Project description:WIN 18,446/RA treatment of neonatal mice was used to synchronize the initial wave of spermatogenesis and identify novel messages expressed within either germ or Sertoli cells as spermatogonia enter meiosis.
Project description:WIN 18,446/RA treatment of neonatal mice was used to synchronize the initial wave of spermatogenesis and identify novel messages expressed within either germ or Sertoli cells as spermatogonia enter meiosis. germ cell-specific (Stra8-cre: RiboTag; or Ngn3-cre:RiboTag) and Sertoli cell-specific (Amh-Cre: RiboTag)
Project description:Network oscillations of different frequencies, durations and amplitudes are hypothesized to coordinate information processing and transfer across brain areas. Among these oscillations, hippocampal sharp wave-ripple complexes (SPW-Rs) are one of the most prominent. SPW-Rs occurring in the hippocampus are suggested to play essential roles in memory consolidation as well as information transfer to the neocortex. To-date, most of the knowledge about SPW-Rs comes from experimental studies averaging responses from neuronal populations monitored by conventional microelectrodes. In this work, we investigate spatiotemporal characteristics of SPW-Rs and how microelectrode size and distance influence SPW-R recordings using a biophysical model of hippocampus. We also explore contributions from neuronal spikes and synaptic potentials to SPW-Rs based on two different types of network activity. Our study suggests that neuronal spikes from pyramidal cells contribute significantly to ripples while high amplitude sharp waves mainly arise from synaptic activity. Our simulations on spatial reach of SPW-Rs show that the amplitudes of sharp waves and ripples exhibit a steep decrease with distance from the network and this effect is more prominent for smaller area electrodes. Furthermore, the amplitude of the signal decreases strongly with increasing electrode surface area as a result of averaging. The relative decrease is more pronounced when the recording electrode is closer to the source of the activity. Through simulations of field potentials across a high-density microelectrode array, we demonstrate the importance of finding the ideal spatial resolution for capturing SPW-Rs with great sensitivity. Our work provides insights on contributions from spikes and synaptic potentials to SPW-Rs and describes the effect of measurement configuration on LFPs to guide experimental studies towards improved SPW-R recordings.
Project description:Numerical simulation of fluids plays an essential role in modeling many physical phenomena, such as weather, climate, aerodynamics, and plasma physics. Fluids are well described by the Navier-Stokes equations, but solving these equations at scale remains daunting, limited by the computational cost of resolving the smallest spatiotemporal features. This leads to unfavorable trade-offs between accuracy and tractability. Here we use end-to-end deep learning to improve approximations inside computational fluid dynamics for modeling two-dimensional turbulent flows. For both direct numerical simulation of turbulence and large-eddy simulation, our results are as accurate as baseline solvers with 8 to 10× finer resolution in each spatial dimension, resulting in 40- to 80-fold computational speedups. Our method remains stable during long simulations and generalizes to forcing functions and Reynolds numbers outside of the flows where it is trained, in contrast to black-box machine-learning approaches. Our approach exemplifies how scientific computing can leverage machine learning and hardware accelerators to improve simulations without sacrificing accuracy or generalization.
Project description:Continual sperm production relies on germ cells undergoing spermatogenesis asynchronously. As a result, the testis always contains a mixed population of germ cells at different stages of their differentiation process. The heterogeneous nature of the testis makes profiling gene expression within Sertoli cells or specific populations of germ cells impossible when a wild-type testis is assessed. We recently reported a unique method for synchronizing spermatogenesis without affecting fertility by manipulating RA levels within the neonatal testis. Using this protocol, combined with the RiboTag transgenic mouse line, we have mapped the Sertoli and germ cell translatome during the initial synchronized wave of spermatogenesis. Using microarray analysis, we identified 392 and 194 germ cell and Sertoli cells transcripts, respectively, that dynamically change during spermatogonial differentiation, division, and the onset of meiosis. Functional annotation clustering revealed that transcripts enriched in germ cells were mostly associated with meiosis (21 transcripts), chromatin organization (12 transcripts), and cell cycle (3 transcripts). In addition, glycoproteins (65 transcripts), cell adhesion (15 transcripts), and cell junction (13 transcripts) transcripts were overrepresented in the Sertoli cell-enriched list. These datasets represent the first transcriptional analysis of spermatogonial differentiation, division, and meiotic onset. These data suggest that several of the genes encoding meiotic proteins are expressed and are actively being translated well before germ cells enter meiosis. In addition, this study provides novel candidate genes, Asf1b and Esyt3, that may be involved in the regulation of spermatogonial chromatin reorganization, germ-Sertoli cell interactions, and/or blood-testis barrier formation.
Project description:This paper reviews the methods, benefits and challenges associated with the adoption and translation of computational fluid dynamics (CFD) modelling within cardiovascular medicine. CFD, a specialist area of mathematics and a branch of fluid mechanics, is used routinely in a diverse range of safety-critical engineering systems, which increasingly is being applied to the cardiovascular system. By facilitating rapid, economical, low-risk prototyping, CFD modelling has already revolutionised research and development of devices such as stents, valve prostheses, and ventricular assist devices. Combined with cardiovascular imaging, CFD simulation enables detailed characterisation of complex physiological pressure and flow fields and the computation of metrics which cannot be directly measured, for example, wall shear stress. CFD models are now being translated into clinical tools for physicians to use across the spectrum of coronary, valvular, congenital, myocardial and peripheral vascular diseases. CFD modelling is apposite for minimally-invasive patient assessment. Patient-specific (incorporating data unique to the individual) and multi-scale (combining models of different length- and time-scales) modelling enables individualised risk prediction and virtual treatment planning. This represents a significant departure from traditional dependence upon registry-based, population-averaged data. Model integration is progressively moving towards 'digital patient' or 'virtual physiological human' representations. When combined with population-scale numerical models, these models have the potential to reduce the cost, time and risk associated with clinical trials. The adoption of CFD modelling signals a new era in cardiovascular medicine. While potentially highly beneficial, a number of academic and commercial groups are addressing the associated methodological, regulatory, education- and service-related challenges.
Project description:Computational Fluid Dynamics (CFD) can be used to simulate different parts of an industrial freeze-drying equipment and to properly design them; in particular data concerning the freeze-dryer chamber and the duct connecting the chamber with the condenser, with the valves and vanes eventually present are given here, and can be used to understand the behavior of the apparatus allowing an improved design. Pilot and large scale freeze-drying chambers have been considered; data of a detailed simulation of a complete pilot scale apparatus, including duct and condenser, are included. Data on conductance of an empty duct with different L/D ratio, on disk valves with different geometry, and on mushroom valve are presented. Velocity, pressure, temperature and composition fields are reported on selected planes for chambers and valves. Results of dynamic simulations are also presented, to evaluate possible performance of monitoring devices in the chamber. Some further data, with detailed interpretation and discussion of the presented data can be found in the related research article by Barresi et al. [1] and Marchisio et al. [2].
Project description:BackgroundIntrathecal drug delivery has a significant role in pain management and central nervous system (CNS) disease therapeutics. A fluid-physics based tool to assist clinicians in choosing specific drug doses to the spine or brain may help improve treatment schedules.MethodsThis study applied computational fluid dynamics (CFD) and in vitro model verification to assess intrathecal drug delivery in an anatomically idealized model of the human CSF system with key anatomic features of the CNS. Key parameters analyzed included the role of (a) injection location including lumbar puncture (LP), cisterna magna (CM) and intracerebroventricular (ICV), (b) LP injection rate, injection volume, and flush volume, (c) physiologic factors including cardiac-induced and deep respiration-induced CSF stroke volume increase. Simulations were conducted for 3-h post-injection and used to quantify spatial-temporal tracer concentration, regional area under the curve (AUC), time to maximum concentration (Tmax), and maximum concentration (Cmax), for each case.ResultsCM and ICV increased AUC to brain regions by ~ 2 logs compared to all other simulations. A 3X increase in bolus volume and addition of a 5 mL flush both increased intracranial AUC to the brain up to 2X compared to a baseline 5 mL LP injection. In contrast, a 5X increase in bolus rate (25 mL/min) did not improve tracer exposure to the brain. An increase in cardiac and respiratory CSF movement improved tracer spread to the brain, basal cistern, and cerebellum up to ~ 2 logs compared to the baseline LP injection.ConclusionThe computational modeling approach provides ability to conduct in silico trials representative of CSF injection protocols. Taken together, the findings indicate a strong potential for delivery protocols to be optimized to reach a target region(s) of the spine and/or brain with a needed therapeutic dose. Parametric modification of bolus rate/volume and flush volume was found to have impact on tracer distribution; albeit to a smaller degree than injection location, with CM and ICV injections resulting in greater therapeutic dose to brain regions compared to LP. CSF stroke volume and frequency both played an important role and may potentially have a greater impact than the modest changes in LP injection protocols analyzed such as bolus rate, volume, and flush.
Project description:PurposeTo investigate the behavior of silicone oil (SiO) at the steady equilibrium and during saccades and calculate SiO-retina contact, shear stress (SS), and shear rate (SR).MethodsA 24 mm phakic eye mesh model underwent 50°/0.137s saccade. The vitreous chamber compartment was divided into superior and inferior 180° sectors: lens, pre-equator, postequator, and macula. SiO-retina contact was evaluated as a function of fill percentages between 80% and 90% for a standing patient, 45° upward gaze, and supine. SS and SR for 1000 mPa-s (SiO1000) and 5000 mPa-s (SiO5000) silicon oil were calculated.ResultsSiO fill between 80% to 90% allowed 55% to 78% retinal contact. The superior retina always kept better contact with SiO, regardless of the fill percentage (P < 0.01). SiO interface thoroughly contacted the macula only in standing position. SS followed a bimodal behavior and was always significantly higher for SiO5000 compared to SiO1000 (P < 0.01) throughout the saccade. The macula suffered the highest mean SS in standing position, while throughout the saccade the average SS was maximum at the SiO-aqueous interface. SR was significantly higher for SiO1000 compared to SiO5000 (P < 0.001).ConclusionsSS on the retinal surface may instantaneously exceed reported retinal adhesiveness values especially at the SiO-aqueous interface and possibly favor redetachment. Despite 90% SiO fill the inferior retina remains extremely difficult to tamponade.Translational relevanceAccurate assessment of retina-tamponade interaction may explain recurrent inferior retinal redetachment, silicone oil emulsification, and help to develop better vitreous substitutes.