Geminivirus replication protein decreases PCNA sumoylation at two acceptor sites

Geminiviruses are plant viruses with circular, single-stranded DNA (ssDNA) genomes that infect a broad range of plants causing substantial crop diseases worldwide. They replicate in nuclei of infected cells by using host DNA replication machinery and an essential protein encoded in their genome designated Rep (replication-associated protein). This multifunctional protein induces the accumulation of the host factors involved in replication and it is capable of interacting with a lot of plant proteins including PCNA (Proliferating Cell Nuclear Antigen), a processivity factor that coordinates a wide range of processes involved in maintenance, duplication and transmission of the genome, and the sumoylation enzyme that conjugates SUMO to target proteins (SUMO-conjugating enzyme- SCE). PCNA modification by SUMO, and also ubiquitin, has long been known to be of key importance for determining how DNA damage is processed by the replisome and for maintenance of overall genome integrity. In yeast, PCNA sumoylation has been associated to DNA repair involving homologous recombination (HR). Previously, we reported that Rep ectopic expression does not result in broad changes in the sumoylation pattern of plant cells, but it modifies the sumoylation state of selected host proteins. In this work, we show, using a reconstituted sumoylation system in Escherichia coli, that tomato PCNA is sumoylated at two residues, K254 and K164, and that co-expression of the Rep protein suppresses PCNA sumoylation at these lysines. Finally, we confirm that PCNA is sumoylated and that Rep also interferes with PCNA sumoylation in planta.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tec

Plan de negocios para determinar la viabilidad del servicio de lavander?a delivery mediante el uso de tecnolog?a (app)

El servicio de lavander?a delivery mediante aplicativo denominado LavadOh, integra un servicio de calidad, rapidez y respeto hacia el cliente de una lavander?a tradicional, junto con una herramienta digital mediante aplicativo m?vil; dicha herramienta funciona de interfaz para las coordinaciones y gesti?n entre los clientes y la empresa, mejorando la experiencia del servicio en relaci?n a lo ofrecido actualmente. Este servicio identifica a un nuevo estilo de consumidor y sus necesidades, es por ello que ofrece el usar medios digitales para la gesti?n del servicio, comodidad al ser delivery y principalmente el disfrutar de su tiempo libre. Este servicio se caracteriza por la posibilidad de programar el recojo y entrega, se?alando el lugar, fecha y hora; recibir la cotizaci?n en tiempo real al momento que las prendas son recogidas, elegir un m?todo de pago mediante tarjetas de cr?dito o d?bito y poder revisar el estado de los pedidos en todo momento. El principal inter?s del servicio es contemplar todos los valores de una lavander?a tradicional y vincularlos a una herramienta digital, permitiendo que el usuario tenga una experiencia satisfactoria de todo el proceso y valore los beneficios de disponer mayor tiempo libre; satisfaciendo con ello las expectativas de nuestros clientes

Constraining the pˉ/p\bar{p}/p Ratio in TeV Cosmic Rays with Observations of the Moon Shadow by HAWC

An indirect measurement of the antiproton flux in cosmic rays is possible as the particles undergo deflection by the geomagnetic field. This effect can be measured by studying the deficit in the flux, or shadow, created by the Moon as it absorbs cosmic rays that are headed towards the Earth. The shadow is displaced from the actual position of the Moon due to geomagnetic deflection, which is a function of the energy and charge of the cosmic rays. The displacement provides a natural tool for momentum/charge discrimination that can be used to study the composition of cosmic rays. Using 33 months of data comprising more than 80 billion cosmic rays measured by the High Altitude Water Cherenkov (HAWC) observatory, we have analyzed the Moon shadow to search for TeV antiprotons in cosmic rays. We present our first upper limits on the $\bar{p}/p$ fraction, which in the absence of any direct measurements, provide the tightest available constraints of $\sim1\%$ on the antiproton fraction for energies between 1 and 10 TeV.Comment: 10 pages, 5 figures. Accepted by Physical Review

Observation of Anisotropy of TeV Cosmic Rays with Two Years of HAWC

After two years of operation, the High-Altitude Water Cherenkov (HAWC) Observatory has analyzed the TeV cosmic-ray sky over an energy range between $2.0$ and $72.8$ TeV. The HAWC detector is a ground-based air-shower array located at high altitude in the state of Puebla, Mexico. Using 300 light-tight water tanks, it collects the Cherenkov light from the particles of extensive air showers from primary gamma rays and cosmic rays. This detection method allows for uninterrupted observation of the entire overhead sky (2~sr instantaneous, 8.5~sr integrated) in the energy range from a few TeV to hundreds of TeV. Like other detectors in the northern and southern hemisphere, HAWC observes an energy-dependent anisotropy in the arrival direction distribution of cosmic rays. The observed cosmic-ray anisotropy is dominated by a dipole moment with phase $\alpha\approx40^{\circ}$ and amplitude that slowly rises in relative intensity from $8\times10^{-4}$ at 2 TeV to $14\times10^{-4}$ around 30.3 TeV, above which the dipole decreases in strength. A significant large-scale ($>60^{\circ}$ in angular extent) signal is also observed in the quadrupole and octupole moments, and significant small-scale features are also present, with locations and shapes consistent with previous observations. Compared to previous measurements in this energy range, the HAWC cosmic-ray sky maps improve on the energy resolution and fit precision of the anisotropy. These data can be used in an effort to better constrain local cosmic-ray accelerators and the intervening magnetic fields.Comment: 22 pages, 14 figures, 2 tables, submission to Ap

Polymorphic variants of SCN1A and EPHX1 influence plasma carbamazepine concentration, metabolism and pharmacoresistance in a population of Kosovar Albanian epileptic patients

Aim The present study aimed to evaluate the effects of gene variants in key genes influencing pharmacokinetic and pharmacodynamic of carbamazepine (CBZ) on the response in patients with epilepsy. Materials & Methods Five SNPs in two candidate genes influencing CBZ transport and metabolism, namely ABCB1 or EPHX1, and CBZ response SCN1A (sodium channel) were genotyped in 145 epileptic patients treated with CBZ as monotherapy and 100 age and sex matched healthy controls. Plasma concentrations of CBZ, carbamazepine-10,11-epoxide (CBZE) and carbamazepine-10,11-trans dihydrodiol (CBZD) were determined by HPLC-UV-DAD and adjusted for CBZ dosage/kg of body weight. Results The presence of the SCN1A IVS5-91G>A variant allele is associated with increased epilepsy susceptibility. Furthermore, carriers of the SCN1A IVS5-91G>A variant or of EPHX1 c.337T>C variant presented significantly lower levels of plasma CBZ compared to carriers of the common alleles (0.71±0.28 vs 1.11±0.69 μg/mL per mg/Kg for SCN1A IVS5-91 AA vs GG and 0.76±0.16 vs 0.94±0.49 μg/mL per mg/Kg for EPHX1 c.337 CC vs TT; PG showed a reduced microsomal epoxide hydrolase activity as reflected by a significantly decreased ratio of CBZD to CBZ (0.13±0.08 to 0.26±0.17, pT SNP and SCN1A 3148A>G variants were not associated with significant changes in CBZ pharmacokinetic. Patients resistant to CBZ treatment showed increased dosage of CBZ (657±285 vs 489±231 mg/day; P<0.001) but also increased plasma levels of CBZ (9.84±4.37 vs 7.41±3.43 μg/mL; P<0.001) compared to patients responsive to CBZ treatment. CBZ resistance was not related to any of the SNPs investigated. Conclusions The SCN1A IVS5-91G>A SNP is associated with susceptibility to epilepsy. SNPs in EPHX1 gene are influencing CBZ metabolism and disposition. CBZ plasma levels are not an indicator of resistance to the therapy

Essential Medicines at the National Level : The Global Asthma Network's Essential Asthma Medicines Survey 2014

Patients with asthma need uninterrupted supplies of affordable, quality-assured essential medicines. However, access in many low- and middle-income countries (LMICs) is limited. The World Health Organization (WHO) Non-Communicable Disease (NCD) Global Action Plan 2013-2020 sets an 80% target for essential NCD medicines' availability. Poor access is partly due to medicines not being included on the national Essential Medicines Lists (EML) and/or National Reimbursement Lists (NRL) which guide the provision of free/subsidised medicines. We aimed to determine how many countries have essential asthma medicines on their EML and NRL, which essential asthma medicines, and whether surveys might monitor progress. A cross-sectional survey in 2013-2015 of Global Asthma Network principal investigators generated 111/120 (93%) responses41 high-income countries and territories (HICs); 70 LMICs. Patients in HICs with NRL are best served (91% HICs included ICS (inhaled corticosteroids) and salbutamol). Patients in the 24 (34%) LMICs with no NRL and the 14 (30%) LMICs with an NRL, however no ICS are likely to have very poor access to affordable, quality-assured ICS. Many LMICs do not have essential asthma medicines on their EML or NRL. Technical guidance and advocacy for policy change is required. Improving access to these medicines will improve the health system's capacity to address NCDs.Peer reviewe