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"Kahn, Victor"
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A portable, ultra-low cost, open-source, pedal-controlled microinjector for laboratory use
In vivo transduction or electroporation often requires sub-microliter volume injection of virus or recombinant DNA/RNA to a precise anatomic site. Two-hand manual manipulation of the injection needle and target tissues is dramatically faster than mechanical manipulation, but technically challenging for operators. Here, we present an all open-source, footswitch-actuated injector for nano- or microliter volumes. Our microinjector is simple, can be assembled in less than 2 hours with ordinary tools, does not require custom fabrication or soldering, and can cost less than $130 USD. This device is completely self-contained, pressure controllable, and offers both aspirate and discharge modes to facilitate multiple injections during the same procedure. Pulse-triggered discharges can reliably deliver nanoliter volumes with dispense errors of around 15%. By reducing technical and financial barriers, we anticipate this microinjector may inspire adoption of in vivo electroporation or genome editing across broader scientific communities where access may be presently limited.
Journal Article
Multisensory gamma stimulation promotes glymphatic clearance of amyloid
The glymphatic movement of fluid through the brain removes metabolic waste
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. Noninvasive 40 Hz stimulation promotes 40 Hz neural activity in multiple brain regions and attenuates pathology in mouse models of Alzheimer’s disease
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. Here we show that multisensory gamma stimulation promotes the influx of cerebrospinal fluid and the efflux of interstitial fluid in the cortex of the 5XFAD mouse model of Alzheimer’s disease. Influx of cerebrospinal fluid was associated with increased aquaporin-4 polarization along astrocytic endfeet and dilated meningeal lymphatic vessels. Inhibiting glymphatic clearance abolished the removal of amyloid by multisensory 40 Hz stimulation. Using chemogenetic manipulation and a genetically encoded sensor for neuropeptide signalling, we found that vasoactive intestinal peptide interneurons facilitate glymphatic clearance by regulating arterial pulsatility. Our findings establish novel mechanisms that recruit the glymphatic system to remove brain amyloid.
Audio and visual stimulation at 40 Hz promote cerebrospinal and interstitial fluid flux in mouse brain and result in amyloid clearance via the glymphatic system in a mouse model of Alzheimer’s disease.
Journal Article
An edge-centric perspective on the human connectome: link communities in the brain
Brain function depends on efficient processing and integration of information within a complex network of neural interactions, known as the connectome. An important aspect of connectome architecture is the existence of community structure, providing an anatomical basis for the occurrence of functional specialization. Typically, communities are defined as groups of densely connected network nodes, representing clusters of brain regions. Looking at the connectome from a different perspective, instead focusing on the interconnecting links or edges, we find that the white matter pathways between brain regions also exhibit community structure. Eleven link communities were identified: five spanning through the midline fissure, three through the left hemisphere and three through the right hemisphere. We show that these link communities are consistently identifiable and investigate the network characteristics of their underlying white matter pathways. Furthermore, examination of the relationship between link communities and brain regions revealed that the majority of brain regions participate in multiple link communities. In particular, the highly connected and central hub regions showed a rich level of community participation, supporting the notion that these hubs play a pivotal role as confluence zones in which neural information from different domains merges.
Journal Article
Precision medicine screening using whole-genome sequencing and advanced imaging to identify disease risk in adults
Reducing premature mortality associated with age-related chronic diseases, such as cancer and cardiovascular disease, is an urgent priority. We report early results using genomics in combination with advanced imaging and other clinical testing to proactively screen for age-related chronic disease risk among adults. We enrolled active, symptom-free adults in a study of screening for age-related chronic diseases associated with premature mortality. In addition to personal and family medical history and other clinical testing, we obtained whole-genome sequencing (WGS), noncontrast whole-bodyMRI, dual-energy X-ray absorptiometry (DXA), global metabolomics, a new blood test for prediabetes (Quantose IR), echocardiography (ECHO), ECG, and cardiac rhythm monitoring to identify age-related chronic disease risks. Precision medicine screening using WGS and advanced imaging along with other testing among active, symptom-free adults identified a broad set of complementary age-related chronic disease risks associated with premature mortality and strengthened WGS variant interpretation. This and other similarly designed screening approaches anchored by WGS and advanced imaging may have the potential to extend healthy life among active adults through improved prevention and early detection of age-related chronic diseases (and their risk factors) associated with premature mortality.
Journal Article
Regulation of Blood and Lymphatic Vascular Separation by Signaling Proteins SLP-76 and Syk
Lymphatic vessels develop from specialized endothelial cells in preexisting blood vessels, but the molecular signals that regulate this separation are unknown. Here we identify a failure to separate emerging lymphatic vessels from blood vessels in mice lacking the hematopoietic signaling protein SLP-76 or Syk. Blood-lymphatic connections lead to embryonic hemorrhage and arteriovenous shunting. Expression of slp-76 could not be detected in endothelial cells, and blood-filled lymphatics also arose in wild-type mice reconstituted with SLP-76-deficient bone marrow. These studies reveal a hematopoietic signaling pathway required for separation of the two major vascular networks in mammals.
Journal Article
Neuroharmony: A new tool for harmonizing volumetric MRI data from unseen scanners
•We present Neuroharmony, a harmonization tool for images from unseen scanners.•We developed Neuroharmony using a total of 15,026 sMRI images.•The tool was able to reduce scanner-related bias from unseen scans.•Neuroharmony represents a significant step towards imaging-based clinical tools.•Neuroharmony is available at https://github.com/garciadias/Neuroharmony.
Journal Article
MIF inhibits the formation and toxicity of misfolded SOD1 amyloid aggregates: implications for familial ALS
Mutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease caused by the progressive loss of motor neurons in the brain and spinal cord. It has been suggested that toxicity of mutant SOD1 results from its misfolding, however, it is yet unclear why misfolded SOD1 accumulates specifically within motor neurons. We recently demonstrated that macrophage migration inhibitory factor (MIF)—a multifunctional protein with cytokine/chemokine activity and cytosolic chaperone-like properties—inhibits the accumulation of misfolded SOD1. Here, we show that MIF inhibits mutant SOD1 nuclear clearance when overexpressed in motor neuron-like NSC-34 cells. In addition, MIF alters the typical SOD1 amyloid aggregation pathway in vitro, and, instead, promotes the formation of disordered aggregates, as measured by Thioflavin T (ThT) assay and transmission electron microscopy (TEM) imaging. Moreover, we report that MIF reduces the toxicity of misfolded SOD1 by directly interacting with it, and that the chaperone function and protective effect of MIF in neuronal cultures do not require its intrinsic catalytic activities. Importantly, we report that the locked-trimeric MIF
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mutant, which exhibits strongly impaired CD74-mediated cytokine functions, has strong chaperone activity, dissociating, for the first time, these two cellular functions. Altogether, our study implicates MIF as a potential therapeutic candidate in the treatment of ALS.
Journal Article