The glymphatic system is a recently defined brain-wide paravascular pathway for cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange that facilitates efficient clearance of solutes and waste from the brain. CSF enters the brain along para-arterial channels to exchange with ISF, which is in turn cleared from the brain along para-venous pathways. Because soluble amyloid β clearance depends on glymphatic pathway function, we proposed that failure of this clearance system contributes to amyloid plaque deposition and Alzheimer's disease progression. Here we provide proof of concept that glymphatic pathway function can be measured using a clinically relevant imaging technique. Dynamic contrast-enhanced MRI was used to visualize CSF-ISF exchange across the rat brain following intrathecal paramagnetic contrast agent administration. Key features of glymphatic pathway function were confirmed, including visualization of para-arterial CSF influx and molecular size-dependent CSF-ISF exchange. Whole-brain imaging allowed the identification of two key influx nodes at the pituitary and pineal gland recesses, while dynamic MRI permitted the definition of simple kinetic parameters to characterize glymphatic CSF-ISF exchange and solute clearance from the brain. We propose that this MRI approach may provide the basis for a wholly new strategy to evaluate Alzheimer's disease susceptibility and progression in the live human brain. IntroductionIn the classical model, cerebrospinal fluid (CSF) is actively secreted by the choroid plexus of the cerebral ventricles and travels by bulk or pulsatile flow through the ventricular system, flowing from the fourth ventricle into the subarachnoid space through the foramina of Luschka and the foramen of Magendie. From the subarachnoid space, CSF is thought to be reabsorbed into the blood stream either via arachnoid granulations of the dural sinuses or by passing out of the cranial cavity along cranial nerve sheathes to be eliminated through the cervical lymphatics (1, 2). Fluid movement along this CSF column is commonly measured by MRI. Phase-contrast MRI allows the visualization of CSF flow dynamics and is used clinically in the evaluation of communicating versus noncommunicating hydrocephalus, normal pressure hydrocephalus, and arachnoid cysts (3). Contrast-enhanced magnetic resonance cisternography can also be used to identify CSF leaks in the treatment of spontaneous intracranial hypotension or CSF rhinorrhea (4,5).In a recent study (6), we reported that, contrary to the textbook model of CSF secretion and reabsorption, a large proportion of subarachnoid CSF recirculates through the brain parenchyma along paravascular spaces and exchanges with the interstitial fluid (ISF) (a process referred to herein as CSF-ISF exchange). The flow of fluid along these paravascular routes and through the interstitium is supported by transglial water movement through astrocytic aquaporin-4 (AQP4) water channels and facilitates the efficient clearance of interstitial solutes, including soluble amyloid...

Clinical hematopoietic transplantation outcomes are strongly correlated with the numbers of cells infused. Anticipated novel therapeutic implementations of hematopoietic stem cells (HSCs) and their derivatives further increase interest in strategies to expand HSCs ex vivo. A fundamental limitation in all HSC-driven culture systems is the rapid generation of differentiating cells and their secreted inhibitory feedback signals. Herein we describe an integrated computational and experimental strategy that enables a tunable reduction in the global levels and impact of paracrine signaling factors in an automated closed-system process by employing a controlled fed-batch media dilution approach. Application of this system to human cord blood cells yielded a rapid (12-day) 11-fold increase of HSCs with self-renewing, multilineage repopulating ability. These results highlight the marked improvements that control of feedback signaling can offer primary stem cell culture and demonstrate a clinically relevant rapid and relatively low culture volume strategy for ex vivo HSC expansion.

Background: Tfh cells regulate B cell-mediated humoral immunity. Results: STAT5 regulated Blimp-1 expression, and STAT5 deficiency in CD4 ϩ T cells resulted in an increase of Tfh generation

In this study, a 3D digital atlas of the live mouse brain based on magnetic resonance microscopy (MRM) is presented. C57BL/6J adult mouse brains were imaged in vivo on a 9.4 Tesla MR instrument at an isotropic spatial resolution of 100 µm. With suffi cient signal-to-noise (SNR) and contrast-to-noise ratio (CNR), 20 brain regions were identifi ed. Several atlases were constructed including 12 individual brain atlases, an average atlas, a probabilistic atlas and average geometrical deformation maps. We also investigated the feasibility of using lower spatial resolution images to improve time effi ciency for future morphological phenotyping. All of the new in vivo data were compared to previous published in vitro C57BL/6J mouse brain atlases and the morphological differences were characterized. Our analyses revealed signifi cant volumetric as well as unexpected geometrical differences between the in vivo and in vitro brain groups which in some instances were predictable (e.g. collapsed and smaller ventricles in vitro) but not in other instances. Based on these fi ndings we conclude that although in vitro datasets, compared to in vivo images, offer higher spatial resolutions, superior SNR and CNR, leading to improved image segmentation, in vivo atlases are likely to be an overall better geometric match for in vivo studies, which are necessary for longitudinal examinations of the same animals and for functional brain activation studies. Thus the new in vivo mouse brain atlas dataset presented here is a valuable complement to the current mouse brain atlas collection and will be accessible to the neuroscience community on our public domain mouse brain atlas website.

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