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"Block, F."
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Autologous transplant therapy alleviates motor and depressive behaviors in parkinsonian monkeys
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.
Journal Article
Taking shape : abstraction from the Arab world, 1950s-1980s
\"'Taking Shape: Abstraction from the Arab World, 1950s-1980s' investigates the development of abstraction in West Asia and North Africa via paintings, sculpture, and drawings made during a period of rapid industrialization, several wars and mass migrations, new state formations, and the rise and fall of Arab nationalism(s). Examining how a diverse group of artists mined the region's rich artistic heritage as well as the expressive capacities of line, color, and texture, this book highlights various abstract practices that arose in the Arab world and its diaspora in the mid-20th century. Alongside vibrant images of nearly ninety works--all drawn from the remarkable collection of the Barjeel Art Foundation, based in Sharjah, United Arab Emirates--'Taking Shape' featuers nine essays by leading scholars who are rethinking art-historical canons and expanding discourses around global modernism.\" --publisher's description, lower cover.
Book
Electrostatic interactions guide substrate recognition of the prokaryotic ubiquitin-like protein ligase PafA
Pupylation, a post-translational modification found in
Mycobacterium tuberculosis
and other Actinobacteria, involves the covalent attachment of prokaryotic ubiquitin-like protein (Pup) to lysines on target proteins by the ligase PafA (proteasome accessory factor A). Pupylated proteins, like ubiquitinated proteins in eukaryotes, are recruited for proteasomal degradation. Proteomic studies suggest that hundreds of potential pupylation targets are modified by the sole existing ligase PafA. This raises intriguing questions regarding the selectivity of this enzyme towards a diverse range of substrates. Here, we show that the availability of surface lysines alone is not sufficient for interaction between PafA and target proteins. By identifying the interacting residues at the pupylation site, we demonstrate that PafA recognizes authentic substrates via a structural recognition motif centered around exposed lysines. Through a combination of computational analysis, examination of available structures and pupylated proteomes, and biochemical experiments, we elucidate the mechanism by which PafA achieves recognition of a wide array of substrates while retaining selective protein turnover.
Pupylation is the bacterial equivalent of ubiquitination. Here, the authors show selective binding of the Pup ligase PafA to substrates is driven by tertiary structure features rather than linear motifs and is achieved by a small number of electrostatic interactions, enabling quick adaption to new substrates.
Journal Article
Use of a platelet-rich plasma-collagen scaffold as a bioenhanced repair treatment for management of partial cruciate ligament rupture in dogs
Dogs are commonly affected with cruciate ligament rupture (CR) and associated osteoarthritis (OA), and frequently develop a second contralateral CR. Platelet rich plasma (PRP) is a component of whole blood that contains numerous growth factors, which in combination with a collagen scaffold may act to promote bioenhanced primary repair of ligament. This study tested the hypothesis that treatment of partial stable CR stifles with an intra-articular collagen scaffold and PRP would decrease the disease progression, synovitis and risk of complete CR over a 12-month study period. We conducted a prospective cohort study of 29 client-owned dogs with an unstable stifle due to complete CR and stable contralateral stifle with partial CR. All dogs were treated with tibial plateau leveling osteotomy (TPLO) on the unstable stifle and a single intra-articular application of PRP-collagen in the stable partial CR stifle. Dogs were evaluated at the time of diagnosis, and at 10-weeks and 12-months after treatment. We evaluated correlation between both development of complete CR and time to complete CR with diagnostic tests including bilateral stifle radiographs, 3.0 Tesla magnetic resonance (MR) imaging, and bilateral stifle arthroscopy. Additionally, histologic evaluation of synovial biopsies, C-reactive protein (CRP) concentrations in serum and synovial fluid, and synovial total nucleated cell count, were determined. Results indicated that a single application of PRP-collagen in partial CR stifles of client owned dogs is not an effective disease-modifying therapy for the prevention of progression to complete CR. Radiographic effusion, arthroscopic evaluation of cranial cruciate ligament (CrCL) damage, and MR assessment of ligament fiber tearing in partial CR stifles correlated with progression to complete CR over the 12-month follow-up period. We determined that the best predictive model for development of complete CR in PRP-collagen treated partial CR stifles included variables from multiple diagnostic modalities.
Journal Article
Tandem Riboswitch Architectures Exhibit Complex Gene Control Functions
Riboswitches are structured RNAs typically located in the 5' untranslated regions of bacterial mRNAs that bind metabolites and control gene expression. Most riboswitches sense one metabolite and function as simple genetic switches. However, we found that the 5' region of the Bacillus clausii metE messenger RNA includes two riboswitches that respond to S-adenosylmethionine and coenzyme B₁₂. This tandem arrangement yields a composite gene control system that functions as a two-input Boolean NOR logic gate. These findings and the discovery of additional tandem riboswitch architectures reveal how simple RNA elements can be assembled to make sophisticated genetic decisions without involving protein factors.
Journal Article
Radiographic and magnetic resonance imaging predicts severity of cruciate ligament fiber damage and synovitis in dogs with cranial cruciate ligament rupture
Cruciate ligament rupture (CR) and associated osteoarthritis (OA) is a common condition in dogs. Dogs frequently develop a second contralateral CR. This study tested the hypothesis that the degree of stifle synovitis and cranial cruciate ligament (CrCL) matrix damage in dogs with CR is correlated with non-invasive diagnostic tests, including magnetic resonance (MR) imaging. We conducted a prospective cohort study of 29 client-owned dogs with an unstable stifle due to complete CR and stable contralateral stifle with partial CR. We evaluated correlation of stifle synovitis and CrCL fiber damage with diagnostic tests including bilateral stifle radiographs, 3.0 Tesla MR imaging, and bilateral stifle arthroscopy. Histologic grading and immunohistochemical staining for CD3+ T lymphocytes, TRAP+ activated macrophages and Factor VIII+ blood vessels in bilateral stifle synovial biopsies were also performed. Serum and synovial fluid concentrations of C-reactive protein (CRP) and carboxy-terminal telopeptide of type I collagen (ICTP), and synovial total nucleated cell count were determined. Synovitis was increased in complete CR stifles relative to partial CR stifles (P<0.0001), although total nucleated cell count in synovial fluid was increased in partial CR stifles (P<0.01). In partial CR stifles, we found that 3D Fast Spin Echo Cube CrCL signal intensity was correlated with histologic synovitis (SR = 0.50, P<0.01) and that radiographic OA was correlated with CrCL fiber damage assessed arthroscopically (SR = 0.61, P<0.001). Taken together, results of this study show that clinical diagnostic tests predict severity of stifle synovitis and cruciate ligament matrix damage in stable partial CR stifles. These data support use of client-owned dogs with unilateral complete CR and contralateral partial CR as a clinical trial model for investigation of disease-modifying therapy for partial CR.
Journal Article
18FFEPPA PET imaging for monitoring CD68-positive microglia/macrophage neuroinflammation in nonhuman primates
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.
Journal Article
Real-Time Intraoperative MRI Intracerebral Delivery of Induced Pluripotent Stem Cell-Derived Neurons
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.
Journal Article
Direct neutrino-mass measurement with sub-electronvolt sensitivity
Since the discovery of neutrino oscillations, we know that neutrinos have non-zero mass. However, the absolute neutrino-mass scale remains unknown. Here we report the upper limits on effective electron anti-neutrino mass,
m
ν
, from the second physics run of the Karlsruhe Tritium Neutrino experiment. In this experiment,
m
ν
is probed via a high-precision measurement of the tritium
β
-decay spectrum close to its endpoint. This method is independent of any cosmological model and does not rely on assumptions whether the neutrino is a Dirac or Majorana particle. By increasing the source activity and reducing the background with respect to the first physics campaign, we reached a sensitivity on
m
ν
of 0.7 eV
c
–2
at a 90% confidence level (CL). The best fit to the spectral data yields
m
ν
2
= (0.26 ± 0.34) eV
2
c
–4
, resulting in an upper limit of
m
ν
< 0.9 eV
c
–2
at 90% CL. By combining this result with the first neutrino-mass campaign, we find an upper limit of
m
ν
< 0.8 eV
c
–2
at 90% CL.
In its second measurement campaign, the Karlsruhe Tritium Neutrino experiment achieved a sub-electronvolt sensitivity on the effective electron anti-neutrino mass.
Journal Article