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Degeneration of dopamine (DA) neurons in the midbrain underlies the pathogenesis of Parkinson’s disease (PD). Supplement of DA via L-DOPA alleviates motor symptoms but does not prevent the progressive loss of DA neurons. A large body of experimental studies, including those in nonhuman primates, demonstrates that transplantation of fetal mesencephalic tissues improves motor symptoms in animals, which culminated in open-label and double-blinded clinical trials of fetal tissue transplantation for PD 1 . Unfortunately, the outcomes are mixed, primarily due to the undefined and unstandardized donor tissues 1 , 2 . Generation of induced pluripotent stem cells enables standardized and autologous transplantation therapy for PD. However, its efficacy, especially in primates, remains unclear. Here we show that over a 2-year period without immunosuppression, PD monkeys receiving autologous, but not allogenic, transplantation exhibited recovery from motor and depressive signs. These behavioral improvements were accompanied by robust grafts with extensive DA neuron axon growth as well as strong DA activity in positron emission tomography (PET). Mathematical modeling reveals correlations between the number of surviving DA neurons with PET signal intensity and behavior recovery regardless autologous or allogeneic transplant, suggesting a predictive power of PET and motor behaviors for surviving DA neuron number. Rescue of motor and behavioral deficits in a primate model of Parkinson’s disease following autologous transplantation of iPSC-derived dopaminergic neural progenitors without immunosuppression.

Between 2004 and 2018, NASA’s rover Opportunity found huge numbers of small, hematite-rich spherules (commonly called blueberries) on the Meridiani Planum of Mars. The standard oxide composition distributions of blueberries have remained poorly constrained, with previous published analyses leaving hematite content somewhere in the broad range of 24–100 wt%. A searching mass-balance analysis is introduced and applied to constrain possible standard oxide composition distributions of blueberries consistent with the non-detection of silicates in blueberries by Opportunity’s instruments. This analysis found three groups of complete solution sets among the mass-balance ions consistent with the non-detection of silicates; although, a simple extension of the analysis indicates that one larger space of solutions incorporates all three groups of solutions. Enforcing consistency with the non-detection of silicates in blueberries constrains the hematite content in most of blueberry samples to between 79.5 and 99.85 wt%. A feature of the largest group of complete solution sets is that five oxides/elements, MgO, P2O5, Na2O, SO3, and Cl, collectively have a summed weight percentage that averages close to 6 wt%, while the weight percentage of nickel is close to 0.3 wt% in all solutions. Searches over multidimensional spaces of filtering composition distributions of basaltic and dusty soils were a methodological advance.

PurposeThe aim of this study was to examine whether the translocator protein 18-kDa (TSPO) PET ligand [18F]FEPPA has the sensitivity for detecting changes in CD68-positive microglial/macrophage activation in hemiparkinsonian rhesus macaques treated with allogeneic grafts of induced pluripotent stem cell-derived midbrain dopaminergic neurons (iPSC-mDA).MethodsIn vivo positron emission tomography (PET) imaging with [18F]FEPPA was used in conjunction with postmortem CD68 immunostaining to evaluate neuroinflammation in the brains of hemiparkinsonian rhesus macaques (n = 6) that received allogeneic iPSC-mDA grafts in the putamen ipsilateral to MPTP administration.ResultsBased on assessment of radiotracer uptake and confirmed by visual inspection of the imaging data, nonhuman primates with allogeneic grafts showed increased [18F]FEPPA binding at the graft sites relative to the contralateral putamen. From PET asymmetry analysis of the images, the mean asymmetry index of the monkeys was AI = − 0.085 ± 0.018. Evaluation and scoring of CD68 immunoreactivity by an investigator blind to the treatment identified significantly more neuroinflammation in the grafted areas of the putamen compared to the contralateral putamen (p = 0.0004). [18F]FEPPA PET AI showed a positive correlation with CD68 immunoreactivity AI ratings in the monkeys (Spearman’s ρ = 0.94; p = 0.005).ConclusionThese findings reveal that [18F]FEPPA PET is an effective marker for detecting increased CD68-positive microglial/macrophage activation and demonstrates sufficient sensitivity to detect changes in neuroinflammation in vivo following allogeneic cell engraftment.

Induced pluripotent stem cell (iPSC)-derived neurons represent an opportunity for cell replacement strategies for neurodegenerative disorders such as Parkinson's disease (PD). Improvement in cell graft targeting, distribution, and density can be key for disease modification. We have previously developed a trajectory guide system for real-time intraoperative magnetic resonance imaging (RT-IMRI) delivery of infusates, such as viral vector suspensions for gene therapy strategies. Intracerebral delivery of iPSC-derived neurons presents different challenges than viral vectors, including limited cell survival if cells are kept at room temperature for prolonged periods of time, precipitation and aggregation of cells in the cannula, and obstruction during injection, which must be solved for successful application of this delivery approach. To develop procedures suitable for RT-IMRI cell delivery, we first performed in vitro studies to tailor the delivery hardware (e.g., cannula) and defined a range of parameters to be applied (e.g., maximal time span allowable between cell loading in the system and intracerebral injection) to ensure cell survival. Then we performed an in vivo study to evaluate the feasibility of applying the system to nonhuman primates. Our results demonstrate that the RT-IMRI delivery system provides valuable guidance, monitoring, and visualization during intracerebral cell delivery that are compatible with cell survival.

Most clinical neurosurgeries today are performed without intraoperative tomographic imaging, instead relying on preoperative images which may be hours or days old. An optical tracking system, used in the operating room while aiming interventional devices, renders updates of the predicted trajectory on the preoperative image by repeatedly measuring fiducials on the device and patient's head. This technique rests on the assumption that the brain does not shift inside the skull, but brain shift is observed. For procedures like biopsy of large tumors, this is acceptable because the shift is much smaller than the target size.When targets are small and interventional devices must be placed very accurately, as in the studies we undertake in this work, the standard method is inadequate. The surgeries we focus on are: implantation of deep brain stimulation (DBS) electrodes, infusion of viral vectors carrying gene-therapy payloads, injection of neural progenitor cells, and intracerebral hemorrhage (ICH) evacuation by administration of thrombolytic drugs directly into clot.The main findings of this work are: Perforating vessels of the basal ganglia are depicted well by bSSFP imaging (compared to TOF), have an enlarged appearance in 12% of the subpopulation near the age of typical Parkinson’s disease onset (50–70 years), and influence the choice of trajectories when planning functional neurosurgeries such as DBS lead placement.Complex and previously unachievable surgical goals are enabled by the development of a physically accurate method for preoperative planning of IMRI-guided surgeries. A computational approach to neurosurgical trajectory guide tracking (rather than an approach based on human interpretation of images) enables rapid interactive feedback, decreased subjectivity, and accurate aiming of the trajectory guide. The usefulness of the preoperative planning and IMRI device tracking methods are borne out by several preclinical studies (totaling over 80 IMRI neurosurgeries to date) in gene delivery, cell delivery, infusion monitoring, and causal fMRI.In clotting blood, MRI is capable of sensing different contrast mechanisms than CT (the standard modality used during intracerebral hemorrhage monitoring) and in vitro models of IMRI-guided clot lysing suggest there is value in applying IMRI to preclinical in vivo ICH evacuation studies.

Anxiety disorders are among the most prevalent psychiatric disorders, with symptoms often beginning early in life. To model the pathophysiology of human pathological anxiety, we utilized Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in a nonhuman primate model of anxious temperament to selectively increase neuronal activity of the amygdala. Subjects included 10 young rhesus macaques; 5 received bilateral infusions of AAV5-hSyn-HA-hM3Dq into the dorsal amygdala, and 5 served as controls. Subjects underwent behavioral testing in the human intruder paradigm following clozapine or vehicle administration, prior to and following surgery. Behavioral results indicated that clozapine treatment post-surgery increased freezing across different threat-related contexts in hM3Dq subjects. This effect was again observed approximately 1.9 years following surgery, indicating the long-term functional capacity of DREADD-induced neuronal activation. [11C]deschloroclozapine PET imaging demonstrated amygdala hM3Dq-HA specific binding, and immunohistochemistry revealed that hM3Dq-HA expression was most prominent in basolateral nuclei. Electron microscopy confirmed expression was predominantly on neuronal membranes. Together, these data demonstrate that activation of primate amygdala neurons is sufficient to induce increased anxiety-related behaviors, which could serve as a model to investigate pathological anxiety in humans.Anxiety disorders are among the most prevalent psychiatric disorders, with symptoms often beginning early in life. To model the pathophysiology of human pathological anxiety, we utilized Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in a nonhuman primate model of anxious temperament to selectively increase neuronal activity of the amygdala. Subjects included 10 young rhesus macaques; 5 received bilateral infusions of AAV5-hSyn-HA-hM3Dq into the dorsal amygdala, and 5 served as controls. Subjects underwent behavioral testing in the human intruder paradigm following clozapine or vehicle administration, prior to and following surgery. Behavioral results indicated that clozapine treatment post-surgery increased freezing across different threat-related contexts in hM3Dq subjects. This effect was again observed approximately 1.9 years following surgery, indicating the long-term functional capacity of DREADD-induced neuronal activation. [11C]deschloroclozapine PET imaging demonstrated amygdala hM3Dq-HA specific binding, and immunohistochemistry revealed that hM3Dq-HA expression was most prominent in basolateral nuclei. Electron microscopy confirmed expression was predominantly on neuronal membranes. Together, these data demonstrate that activation of primate amygdala neurons is sufficient to induce increased anxiety-related behaviors, which could serve as a model to investigate pathological anxiety in humans.

Purpose: The aim of this study was to examine whether the translocator protein 18-kDa (TSPO) PET ligand [18F]FEPPA has the sensitivity for detecting changes in CD68 positive microglial/macrophage activation in hemiparkinsonian rhesus macaques treated with allogeneic grafts of induced pluripotent stem cell-derived midbrain dopaminergic neurons (iPSC-mDA). Methods: In vivo positron emission tomography (PET) imaging with [18F]FEPPA was used in conjunction with postmortem CD68 immunostaining to evaluate neuroinflammation in the brains of hemiparkinsonian rhesus macaques (n = 6) that received allogeneic iPSC-mDA grafts in the putamen ipsilateral to MPTP administration. Results: Based on assessment of radiotracer uptake and confirmed by visual inspection of the imaging data, nonhuman primates with allogeneic grafts showed increased [18F]FEPPA binding at the graft sites relative to the contralateral putamen. From PET asymmetry analysis of the images, the mean asymmetry index of the monkeys was AI = -0.085 ± 0.018. Evaluation and scoring of CD68 immunoreactivity by an investigator blind to the treatment identified significantly more neuroinflammation in the grafted areas of the putamen compared to the contralateral putamen (p = 0.0004). [18F]FEPPA PET AI showed a positive correlation with CD68 immunoreactivity AI ratings in the monkeys (Spearman’s ρ = 0.94; p = 0.005). Conclusion: These findings reveal that [18F]FEPPA PET is an effective marker for detecting increased CD68 positive microglial/macrophage activation and demonstrate sufficient sensitivity to detect changes in neuroinflammation in vivo following allogeneic cell engraftment.

A study is made of the patterns and rates of amino acid replacements observed between (likely) orthologous proteins sequences. These sequences are from 15 eukaryotic organisms with representatives from several of large taxonomic groups (animals, plants, yeasts, Conosa, protists). These organisms are not very closely related, the lineage divergences between the major groups occurred approximately 1 to 1½ billion years ago. The primary means of studying the observed amino acid replacements is by the design and optimization of a probabilistic model of amino acid replacements. The model of amino acid replacements is part of a larger model, intended for sequence homology classification, which was used to iteratively define the model estimation training datasets. The homology classification techniques include: the introduction of terms for relationships between clusters of phylogenetic characters; (i) comparative hypothesis tests; (ii) a proof about the limit distributions of and characterization of finite size distributions for sequence alignment scores which have different features to standard scoring systems. Simple counting studies were also done to. (i) investigate whether patterns of replacements differ with timescale; (ii) to test whether amino acids replacements are reversible; (iii) establish the correlation, on long time scales, between replacements and similarity of amino acid physical properties. Some of the empirical results of the thesis are that. (i) patterns of replacements differ with timescale and the differences on shorter timescales can be correlated to the genetic code; (ii) the hypothesis that replacements are reversible was not rejected; (iii) on timescales of a billion years replacements in protein sequences are correlated to similarities of amino acid physical properties; (iv) averaged across the timescales associated with the divergences separating the 15 eukaryotes represented in the dataset, bias in amino acid replacements is largely correlated to similarity of physical properties. The major achievement of the thesis was the development of a design procedure for reversible Markov transition matrices which can incorporate prior knowledge about amino acid replacements into the structure of the matrices and which could be applied to similar model building problems. It came through studies into the formal properties of these matrices. Design facilitated. (i) model estimation on datasets that others thought unfeasibly large; (ii) a model with superior performance to the current standard model for phylogenies on moderately large datasets.

Women with metastatic breast cancer that had progressed during treatment with trastuzumab plus a taxane were assigned to lapatinib plus capecitabine or to trastuzumab emtansine. The response rate and survival were significantly better with trastuzumab emtansine. Amplification of human epidermal growth factor receptor 2 (HER2, also called ErbB2) occurs in approximately 20% of breast cancers and is associated with shortened survival. 1 – 3 Combining HER2-targeted agents with standard chemotherapy is an effective therapeutic approach for patients with HER2-positive metastatic breast cancer. When combined with first-line chemotherapy, trastuzumab increases the time to progression and overall survival among patients with metastatic disease. 4 , 5 The addition of lapatinib to capecitabine increases the time to progression in patients previously treated with trastuzumab, an anthracycline, and a taxane, 6 and this combination is a standard option for disease progression with trastuzumab. Trastuzumab emtansine . . .