A host-microbiota interactome reveals extensive transkingdom connectivity.

The myriad microorganisms that live in close association with humans have diverse effects on physiology, yet the molecular bases for these impacts remain mostly unknown1-3. Classical pathogens often invade host tissues and modulate immune responses through interactions with human extracellular and secreted proteins (the 'exoproteome'). Commensal microorganisms may also facilitate niche colonization and shape host biology by engaging host exoproteins; however, direct exoproteome-microbiota interactions remain largely unexplored. Here we developed and validated a novel technology, BASEHIT, that enables proteome-scale assessment of human exoproteome-microbiome interactions. Using BASEHIT, we interrogated more than 1.7 million potential interactions between 519 human-associated bacterial strains from diverse phylogenies and tissues of origin and 3,324 human exoproteins. The resulting interactome revealed an extensive network of transkingdom connectivity consisting of thousands of previously undescribed host-microorganism interactions involving 383 strains and 651 host proteins. Specific binding patterns within this network implied underlying biological logic; for example, conspecific strains exhibited shared exoprotein-binding patterns, and individual tissue isolates uniquely bound tissue-specific exoproteins. Furthermore, we observed dozens of unique and often strain-specific interactions with potential roles in niche colonization, tissue remodelling and immunomodulation, and found that strains with differing host interaction profiles had divergent interactions with host cells in vitro and effects on the host immune system in vivo. Overall, these studies expose a previously unexplored landscape of molecular-level host-microbiota interactions that may underlie causal effects of indigenous microorganisms on human health and disease.

Highly multiplexed bioactivity screening reveals human and microbiota metabolome-GPCRome interactions.

The human body contains thousands of metabolites derived from mammalian cells, the microbiota, food, and medical drugs. Many bioactive metabolites act through the engagement of G-protein-coupled receptors (GPCRs); however, technological limitations constrain current explorations of metabolite-GPCR interactions. Here, we developed a highly multiplexed screening technology called PRESTO-Salsa that enables simultaneous assessment of nearly all conventional GPCRs (>300 receptors) in a single well of a 96-well plate. Using PRESTO-Salsa, we screened 1,041 human-associated metabolites against the GPCRome and uncovered previously unreported endogenous, exogenous, and microbial GPCR agonists. Next, we leveraged PRESTO-Salsa to generate an atlas of microbiome-GPCR interactions across 435 human microbiome strains from multiple body sites, revealing conserved patterns of cross-tissue GPCR engagement and activation of CD97/ADGRE5 by the Porphyromonas gingivalis protease gingipain K. These studies thus establish a highly multiplexed bioactivity screening technology and expose a diverse landscape of human, diet, drug, and microbiota metabolome-GPCRome interactions.

Commensal microbiota from patients with inflammatory bowel disease produce genotoxic metabolites.

Microbiota-derived metabolites that elicit DNA damage can contribute to colorectal cancer (CRC). However, the full spectrum of genotoxic chemicals produced by indigenous gut microbes remains to be defined. We established a pipeline to systematically evaluate the genotoxicity of an extensive collection of gut commensals from inflammatory bowel disease patients. We identified isolates from divergent phylogenies whose metabolites caused DNA damage and discovered a distinctive family of genotoxins-termed the indolimines-produced by the CRC-associated species Morganella morganii. A non-indolimine-producing M. morganii mutant lacked genotoxicity and failed to exacerbate colon tumorigenesis in mice. These studies reveal the existence of a previously unexplored universe of genotoxic small molecules from the microbiome that may affect host biology in homeostasis and disease.

High-throughput identification of autoantibodies that target the human exoproteome.

Autoantibodies that recognize extracellular proteins (the exoproteome) exert potent biological effects but are challenging to detect. Here, we developed rapid extracellular antigen profiling (REAP), a high-throughput technique for the comprehensive discovery of exoproteome-targeting autoantibodies. Patient samples are applied to a genetically barcoded yeast surface display library containing 2,688 human extracellular proteins. Antibody-coated yeast are isolated, and sequencing of barcodes is used to identify displayed antigens. To benchmark REAP's performance, we screened 77 patients with autoimmune polyglandular syndrome type 1 (APS-1). REAP sensitively and specifically detected both known and previously unidentified autoantibodies in APS-1. We further screened 106 patients with systemic lupus erythematosus (SLE) and identified numerous autoantibodies, several of which were associated with disease severity or specific clinical manifestations and exerted functional effects on cell signaling ex vivo. These findings demonstrate the utility of REAP to atlas the expansive landscape of exoproteome-targeting autoantibodies and their impacts on patient health outcomes.

Cierre percutáneo de fístula arteriovenosa pulmonar en una adolescente: Reporte de un caso / Transcatheter closure of pulmonary arteriovenous fistula in adolescent: Case report

Las fístulas arteriovenosas, también llamadas malformaciones arteriovenosas pulmonares (MAVP), corresponden a un reducido grupo de patologías vasculares que en un 85% se originan de la comunicación de una arteria aferente con una vena eferente. Las congénitas son las menos frecuentes. Se presenta el caso de una adolescente de 13 años, asintomática, con soplo continuo y saturación periférica de 88%. Mediante estudios de imagen se corrobora la presencia de una fistula arteriovenosa a nivel pulmonar, que es cerrada por intervencionismo con dispositivo oclusor. Una vez tratado el defecto, la evolución de la paciente es satisfactoria. Conclusiones: Mediante el caso se abordan las herramientas clínicas y diagnósticas de las MAVP, así como las indicaciones de los modos terapéuticos.

Arteriovenous fistulas also called pulmonary arteriovenous malformations (PAVM) are a small group of vascular pathologies in 85% originate from the communication afferent efferent artery to a vein. Congenital are less frequent. The case of a 13-year-old asymptomatic continuous murmur and peripheral saturation of 88% is presented. By imaging the presence of an arteriovenous fistula in the lung, which is closed by intervention with occluder device is corroborated. Once treated the defect, the evolution of the patient is satisfactory. Conclusions: Using the case of clinical and diagnostic tools MAVP addresses, and the particulars of the therapeutic modes.

Early rheumatoid arthritis in Latin America: low socioeconomic status related to high disease activity at baseline.

OBJECTIVE: To determine the influence of socioeconomic factors on disease activity in a Latin American (LA) early rheumatoid arthritis (RA) multinational inception cohort at baseline. METHODS: Clinical evaluation, ethnicity, socioeconomic status (SES), 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR), Health Assessment Questionnaire (HAQ) disability index (DI), and erosions were recorded in 1,093 patients with early RA (<1 year from onset). Multivariate analyses evaluated influences of sex, age, marital status, education, medical coverage, SES, and ethnicity on HAQ DI, DAS28-ESR, and presence of erosions. RESULTS: Ethnicities included 43% Mestizo, 31% Caucasian, 19% African LA, 4% Amerindian, and 3% other. Fifty-eight percent were of low/low-middle SES, 42% had <8 years of education, 21% had no medical coverage, median disease duration was 6 months (25th, 75th percentiles 4, 9 months), median HAQ DI score was 1.25 (25th, 75th percentiles 0.63, 2.00), median DAS28-ESR score was 6.2 (25th, 75th percentiles 4.9, 7.2), and 25% had erosions. Women and Mestizos, African LA, and Amerindians had earlier onset than men or Caucasians (P < 0.01). When adjusted by country, the analysis of covariance model showed that low/low-middle SES, female sex, partial coverage, and older age were associated with worse HAQ DI scores; only low/low-middle SES was associated with higher DAS28 scores. Statistically significant differences were found in HAQ DI and DAS28 scores between countries. When excluding country, low/low-middle SES, female sex, and no coverage were associated with worse HAQ DI and DAS28 scores, whereas separated/divorced/widowed status was associated with worse HAQ DI scores and age was associated with worse DAS28 scores. Logistic regression showed that older age, no coverage, and the Amerindian and other ethnic groups were associated with erosions. CONCLUSION: We compared early RA patients from the main LA ethnic groups. Our findings suggest that low/low-middle SES is important in determining disease activity. A more genetic-related background for erosions is possible.

Modelo para la inducción de granulocitopenia en pollos de engorda mediante la administración de 5-fluorouracilo / A polymorphonuclear leukocyte depletion model in 5-fluorouracil treatment chickens

Se utilizaron 50 pollitos de engorda de un día de edad que fueron distribuidos aleatoriamente en 3 grupos con 15 aves cada uno, más 5 para muestreo bacteriológico. A los 17 días de edad, se inoculó en promedio 2 ml de solución salina fosfatada estéril, por vía endovenosa a las aves del grupo 1, mientras que en los grupos 2 y 3 se les administró 5-fluorouracilo (5-FU) en solución a dosis de 200 y 300 mg/kg de peso, respectivamente. A 10 aves de cada grupo se les tomó una muestra sanguínea durante los días 1, 3, 5, 6, 7, 8, 9, 10, 12 y 15 postratamiento (PT) para realizar un conteo total y diferencial de leucocitos; posteriormente se obtuvo la proporción de leucocitos polimorfonucleares/leucocitos totales (PMN/L T). Los resultados obtenidos en este estudio mostraron que la proporción de PMN/L T en los grupos tratados con 5-FU disminuyó a partir del día 1 hasta el día 9 PT, los valores más bajos se presentaron al día 9 PT y los valores normales se recuperaron hasta el día 15 PT. Se encontraron diferencias altamente significativas (P< 0.001) entre grupos, entre los días de muestreo, así como en la interacción de la dosis de 5-FU y el tiempo PT en relación con los valores de las proporciones de PMN/L T. Asimismo, se observaron diferencias (P< 0.05) entre las proporciones de PMN/L T de las aves tratadas con 5-FU en comparación con las aves del grupo testigo, así como entre los días de muestreo en los grupos tratados. Las aves tratadas con 300 mg de 5.FU/kg de peso presentaron signos de toxicidad