Meat-Borne-Parasite: A Nanopore-Based Meta-Barcoding Work-Flow for Parasitic Microbiodiversity Assessment in the Wild Fauna of French Guiana.

French Guiana, located in the Guiana Shield, is a natural reservoir for many zoonotic pathogens that are of considerable medical or veterinary importance. Until now, there has been limited data available on the description of parasites circulating in this area, especially on protozoan belonging to the phylum Apicomplexa; conversely, the neighbouring countries describe a high parasitic prevalence in animals and humans. Epidemiological surveillance is necessary, as new potentially virulent strains may emerge from these forest ecosystems, such as Amazonian toxoplasmosis. However, there is no standard tool for detecting protozoa in wildlife. In this study, we developed Meat-Borne-Parasite, a high-throughput meta-barcoding workflow for detecting Apicomplexa based on the Oxford Nanopore Technologies sequencing platform using the 18S gene of 14 Apicomplexa positive samples collected in French Guiana. Sequencing reads were then analysed with MetONTIIME pipeline. Thanks to a scoring rule, we were able to classify 10 samples out of 14 as Apicomplexa positive and reveal the presence of co-carriages. The same samples were also sequenced with the Illumina platform for validation purposes. For samples identified as Apicomplexa positive by both platforms, a strong positive correlation at up to the genus level was reported. Overall, the presented workflow represents a reliable method for Apicomplexa detection, which may pave the way for more comprehensive biomonitoring of zoonotic pathogens.

Risk of agranulocytosis with metamizole in comparison with alternative medications based on health records in Spain.

PURPOSE: We aimed to estimate the absolute (incidence) and relative (hazard ratio; HR) risk of agranulocytosis associated with metamizole in comparison with non-steroidal antiinflammatory drugs (NSAIDs). METHODS: A cohort study of new users of metamizole versus NSAIDs was performed with BIFAP (Pharmacoepidemiologic Research Database in Public Health Systems; Spain). Patients aged ≥ 2 years in 2005-2022 were followed up from the day after their first metamizole or NSAID dispensation till the end of the treatment period to identify patients hospitalized due to idiosyncratic agranulocytosis. Incidence rate (IR) and adjusted HR of agranulocytosis with metamizole versus NSAID were estimated assuming the onset date of agranulocytosis was the date of hospitalization sensitivity analysis or 7 days before (main analysis). In secondary analyses, we used (1) opioids-paracetamol as negative control and (2) any hospitalized neutropenia as outcome (assuming the onset was 7 days before). RESULTS: The cohorts included 444,972 new users of metamizole, 3,814,367 NSAID, and 3,129,221 opioids-paracetamol on continuous treatment during a median of 37-40 days. Overall, 26 hospitalized agranulocytosis occurred, 5 in the first week (and so removed in main analysis) and 21 thereafter. IR of agranulocytosis was 14.20 (N = 5 cases) and 8.52 (N = 3), 1.95 (N = 6) and 1.62 (N = 5), and 4.29 (N = 15) and 3.72 (N = 13)/107 person-weeks of continuous treatment using the date of hospitalization or 7 days before, respectively. Two, 0 and 2 of cases identified in both analyses had neoplasia in every cohort, respectively. HR of agranulocytosis associated with metamizole was 7.20 [95% CI: 1.92-26.99] and 4.40 [0.90-21.57] versus NSAID, and 3.31 [1.17-9.34] and 2.45 [0.68-8.83] versus opioid-paracetamol, respectively. HR of neutropenia with metamizole was 2.98 [1.57-5.65] versus NSAID. CONCLUSIONS: Agranulocytosis was very rare but more common (above 4 times more) with metamizole than other analgesics. The impact of the drug-induced agranulocytosis was less precise with metamizole than the comparators due to its lower use, which precluded to find statistical differences in main analysis. The increased risk of hospitalized neutropenias with metamizole supports the link with its severity although triggers unavailable during the follow-up (ex. cytotoxic medication) can not be discarded.

Young children's attributes are better conveyed by voices than by faces.

The purpose of this study was to explore how young children's vocal and facial cues contribute to conveying to adults important information about children's attributes when presented together. In particular, the study aimed to disentangle whether children's vocal or facial cues, if either, are more dominant when both types of cues are displayed in a contradictory mode. To do this, we assigned 127 college students to one of three between-participants conditions. In the Voices-Only condition, participants listened to four pairs of synthetized voices simulating the voices of 4-5-year-old and 9-10-year-old children verbalizing a neutral-content sentence. Participants needed to indicate which voice was better associated with a series of 14 attributes organized into four trait dimensions (Positive Affect, Negative Affect, Intelligence, and Helpless), potentially meaningful in young child-adult interactions. In the Consistent condition, the same four pairs of voices delivered in the Voices-Only condition were presented jointly with morphed photographs of children's faces of equivalent age. In the Inconsistent condition, the four pairs of voices and faces were paired in a contradictory manner (immature voices with mature faces vs. mature voices with immature faces). Results revealed that vocal cues were more effective than facial cues in conveying young children's attributes to adults and that women were more efficient (i.e., faster) than men in responding to children's cues. These results confirm and extend previous evidence on the relevance of children's vocal cues to signaling important information about children's attributes and needs during their first 6 years of life.

Optical signatures of multifold fermions in the chiral topological semimetal CoSi.

We report the optical conductivity in high-quality crystals of the chiral topological semimetal CoSi, which hosts exotic quasiparticles known as multifold fermions. We find that the optical response is separated into several distinct regions as a function of frequency, each dominated by different types of quasiparticles. The low-frequency intraband response is captured by a narrow Drude peak from a high-mobility electron pocket of double Weyl quasiparticles, and the temperature dependence of the spectral weight is consistent with its Fermi velocity. By subtracting the low-frequency sharp Drude and phonon peaks at low temperatures, we reveal two intermediate quasilinear interband contributions separated by a kink at 0.2 eV. Using Wannier tight-binding models based on first-principle calculations, we link the optical conductivity above and below 0.2 eV to interband transitions near the double Weyl fermion and a threefold fermion, respectively. We analyze and determine the chemical potential relative to the energy of the threefold fermion, revealing the importance of transitions between a linearly dispersing band and a flat band. More strikingly, below 0.1 eV our data are best explained if spin-orbit coupling is included, suggesting that at these energies, the optical response is governed by transitions between a previously unobserved fourfold spin-3/2 node and a Weyl node. Our comprehensive combined experimental and theoretical study provides a way to resolve different types of multifold fermions in CoSi at different energy. More broadly, our results provide the necessary basis to interpret the burgeoning set of optical and transport experiments in chiral topological semimetals.

Plitidepsin: a Repurposed Drug for the Treatment of COVID-19.

Finding antivirals to reduce coronavirus disease 2019 (COVID-19) morbidity and mortality has been challenging. Large randomized clinical trials that aimed to test four repurposed drugs, hydroxychloroquine, lopinavir-ritonavir, interferon beta 1a, and remdesivir, have shown that these compounds lack an impact on the COVID-19 course. Although the phase III COVID-19 vaccine trial results are encouraging, the search for effective COVID-19 therapeutics should not stop. Recently, plitidepsin (aplidin) demonstrated highly effective preclinical activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Its antiviral activity was 27.5-fold more potent than that of remdesivir (K. M. White, R. Rosales, S. Yildiz, T. Kehrer, et al., Science, 2021, https://science.sciencemag.org/content/early/2021/01/22/science.abf4058). Plitidepsin, a repurposed drug developed for the treatment of multiple myeloma, targets the host translation cofactor eEF1A. Plitidepsin has shown efficacy in animal models and phase I/II human trials. Although plitidepsin is administered intravenously and its toxicity profile remains to be fully characterized, this compound may be a promising alternative COVID-19 therapeutic.

HIV-1 Lethality and Loss of Env Protein Expression Induced by Single Synonymous Substitutions in the Virus Genome Intronic-Splicing Silencer.

Synonymous genome recoding has been widely used to study different aspects of virus biology. Codon usage affects the temporal regulation of viral gene expression. In this study, we performed synonymous codon mutagenesis to investigate whether codon usage affected HIV-1 Env protein expression and virus viability. We replaced the codons AGG, GAG, CCU, ACU, CUC, and GGG of the HIV-1 env gene with the synonymous codons CGU, GAA, CCG, ACG, UUA, and GGA, respectively. We found that recoding the Env protein gp120 coding region (excluding the Rev response element [RRE]) did not significantly affect virus replication capacity, even though we introduced 15 new CpG dinucleotides. In contrast, changing a single codon (AGG to CGU) located in the gp41 coding region (HXB2 env position 2125 to 2127), which was included in the intronic splicing silencer (ISS), completely abolished virus replication and Env expression. Computational analyses of this mutant revealed a severe disruption in the ISS RNA secondary structure. A variant that restored ISS secondary RNA structure also reestablished Env production and virus viability. Interestingly, this codon variant prevented both virus replication and Env translation in a eukaryotic expression system. These findings suggested that disrupting mRNA splicing was not the only means of inhibiting translation. Our findings indicated that synonymous gp120 recoding was not always deleterious to HIV-1 replication. Importantly¸ we found that disrupting an external ISS loop strongly affected HIV-1 replication and Env translation.IMPORTANCE Synonymous substitutions can influence virus phenotype, replication capacity, and virulence. In this study, we explored how synonymous codon mutations impacted HIV-1 Env protein expression and virus replication capacity. We changed a single codon, AGG to CGU, which was located in the gp41 coding region (env nucleotide residues 2125 to 2127) and was included in the HIV-1 intronic splicing silencer. This change completely abolished virus replication and Env expression. We also found that changing codon usage in the gp120 region by including an increased number of CpG dinucleotides did not significantly affect Env expression or virus viability. Our findings showed that synonymous recoding was useful for altering viral phenotype and exploring virus biology.

A strategy for assessment and validation of major bleeding cases in a primary health care database in Spain.

PURPOSE: This study aims to validate major bleeding (MB) cases within a cohort of new users of direct oral anticoagulants (DOACs) in Electronic health records (EHRs) from primary care in Spain (BIFAP), introducing more efficient techniques and automating the process of validation in the pharmacoepidemiologic research with EHR data as much as possible. METHODS: Registered bleedings were identified in a cohort of new users of DOACs in BIFAP using ICPC 2 and ICD 9 codes; we ascertained these bleedings as MB through a validation strategy based on the MB definition from the International Society on Thrombosis and Hemostasis, which used hospitalization and critical localization as proxies. We assessed hospitalization with hospital discharge information (only available for some years and regions) and a free text-based algorithm created to identify hospitalization in EHR's clinical notes. Incidence rates (IR) of MB were evaluated by bleeding type. RESULTS: The study cohort included 104 614 patients, with 274521.5 p-y of follow up. There were 6143 registered bleedings during the study period (519 intracranial bleeding - ICB, 4606 gastrointestinal bleeding - GIB, 1018 extracranial bleeding - ECB), from which 1679 were confirmed as MB (416 ICB, 1086 GIB, and 177 ECB). The free text-based semi-automatic algorithm had moderate recall (0.59), but high specificity (0.99), and precision (0.94). CONCLUSION: The combination of hospitalization and critical localization is a valid approach to validate MB in EHRs with incomplete information. The use of more automatic methods for case validation instead of manual review of clinical notes is favored.

Synonymous genome recoding: a tool to explore microbial biology and new therapeutic strategies.

Synthetic genome recoding is a new means of generating designed organisms with altered phenotypes. Synonymous mutations introduced into the protein coding region tolerate modifications in DNA or mRNA without modifying the encoded proteins. Synonymous genome-wide recoding has allowed the synthetic generation of different small-genome viruses with modified phenotypes and biological properties. Recently, a decreased cost of chemically synthesizing DNA and improved methods for assembling DNA fragments (e.g. lambda red recombination and CRISPR-based editing) have enabled the construction of an Escherichia coli variant with a 4-Mb synthetic synonymously recoded genome with a reduced number of sense codons (n = 59) encoding the 20 canonical amino acids. Synonymous genome recoding is increasing our knowledge of microbial interactions with innate immune responses, identifying functional genome structures, and strategically ameliorating cis-inhibitory signaling sequences related to splicing, replication (in eukaryotes), and complex microbe functions, unraveling the relevance of codon usage for the temporal regulation of gene expression and the microbe mutant spectrum and adaptability. New biotechnological and therapeutic applications of this methodology can easily be envisaged. In this review, we discuss how synonymous genome recoding may impact our knowledge of microbial biology and the development of new and better therapeutic methodologies.

Discovery and Development of Antiviral Therapies for Chronic Hepatitis C Virus Infection.

At the beginning of this decade, an estimated 71 million people were living with chronic hepatitis C virus (HCV) infection worldwide. After the acute stage of HCV infection, 18-34% of individuals exhibit spontaneous clearance. However, the remaining 66-82% of infected individuals progress to chronic HCV infection and are at subsequent risk of progression to hepatic fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Chronic hepatitis C progression is generally slow during the first two decades of infection, but can be accelerated during this time in association with advancing age and cofactors, such as heavy alcohol intake and human immunodeficiency virus (HIV) co-infection. Since acute HCV infection is generally asymptomatic, HCV goes undiagnosed in a significant percentage of infected individuals. In 2014, direct-acting antiviral (DAA) therapy for chronic HCV was developed, which has increased the cure rates to nearly 100%. DAA therapy is among the best examples of success in the fight against viral infections. DAAs have transformed HCV management and have opened the door for the global eradication of HCV.

Compounds with Therapeutic Potential against Novel Respiratory 2019 Coronavirus.

Currently, the expansion of the novel human respiratory coronavirus (known as SARS-CoV-2 [severe acute respiratory syndrome coronavirus 2], COVID-2019 [coronavirus disease 2019], or 2019-nCoV [2019 novel coronavirus]) has stressed the need for therapeutic alternatives to alleviate and stop this new epidemic. The previous epidemics of infections by high-morbidity human coronaviruses, such as SARS-CoV in 2003 and the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, prompted the characterization of compounds that could be potentially active against the currently emerging novel coronavirus, SARS-CoV-2. The most promising compound is remdesivir (GS-5734), a nucleotide analog prodrug currently in clinical trials for treating Ebola virus infections. Remdesivir inhibited the replication of SARS-CoV and MERS-CoV in tissue cultures, and it displayed efficacy in nonhuman animal models. In addition, a combination of the human immunodeficiency virus type 1 (HIV-1) protease inhibitors lopinavir/ritonavir and interferon beta (LPV/RTV-IFN-ß) was shown to be effective in patients infected with SARS-CoV. LPV/RTV-IFN-ß also improved clinical parameters in marmosets and mice infected with MERS-CoV. Remarkably, the therapeutic efficacy of remdesivir appeared to be superior to that of LPV/RTV-IFN-ß against MERS-CoV in a transgenic humanized mouse model. The relatively high mortality rates associated with these three novel human coronavirus infections, SARS-CoV, MERS-CoV, and SARS-CoV-2, have suggested that proinflammatory responses might play a role in the pathogenesis. It remains unknown whether the generated inflammatory state should be targeted. Therapeutics that target the coronavirus alone might not be able to reverse highly pathogenic infections. This minireview aims to provide a summary of therapeutic compounds that have shown potential in fighting SARS-CoV-2 infections.

Clinical Trials of Repurposed Antivirals for SARS-CoV-2.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has prompted the repurposing of drugs on the basis of promising in vitro and therapeutic results with other human coronavirus diseases, such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). These repurposed drugs have mainly included remdesivir, favipiravir, lopinavir-ritonavir, ribavirin, interferons, and hydroxychloroquine. Unfortunately, the first open-label, randomized, controlled trials are showing poor efficacy of these repurposed drugs. These results highlight the necessity of identifying and characterizing specific and potent SARS-CoV-2 antivirals.

Base de Datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP): A data resource for pharmacoepidemiology in Spain.

PURPOSE: Base de Datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP) is a population based database administered by the AEMPS (Spanish Agency for Medicines) of longitudinal electronic medical records (EMR) of patients attended in primary care. Its main purpose is to serve as source of information for independent studies on drug safety and support of medicines regulation activities. This article aim is to describe the characteristics of BIFAP, how to access the database and a summary of its potential for research. METHODS: Health problems are registered by primary care physicians as episodes of care and include socio-demographic data, results of diagnostic procedures, lifestyle data, general data, and interventions. A proportion of data on hospitalizations and specialist care are currently available through linkage with other data sources. EMRs of the Spanish healthcare system are provided by the regional administrations. Specific data extraction and standardization processes are performed. RESULTS: BIFAP includes data from 12 million patients starting in 2001 and updated annually. Validation of drug and diagnosis definitions has been ascertained. Participation in international collaborative projects and a number of articles in peer reviewed journals reflect its contribution to the knowledge of the risks associated with medicines and drug utilization patterns. CONCLUSIONS: BIFAP is a useful tool for generating scientific evidence on medicines related issues, helping regulatory decision making in Europe. The main strengths of BIFAP are related to large sample size, population-based, longitudinal nature and annual update of data. BIFAP shares common challenges with similar data sources including accurate and efficient identification of health outcomes and of treatment exposure.

HIV-1 Protease Evolvability Is Affected by Synonymous Nucleotide Recoding.

One unexplored aspect of HIV-1 genetic architecture is how codon choice influences population diversity and evolvability. Here we compared the levels of development of HIV-1 resistance to protease inhibitors (PIs) between wild-type (WT) virus and a synthetic virus (MAX) carrying a codon-pair-reengineered protease sequence including 38 (13%) synonymous mutations. The WT and MAX viruses showed indistinguishable replication in MT-4 cells or peripheral blood mononuclear cells (PBMCs). Both viruses were subjected to serial passages in MT-4 cells, with selective pressure from the PIs atazanavir (ATV) and darunavir (DRV). After 32 successive passages, both the WT and MAX viruses developed phenotypic resistance to PIs (50% inhibitory concentrations [IC50s] of 14.6 ± 5.3 and 21.2 ± 9 nM, respectively, for ATV and 5.9 ± 1.0 and 9.3 ± 1.9, respectively, for DRV). Ultradeep sequence clonal analysis revealed that both viruses harbored previously described mutations conferring resistance to ATV and DRV. However, the WT and MAX virus proteases showed different resistance variant repertoires, with the G16E and V77I substitutions observed only in the WT and the L33F, S37P, G48L, Q58E/K, and L89I substitutions detected only in the MAX virus. Remarkably, the G48L and L89I substitutions are rarely found in vivo in PI-treated patients. The MAX virus showed significantly higher nucleotide and amino acid diversity of the propagated viruses with and without PIs (P < 0.0001), suggesting a higher selective pressure for change in this recoded virus. Our results indicate that the HIV-1 protease position in sequence space delineates the evolution of its mutant spectrum. Nevertheless, the investigated synonymously recoded variant showed mutational robustness and evolvability similar to those of the WT virus.IMPORTANCE Large-scale synonymous recoding of virus genomes is a new tool for exploring various aspects of virus biology. Synonymous virus genome recoding can be used to investigate how a virus's position in sequence space defines its mutant spectrum, evolutionary trajectory, and pathogenesis. In this study, we evaluated how synonymous recoding of the human immunodeficiency virus type 1 (HIV-1) protease affects the development of protease inhibitor (PI) resistance. HIV-1 protease is a main target of current antiretroviral therapies. Our present results demonstrate that the wild-type (WT) virus and a virus with recoded protease exhibited different patterns of resistance mutations after PI treatment. Nevertheless, the developed PI resistance phenotypes were indistinguishable between the recoded virus and the WT virus, suggesting that the HIV-1 strain with synonymously recoded protease and the WT virus are equally robust and evolvable.

Computational analysis of the interactions of a novel cephalosporin derivative with ß-lactamases.

BACKGROUND: One of the main concerns of the modern medicine is the frightening spread of antimicrobial resistance caused mainly by the misuse of antibiotics. The researchers worldwide are actively involved in the search for new classes of antibiotics, and for the modification of known molecules in order to face this threatening problem. We have applied a computational approach to predict the interactions between a new cephalosporin derivative containing an additional ß-lactam ring with different substituents, and several serine ß-lactamases representative of the different classes of this family of enzymes. RESULTS: The results of the simulations, performed by using a covalent docking approach, has shown that this compound, although able to bind the selected ß-lactamases, has a different predicted binding score for the two ß-lactam rings, suggesting that one of them could be more resistant to the attack of these enzymes and stay available to perform its bactericidal activity. CONCLUSIONS: The detailed analysis of the complexes obtained by these simulations suggests possible hints to modulate the affinity of this compound towards these enzymes, in order to develop new derivatives with improved features to escape to degradation.

Modulating receptor-ligand binding in biorecognition by setting surface wettability.

Modulation of support wettability used for microarray format biosensing has led to an improvement of results. Hydrophobicity of glass chips was set by derivatizing with single vinyl organosilanes of different chain length and silane mixtures. Thiol-ene photochemical linking has been used as effective chemistry for covalent anchoring of thiolated probes. Lowest unspecific binding and highest signal intensity and SNR were obtained with large hydrocarbon chain (C22) silanes or a shorter one (C10) containing fluorine atoms. SNR resulting values are improved, reaching levels higher than 1500 in some cases, when using vinyl silanes modified with 1% C10 alkyl fluorinated one, because mild hydrophobicity was achieved (water contact angle ca. 110°) for all silanes, including the short C2 and C3, thus giving rise to smaller and better defined array spots. In addition, unspecific binding of reagents and targets was totally withdrawn. Hence, good-performing surfaces for biosensing applications can be built using appropriate organosilane reagent selection, including fluorinated ones. Graphical abstract ᅟ.

Remission of Hematuria Improves Renal Survival in IgA Nephropathy.

Hematuria is a cardinal symptom in IgA nephropathy, but its influence on the risk of disease progression has been scarcely investigated. We followed a cohort of 112 patients with IgA nephropathy for a mean±SEM period of 14±10.2 years, during which clinical and analytic risk factors (including urine sediment examination) were regularly recorded. According to the magnitude of time-averaged hematuria, we classified patients as those with persistent hematuria and those with negative or minimal hematuria. We also classified patients according to the magnitude of time-averaged proteinuria (>0.75 or ≤0.75 g/d). The proportion of patients reaching ESRD or a 50% reduction of renal function was significantly greater among patients with persistent hematuria than patients with minimal or negative hematuria (30.4% and 37.0% versus 10.6% and 15.2%, respectively; P=0.01). Multivariable analysis revealed time-averaged hematuria, time-averaged proteinuria, renal function at baseline, and the presence of tubulointerstitial fibrosis on renal biopsy as independent predictors of ESRD. After hematuria disappearance, which occurred in 46% of the patients, the rate of renal function decline changed from -6.45±14.66 to -0.18±2.56 ml/min per 1.73 m2 per year (P=0.001). Patients with time-averaged proteinuria >0.75 g/d had significantly poorer renal survival than those with time-averaged proteinuria ≤0.75 g/d. However, on further classification by time-averaged hematuria, only those patients with time-averaged proteinuria >0.75 g/d and persistent hematuria had significantly worse renal survival than those in the other three groups. In conclusion, remission of hematuria may have a significant favorable effect on IgA nephropathy outcomes.

Whole-exome sequencing reveals ZNF408 as a new gene associated with autosomal recessive retinitis pigmentosa with vitreal alterations.

Retinitis pigmentosa (RP) is a group of progressive inherited retinal dystrophies that cause visual impairment as a result of photoreceptor cell death. RP is heterogeneous, both clinically and genetically making difficult to establish precise genotype-phenotype correlations. In a Spanish family with autosomal recessive RP (arRP), homozygosity mapping and whole-exome sequencing led to the identification of a homozygous mutation (c.358_359delGT; p.Ala122Leufs*2) in the ZNF408 gene. A screening performed in 217 additional unrelated families revealed another homozygous mutation (c.1621C>T; p.Arg541Cys) in an isolated RP case. ZNF408 encodes a transcription factor that harbors 10 predicted C2H2-type fingers thought to be implicated in DNA binding. To elucidate the ZNF408 role in the retina and the pathogenesis of these mutations we have performed different functional studies. By immunohistochemical analysis in healthy human retina, we identified that ZNF408 is expressed in both cone and rod photoreceptors, in a specific type of amacrine and ganglion cells, and in retinal blood vessels. ZNF408 revealed a cytoplasmic localization and a nuclear distribution in areas corresponding with the euchromatin fraction. Immunolocalization studies showed a partial mislocalization of the p.Arg541Cys mutant protein retaining part of the WT protein in the cytoplasm. Our study demonstrates that ZNF408, previously associated with Familial Exudative Vitreoretinopathy (FEVR), is a new gene causing arRP with vitreous condensations supporting the evidence that this protein plays additional functions into the human retina.

New CDH3 mutation in the first Spanish case of hypotrichosis with juvenile macular dystrophy, a case report.

BACKGROUND: CDH3 on 16q22.1 is responsible for two rare autosomal recessive disorders with hypotrichosis and progressive macular dystrophy: Hypotrichosis with Juvenile Macular Dystrophy and Ectodermal Dysplasia, Ectrodactyly and Macular Dystrophy. We present a new case of Hypotrichosis with Juvenile Macular Dystrophy. CASE PRESENTATION: A Spanish male born in 1998 from non-consanguineous healthy parents with a suspected diagnosis of Keratosis Follicularis Spinulosa Decalvans and Retinitis Pigmentosa Inversa referred to our Genetics Department (IIS-Fundación Jiménez Díaz). Molecular study of ABCA4 was performed, and a heterozygous missense p.Val2050Leu variant in ABCA4 was found. Clinical revision reclassified this patient as Hypotrichosis with Juvenile Macular Dystrophy. Therefore, further CDH3 sequencing was performed showing a novel maternal missense change p.Val205Met (probably pathogenic by in silico analysis), and a previously reported paternal frameshift c.830del;p.Gly277Alafs*20, thus supporting the clinical diagnosis.. CONCLUSIONS: This is not only the first Spanish case with this clinical and molecular diagnosis, but a new mutation has been described in CDH3. Moreover, this work reflects the importance of joint assessment of clinical signs and evaluation of pedigree for a correct genetic study approach and diagnostic.

A Grid Connected Photovoltaic Inverter with Battery-Supercapacitor Hybrid Energy Storage.

The power generation from renewable power sources is variable in nature, and may contain unacceptable fluctuations, which can be alleviated by using energy storage systems. However, the cost of batteries and their limited lifetime are serious disadvantages. To solve these problems, an improvement consisting in the collaborative association of batteries and supercapacitors has been studied. Nevertheless, these studies don't address in detail the case of residential and large-scale photovoltaic systems. In this paper, a selected combined topology and a new control scheme are proposed to control the power sharing between batteries and supercapacitors. Also, a method for sizing the energy storage system together with the hybrid distribution based on the photovoltaic power curves is introduced. This innovative contribution not only reduces the stress levels on the battery, and hence increases its life span, but also provides constant power injection to the grid during a defined time interval. The proposed scheme is validated through detailed simulation and experimental tests.

A Smart Power Electronic Multiconverter for the Residential Sector.

The future of the grid includes distributed generation and smart grid technologies. Demand Side Management (DSM) systems will also be essential to achieve a high level of reliability and robustness in power systems. To do that, expanding the Advanced Metering Infrastructure (AMI) and Energy Management Systems (EMS) are necessary. The trend direction is towards the creation of energy resource hubs, such as the smart community concept. This paper presents a smart multiconverter system for residential/housing sector with a Hybrid Energy Storage System (HESS) consisting of supercapacitor and battery, and with local photovoltaic (PV) energy source integration. The device works as a distributed energy unit located in each house of the community, receiving active power set-points provided by a smart community EMS. This central EMS is responsible for managing the active energy flows between the electricity grid, renewable energy sources, storage equipment and loads existing in the community. The proposed multiconverter is responsible for complying with the reference active power set-points with proper power quality; guaranteeing that the local PV modules operate with a Maximum Power Point Tracking (MPPT) algorithm; and extending the lifetime of the battery thanks to a cooperative operation of the HESS. A simulation model has been developed in order to show the detailed operation of the system. Finally, a prototype of the multiconverter platform has been implemented and some experimental tests have been carried out to validate it.