DNA methylation-based classification of glioneuronal tumours synergises with histology and radiology to refine accurate molecular stratification.

AIMS: Glioneuronal tumours (GNTs) are poorly distinguished by their histology and lack robust diagnostic indicators. Previously, we showed that common GNTs comprise two molecularly distinct groups, correlating poorly with histology. To refine diagnosis, we constructed a methylation-based model for GNT classification, subsequently evaluating standards for molecular stratification by methylation, histology and radiology. METHODS: We comprehensively analysed methylation, radiology and histology for 83 GNT samples: a training cohort of 49, previously classified into molecularly defined groups by genomic profiles, plus a validation cohort of 34. We identified histological and radiological correlates to molecular classification and constructed a methylation-based support vector machine (SVM) model for prediction. Subsequently, we contrasted methylation, radiological and histological classifications in validation GNTs. RESULTS: By methylation clustering, all training and 23/34 validation GNTs segregated into two groups, the remaining 11 clustering alongside control cortex. Histological review identified prominent astrocytic/oligodendrocyte-like components, dysplastic neurons and a specific glioneuronal element as discriminators between groups. However, these were present in only a subset of tumours. Radiological review identified location, margin definition, enhancement and T2 FLAIR-rim sign as discriminators. When validation GNTs were classified by SVM, 22/23 classified correctly, comparing favourably against histology and radiology that resolved 17/22 and 15/21, respectively, where data were available for comparison. CONCLUSIONS: Diagnostic criteria inadequately reflect glioneuronal tumour biology, leaving a proportion unresolvable. In the largest cohort of molecularly defined glioneuronal tumours, we develop molecular, histological and radiological approaches for biologically meaningful classification and demonstrate almost all cases are resolvable, emphasising the importance of an integrated diagnostic approach.

Development of a Measure of Calculative Mindset (CM): Establishing a Nomological Net and Predictive Utility of the CM Measure.

A calculative mindset (CM) describes the tendency to analyze and convert qualitative social values into numeric or monetary metrics and is a predisposition that shapes behaviors and actions of the employee. CM has been manipulated in experimental studies, but it has not been investigated in field research due to the absence of a scale to measure CM. In study 1, we followed Hinkin's scale development protocol to conceptualize, develop, and validate a measure of CM to facilirate research in organizational contexts. In Study 2, we examined the relationship between CM and measures of performance, counterproductive work behavior (CWB), organizational citizenship behaviors (OCB), and in role-performance (IRP). Results from hierarchical regression analyses indicate that CM is related to these performance outcomes and explains incremental variance over established measures of the Five-Factor Model of personality. Implications for personality research, selection of human resources, and facilitation of an ethical workplace are discussed.

Lessons learned from SARS-CoV-2 measurements in wastewater.

Standardized protocols for wastewater-based surveillance (WBS) for the RNA of SARS-CoV-2, the virus responsible for the current COVID-19 pandemic, are being developed and refined worldwide for early detection of disease outbreaks. We report here on lessons learned from establishing a WBS program for SARS-CoV-2 integrated with a human surveillance program for COVID-19. We have established WBS at three campuses of a university, including student residential dormitories and a hospital that treats COVID-19 patients. Lessons learned from this WBS program address the variability of water quality, new detection technologies, the range of detectable viral loads in wastewater, and the predictive value of integrating environmental and human surveillance data. Data from our WBS program indicated that water quality was statistically different between sewer sampling sites, with more variability observed in wastewater coming from individual buildings compared to clusters of buildings. A new detection technology was developed based upon the use of a novel polymerase called V2G. Detectable levels of SARS-CoV-2 in wastewater varied from 102 to 106 genomic copies (gc) per liter of raw wastewater (L). Integration of environmental and human surveillance data indicate that WBS detection of 100 gc/L of SARS-CoV-2 RNA in wastewater was associated with a positivity rate of 4% as detected by human surveillance in the wastewater catchment area, though confidence intervals were wide (ß ~ 8.99 ∗ ln(100); 95% CI = 0.90-17.08; p < 0.05). Our data also suggest that early detection of COVID-19 surges based on correlations between viral load in wastewater and human disease incidence could benefit by increasing the wastewater sample collection frequency from weekly to daily. Coupling simpler and faster detection technology with more frequent sampling has the potential to improve the predictive potential of using WBS of SARS-CoV-2 for early detection of the onset of COVID-19.

Investigating the Relationships Between Three Important Functional Tasks Early After Stroke: Movement Characteristics of Sit-To-Stand, Sit-To-Walk, and Walking.

Background: Walking, sit-to-stand (STS) and sit-to-walk (STW) are all considered important functional tasks in achieving independence after stroke. Despite knowledge that sensitive measurement of movement patterns is crucial to understanding neuromuscular restitution, there is surprisingly little information available about the detailed biomechanical characteristics of, and relationships between, walking, sit-to-stand and sit-to-walk, particularly in the important time window early after stroke. Hence, here, the study aimed to: Identify the biomechanical characteristics of and determine any differences in both movement fluidity (hesitation, coordination and smoothness) and duration of movement phases, between sit-to-stand (STS) and sit-to-walk (STW) in people early after stroke.Determine whether measures of movement fluidity (hesitation, coordination, and smoothness) and movement phases during sit-to-stand (STS) and/or sit-to-walk (STW) are correlated strongly to commonly used measures of walking speed and/or step length ratio in people early after stroke. Methods: This study consisted of secondary data analysis from the SWIFT Cast Trial. Specifically, we investigated movement fluidity using established assessments of smoothness, hesitation and coordination and the time duration for specific movement phases in a group of 48 people after stroke. Comparisons were made between STS and STW and relationships to walking measures were explored. Results: Participants spent significantly more time in the initial movement phase, flexion momentum, during STS [mean time (SD) 1.74 ±1.45 s] than they did during STW [mean time (SD) 1.13 ± 1.03 s]. STS was also completed more smoothly but with more hesitation and greater coordination than the task of STW. No strong relationships were found between movement fluidity or duration with walking speed or step length symmetry. Conclusions: Assessment of movement after stroke requires a range of functional tasks and no one task should predominate over another. Seemingly similar or overlapping tasks such as STS and STW create distinct biomechanical characteristics which can be identified using sensitive, objective measures of fluidity and movement phases but there are no strong relationships between the functional tasks of STS and STW with walking speed or with step-length symmetry.

Identifying cellular signalling molecules in developmental disorders of the brain: Evidence from focal cortical dysplasia and tuberous sclerosis.

AIMS: We understand little of the pathogenesis of developmental cortical lesions, because we understand little of the diversity of the cell types that contribute to the diseases or how those cells interact. We tested the hypothesis that cellular diversity and cell-cell interactions play an important role in these disorders by investigating the signalling molecules in the commonest cortical malformations that lead to childhood epilepsy, focal cortical dysplasia (FCD) and tuberous sclerosis (TS). METHODS: Transcriptional profiling clustered cases into molecularly distinct groups. Using gene expression data, we identified the secretory signalling molecules in FCD/TS and characterised the cell types expressing these molecules. We developed a functional model using organotypic cultures. RESULTS: We identified 113 up-regulated secretory molecules in FCDIIB/TS. The top 12 differentially expressed genes (DEGs) were validated by immunohistochemistry. This highlighted two molecules, Chitinase 3-like protein 1 (CHI3L1) and C-C motif chemokine ligand 2 (CCL2) (MCP1) that were expressed in a unique population of small cells in close proximity to balloon cells (BC). We then characterised these cells and developed a functional model in organotypic slice cultures. We found that the number of CHI3L1 and CCL2 expressing cells decreased following inhibition of mTOR, the main aberrant signalling pathway in TS and FCD. CONCLUSIONS: Our findings highlight previously uncharacterised small cell populations in FCD and TS which express specific signalling molecules. These findings indicate a new level of diversity and cellular interactions in cortical malformations and provide a generalisable approach to understanding cell-cell interactions and cellular heterogeneity in developmental neuropathology.

Virtual Environment Rehabilitation for Patients with Motor Neglect Trial (VERMONT): A Single-Center Randomized Controlled Feasibility Trial.

BACKGROUND: Motor neglect occurs in patients with chronic pain conditions. Virtual environments (VE) help rehabilitation through biofeedback and improving motivation. AIM: To assess the feasibility of a VE for patients with motor neglect with chronic pain. METHODS: 10 subjects with chronic pain (Fibromyalgia, Sciatica, and Complex Regional Pain Syndrome) underwent a treadmill task three times per week for two weeks. Groups were randomized to receive real-time biofeedback from the VE (intervention) or shown still images (control). Primary outcomes were: (i) distance walked at baseline compared to the final 5 min cycle of week 2; (ii) the Lower Extremity Functional Index (LEFI) questionnaire. A satisfaction questionnaire was used. Follow up was to 24 weeks. RESULTS: Total distance walked was significantly higher in the intervention group (p < 0.05), and 33% (2/6) of the intervention group had a clinically important LEFI improvement compared to 0/4 in the control group at week 2. No secondary outcome measures demonstrated any significant differences. The intervention received high satisfaction scores, significantly greater than the control group at week 24. No harms were recorded. DISCUSSION: This feasibility study showed that VE and treadmill-walking improved walking distances and function for subjects with motor neglect. This is a promising novel approach and requires further validation through larger study.

Evaluating the Epley Canalolith Repositioning Procedure With and Without a Visual Assistive Device.

HYPOTHESIS: The primary goal of this study was to examine how accuracy is affected when we employ a guidance device to assist with the execution of the Epley canalolith repositioning procedure. BACKGROUND: Benign paroxysmal positional vertigo is a common cause of vestibular vertigo. Treatment is noninvasive and generally effective when performed correctly. Deficiencies in clinical application result in unnecessary failures in response for those affected. METHODS: Ten participants were each taken through six iterations of the Epley canalolith repositioning procedure. Iterations were divided evenly between those conducted with and without the use of a guidance device. One clinician performed all 60 procedures. Head movements were recorded using motion capture cameras and strategically placed motion tracking markers. RESULTS: Results showed that the guidance device significantly improved the latter phase maneuver accuracy. Rotation error was significantly reduced for hold3 with-device (M = 20.23°, SD = 12.08°) versus without-device (M = 40.13°, SD = 14.62°, p  =  0.001). Maximal rotation error during rotation4 of the maneuver demonstrated a similar reduction of error with-device (M = 24.44°, SD = 10.43°) versus without-device (M = 41.36°, SD = 12.89°, p  =  0.002). CONCLUSION: A simple visual guidance device can increase the execution accuracy of canalith repositioning procedures. Further research is required to show how such improvements influence treatment efficacy.

A case series of Diffuse Glioneuronal Tumours with Oligodendroglioma-like features and Nuclear Clusters (DGONC).

In this study, we report three paediatric cases of Diffuse Glioneuronal Tumours with Oligodendroglioma-like features and Nuclear Clusters (DGONC).

Consolidation of Imaging Modalities Utilizing Digitally Assisted Visualization Systems: The Development of a Surgical Information Handling Cockpit.

The management of vitreoretinal cases is ever-evolving, paralleled by rapid advancements in operative imaging modalities. In this article, we describe an advanced application of digitally assisted vitreoretinal surgery (DAVS) that involves the consolidation of pre-existing ancillary imaging technology into a single same-screen viewing platform. Forty-four eyes of 44 patients were operated using same screen simultaneous viewing of the primary three-dimensional high definition (3DHD) surgical field and simultaneous auxiliary video feed viewing of all currently approved ocular endoscopy (n=12), intraoperative optical coherence tomography (iOCT) units (n=24), or computer feeds from the EHR/image management software (n=8). All surgeries were successful with excellent functional and anatomic outcomes. DAVS facilitated same screen viewing of multiple video/information feeds was notable for improved ergonomics, surgical efficiency, and precision when compared to viewing the surgical field and auxiliary video feeds separately. We describe a new concept for the vitreoretinal operating room - a DAVS-based surgical information handling cockpit - integrating FDA approved ocular endoscopy (n=1), microscope-integrated iOCT units (n=3), and one EHR/Image management solution with the primary surgical field 3DHD feed. We suggest same screen viewing of multiple video and other clinical information feeds is a promising modality that may be considered in the management of patients with surgical vitreoretinal disease and should be purposefully incorporated into future iterations of DAVS technology platforms.

Methylation-based algorithms for diagnosis: experience from neuro-oncology.

Brain tumours are the most common tumour-related cause of death in young people. Survivors are at risk of significant disability, at least in part related to the effects of treatment. Therefore, there is a need for a precise diagnosis that stratifies patients for the most suitable treatment, matched to the underlying biology of their tumour. Although traditional histopathology has been accurate in predicting treatment responses in many cases, molecular profiling has revealed a remarkable, previously unappreciated, level of biological complexity in the classification of these tumours. Among different molecular technologies, DNA methylation profiling has had the most pronounced impact on brain tumour classification. Furthermore, using machine learning-based algorithms, DNA methylation profiling is changing diagnostic practice. This can be regarded as an exemplar for how molecular pathology can influence diagnostic practice and illustrates some of the unanticipated benefits and risks. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

DNA methylation-based profiling for paediatric CNS tumour diagnosis and treatment: a population-based study.

BACKGROUND: Marked variation exists in the use of genomic data in tumour diagnosis, and optimal integration with conventional diagnostic technology remains uncertain despite several studies reporting improved diagnostic accuracy, selection for targeted treatments, and stratification for trials. Our aim was to assess the added value of molecular profiling in routine clinical practice and the impact on conventional and experimental treatments. METHODS: This population-based study assessed the diagnostic and clinical use of DNA methylation-based profiling in childhood CNS tumours using two large national cohorts in the UK. In the diagnostic cohort-which included routinely diagnosed CNS tumours between Sept 1, 2016, and Sept 1, 2018-we assessed how the methylation profile altered or refined diagnosis in routine clinical practice and estimated how this would affect standard patient management. For the archival cohort of diagnostically difficult cases, we established how many cases could be solved using modern standard pathology, how many could only be solved using the methylation profile, and how many remained unsolvable. FINDINGS: Of 484 patients younger than 20 years with CNS tumours, 306 had DNA methylation arrays requested by the neuropathologist and were included in the diagnostic cohort. Molecular profiling added a unique contribution to clinical diagnosis in 107 (35%; 95% CI 30-40) of 306 cases in routine diagnostic practice-providing additional molecular subtyping data in 99 cases, amended the final diagnosis in five cases, and making potentially significant predictions in three cases. We estimated that it could change conventional management in 11 (4%; 95% CI 2-6) of 306 patients. Among 195 historically difficult-to-diagnose tumours in the archival cohort, 99 (51%) could be diagnosed using standard methods, with the addition of methylation profiling solving a further 34 (17%) cases. The remaining 62 (32%) cases were unresolved despite specialist pathology and methylation profiling. INTERPRETATION: Together, these data provide estimates of the impact that could be expected from routine implementation of genomic profiling into clinical practice, and indicate limitations where additional techniques will be required. We conclude that DNA methylation arrays are a useful diagnostic adjunct for childhood CNS tumours. FUNDING: The Brain Tumour Charity, Children with Cancer UK, Great Ormond Street Hospital Children's Charity, Olivia Hodson Cancer Fund, Cancer Research UK, and the National Institute of Health Research.

The Central Complex as a Potential Substrate for Vector Based Navigation.

Insects use path integration (PI) to maintain a home vector, but can also store and recall vector-memories that take them from home to a food location, and even allow them to take novel shortcuts between food locations. The neural circuit of the Central Complex (a brain area that receives compass and optic flow information) forms a plausible substrate for these behaviors. A recent model, grounded in neurophysiological and neuroanatomical data, can account for PI during outbound exploratory routes and the control of steering to return home. Here, we show that minor, hypothetical but neurally plausible, extensions of this model can additionally explain how insects could store and recall PI vectors to follow food-ward paths, take shortcuts, search at the feeder and re-calibrate their vector-memories with experience. In addition, a simple assumption about how one of multiple vector-memories might be chosen at any point in time can produce the development and maintenance of efficient routes between multiple locations, as observed in bees. The central complex circuitry is therefore well-suited to allow for a rich vector-based navigational repertoire.

Association of low income with pulmonary disease progression in smokers with and without chronic obstructive pulmonary disease.

Low socioeconomic status has been associated with chronic obstructive pulmonary disease (COPD) but little is known about its impact on disease progression. We assessed the association of income to symptoms, pulmonary disease severity and progression in smokers with and without COPD. The COPDGene cohort of 4826 smokers who reported annual income in phase 2 was analysed. Those who reported annual income

Rotation invariant visual processing for spatial memory in insects.

Visual memory is crucial to navigation in many animals, including insects. Here, we focus on the problem of visual homing, that is, using comparison of the view at a current location with a view stored at the home location to control movement towards home by a novel shortcut. Insects show several visual specializations that appear advantageous for this task, including almost panoramic field of view and ultraviolet light sensitivity, which enhances the salience of the skyline. We discuss several proposals for subsequent processing of the image to obtain the required motion information, focusing on how each might deal with the problem of yaw rotation of the current view relative to the home view. Possible solutions include tagging of views with information from the celestial compass system, using multiple views pointing towards home, or rotation invariant encoding of the view. We illustrate briefly how a well-known shape description method from computer vision, Zernike moments, could provide a compact and rotation invariant representation of sky shapes to enhance visual homing. We discuss the biological plausibility of this solution, and also a fourth strategy, based on observed behaviour of insects, that involves transfer of information from visual memory matching to the compass system.

External and local controls on land-sea coupling assessed by stable isotopic signatures of mangrove producers in estuaries of Pacific Panama.

Foliar stable isotopic signatures of nitrogen, carbon, and sulfur in mangrove vegetation from the Pacific coast of Panama were insensitive to inputs from watersheds with different area of forest land cover, and to seasonal, inter-annual, and global-scale-driven contrasts in rainfall and upwelling. N, C, and S content of mangrove vegetation were not affected by inputs from watersheds with different degrees of deforestation, but showed some influence of down-estuary transformations. While there was substantial variation that remained un-explained, isotopic signatures and nutrient contents were largely determined by species-specific features, and showed substantial small-scale variation reflecting local differences, within-estuary plant-sediment links. The ability of mangrove estuaries to erase effects of deforestation points out that conservation of these wetland ecosystems is important, because, at least in the sites we studied, transformations within mangrove estuaries were strong enough to protect water quality in receiving coastal waters.

Tumour compartment transcriptomics demonstrates the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identifies the MAPK/ERK pathway as a novel therapeutic target.

Adamantinomatous craniopharyngiomas (ACPs) are clinically challenging tumours, the majority of which have activating mutations in CTNNB1. They are histologically complex, showing cystic and solid components, the latter comprised of different morphological cell types (e.g. ß-catenin-accumulating cluster cells and palisading epithelium), surrounded by a florid glial reaction with immune cells. Here, we have carried out RNA sequencing on 18 ACP samples and integrated these data with an existing ACP transcriptomic dataset. No studies so far have examined the patterns of gene expression within the different cellular compartments of the tumour. To achieve this goal, we have combined laser capture microdissection with computational analyses to reveal groups of genes that are associated with either epithelial tumour cells (clusters and palisading epithelium), glial tissue or immune infiltrate. We use these human ACP molecular signatures and RNA-Seq data from two ACP mouse models to reveal that cell clusters are molecularly analogous to the enamel knot, a critical signalling centre controlling normal tooth morphogenesis. Supporting this finding, we show that human cluster cells express high levels of several members of the FGF, TGFB and BMP families of secreted factors, which signal to neighbouring cells as evidenced by immunostaining against the phosphorylated proteins pERK1/2, pSMAD3 and pSMAD1/5/9 in both human and mouse ACP. We reveal that inhibiting the MAPK/ERK pathway with trametinib, a clinically approved MEK inhibitor, results in reduced proliferation and increased apoptosis in explant cultures of human and mouse ACP. Finally, we analyse a prominent molecular signature in the glial reactive tissue to characterise the inflammatory microenvironment and uncover the activation of inflammasomes in human ACP. We validate these results by immunostaining against immune cell markers, cytokine ELISA and proteome analysis in both solid tumour and cystic fluid from ACP patients. Our data support a new molecular paradigm for understanding ACP tumorigenesis as an aberrant mimic of natural tooth development and opens new therapeutic opportunities by revealing the activation of the MAPK/ERK and inflammasome pathways in human ACP.

Tropical land-sea couplings: Role of watershed deforestation, mangrove estuary processing, and marine inputs on N fluxes in coastal Pacific Panama.

We review data from coastal Pacific Panama and other tropical coasts with two aims. First, we defined inputs and losses of nitrogen (N) mediating connectivity of watersheds, mangrove estuaries, and coastal sea. N entering watersheds-mainly via N fixation (79-86%)-was largely intercepted; N discharges to mangrove estuaries (3-6%), small compared to N inputs to watersheds, nonetheless significantly supplied N to mangrove estuaries. Inputs to mangrove estuaries (including watershed discharges, and marine inputs during flood tides) were matched by losses (mainly denitrification and export during ebb tides). Mangrove estuary subsidies of coastal marine food webs take place by export of forms of N [DON (62.5%), PN (9.1%), and litter N (12.9%)] that provide dissimilative and assimilative subsidies. N fixation, denitrification, and tidal exchanges were major processes, and DON was major form of N involved in connecting fluxes in and out of mangrove estuaries. Second, we assessed effects of watershed forest cover on connectivity. Decreased watershed forest cover lowered N inputs, interception, and discharge into receiving mangrove estuaries. These imprints of forest cover were erased during transit of N through estuaries, owing to internal N cycle transformations, and differences in relative area of watersheds and estuaries. Largest losses of N consisted of water transport of energy-rich compounds, particularly DON. N losses were similar in magnitude to N inputs from sea, calculated without considering contribution by intermittent coastal upwelling, and hence likely under-estimated. Pacific Panama mangrove estuaries are exposed to major inputs of N from land and sea, which emphasizes the high degree of bi-directional connectivity in these coupled ecosystems. Pacific Panama is still lightly affected by human or global changes. Increased deforestation can be expected, as well as changes in ENSO, which will surely raise watershed-derived loads of N, as well as significantly change marine N inputs affecting coastal coupled ecosystems.

PRN Ranibizumab in the Treatment of Choroidal Neovascularization Secondary to Ocular Histoplasmosis.

BACKGROUND AND OBJECTIVE: Ranibizumab (Lucentis; Genentech, South San Francisco, CA) is used off-label for the treatment of choroidal neovascularization secondary to ocular histoplasmosis syndrome (OHS). This study prospectively evaluates the safety and efficacy of two treatment paradigms utilizing ranibizumab 0.5 mg: one or three initial injections followed by monthly visits with PRN treatment through Month 12. PATIENTS AND METHODS: In this prospective, open-label study, 21 subjects were evaluated monthly and retreated during the pro re nata treatment phase if specific criteria were met, including loss of vision, increase in subretinal fluid, or hemorrhage. Adverse events, best-corrected visual acuity (BCVA), and central subfield retinal thickness (CST) were evaluated. RESULTS: No adverse events were observed. Mean BCVA improved in both groups by approximately 2 lines, and mean CST decreased by approximately 100 µm at month 12. The number of injections was the same (5.7 and 5.8 injections). CONCLUSION: Results suggest that ranibizumab is safe and efficacious for treatment of CNV secondary to OHS. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:20-26.].

Comprehensive molecular characterisation of epilepsy-associated glioneuronal tumours.

Glioneuronal tumours are an important cause of treatment-resistant epilepsy. Subtypes of tumour are often poorly discriminated by histological features and may be difficult to diagnose due to a lack of robust diagnostic tools. This is illustrated by marked variability in the reported frequencies across different epilepsy surgical series. To address this, we used DNA methylation arrays and RNA sequencing to assay the methylation and expression profiles within a large cohort of glioneuronal tumours. By adopting a class discovery approach, we were able to identify two distinct groups of glioneuronal tumour, which only partially corresponded to the existing histological classification. Furthermore, by additional molecular analyses, we were able to identify pathogenic mutations in BRAF and FGFR1, specific to each group, in a high proportion of cases. Finally, by interrogating our expression data, we were able to show that each molecular group possessed expression phenotypes suggesting different cellular differentiation: astrocytic in one group and oligodendroglial in the second. Informed by this, we were able to identify CCND1, CSPG4, and PDGFRA as immunohistochemical targets which could distinguish between molecular groups. Our data suggest that the current histological classification of glioneuronal tumours does not adequately represent their underlying biology. Instead, we show that there are two molecular groups within glioneuronal tumours. The first of these displays astrocytic differentiation and is driven by BRAF mutations, while the second displays oligodendroglial differentiation and is driven by FGFR1 mutations.

An Anatomically Constrained Model for Path Integration in the Bee Brain.

Path integration is a widespread navigational strategy in which directional changes and distance covered are continuously integrated on an outward journey, enabling a straight-line return to home. Bees use vision for this task-a celestial-cue-based visual compass and an optic-flow-based visual odometer-but the underlying neural integration mechanisms are unknown. Using intracellular electrophysiology, we show that polarized-light-based compass neurons and optic-flow-based speed-encoding neurons converge in the central complex of the bee brain, and through block-face electron microscopy, we identify potential integrator cells. Based on plausible output targets for these cells, we propose a complete circuit for path integration and steering in the central complex, with anatomically identified neurons suggested for each processing step. The resulting model circuit is thus fully constrained biologically and provides a functional interpretation for many previously unexplained architectural features of the central complex. Moreover, we show that the receptive fields of the newly discovered speed neurons can support path integration for the holonomic motion (i.e., a ground velocity that is not precisely aligned with body orientation) typical of bee flight, a feature not captured in any previously proposed model of path integration. In a broader context, the model circuit presented provides a general mechanism for producing steering signals by comparing current and desired headings-suggesting a more basic function for central complex connectivity, from which path integration may have evolved.