicly accessible as a resource for the neuroscience community. J. Comp. Neurol. 524:3127-3481, 2016. © 2016 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.

J.G. Crowther's War: Institutional strife at the BBC and British Council.

Science writer, historian and administrator J.G. Crowther (1899-1983) had an uneasy relationship with the BBC during the 1920s and 1930s, and was regarded with suspicion by the British security services because of his left politics. Nevertheless the Second World War saw him working for 'establishment' institutions. He was closely associated with the BBC's Overseas Service and employed by the British Council's Science Committee. Both organizations found Crowther useful because of his wide, international knowledge of science and scientists. Crowther's political views, and his international aspirations for the British Council's Science Committee, increasingly embroiled him in an institutional conflict with the Royal Society and with its president, Sir Henry Dale, who was also chairman of the British Council's Science Committee. The conflict centred on the management of international scientific relations, a matter close Crowther's heart, and to Dale's. Dale considered that the formal conduct of international scientific relations was the Royal Society's business rather than the British Council's. Crowther disagreed, and eventually resigned from the British Council Science Committee in 1946. The article expands knowledge of Crowther by drawing on archival documents to elucidate a side of his career that is only lightly touched on in his memoirs. It shows that 'Crowther's war' was also an institutional war between the Science Committee of the British Council and the Royal Society. Crowther's unhappy experience of interference by the Royal Society plausibly accounts for a retreat from his pre-war view that institutional science should plan and manage BBC science broadcasts.