Editorial: Genotype-Phenotype Correlation in Parkinsonian Conditions

With the diffusion of cost-effective genetic analyses, an increase in the spectrum of reported genetic variants associated with sporadic Parkinson’s disease (sPD) (e.g., glucocerebrosidase— GBA) and monogenic parkinsonisms (dominant, recessive, and atypical forms) has been achieved. Each single variant may be associated to distinct prominent phenotypic characteristics helpful for diagnostic and prognostic purposes, thus ushering the era of precision medicine for movement disorders.Fil: Marsili, Luca. University of Cincinnati; Estados UnidosFil: Mata, Ignacio F.. Cleveland Clinic Foundation; Estados UnidosFil: Kauffman, Marcelo Andres. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Centro Universitario de Neurología "Dr. José María Ramos Mejía".; Argentin

Electrogenic uptake of nucleosides and nucleoside-derived drugs by the human nucleoside transporter 1 (hCNT1) expressed in Xenopus laevis oocytes

AbstractThe concentrative pyrimidine-preferring nucleoside transporter 1 (hCNT1), cloned from human fetal liver, was expressed in Xenopus laevis oocytes. Using the two-electrode voltage-clamp technique, it is shown that translocation of nucleosides by this transporter generates sodium inward currents. Membrane hyperpolarization (from −50 to −150 mV) did not affect the K0.5 for uridine, although it increased the transport current approximately 3-fold. Gemcitabine (a pyrimidine nucleoside-derived drug) but not fludarabine (a purine nucleoside-derived drug) induced currents in oocytes expressing the hCNT1 transporter. The K0.5 value for gemcitabine at −50 mV membrane potential was lower than that for natural substrates, although this drug induced a lower current than uridine and cytidine, thus suggesting that the affinity binding of the drug transporter is high but that translocation occurs more slowly. The analysis of the currents generated by the hCNT1-mediated transport of nucleoside-derived drugs used in anticancer and antiviral therapies will be useful in the characterization of the pharmacological profile of this family of drug transporters and will allow rapid screening for uptake of newly developed nucleoside-derived drugs

Phase space contraction and quantum operations

We give a criterion to differentiate between dissipative and diffusive quantum operations. It is based on the classical idea that dissipative processes contract volumes in phase space. We define a quantity that can be regarded as ``quantum phase space contraction rate'' and which is related to a fundamental property of quantum channels: non-unitality. We relate it to other properties of the channel and also show a simple example of dissipative noise composed with a chaotic map. The emergence of attaractor-like structures is displayed.Comment: 8 pages, 6 figures. Changes added according to refferee sugestions. (To appear in PRA

Driving superconducting qubits into chaos

Kerr parametric oscillators are potential building blocks for fault-tolerant quantum computers. They can stabilize Kerr-cat qubits, which offer advantages towards the encoding and manipulation of error-protected quantum information. Kerr-cat qubits have been recently realized with the SNAIL transmon superconducting circuit by combining nonlinearities and a squeezing drive. These superconducting qubits can lead to fast gate times due to their access to large anharmonicities. However, we show that when the nonlinearities are large and the drive strong, chaos sets in and melts the qubit away. We provide an equation for the border between regularity and chaos and determine the regime of validity of the Kerr-cat qubit, beyond which it disintegrates. This is done through the quantum analysis of the quasienergies and Floquet states of the driven system, and is complemented with classical tools that include Poincar\'e sections and Lyapunov exponents. By identifying the danger zone for parametric quantum computation, we uncover another application for driven superconducting circuits, that of devices to investigate quantum chaos.Comment: 12 pages, 5 figure

Mosaicism of alpha-synuclein gene rearrangements: Report of two unrelated cases of early-onset parkinsonism

Dear Sir, In genetics, the term ‘mosaicism’ describes the situation in which groups of cells have a different genetic composition to other cells in an organism. Somatic gene rearrangements due to multiplication or deletion of genes (copy number variation) and/or sections of chromosomes can lead to mosaicism. The presence of multiple copies of the alpha-synuclein gene (SNCA) is known to be associated with Parkinson’s disease (PD) and the severity of symptoms increases with the number of copies of the gene [1]. While the features of PD associated with duplication of SNCA are usually (but not always) typical of the condition [2–3], patients with triplicate copies have atypical features, including rapidly evolving symptoms, severe cognitive impairment, limited response to levodopa, more severe symptoms of dementia and more..

Role of the human concentrative nucleoside transporter (hCNT1) in the cytotoxic action of 5[Prime]-deoxy-5-fluorouridine, an active intermediate metabolite of capecitabine, a novel oral anticancer drug.

We attempt to identify the plasma membrane transporter involved in the uptake of 5'-deoxy-5-fluorouridine (5'-DFUR), an intermediate metabolite of capecitabine. This novel oral fluoropyrimidine is used in cancer treatments and is a direct precursor of the cytostatic agent 5'-fluorouracil. We also examine the role of the transporter in 5'-DFUR cytotoxicity. The human concentrative nucleoside transporter (hCNT1) was cloned from human fetal liver and expressed in Xenopus laevis oocytes. The two-electrode voltage-clamp technique was used to demonstrate that 5'-DFUR, but not capecitabine or 5'-FU, is an hCNT1 substrate. Then, hCNT1 was heterologously expressed in the mammalian cell line Chinese hamster ovary-K1. Functional expression was demonstrated by monitoring transport of radiolabeled substrates and by using a monospecific polyclonal antibody generated against the transporter. hCNT1-expressing cells were more sensitive to 5'-DFUR than vector-transfected or wild-type cells. The sensitivity of the three cell types to other agents such as cisplatin or 5'-FU was identical. In conclusion, this study shows that 1) the pharmacological profile of a nucleoside transporter can be determined by an electrophysiological approach; 2) the hCNT1 transporter is involved in 5'-DFUR uptake; and 3) hCNT1 expression may increase cell sensitivity to 5'-DFUR treatment. This study also reports for the first time the generation of an antibody against hCNT1, which may be useful in the elucidation of the relationship between hCNT1 expression and tumor response to capecitabine treatmen

Analysis of the mutational landscape of classic Hodgkin lymphoma identifies disease heterogeneity and potential therapeutic targets

Defining the mutational landscape of classic Hodgkin lymphoma is still a major research goal. New targeted next-generation sequencing (NGS) techniques may identify pathogenic mechanisms and new therapeutic opportunities related to this disease. We describe the mutational profile of a series of 57 cHL cases, enriched in Hodgkin and Reed-Sternberg (HRS) cells. Overall, the results confirm the presence of strong genomic heterogeneity. However, several variants were consistently detected in genes related to relevant signaling pathways, such as GM-CSF/IL-3, CBP/EP300, JAK/STAT, NF-kappaB, and numerous variants of genes affecting the B-cell receptor (BCR) pathway, such as BTK, CARD11, BCL10, among others. This unexpectedly high prevalence of mutations affecting the BCR pathway suggests some requirement for active BCR signaling for cHL cell viability. Additionally, incubation of a panel of cHL cellular models with selective BTK inhibitors in vitro constrains cell proliferation and causes cell death. Our results indicate new pathogenic mechanisms and therapeutic opportunities in this disease

Purcell Enhancement and Wavelength Shift of Emitted Light by CsPbI3 Perovskite Nanocrystals Coupled to Hyperbolic Metamaterials

Manipulation of the exciton emission rate in nanocrystals of lead halide perovskites (LHPs) was demonstrated by means of coupling of excitons with a hyperbolic metamaterial (HMM) consisting of alternating thin metal (Ag) and dielectric (LiF) layers. Such a coupling is found to induce an increase of the exciton radiative recombination rate by more than a factor of three due to the Purcell effect when the distance between the quantum emitter and HMM is nominally as small as 10 nm, which coincides well with the results of our theoretical analysis. Besides, an effect of the coupling-induced long wavelength shift of the exciton emission spectrum is detected and modeled. These results can be of interest for quantum information applications of single emitters on the basis of perovskite nanocrystals with high photon emission rates

Infrared permittivity of the biaxial van der Waals semiconductor α\alpha-MoO3_3 from near- and far-field correlative studies

The biaxial van der Waals semiconductor $\alpha$-phase molybdenum trioxide ($\alpha$-MoO$_3$) has recently received significant attention due to its ability to support highly anisotropic phonon polaritons (PhPs) -infrared (IR) light coupled to lattice vibrations in polar materials-, offering an unprecedented platform for controlling the flow of energy at the nanoscale. However, to fully exploit the extraordinary IR response of this material, an accurate dielectric function is required. Here, we report the accurate IR dielectric function of $\alpha$-MoO$_3$ by modelling far-field, polarized IR reflectance spectra acquired on a single thick flake of this material. Unique to our work, the far-field model is refined by contrasting the experimental dispersion and damping of PhPs, revealed by polariton interferometry using scattering-type scanning near-field optical microscopy (s-SNOM) on thin flakes of $\alpha$-MoO$_3$, with analytical and transfer-matrix calculations, as well as full-wave simulations. Through these correlative efforts, exceptional quantitative agreement is attained to both far- and near-field properties for multiple flakes, thus providing strong verification of the accuracy of our model, while offering a novel approach to extracting dielectric functions of nanomaterials, usually too small or inhomogeneous for establishing accurate models only from standard far-field methods. In addition, by employing density functional theory (DFT), we provide insights into the various vibrational states dictating our dielectric function model and the intriguing optical properties of $\alpha$-MoO$_3$

Clinical and Genetic Analysis of Costa Rican Patients With Parkinson's Disease

Background: Most research in genomics of Parkinson’s disease (PD) has been done in subjects of European ancestry, leading to sampling bias and leaving Latin American populations underrepresented. We sought to clinically characterize PD patients of Costa Rican origin and to sequence familial PD and atypical parkinsonism-associated genes in cases and controls. Methods: We enrolled 118 PD patients with 97 unrelated controls. Collected information included demographics, exposure to risk and protective factors, and motor and cognitive assessments. We sequenced coding and untranslated regions in familial PD and atypical parkinsonism-associated genes including GBA, SNCA, VPS35, LRRK2, GCH1, PRKN, PINK1, DJ-1, VPS13C, and ATP13A2. Results: Mean age of PD probands was 62.12 ± 13.51 years; 57.6% were male. The frequency of risk and protective factors averaged ∼45%. Physical activity significantly correlated with better motor performance despite years of disease. Increased years of education were significantly associated with better cognitive function, whereas hallucinations, falls, mood disorders, and coffee consumption correlated with worse cognitive performance. We did not identify an association between tested genes and PD or any damaging homozygous or compound heterozygous variants. Rare variants in LRRK2 were nominally associated with PD; six were located between amino acids p.1620 and 1623 in the C-terminal-of-ROC (COR) domain of Lrrk2. Non-synonymous GBA variants (p.T369M, p.N370S, and p.L444P) were identified in three healthy individuals. One PD patient carried a pathogenic GCH1 variant, p.K224R. Discussion: This is the first study that describes sociodemographics, risk factors, clinical presentation, and genetics of Costa Rican patients with PD, adding information to genomics research in a Latino population.Antecedentes: la mayor parte de la investigación en genómica de la enfermedad de Parkinson (EP) se ha realizado en sujetos de ascendencia europea, lo que provoca un sesgo de muestreo y deja a las poblaciones latinoamericanas infrarrepresentadas. Buscamos caracterizar clínicamente a los pacientes con EP de origen costarricense y secuenciar la EP familiar y los genes asociados con el parkinsonismo atípico en casos y controles. Métodos: Inscribimos a 118 pacientes con EP con 97 controles no relacionados. La información recopilada incluyó datos demográficos, exposición a factores de riesgo y de protección, y evaluaciones motoras y cognitivas. Se secuenciaron las regiones codificantes y no traducidas en la EP familiar y los genes asociados con el parkinsonismo atípico, incluidos GBA, SNCA, VPS35, LRRK2, GCH1, PRKN, PINK1, DJ-1, VPS13C y ATP13A2. Resultados: La edad media de los probandos de EP fue de 62,12 ± 13,51 años; El 57,6% eran hombres. La frecuencia de los factores de riesgo y protección promedió ~ 45%. La actividad física se correlacionó significativamente con un mejor rendimiento motor a pesar de años de enfermedad. El aumento de años de educación se asoció significativamente con una mejor función cognitiva, mientras que las alucinaciones, las caídas, los trastornos del estado de ánimo y el consumo de café se correlacionaron con un peor rendimiento cognitivo. No identificamos una asociación entre los genes probados y la EP ni ninguna variante heterocigótica homocigótica o compuesta dañina. Las variantes raras en LRRK2 se asociaron nominalmente con la EP; seis estaban ubicados entre los aminoácidos p.1620 y 1623 en el dominio C-terminal-de-ROC (COR) de Lrrk2. Se identificaron variantes de GBA no sinónimas (p.T369M, p.N370S y p.L444P) en tres individuos sanos. Un paciente con EP portaba una variante patógena de GCH1, p.K224R.Universidad de Costa Rica/[837-B5-304]/UCR/Costa RicaCanadian Consortium on Neurodegeneration in Aging/[]/CCNA/CanadáCanada First Research Excellence Fund/[]/CFREF/CanadáHealthy Brains for Healthy Lives/[]/HBHL/CanadáUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Centro de Investigación en Neurociencias (CIN)UCR::Vicerrectoría de Docencia::Salud::Facultad de Medicina::Escuela de Medicin