The Berry phase and the pump flux in stochastic chemical kinetics

We study a classical two-state stochastic system in a sea of substrates and products (absorbing states), which can be interpreted as a single Michaelis-Menten catalyzing enzyme or as a channel on a cell surface. We introduce a novel general method and use it to derive the expression for the full counting statistics of transitions among the absorbing states. For the evolution of the system under a periodic perturbation of the kinetic rates, the latter contains a term with a purely geometrical (the Berry phase) interpretation. This term gives rise to a pump current between the absorbing states, which is due entirely to the stochastic nature of the system. We calculate the first two cumulants of this current, and we argue that it is observable experimentally

Agarose gel as a medium for growing and tailoring protein crystals

The nucleation inducing ability of agarose gels has been exploited to study the crystallization of proteins in diffusion-dominated environments. The crystal size was successfully tuned in a wide range of gel, protein, and precipitant concentrations. The impact of the gel content on crystal size was independent of the specific protein, allowing the mathematical prediction of crystal size and pointing out the exclusivity of physical interactions between the gel and the protein. The versatility of the technique and the fine-tuning of the nucleation flux was demonstrated by crystallizing five different proteins and implementing batch and counter-diffusion crystallization. In addition, the potential of agarose gel to be used not only as a growth but also as a delivery medium for serial crystallography applications has been proven by preparing unidimensional microcrystal slurries with 0.1% (w/v) gel

The ubiquitin-like modifier FAT10 inhibits retinal PDE6 activity and mediates its proteasomal degradation

The retina-specific chaperone aryl hydrocarbon interacting protein-like 1 (AIPL1) is essential for the correct assembly of phosphodiesterase 6 (PDE6), which is a pivotal effector enzyme for phototransduction and vision because it hydrolyzes cGMP. AIPL1 interacts with the cytokine-inducible ubiquitin-like modifier FAT10, which gets covalently conjugated to hundreds of proteins and targets its conjugation substrates for proteasomal degradation, but whether FAT10 affects PDE6 function or turnover is unknown. Here, we show that FAT10 mRNA is expressed in human retina and identify rod PDE6 as a retina-specific substrate of FAT10 conjugation. We found that AIPL1 stabilizes the FAT10 monomer and the PDE6-FAT10 conjugate. Additionally, we elucidated the functional consequences of PDE6 FAT10ylation. On the one hand, we demonstrate that FAT10 targets PDE6 for proteasomal degradation by formation of a covalent isopeptide linkage. On the other hand, FAT10 inhibits PDE6 cGMP hydrolyzing activity by noncovalently interacting with the PDE6 GAFa and catalytic domains. Therefore, FAT10 may contribute to loss of PDE6 and, as a consequence, degeneration of retinal cells in eye diseases linked to inflammation and inherited blindness-causing mutations in AIPL1

Time-Frequency Coupled Proportional Fair Scheduler with Multicarrier Awareness for LTE Downlink

Abstract-Proportional fair schedulers have been thoroughly used in Long Term Evolution (LTE) due to their ability to provide a good trade-off between cell spectral efficiency and user fairness. Current algorithms provide suboptimum solutions at a low computational cost, but present several drawbacks. This paper proposes a Coupled and Multicarrier Aware PFS (CMA-PFS) for LTE downlink that increases efficiency as compared with current algorithms with independent time and frequency domain scheduling, referred to as Decoupled PFS (D-PFS). The proposed algorithm includes new features such as tight coupling between time and frequency domain scheduling and multicarrier transmission awareness. Simulations have been conducted using an International Mobile Telecommunications Advanced (IMT-Advanced) compliant semi-static simulator. Results show that the CMA-PFS improves proportional fairness as compared with D-PFS that is reflected both in an increase of cell spectral efficiency (around +2%) and a higher cell-edge user spectral efficiency (around +10%) in a Single User MIMO (SU-MIMO) system

Novel utility-scale photovoltaic plant electroluminescence maintenance technique by means of bidirectional power inverter controller

Nowadays, photovoltaic (PV) silicon plants dominate the growth in renewable energies generation. Utility-scale photovoltaic plants (USPVPs) have increased exponentially in size and power in the last decade and, therefore, it is crucial to develop optimum maintenance techniques. One of the most promising maintenance techniques is the study of electroluminescence (EL) images as a complement of infrared thermography (IRT) analysis. However, its high cost has prevented its use regularly up to date. This paper proposes a maintenance methodology to perform on-site EL inspections as efficiently as possible. First, current USPVP characteristics and the requirements to apply EL on them are studied. Next, an increase over the automation level by means of adding automatic elements in the current PV plant design is studied. The new elements and their configuration are explained, and a control strategy for applying this technique on large photovoltaic plants is developed. With the aim of getting on-site EL images on a real plant, a PV inverter has been developed to validate the proposed methodology on a small-scale solar plant. Both the electrical parameters measured during the tests and the images taken have been analysed. Finally, the implementation cost of the solution has been calculated and optimised. The results conclude the technical viability to perform on-site EL inspections on PV plants without the need to measure and analyse the panel defects out of the PV installation

Mapping the mechanisms of retinal degeneration caused by mutations in the co-chaperone AIPL1

Mutations in the photoreceptor/pineal-expressed gene AIPL1 cause Leber congenital amaurosis (LCA), the most severe form of childhood inherited retinopathy. AIPL1 is a photoreceptor-specific co-chaperone that interacts with HSP90 via a C-terminal tetratricopeptide repeat (TPR) domain to facilitate the correct assembly and activity of retinal cGMP phosphodiesterase (PDE6). The AIPL1 N-terminal FKBP-like domain interacts directly with the isoprenyl moiety of the PDE6 catalytic subunits. We investigated the functional impact of novel LCA-associated AIPL1 variants. Our data reveal that the relative domain organization and integrity of AIPL1 is important for PDE6-mediated catalysis, with variants mapping to one domain also affecting the activity of the other independently folded domain. The functional assessment and confirmation of likely pathogenic AIPL1 variants is moreover important for the accurate diagnosis and effective triage of patients for AIPL1-targeted gene replacement therapy

Epidemiology and molecular characterization of Carnivore protoparvovirus-1 infection in the wild felid Leopardus guigna in Chile

Landscape anthropization has been identified as one of the main drivers of pathogen emergence worldwide, facilitating pathogen spillover between domestic species and wildlife. The present study investigated Carnivore protoparvovirus-1 infection using molecular methods in 98 free-ranging wild guignas (Leopardus guigna) and 262 co-occurring owned, free-roaming rural domestic cats. We also assessed landscape anthropization variables as potential drivers of infection. Protoparvovirus DNA was detected in guignas across their entire distribution range, with observed prevalence of 13.3% (real-time PCR) and 9% (conventional PCR) in guignas, and 6.1% (conventional PCR) in cats. Prevalence in guigna did not vary depending on age, sex, study area or landscape variables. Prevalence was higher in juvenile cats (16.7%) than in adults (4.4%). Molecular characterization of the virus by amplification and sequencing of almost the entire vp2 gene (1, 746 bp) from one guigna and five domestic cats was achieved, showing genetic similarities to canine parvovirus 2c (CPV-2c) (one guigna and one cat), feline panleukopenia virus (FPV) (one cat), CPV-2 (no subtype identified) (two cats), CPV-2a (one cat). The CVP-2c-like sequence found in a guigna clustered together with domestic cat and dog CPV-2c sequences from South America, suggesting possible spillover from a domestic to a wild species as the origin of infection in guigna. No clinical signs of disease were found in PCR-positive animals except for a CPV-2c-infected guigna, which had haemorrhagic diarrhoea and died a few days after arrival at a wildlife rescue centre. Our findings reveal widespread presence of Carnivore protoparvovirus-1 across the guigna distribution in Chile and suggest that virus transmission potentially occurs from domestic to wild carnivores, causing severe disease and death in susceptible wild guignas

Investigation of PTC124-mediated translational readthrough in a retinal organoid model of AIPL1-associated Leber congenital amaurosis

Leber congenital amaurosis type 4 (LCA4), caused by AIPL1 mutations, is characterized by severe sight impairment in infancy and rapidly progressing degeneration of photoreceptor cells. We generated retinal organoids using induced pluripotent stem cells (iPSCs) from renal epithelial cells obtained from four children with AIPL1 nonsense mutations. iPSC-derived photoreceptors exhibited the molecular hallmarks of LCA4, including undetectable AIPL1 and rod cyclic guanosine monophosphate (cGMP) phosphodiesterase (PDE6) compared with control or CRISPR-corrected organoids. Increased levels of cGMP were detected. The translational readthrough-inducing drug (TRID) PTC124 was investigated as a potential therapeutic agent. LCA4 retinal organoids exhibited low levels of rescue of full-length AIPL1. However, this was insufficient to fully restore PDE6 in photoreceptors and reduce cGMP. LCA4 retinal organoids are a valuable platform for in vitro investigation of novel therapeutic agents