Stenotrophomonas maltophilia responds to exogenous AHL signals through the LuxR solo SmoR (Smlt1839)

Quorum Sensing (QS) mediated by Acyl Homoserine Lactone (AHL) molecules are probably the most widespread and studied among Gram-negative bacteria. Canonical AHL systems are composed by a synthase (LuxI family) and a regulator element (LuxR family), whose genes are usually adjacent in the genome. However, incomplete AHL-QS machinery lacking the synthase LuxI is frequently observed in Proteobacteria, and the regulator element is then referred as LuxR solo. It has been shown that certain LuxR solos participate in interspecific communication by detecting signals produced by different organisms. In the case of Stenotrophomonas maltophilia, a preliminary genome sequence analysis revealed numerous putative luxR genes, none of them associated to a luxI gene. From these, the hypothetical LuxR solo Smlt1839, here designated SmoR, presents a conserved AHL binding domain and a helix-turn-helix DNA binding motif. Its genomic organization-adjacent to hchA gene-indicate that SmoR belongs to the new family "LuxR regulator chaperone HchA-associated." AHL-binding assays revealed that SmoR binds to AHLs in-vitro, at least to oxo-C8-homoserine lactone, and it regulates operon transcription, likely by recognizing a conserved palindromic regulatory box in the hchA upstream region. Supplementation with concentrated supernatants from Pseudomonas aeruginosa, which contain significant amounts of AHLs, promoted swarming motility in S. maltophilia. Contrarily, no swarming stimulation was observed when the P. aeruginosa supernatant was treated with the lactonase AiiA from Bacillus subtilis, confirming that AHL contributes to enhance the swarming ability of S. maltophilia. Finally, mutation of smoR resulted in a swarming alteration and an apparent insensitivity to the exogenous AHLs provided by P. aeruginosa. In conclusion, our results demonstrate that S. maltophilia senses AHLs produced by neighboring bacteria through the LuxR solo SmoR, regulating population behaviors such as swarming motility

Impact of a Primary Care Antimicrobial Stewardship Program on Bacterial Resistance Control and Ecological Imprint in Urinary Tract Infections

Antimicrobial stewardship programs (ASPs) are a central component in reducing the overprescription of unnecessary antibiotics, with multiple studies showing benefits in the reduction of bacterial resistance. Less commonly, ASPs have been performed in outpatient settings, but there is a lack of available data in these settings. We implemented an ASP in a large regional outpatient setting to assess its feasibility and effectiveness. Over a 5-year post-implementation period, compared to the pre-intervention period, a significant reduction in antibiotic prescription occurred, with a reduction in resistance in E. coli urinary isolates. ASP activities also were found to be cost-effective, with a reduction in medication prescription

Socio-Demographic Health Determinants Are Associated with Poor Prognosis in Spanish Patients Hospitalized with COVID-19

Introduction Social vulnerability is a known determinant of health in respiratory diseases. Our aim was to identify whether there are socio-demographic factors among COVID-19 patients hospitalized in Spain and their potential impact on health outcomes during the hospitalization. Methods A multicentric retrospective case series study based on administrative databases that included all COVID-19 cases admitted in 19 Spanish hospitals from 1 March to 15 April 2020. Socio-demographic data were collected. Outcomes were critical care admission and in-hospital mortality. Results We included 10,110 COVID-19 patients admitted to 18 Spanish hospitals (median age 68 (IQR 54–80) years old; 44.5% female; 14.8% were not born in Spain). Among these, 779 (7.7%) cases were admitted to critical care units and 1678 (16.6%) patients died during the hospitalization. Age, male gender, being immigrant, and low hospital saturation were independently associated with being admitted to an intensive care unit. Age, male gender, being immigrant, percentile of average per capita income, and hospital experience were independently associated with in-hospital mortality. Conclusions Social determinants such as residence in low-income areas and being born in Latin American countries were associated with increased odds of being admitted to an intensive care unit and of in-hospital mortality. There was considerable variation in outcomes between different Spanish centers.JPA is under contract within the Ramón y Cajal Program (RYC-2016-20155, Ministerio de Economía, Industria y Competitividad, Spain). Investigators of Spanish Social-Environmental COVID-19 Register: Steering Committee: F. Javier Martín-Sánchez, Adrián Valls Carbó, Carmen Martínez Valero, Juan de D. Miranda, Juan Pedro Arrebola, Marta Esteban López, Annika Parviainen, Òscar Miró, Pere Llorens, Sònia Jiménez, Pascual Piñera, Guillermo Burillo, Alfonso Martín, Jorge García Lamberechts, Javier Jacob, Aitor Alquézar, Juan González del Castillo, Amanda López Picado and Iván Núñez. Participating centers: Oscar Miró y Sonia Jimenez. Hospital Clinic de Barcelona. José María Ferreras Amez. Hospital Clínico Universitario Lozano Blesa. Rafael Rubio Díaz. Complejo Hospitalario de Toledo. Julio Javier Gamazo del Rio. Hospital Universitario de Galdakao. Héctor Alonso. Hospital Universitario Miguel de Valdecilla. Pablo Herrero. Hospital Universitario Central de Asturias. Noemí Ruiz de Lobera. Hospital San Pedro de Logroño. Carlos Ibero. Complejo Hospitalario de Navarra. Plácido Mayan. Hospital Clínico Universitario de Santiago. Rosario Peinado. Complejo Hospitalario Universitario de Badajoz. Carmen Navarro Bustos. Hospital Universitario Virgen de la Macarena. Jesús Álvarez Manzanares. Hospital Universitario Rio Hortega. Francisco Román. Hospital Universitario General de Alicante. Pascual Piñera. Hospital Universitario Reina Sofia de Murcia. Guillermo Burillo. Hospital Universitario de Canarias de Tenerife. Javier Jacob. Hospital Universitario de Bellvitge. Carlos Bibiano. Hospital Universitario Infanta Leonor.Peer reviewe

Stenotrophomonas maltophilia responds to exogenous AHL signals through the LuxR solo SmoR (Smlt1839)

Quorum Sensing (QS) mediated by Acyl Homoserine Lactone (AHL) molecules are probably the most widespread and studied among Gram-negative bacteria. Canonical AHL systems are composed by a synthase (LuxI family) and a regulator element (LuxR family), whose genes are usually adjacent in the genome. However, incomplete AHL-QS machinery lacking the synthase LuxI is frequently observed in Proteobacteria, and the regulator element is then referred as LuxR solo. It has been shown that certain LuxR solos participate in interspecific communication by detecting signals produced by different organisms. In the case of Stenotrophomonas maltophilia, a preliminary genome sequence analysis revealed numerous putative luxR genes, none of them associated to a luxI gene. From these, the hypothetical LuxR solo Smlt1839, here designated SmoR, presents a conserved AHL binding domain and a helix-turn-helix DNA binding motif. Its genomic organization-adjacent to hchA gene-indicate that SmoR belongs to the new family "LuxR regulator chaperone HchA-associated." AHL-binding assays revealed that SmoR binds to AHLs in-vitro, at least to oxo-C8-homoserine lactone, and it regulates operon transcription, likely by recognizing a conserved palindromic regulatory box in the hchA upstream region. Supplementation with concentrated supernatants from Pseudomonas aeruginosa, which contain significant amounts of AHLs, promoted swarming motility in S. maltophilia. Contrarily, no swarming stimulation was observed when the P. aeruginosa supernatant was treated with the lactonase AiiA from Bacillus subtilis, confirming that AHL contributes to enhance the swarming ability of S. maltophilia. Finally, mutation of smoR resulted in a swarming alteration and an apparent insensitivity to the exogenous AHLs provided by P. aeruginosa. In conclusion, our results demonstrate that S. maltophilia senses AHLs produced by neighboring bacteria through the LuxR solo SmoR, regulating population behaviors such as swarming motility

Seven-year follow-up of durability and safety of AAV CNS gene therapy for a lysosomal storage disorder in a large animal

Altres ajuts: Generalitat de Catalunya 2017SGR-01508Delivery of adeno-associated viral vectors (AAVs) to cerebrospinal fluid (CSF) has emerged as a promising approach to achieve widespread transduction of the central nervous system (CNS) and peripheral nervous system (PNS), with direct applicability to the treatment of a wide range of neurological diseases, particularly lysosomal storage diseases. Although studies in small animal models have provided proof of concept and experiments in large animals demonstrated feasibility in bigger brains, there is not much information on long-term safety or durability of the effect. Here, we report a 7-year study in healthy beagle dogs after intra-CSF delivery of a single, clinically relevant dose (2 × 10 13 vg/dog) of AAV9 vectors carrying the canine sulfamidase, the enzyme deficient in mucopolysaccharidosis type IIIA. Periodic monitoring of CSF and blood, clinical and neurological evaluations, and magnetic resonance and ultrasound imaging of target organs demonstrated no toxicity related to treatment. AAV9-mediated gene transfer resulted in detection of sulfamidase activity in CSF throughout the study. Analysis at tissue level showed widespread sulfamidase expression and activity in the absence of histological findings in any region of encephalon, spinal cord, or dorsal root ganglia. Altogether, these results provide proof of durability of expression and long-term safety for intra-CSF delivery of AAV-based gene transfer vectors encoding therapeutic proteins to the CNS. Seven-year follow-up of dogs after intra-CSF administration of AAV9-sulfamidase vectors results in detection of sulfamidase activity in CSF and widespread transgene expression in CNS, PNS, and liver, in the absence of any adverse events. Proof of durability and safety of this gene therapy support its clinical translation to treat CNS diseases

The genome sequencing of an albino Western lowland gorilla reveals inbreeding in the wild

BACKGROUND: The only known albino gorilla, named Snowflake, was a male wild born individual from Equatorial Guinea who lived at the Barcelona Zoo for almost 40 years. He was diagnosed with non-syndromic oculocutaneous albinism, i.e. white hair, light eyes, pink skin, photophobia and reduced visual acuity. Despite previous efforts to explain the genetic cause, this is still unknown. Here, we study the genetic cause of his albinism and making use of whole genome sequencing data we find a higher inbreeding coefficient compared to other gorillas./n/nRESULTS: We successfully identified the causal genetic variant for Snowflake's albinism, a non-synonymous single nucleotide variant located in a transmembrane region of SLC45A2. This transporter is known to be involved in oculocutaneous albinism type 4 (OCA4) in humans. We provide experimental evidence that shows that this amino acid replacement alters the membrane spanning capability of this transmembrane region. Finally, we provide a comprehensive study of genome-wide patterns of autozygogosity revealing that Snowflake's parents were related, being this the first report of inbreeding in a wild born Western lowland gorilla./n/nCONCLUSIONS: In this study we demonstrate how the use of whole genome sequencing can be extended to link genotype and phenotype in non-model organisms and it can be a powerful tool in conservation genetics (e.g., inbreeding and genetic diversity) with the expected decrease in sequencing cost.This work was supported by an ERC Starting Grant (StG_20091118) to TM-