Constructing a new nigrostriatal pathway in the Parkinsonian model with bridged neural transplantation in substantia nigra

The physical repair and restoration of a completely damaged pathway in the brain has not been achieved previously. In a previous study, using excitatory amino acid bridging and fetal neural transplantation, we demonstrated that a bridged mesencephalic transplant in the substantia nigra generated an artificial nerve pathway that reinnervated the striatum of 6-hydroxydopamine (6-OHDA)-lesioned rats. In the current study, we report that a bridged mesencephalic transplant can anatomically, neurochemically, and functionally reinstate the 6-OHDA-eradicated nigro-striatal pathway. An excitatory amino acid, kainic acid, laid down in a track during the transplant generated a trophic environment that effectively guided the robust growth of transplanted neuronal fibers in a bundle to innervate the distal striatum. Growth occurred at the remarkable speed of approximately 200 microm/d. Two separate and distinct types of dopamine (DA) innervation from the transplant have been achieved for the first time: (1) DA innervation of the striatum, and (2) DA innervation of the pars reticularis of the substantia nigra. In addition, neuronal tracing revealed that reciprocal connections were achieved. The grafted DA neurons in the SNr innervated the host's striatum, whereas the host's striatal neurons, in turn, innervated the graft within 3-8 weeks. Electrochemical volt- ammetry recording revealed the restoration of DA release and clearance in a broad striatal area associated with the DA reinnervation. Furthermore, the amphetamine-induced rotation was attenuated, which indicates that the artificial pathways were motor functional. This study provides additional evidences that our bridged transplantation technique is a potential means for the repair of a completely damaged neuronal pathway

Opportunities in posthemorrhagic hydrocephalus research: outcomes of the Hydrocephalus Association Posthemorrhagic Hydrocephalus Workshop

Abstract The Hydrocephalus Association Posthemorrhagic Hydrocephalus Workshop was held on July 25 and 26, 2016 at the National Institutes of Health. The workshop brought together a diverse group of researchers including pediatric neurosurgeons, neurologists, and neuropsychologists with scientists in the fields of brain injury and development, cerebrospinal and interstitial fluid dynamics, and the blood–brain and blood–CSF barriers. The goals of the workshop were to identify areas of opportunity in posthemorrhagic hydrocephalus research and encourage scientific collaboration across a diverse set of fields. This report details the major themes discussed during the workshop and research opportunities identified for posthemorrhagic hydrocephalus. The primary areas include (1) preventing intraventricular hemorrhage, (2) stopping primary and secondary brain damage, (3) preventing hydrocephalus, (4) repairing brain damage, and (5) improving neurodevelopment outcomes in posthemorrhagic hydrocephalus.https://deepblue.lib.umich.edu/bitstream/2027.42/142869/1/12987_2018_Article_96.pd

Lysophospholipid (LPA) receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Lysophosphatidic acid (LPA) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid Receptors [50, 18]) are activated by the endogenous phospholipid LPA. The first receptor, LPA1, was identified as ventricular zone gene-1 (vzg-1) [38], leading to deorphanisation of members of the endothelial differentiation gene (edg) family as other LPA receptors along with sphingosine 1-phosphate (S1P) receptors. Additional LPA receptor GPCRs were later identified. Gene names have been codified as LPAR1, etc. to reflect the receptor function of proteins. The crystal structure of LPA1 was solved and demonstrates extracellular LPA access to the binding pocket, consistent with proposed delivery via autotaxin [12]. These studies have also implicated cross-talk with endocannabinoids via phosphorylated intermediates that can also activate these receptors. The identified receptors can account for most, although not all, LPA-induced phenomena in the literature, indicating that a majority of LPA-dependent phenomena are receptor-mediated. Binding affinities of unlabeled, natural LPA and AEAp to LPA1 were measured using backscattering interferometry (pKd = 9) [73]. Binding affinities were 77-fold lower than than values obtained using radioactivity [111]. Targeted deletion of LPA receptors has clarified signalling pathways and identified physiological and pathophysiological roles. Independent validation by multiple groups has been reported in the peer-reviewed literature for all six LPA receptors described in the tables, including further validation using a distinct read-out via a novel TGFα "shedding" assay [45]. LPA has also been described as an agonist for the transient receptor potential (Trp) ion channel TRPV1 [76] and TRPA1 [53]. LPA was originally proposed to be a ligand for GPCR35, but data show that in fact it is a receptor for CXCL17 [68]. All of these proposed non-GPCR receptor identities require confirmation and are not currently recognized as bona fide LPA receptors

Mediated gates between spin qubits

In a typical quantum circuit, nonlocal quantum gates are applied to nonproximal qubits. If the underlying physical interactions are short-range (e.g., exchange interactions between spins), intermediate swap operations must be introduced, thus increasing the circuit depth. Here we develop a class of "mediated" gates for spin qubits, which act on nonproximal spins via intermediate ancilla qubits. At the end of the operation, the ancillae return to their initial states. We show how these mediated gates can be used (1) to generate arbitrary quantum states and (2) to construct arbitrary quantum gates. We provide some explicit examples of circuits that generate common states [e.g., Bell, Greenberger-Horne-Zeilinger (GHZ), W, and cluster states] and gates (e.g.,square-root-SWAP, SWAP, CNOT, and Toffoli gates). We show that the depths of these circuits are often shorter than those of conventional swap-based circuits. We also provide an explicit experimental proposal for implementing a mediated gate in a triple-quantum-dot system.Comment: 12 pages, 8 figures, 2 table

Decreased Level of Nurr1 in Heterozygous Young Adult Mice Leads to Exacerbated Acute and Long-Term Toxicity after Repeated Methamphetamine Exposure

The abuse of psychostimulants, such as methamphetamine (METH), is prevalent in young adults and could lead to long-term adaptations in the midbrain dopamine system in abstinent human METH abusers. Nurr1 is a gene that is critical for the survival and maintenance of dopaminergic neurons and has been implicated in dopaminergic neuron related disorders. In this study, we examined the synergistic effects of repeated early exposure to methamphetamine in adolescence and reduction in Nurr1 gene levels. METH binge exposure in adolescence led to greater damage in the nigrostrial dopaminergic system when mice were exposed to METH binge later in life, suggesting a long-term adverse effect on the dopaminergic system. Compared to naïve mice that received METH binge treatment for the first time, mice pretreated with METH in adolescence showed a greater loss of tyrosine hydroxylase (TH) immunoreactivity in striatum, loss of THir fibers in the substantia nigra reticulata (SNr) as well as decreased dopamine transporter (DAT) level and compromised DA clearance in striatum. These effects were further exacerbated in Nurr1 heterozygous mice. Our data suggest that a prolonged adverse effect exists following adolescent METH binge exposure which may lead to greater damage to the dopaminergic system when exposed to repeated METH later in life. Furthermore, our data support that Nurr1 mutations or deficiency could be a potential genetic predisposition which may lead to higher vulnerability in some individuals

Diagnostic performance of contrast enhanced CT and 18F-FDG PET/CT in suspicious recurrence of biliary tract cancer after curative resection

<p>Abstract</p> <p>Background</p> <p>Because of the late clinical presentation of biliary tract cancer (BTC), only 10% of patients are eligible for curative surgery. Even among those patients who have undergone curative surgery, most patients develop recurrent cancer. This study is to determine the clinical role of ¹⁸F-FDG PET/CT during post-operative surveillance of suspected recurrent BTC based on symptoms, laboratory findings and contrast-enhanced CT (ceCT) findings.</p> <p>Methods</p> <p>We consecutively enrolled 50 patients with BTC who underwent curative surgery. An ¹⁸F-FDG PET/CT was obtained for assessment of recurrence based on clinical suspicion during post-operative surveillance. The final confirmation of recurrence was determined pathologically or clinically. When a pathologic confirmation was impossible or inconclusive, a clinical confirmation was used by radiologic correlation with subsequent follow-up ceCT at a minimum of 3-month intervals. Diagnostic efficacy was evaluated by comparing the results of ceCT and ¹⁸F-FDG PET/CT with the final diagnosis.</p> <p>Results</p> <p>Among the 50 patients, 34(68%) were confirmed to have a recurrence. PET/CT showed higher sensitivity (88% <it>vs</it>. 76%, <it>p </it>= 0.16) and accuracy (82% <it>vs</it>. 66%, <it>p </it>= 0.11) for recurrence compared to ceCT, even though the difference was not significant. The positive (86% <it>vs</it>. 74%, <it>p </it>= 0.72) and negative predictive values for recurrence (73% <it>vs</it>. 47%, <it>p </it>= 0.55) were not significantly different between PET/CT and ceCT. However, an additional PET/CT on ceCT significantly improved the sensitivity than did a ceCT alone (94% [32/34] for PET/CT on ceCT <it>vs</it>. 76% [26/34] for ceCT alone, <it>p </it>= 0.03) without increasing the specificity, positive predictive value, and negative predictive value.</p> <p>Conclusions</p> <p>¹⁸F-FDG PET/CT alone is not more sensitive or specific than ceCT in the detection of recurrent BTC after curative surgery. These results do not reach statistical significance, probably due to the low number of patients. However, an additional ¹⁸F-FDG PET/CT on ceCT significantly improves the sensitivity of detecting recurrences.</p

Dephosphorylation of Nucleophosmin by PP1β Facilitates pRB Binding and Consequent E2F1-dependent DNA Repair

We report a new pathway through which PP1β signals to nucleophosmin (NPM) in response to DNA damage. UV induces dephosphorylation of NPM at multiple sites, leading to enhancement of complex formation between NPM and retinoblastoma tumor suppressor protein and the subsequent upregulation of E2F1. Consequently, such signaling pathway potentiates the cellular DNA repair capacity

Chromosomal polymorphism of ribosomal genes in the genus Oryza

The genes encoding for 18S–5.8S–28S ribosomal RNA (rDNA) are both conserved and diversified. We used rDNA as probe in the fluorescent in situ hybridization (rDNA-FISH) to localized rDNAs on chromosomes of 15 accessions representing ten Oryza species. These included cultivated and wild species of rice, and four of them are tetraploids. Our results reveal polymorphism in the number of rDNA loci, in the number of rDNA repeats, and in their chromosomal positions among Oryza species. The numbers of rDNA loci varies from one to eight among Oryza species. The rDNA locus located at the end of the short arm of chromosome 9 is conserved among the genus Oryza. The rDNA locus at the end of the short arm of chromosome 10 was lost in some of the accessions. In this study, we report two genome specific rDNA loci in the genus Oryza. One is specific to the BB genome, which was localized at the end of the short arm of chromosome 4. Another may be specific to the CC genome, which was localized in the proximal region of the short arm of chromosome 5. A particular rDNA locus was detected as stretched chromatin with bright signals at the proximal region of the short arm of chromosome 4 in O.grandiglumis by rDNA-FISH. We suggest that chromosomal inversion and the amplification and transposition of rDNA might occur during Oryza species evolution. The possible mechanisms of cyto-evolution in tetraploid Oryza species are discussed

Normal Human Pluripotent Stem Cell Lines Exhibit Pervasive Mosaic Aneuploidy

Human pluripotent stem cell (hPSC) lines have been considered to be homogeneously euploid. Here we report that normal hPSC – including induced pluripotent - lines are karyotypic mosaics of euploid cells intermixed with many cells showing non-clonal aneuploidies as identified by chromosome counting, spectral karyotyping (SKY) and fluorescent in situ hybridization (FISH) of interphase/non-mitotic cells. This mosaic aneuploidy resembles that observed in progenitor cells of the developing brain and preimplantation embryos, suggesting that it is a normal, rather than pathological, feature of stem cell lines. The karyotypic heterogeneity generated by mosaic aneuploidy may contribute to the reported functional and phenotypic heterogeneity of hPSCs lines, as well as their therapeutic efficacy and safety following transplantation

Preferential binding to elk-1 by sle-associated il10 risk allele upregulates il10 expression

Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (P = 2.7×10−8, OR = 1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans