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Progressive multifocal leukoencephalopathy (PML) is a rare, fatal demyelinating disease of the brain caused by the polyomavirus JC (JCV) under immunosuppressive conditions. It is pathologically characterized by progressive damage of white matter of the brain by destroying oligodendrocytes at multiple locations. Clinically, PML symptoms include weakness or paralysis, vision loss, impaired speech, and cognitive deterioration. The prognosis of PML is generally poor. No effective therapy for PML has been established.

Investigators at the NIH have identified a series of novel, small molecule antagonists of the dopamine D2 receptor. Among the dopamine receptor (DAR) subtypes, D2 DAR is arguably one of the most validated drug targets in neurology and psychiatry. For instance, all receptor-based anti-Parkinsonian drugs work via stimulating the D2 DAR, whereas all FDA approved antipsychotic agents are antagonists of this receptor. Unfortunately, most agents that act as antagonists of D2 DAR are problematic, either they are less efficacious than desired or cause multiple adverse effects.

The magnetic resonance imaging (MRI) systems are used for a variety of imaging application. The present invention discloses an improving MRI device and method by amplifying signals received by resonant NMR coils of MRI systems. It utilizes positive feedback from low-noise Field-Effect Transistor to amplify the signal current that can be coupled out to receiving loops positioned externally without loss in sensitivity. Therefore, the NMR coil can be flexibly positioned near internal tissues and used to develop high-resolution images in highly invasive situations.

This invention includes the generation and use of two polyclonal antibodies that specifically recognizes the phosphorylation site pThr707 of Neuroligin 4 and pThr739 of Neuroligin 1. A peptide of the site around the phosphorylation site was generated and injected into rabbits to create an immune response. Serum was collected from the rabbits that was then affinity purified. The specificity of the resulting polyclonal antibodies was then determined using biochemical techniques.

This invention relates to two devices that reliably, sensitively, and accurately measures force during handgrip contraction and subsequent relaxation. A delayed relaxation after a sustained and forceful handgrip is a cardinal symptom of myotonic dystrophies (DM). This delayed relaxation, handgrip myotonia, may be a therapeutic response biomarker in clinical trials.

This invention is a novel statistical method for automatically detecting lesions in cross-sectional brain magnetic resonance imaging (MRI) studies. OASIS uses multimodal MRI from one image acquisition session and produces voxel-level probability maps of the brain that quantifies the likelihood that each voxel is part of a lesion. Binary lesion segmentations are created from these probability maps using a validated population-level threshold. In this application, fluid attenuated inversion recovery (FLAIR), proton density (PD), T2-weighted, and Tl-weighted volumes were used.

This invention includes human induced pluripotent stem cell (iPSC) lines that harbor a single copy dCas9-BFP-KRAB at the CLYBL safe harbor locus (mediating CRISPR inhibition of human gene expression) and/or a single copy of dox-inducible NGN2 at the AAVS1 locus (enabling the differentiation of the iPSCs into neurons). The CRISPR-mediated inhibition of human gene expression is maintained into the differentiated neurons, permitting functional studies of targeted genes in neurons.

This technology includes a system that allows for robust differentiation of human-induced pluripotent stem cells (iPSC) into motor neurons within a time frame of 7 to 10 days. To differentiate the iPSC, a stable transgene is inserted into the CLYBL safe harbor locus in the human genome using TALENs. The transgene allows for doxycycline-inducible expression of the transcription factors (NGN2, ISL1, and LHX3) that are needed for the cells to differentiate to motor neurons. The technology is described in detail in the protocol paper published by Fernandopulle et al, cited below.

The technology includes Pink1 knockout HeLa cells that were generated using CRISPR technology. Pink1 is the key master gene to trigger degradation of mitochondria, mitophagy, and is implicated in familial Parkinson Disease. Knocking out Pink1 allows us to study the roles of Pink1 in many aspects of mitophagy and to display Pink1-dependent or independent activity. To create the HeLa cells, two CRISPR gRNAs targeting exon 1 and exon 7 of the Pink1 genome were used for transfection with Cas9 and GFP-C1 reporter. Cells were sorted 2 days after transfection and plated out in 96-well plates.

This invention includes HeLa cells that are engineered to inducibly express a mutant form of ornithine decarboxylase that is targeted to the mitochondrial matrix and forms insoluble protein aggregates. The presence of unfolded proteins in the matrix causes the accumulation of the mitochondrial kinase PINK1 and the E3 ubiquitin ligase PARK2/Parkin. These proteins play a critical role in degrading the mitochondria where they are expressed, a process call mitophagy. Mutations in these two genes are associated with familial Parkinson disease.