Modulation of Salmonella virulence by a novel SPI-2 injectisome effector that interacts with the dystrophin-associated protein complex.

The injectisome encoded by Salmonella pathogenicity island 2 (SPI-2) had been thought to translocate 28 effectors. Here, we used a proteomic approach to characterize the secretome of a clinical strain of invasive non-typhoidal Salmonella enterica serovar Enteritidis that had been mutated to cause hyper-secretion of the SPI-2 injectisome effectors. Along with many known effectors, we discovered the novel SseM protein. sseM is widely distributed among the five subspecies of Salmonella enterica, is found in many clinically relevant serovars, and is co-transcribed with pipB2, a SPI-2 effector gene. The translocation of SseM required a functional SPI-2 injectisome. Following expression in human cells, SseM interacted with five components of the dystrophin-associated protein complex (DAPC), namely, ß-2-syntrophin, utrophin/dystrophin, α-catulin, α-dystrobrevin, and ß-dystrobrevin. The interaction between SseM and ß-2-syntrophin and α-dystrobrevin was verified in Salmonella Typhimurium-infected cells and relied on the postsynaptic density-95/discs large/zonula occludens-1 (PDZ) domain of ß-2-syntrophin and a sequence corresponding to a PDZ-binding motif (PBM) in SseM. A ΔsseM mutant strain had a small competitive advantage over the wild-type strain in the S. Typhimurium/mouse model of systemic disease. This phenotype was complemented by a plasmid expressing wild-type SseM from S. Typhimurium or S. Enteritidis and was dependent on the PBM of SseM. Therefore, a PBM within a Salmonella effector mediates interactions with the DAPC and modulates the systemic growth of bacteria in mice. Furthermore, the ΔsseM mutant strain displayed enhanced replication in bone marrow-derived macrophages, demonstrating that SseM restrains intracellular bacterial growth to modulate Salmonella virulence. IMPORTANCE: In Salmonella enterica, the injectisome machinery encoded by Salmonella pathogenicity island 2 (SPI-2) is conserved among the five subspecies and delivers proteins (effectors) into host cells, which are required for Salmonella virulence. The identification and functional characterization of SPI-2 injectisome effectors advance our understanding of the interplay between Salmonella and its host(s). Using an optimized method for preparing secreted proteins and a clinical isolate of the invasive non-typhoidal Salmonella enterica serovar Enteritidis strain D24359, we identified 22 known SPI-2 injectisome effectors and one new effector-SseM. SseM modulates bacterial growth during murine infection and has a sequence corresponding to a postsynaptic density-95/discs large/zonula occludens-1 (PDZ)-binding motif that is essential for interaction with the PDZ-containing host protein ß-2-syntrophin and other components of the dystrophin-associated protein complex (DAPC). To our knowledge, SseM is unique among Salmonella effectors in containing a functional PDZ-binding motif and is the first bacterial protein to target the DAPC.

Governance of advanced materials: Shaping a safe and sustainable future.

The past few decades of managing the uncertain risks associated with nanomaterials have provided valuable insights (knowledge gaps, tools, methods, etc.) that are equally important to promote safe and sustainable development and use of advanced materials. Based on these insights, the current paper proposes several actions to optimize the risk and sustainability governance of advanced materials. We emphasise the importance of establishing a European approach for risk and sustainability governance of advanced materials as soon as possible to keep up with the pace of innovation and to manage uncertainty among regulators, industry, SMEs and the public, regarding potential risks and impacts of advanced materials. Coordination of safe and sustainable advanced material research efforts, and data management according to the Findable, Accessible, Interoperable and Reusable (FAIR) principles will enhance the generation of regulatory-relevant knowledge. This knowledge is crucial to identify whether current regulatory standardised and harmonised test methods are adequate to assess advanced materials. At the same time, there is urgent need for responsible innovation beyond regulatory compliance which can be promoted through the Safe and Sustainable Innovation Approach. that combines the Safe and Sustainable by Design concept with Regulatory Preparedness, supported by a trusted environment. We further recommend consolidating all efforts and networks related to the risk and sustainability governance of advanced materials in a single, easy-to-use digital portal. Given the anticipated complexity and tremendous efforts required, we identified the need of establishing an organisational structure dedicated to aligning the fast technological developments in advanced materials with proper risk and sustainability governance. Involvement of multiple stakeholders in a trusted environment ensures a coordinated effort towards the safe and sustainable development, production, and use of advanced materials. The existing infrastructures and network of experts involved in the governance of nanomaterials would form a solid foundation for such an organisational structure.

Cultural context and self-care impact on medical students' quality of life. A mixed-methods approach.

BACKGROUND: Medical education can make it difficult for students to take actions to improve their health. OBJECTIVE: To evaluate the influence of the university context on self-care behaviors and quality of life. MATERIAL AND METHODS: A mixed-methods approach was used, with surveys being combined to assess self-care and quality of life, with in-depth interviews to explore cultural influences and perceptions. Statistical analysis and qualitative data coding were carried out, with methods being integrated through network analysis. RESULTS: Self-care scores exceeded 50 points, and quality of life scores exceeded 60 points. Medical students' context is shaped by motivations, expectations, skills, and goals that influence identity formation and contribute to the medical profession. CONCLUSIONS: There is a positive connection between self-care practices and quality of life. However, academic stress can potentially disrupt self-care routines. Furthermore, an association between obesity and a decrease in quality of life stands out, which emphasizes the need for health promotion actions.

ANTECEDENTES: La educación médica puede dificultar que los estudiantes realicen acciones para mejorar su salud. OBJETIVO: Evaluar la influencia del contexto universitario en los comportamientos de autocuidado y la calidad de vida. ­. MATERIAL Y MÉTODOS: Se empleó un enfoque de métodos mixtos, combinando encuestas para evaluar el autocuidado y la calidad de vida, con entrevistas en profundidad para explorar influencias culturales y percepciones. Se llevaron a cabo análisis estadísticos y codificación de datos cualitativos; los métodos se integraron a través del análisis de redes. RESULTADOS: Las puntuaciones de autocuidado superaron los 50 puntos y las de calidad de vida, los 60 puntos. El contexto de los estudiantes de medicina está moldeado por motivaciones, expectativas, habilidades y metas que influyen en la formación de la identidad y contribuyen a la profesión médica. CONCLUSIONES: Existe una conexión positiva entre prácticas de autocuidado y la calidad de vida; sin embargo, el estrés académico pueden interrumpir potencialmente las rutinas de autocuidado. Además, se destaca la asociación entre la obesidad y la afectación en la calidad de vida, lo que enfatiza la necesidad de acciones de promoción de la salud.

Contexto cultural e impacto del autocuidado en la calidad de vida de los estudiantes de medicina. Enfoque de métodos mixtos / Cultural context and self-care impact on medical students’ quality of life. A mixed-methods approach

Resumen Antecedentes: La educación médica puede dificultar que los estudiantes realicen acciones para mejorar su salud. Objetivo: Evaluar la influencia del contexto universitario en los comportamientos de autocuidado y la calidad de vida. Material y métodos: Se empleó un enfoque de métodos mixtos, combinando encuestas para evaluar el autocuidado y la calidad de vida, con entrevistas en profundidad para explorar influencias culturales y percepciones. Se llevaron a cabo análisis estadísticos y codificación de datos cualitativos; los métodos se integraron a través del análisis de redes. Resultados: Las puntuaciones de autocuidado superaron los 50 puntos y las de calidad de vida, los 60 puntos. El contexto de los estudiantes de medicina está moldeado por motivaciones, expectativas, habilidades y metas que influyen en la formación de la identidad y contribuyen a la profesión médica. Conclusiones: Existe una conexión positiva entre prácticas de autocuidado y la calidad de vida; sin embargo, el estrés académico pueden interrumpir potencialmente las rutinas de autocuidado. Además, se destaca la asociación entre la obesidad y la afectación en la calidad de vida, lo que enfatiza la necesidad de acciones de promoción de la salud.

Abstract Background: Medical education can make it difficult for students to take actions to improve their health. Objective: To evaluate the influence of the university context on self-care behaviors and quality of life. Material and methods: A mixed-methods approach was used, with surveys being combined to assess self-care and quality of life, with in-depth interviews to explore cultural influences and perceptions. Statistical analysis and qualitative data coding were carried out, with methods being integrated through network analysis. Results: Self-care scores exceeded 50 points, and quality of life scores exceeded 60 points. Medical students’ context is shaped by motivations, expectations, skills, and goals that influence identity formation and contribute to the medical profession. Conclusions: There is a positive connection between self-care practices and quality of life. However, academic stress can potentially disrupt self-care routines. Furthermore, an association between obesity and a decrease in quality of life stands out, which emphasizes the need for health promotion actions.

Antithrombotic and risk of hemorrhagic complications in over-60-year-olds after mild-minimal traumatic brain injury.

PRIMARY OBJECTIVE: to identify if antithombotics are risk factors for intracereral lesion in older adults with minimal-mild traumatic brain injury (m-mTBI). RESEARCH DESING: prospective cohort study. METHODS AND PROCEDURES: We included 2,303 patients over 60 years arriving at our Emergency Department within 24 hours of an mTBI with a Glasgow Coma Scale (GSC) of 14-15. Data were gathered on clinical history, cranial CT scans, blood analyses. OUTCOMES AND RESULTS: 91.1% had an admission GSC score of 15, and 23.6% developed intracranial complications. In bivariate analyses, statins were associated with a 1.28-fold lower risk of IC. Hemorrhagic progression was 29.76-fold higher in patients receiving anticoagulants, with no difference among anticoagulant types. Male sex, GSC of 14, alcohol consumption, and the presence of tumor were risk factors for IC. In multivariate analysis, GSC of 14, alcohol consumption, and malignancy emerged as risk factors for these complications, neurological disease and diabetes as protective factors. After exclusion of neurological disease and diabetes from the multivariate model, a GSC of 14 showed the highest predictive capacity. CONCLUSIONS: Antithrombotics intake are not risks factor for intracranial injury in minimal-mild brain injury trauma. Further research is needed taking account of their fragility and comorbidities.

A One Health approach based on genomics for enhancing the Salmonella enterica surveillance in Colombia.

Objectives: This study aimed to provide evidence of the domestic benefits of introducing an integrative genomic analysis from the One Health approach in the national surveillance of Salmonella enterica between 1997-2017 in Colombia. Methods: Data on Salmonella from clinical laboratory-based surveillance between 1997-2017 and from a national cross-sectional study at chicken retail stores in Colombia were compared using a phenotypic, molecular, and genomic approaches. Additional analysis by serovar using single nucleotide polymorphism was developed to increase the resolution of the relatedness between the interfaces. Results: Locally, the diversity and pathogenic factors of the prevalent S. enterica serovars associated with foodborne disease in Colombia were described using laboratory, pulse field gel electrophoresis, and whole genome sequencing data. For example, the resolution of pulse field gel electrophoresis allowed the description of two main foodborne clusters of Salmonella Enteritidis isolates, which were expanded to eight foodborne clades using whole genome sequencing. Likewise, virulence factors and antimicrobial resistance determinants, and mobile genetic elements that converged in the foodborne clades should be considered a public health concern in Colombia. All results by serovar were compiled in an interactive easy to share report. Conclusion: Whole genome sequencing is a technology that provides a precise assessment of emerging foodborne risks such as the Salmonella foodborne clades, but it requires an integrative and continued collaboration between the stakeholders across the One Health sectors to promote appropriated actions and policies in public health.

Terapia medico nutricional en pacientes que reciben terapia de oxigenación por membrana extracorpórea: conocimiento en progreso / Medical nutrition therapy in patients receiving extracorporeal membrane oxygenation: knowledge in progress

Resumen El soporte nutricional (SN) en pacientes adultos que reciben terapia de oxigenación por membrana extracorpórea (ECMO, extracorporeal membrane oxygenation) es controvertido. Si bien existen guías para el SN en pacientes pediátricos con ECMO, en adultos no se cuenta con estos lineamientos para el uso, tipo, ruta y momento de la terapia nutricional. En pacientes críticamente enfermos es bien sabido que la nutrición enteral (NE) temprana es beneficiosa, no obstante existe la posibilidad de que en pacientes con ECMO la NE temprana condicione complicaciones gastrointestinales. Asimismo, no se han establecido metas calóricas, proteicas y dosis o tipos de micronutrimentos que usar para esta población en específico, siendo un reto para el clínico encargado de brindar el SN. Aunado a esto los pacientes con ECMO son algunos de los más gravemente enfermos en las unidades de cuidados intensivos, donde la desnutrición se asocia con una mayor morbilidad y mortalidad. En cuanto al uso de nutrición parenteral (NP), no se tiene descrito si implica riesgo de falla en el circuito al momento de introducir lípidos al oxigenador. Por lo anterior es imperativa una correcta evaluación e intervención nutricional específica, realizada por expertos en el tema para mejorar el pronóstico y la calidad de vida en esta población, siendo un objetivo primordial en los cuidados de los pacientes adultos que reciben terapia de ECMO.

Abstract Nutritional support in adult patients receiving extracorporeal membrane oxygenation (ECMO) therapy is controversial. Although there are guidelines for the NS (Nutritional support) in pediatric patients with ECMO, in adults these guidelines are not available for the use, type, route and timing of nutritional therapy. In critically ill patients it is well known that early enteral nutrition is beneficial, however there is the possibility that in patients with ECMO early enteral nutrition leads to gastrointestinal complications. Likewise, there have not been established caloric targets, proteins and doses or types of micronutrients to use for this specific population being a challenge for the clinician. In addition, patients with ECMO are some of the most seriously ill in intensive care units, where malnutrition is associated with increased morbidity and mortality. Regarding the use of parenteral nutrition (NP) it has not been described if it implies a risk of circuit failure at the time of introducing lipids to the oxygenator. Therefore, a correct evaluation and specific nutritional intervention by experts in the field is imperative to improve the prognosis and quality of life in this population, which is a primary goal in the care of adult patients receiving extracorporeal membrane oxygen.

Medical nutrition therapy in patients receiving extracorporeal membrane oxygenation: knowledge in progress.

Nutritional support in adult patients receiving extracorporeal membrane oxygenation (ECMO) therapy is controversial. Although there are guidelines for the NS (Nutritional support) in pediatric patients with ECMO, in adults these guidelines are not available for the use, type, route and timing of nutritional therapy. In critically ill patients it is well known that early enteral nutrition is beneficial, however there is the possibility that in patients with ECMO early enteral nutrition leads to gastrointestinal complications. Likewise, there have not been established caloric targets, proteins and doses or types of micronutrients to use for this specific population being a challenge for the clinician. In addition, patients with ECMO are some of the most seriously ill in intensive care units, where malnutrition is associated with increased morbidity and mortality. Regarding the use of parenteral nutrition (NP) it has not been described if it implies a risk of circuit failure at the time of introducing lipids to the oxygenator. Therefore, a correct evaluation and specific nutritional intervention by experts in the field is imperative to improve the prognosis and quality of life in this population, which is a primary goal in the care of adult patients receiving extracorporeal membrane oxygen.

El soporte nutricional (SN) en pacientes adultos que reciben terapia de oxigenación por membrana extracorpórea (ECMO, extracorporeal membrane oxygenation) es controvertido. Si bien existen guías para el SN en pacientes pediátricos con ECMO, en adultos no se cuenta con estos lineamientos para el uso, tipo, ruta y momento de la terapia nutricional. En pacientes críticamente enfermos es bien sabido que la nutrición enteral (NE) temprana es beneficiosa, no obstante existe la posibilidad de que en pacientes con ECMO la NE temprana condicione complicaciones gastrointestinales. Asimismo, no se han establecido metas calóricas, proteicas y dosis o tipos de micronutrimentos que usar para esta población en específico, siendo un reto para el clínico encargado de brindar el SN. Aunado a esto los pacientes con ECMO son algunos de los más gravemente enfermos en las unidades de cuidados intensivos, donde la desnutrición se asocia con una mayor morbilidad y mortalidad. En cuanto al uso de nutrición parenteral (NP), no se tiene descrito si implica riesgo de falla en el circuito al momento de introducir lípidos al oxigenador. Por lo anterior es imperativa una correcta evaluación e intervención nutricional específica, realizada por expertos en el tema para mejorar el pronóstico y la calidad de vida en esta población, siendo un objetivo primordial en los cuidados de los pacientes adultos que reciben terapia de ECMO.

Genetic Basis of Inflammatory Demyelinating Diseases of the Central Nervous System: Multiple Sclerosis and Neuromyelitis Optica Spectrum.

Demyelinating diseases alter myelin or the coating surrounding most nerve fibers in the central and peripheral nervous systems. The grouping of human central nervous system demyelinating disorders today includes multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) as distinct disease categories. Each disease is caused by a complex combination of genetic and environmental variables, many involving an autoimmune response. Even though these conditions are fundamentally similar, research into genetic factors, their unique clinical manifestations, and lesion pathology has helped with differential diagnosis and disease pathogenesis knowledge. This review aims to synthesize the genetic approaches that explain the differential susceptibility between these diseases, explore the overlapping clinical features, and pathological findings, discuss existing and emerging hypotheses on the etiology of demyelination, and assess recent pathogenicity studies and their implications for human demyelination. This review presents critical information from previous studies on the disease, which asks several questions to understand the gaps in research in this field.

Efficacy and Safety of Leuprolide Acetate 6-Month Depot for the Treatment of Central Precocious Puberty: A Phase 3 Study.

Context: Treatment options for central precocious puberty (CPP) are important for individualization of therapy. Objective: We evaluated the efficacy and safety of 6-month 45-mg leuprolide acetate (LA) depot with intramuscular administration. Methods: LA depot was administered at weeks 0 and 24 to treatment-naïve (n = 27) or previously treated (n = 18) children with CPP in a phase 3, multicenter, single-arm, open-label study (NCT03695237). Week 24 peak-stimulated luteinizing hormone (LH) suppression (<4 mIU/mL) was the primary outcome. Secondary/other outcomes included basal sex hormone suppression (girls, estradiol <20 pg/mL; boys, testosterone <30 ng/dL), suppression of physical signs, height velocity, bone age, patient/parent-reported outcomes, and adverse events. Results: All patients (age, 7.8 ± 1.27 years) received both scheduled study doses. At 24 weeks, 39/45 patients (86.7%) had LH suppressed. Six were counted as unsuppressed; 2 because of missing data, 3 with LH of 4.35-5.30 mIU/mL and 1 with LH of 21.07 mIU/mL. Through 48 weeks, LH, estradiol, and testosterone suppression was achieved in ≥86.7%, ≥97.4%, and 100%, respectively (as early as week 4 for LH and estradiol and week 12 for testosterone). Physical signs were suppressed at week 48 (girls, 90.2%; boys, 75.0%). Mean height velocity ranged 5.0 to 5.3 cm/year post-baseline in previously treated patients and declined from 10.1 to 6.5 cm/year at week 20 in treatment-naïve patients. Mean bone age advanced slower than chronological age. Patient/parent-reported outcomes remained stable. No new safety signals were identified. No adverse event led to treatment discontinuation. Conclusion: Six-month intramuscular LA depot demonstrated 48-week efficacy with a safety profile consistent with other GnRH agonist formulations.

A global genomic analysis of Salmonella Concord reveals lineages with high antimicrobial resistance in Ethiopia.

Antimicrobial resistant Salmonella enterica serovar Concord (S. Concord) is known to cause severe gastrointestinal and bloodstream infections in patients from Ethiopia and Ethiopian adoptees, and occasional records exist of S. Concord linked to other countries. The evolution and geographical distribution of S. Concord remained unclear. Here, we provide a genomic overview of the population structure and antimicrobial resistance (AMR) of S. Concord by analysing genomes from 284 historical and contemporary isolates obtained between 1944 and 2022 across the globe. We demonstrate that S. Concord is a polyphyletic serovar distributed among three Salmonella super-lineages. Super-lineage A is composed of eight S. Concord lineages, of which four are associated with multiple countries and low levels of AMR. Other lineages are restricted to Ethiopia and horizontally acquired resistance to most antimicrobials used for treating invasive Salmonella infections in low- and middle-income countries. By reconstructing complete genomes for 10 representative strains, we demonstrate the presence of AMR markers integrated in structurally diverse IncHI2 and IncA/C2 plasmids, and/or the chromosome. Molecular surveillance of pathogens such as S. Concord supports the understanding of AMR and the multi-sector response to the global AMR threat. This study provides a comprehensive baseline data set essential for future molecular surveillance.

The big four of plant taxonomy - a comparison of global checklists of vascular plant names.

Taxonomic checklists used to verify published plant names and identify synonyms are a cornerstone of biological research. Four global authoritative checklists for vascular plants exist: Leipzig Catalogue of Vascular Plants, World Checklist of Vascular Plants, World Flora Online (successor of The Plant List, TPL), and WorldPlants. We compared these four checklists in terms of size and differences across taxa. We matched taxon names of these checklists and TPL against each other, identified differences across checklists, and evaluated the consistency of accepted names linked to individual taxon names. We assessed geographic and phylogenetic patterns of variance. All checklists differed strongly compared with TPL and provided identical information on c. 60% of plant names. Geographically, differences in checklists increased from low to high latitudes. Phylogenetically, we detected strong variability across families. A comparison of name-matching performance on taxon names submitted to the functional trait database TRY, and a check of completeness of accepted names evaluated against an independent, expert-curated checklist of the family Meliaceae, showed a similar performance across checklists. This study raises awareness on the differences in data and approach across these checklists potentially impacting analyses. We propose ideas on the way forward exploring synergies and harmonizing the four global checklists.

Reproductive performance of hair ewes and rams implanted with melatonin previous to the anestrus season in northwest Mexico.

Ovine reproductive behavior depends on annual photoperiodic cycle and its impact on endogenous melatonin secretion. In this regard, exogenous melatonin administration previous to the physiological anestrus period could modify the reproductive performance of sheep in the northwest of Mexico. Two independent studies were performed to evaluate such hypothesis in hair sheep implanted with melatonin prior to the anestrus season in latitudes 24° and 25° of Mexico. Study 1 involved 15 rams assigned to one of three treatments receiving 0mg (n=5), 18mg (n=5), or 36mg (n=5) of melatonin subcutaneously. Study variables were measured monthly since implantation (d0) and included testosterone concentration, scrotal circumference, mass motility, individual motility, and sperm concentration. Study 2 included 50 ewes assigned to one of two treatments receiving 0mg (n=25) or 18mg (n=25) of melatonin subcutaneously. In ewes, progesterone concentration and the frequency of females in anestrus were measured during the implantation (-30d), as well as at the beginning (0d) and at the end (45d) of the mating period, while pregnancy rate was determined by ultrasonography 45d after. Continuous variables were analyzed using a mixed effects model considering treatment, time, and the treatment by time interaction as fixed effects. Animal nested within treatment was the random effect. Binary variables were analyzed using the chi-square test. In males, melatonin improved testosterone and sperm concentrations (P<0.05), while in females, a 28% higher pregnancy rate was observed in implanted ewes (P<0.05). Therefore, melatonin enhanced reproductive parameters in both sexes and its exogenous administration previous to the anestrus season in northwest Mexico could be more effective in rams.

Latin American anaphylaxis registry.

Background: Recent data about clinical features, triggers and management of anaphylaxis in Latin America is lacking. Objective: To provide updated and extended data on anaphylaxis in this region. Method: An online questionnaire was used, with 67 allergy units involved from 12 Latin-American countries and Spain. Among data recorded, demographic information, clinical features, severity, triggering agents, and treatment were received. Results: Eight hundred and seventeen anaphylactic reactions were recorded. No difference in severity, regardless of pre-existing allergy or asthma history was found. Drug induced anaphylaxis (DIA) was most frequent (40.6%), followed by food induced anaphylaxis (FIA) (32.9%) and venom induced anaphylaxis (VIA) (12%). FIA and VIA were more common in children-adolescents. Non-steroidal anti-inflammatory drugs (NSAIDs) and beta-lactam antibiotics (BLA) were the most frequent drugs involved. Milk (61.1% of FIA) and egg (15.4% of FIA) in children, and shellfish (25.5% of FIA), fresh fruits (14.2% of FIA), and fish (11.3% of FIA) in adults were the most common FIA triggers. Fire ants were the most frequent insect triggers, and they induced more severe reactions than triggers of FIA and DIA (p < 0.0001). Epinephrine was used in 43.8% of anaphylaxis episodes. After Emergency Department treatment, epinephrine was prescribed to 13% of patients. Conclusions: Drugs (NSAIDs and BLA), foods (milk and egg in children and shellfish, fruits and fish in adults) and fire ants were the most common inducers of anaphylaxis. Epinephrine was used in less than half of the episodes emphasizing the urgent need to improve dissemination and implementation of anaphylaxis guidelines.

ACVR1-activating mutation causes neuropathic pain and sensory neuron hyperexcitability in humans.

ABSTRACT: Altered bone morphogenetic protein (BMP) signaling is associated with many musculoskeletal diseases. However, it remains unknown whether BMP dysfunction has direct contribution to debilitating pain reported in many of these disorders. Here, we identified a novel neuropathic pain phenotype in patients with fibrodysplasia ossificans progressiva (FOP), a rare autosomal-dominant musculoskeletal disorder characterized by progressive heterotopic ossification. Ninety-seven percent of these patients carry an R206H gain-of-function point mutation in the BMP type I receptor ACVR1 (ACVR1 R206H ), which causes neofunction to Activin A and constitutively activates signaling through phosphorylated SMAD1/5/8. Although patients with FOP can harbor pathological lesions in the peripheral and central nervous system, their etiology and clinical impact are unclear. Quantitative sensory testing of patients with FOP revealed significant heat and mechanical pain hypersensitivity. Although there was no major effect of ACVR1 R206H on differentiation and maturation of nociceptive sensory neurons (iSNs) derived from FOP induced pluripotent stem cells, both intracellular and extracellular electrophysiology analyses of the ACVR1 R206H iSNs displayed ACVR1-dependent hyperexcitability, a hallmark of neuropathic pain. Consistent with this phenotype, we recorded enhanced responses of ACVR1 R206H iSNs to TRPV1 and TRPA1 agonists. Thus, activated ACVR1 signaling can modulate pain processing in humans and may represent a potential target for pain management in FOP and related BMP pathway diseases.

Multiplex PCR Assay for Clade Typing of Salmonella enterica Serovar Enteritidis.

Salmonella enterica serovar Enteritidis is one of the most commonly reported serovars of nontyphoidal Salmonella causing human disease and is responsible for both gastroenteritis and invasive nontyphoidal Salmonella (iNTS) disease worldwide. Whole-genome sequence (WGS) comparison of Salmonella Enteritidis isolates from across the world has identified three distinct clades, global epidemic, Central/East African, and West African, all of which have been implicated in epidemics: the global epidemic clade was linked to poultry-associated gastroenteritis, while the two African clades were related to iNTS disease. However, the distribution and epidemiology of these clades across Africa are poorly understood because identification of these clades currently requires whole-genome sequencing capacity. Here, we report a sensitive, time- and cost-effective real-time PCR assay capable of differentiating between the Salmonella Enteritidis clades to facilitate surveillance and to inform public health responses. The assay described here is limited to previously confirmed S. Enteritidis isolates. IMPORTANCE Challenges in the diagnosis and treatment of invasive Salmonella Enteritidis bloodstream infections in sub-Saharan Africa are responsible for a case fatality rate of approximately 15%. It is important to identify distinct clades of S. Enteritidis in diagnostic laboratories in the African setting to determine the different health outcomes associated with particular outbreaks. Here, we describe the development of a high-quality molecular classification assay for clade typing of S. Enteritidis that is ideal for use in public health laboratories in resource-limited settings.

Dietary fish oil increases catalase activity in patients with probable Alzheimer's disease.

Introduction: Background: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence of neuritic plaques and neurofibrillary tangles that finally result in synaptic and neuronal loss. Oxidative stress accompanies pathological changes in AD. Objective: to assess the efficacy of dietary omega 3 polyunsaturated fatty acids supplementation on the levels of proteins oxidation, hydroperoxides and enzymatic activities of catalase and superoxide dismutase in AD patients. Methods: clinical, controlled, randomized, double-blind trial. Patients consumed fish oil or placebo for one year. Oxidative stress markers were assessed in plasma using spectrophotometric methods. Results: carbonyl groups in proteins and hydroperoxides in plasma have similar values in both treatment groups at the beginning of the study. At six and 12 months of treatment, these values decreased significantly in the fish oil group, while in the placebo group no changes were observed in both oxidative stress markers. Catalase activity increased significantly at six and twelve months after treatment in patients treated with fish oil. While the superoxide dismutase activity was not modified in both study groups. Conclusions: patients who consume omega 3 polyunsaturated fatty acids at a stable dose of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) show decreased oxidation of proteins and lipids in plasma. In addition, an increase in catalase activity was detected. Thus, the presented data warrants further studies evaluating the antioxidant effect of omega 3 polyunsaturated fatty acids.

Introducción: Antecedentes: la enfermedad de Alzheimer (EA) es un trastorno neurodegenerativo caracterizado por la presencia de placas neuríticas y ovillos neurofibrilares que finalmente resultan en pérdida sináptica y neuronal. El estrés oxidativo acompaña los cambios patológicos en la EA. Objetivo: evaluar la eficacia de la suplementación dietética con ácidos grasos poliinsaturados omega 3 sobre los niveles de oxidación de proteínas, hidroperóxidos y actividades enzimáticas de catalasa y superóxido dismutasa en pacientes con EA. Métodos: ensayo clínico, controlado, aleatorizado, doble ciego. Los pacientes consumieron aceite de pescado o placebo durante un año. Los marcadores de estrés oxidativo se evaluaron en plasma mediante métodos espectrofotométricos. Resultados: los grupos carbonilo en proteínas e hidroperóxidos en plasma tuvieron valores similares en ambos grupos de tratamiento al inicio del estudio. A los seis y 12 meses de tratamiento estos valores disminuyeron significativamente en el grupo de aceite de pescado, mientras que en el grupo placebo no se observaron cambios en ambos marcadores. La actividad de catalasa aumentó significativamente a los seis y doce meses después del tratamiento en pacientes tratados con aceite de pescado; sin embargo, la actividad superóxido dismutasa no se modificó en ambos grupos de estudio. Conclusiones: los pacientes que consumieron los ácidos grasos poliinsaturados omega 3 a una dosis estable de ácido docosahexaenoico (DHA) y ácido eicosapentaenoico (EPA) muestran una oxidación reducida de proteínas y lípidos en plasma. Además, se detectó un aumento en la actividad de la catalasa. Por tanto, los datos presentados justifican más estudios que evalúen el efecto antioxidante de dichos ácidos grasos.

Divergent Pd-catalyzed Functionalization of 4-Oxazolin-2-ones and 4-Methylene-2-oxazolidinones and Synthesis of Heterocyclic-Fused Indoles.

Palladium-catalyzed functionalization was presently performed on two building blocks: 4-oxazolin-2-ones and 4-methylene-2-oxazolidinones. Direct Heck arylation of 4-oxazolin-2-ones led to a series of 5-aryl-4-oxazolin-2-ones, including analogues with N-chiral auxiliary, in an almost quantitative yield. The Pd(II)-catalyzed homocoupling reaction of 4-oxazolin-2-ones provided novel heterocyclic across-ring dienes. Meanwhile, the intramolecular cross-coupling of N-aryl-4-methylene-2-oxazolidinones furnished a series of oxazolo[3,4-a]indol-3-ones. Further functionalization of 4-methylene-2-oxazolidinones afforded substituted indoles and heterocyclic-fused indoles with aryl, bromo, carbinol, formyl, and vinyl groups. A computational study was carried out to account for the behavior of the formylated derivatives. The currently developed methodology was applied to a new formal total synthesis of ellipticine.

PVA-Based Electrospun Biomembranes with Hydrolyzed Collagen and Ethanolic Extract of Hypericum perforatum for Potential Use as Wound Dressing: Fabrication and Characterization.

Biological, physicochemical, structural, and thermal properties of PVA-based electrospun wound dressings added with hydrolyzed collagen (HC) and different concentrations of Hypericum perforatum ethanolic extract (EEHP) were studied. Membrane characterization was carried out by X-ray diffraction, Fourier infrared spectroscopy, differential scanning calorimetry, barrier properties, scanning electron microscopy, image analysis (diameter and pore size), as well as antimicrobial and anti-inflammatory activities. Results showed that the PVA/HC/EEHP materials, fabricated under controlled conditions of temperature and humidity, generated fiber membranes with diameters between 140−390 nm, adequate porosity and pore size for cell growth (67−90% and 4−16 µm, respectively), and good barrier properties (0.005−0.032 g·m−2 s−1) to be used in the treatment of conditions on the skin, and was even better than some commercial products. Finally, they showed to have anti-inflammatory (>80%), and antimicrobial activity against S. aureus and S. epiderm. Furthermore, higher crystalline structure was observed according to the EEHP concentration. In addition, this is the first report in which PVA/HC/EEHP membranes are successfully fabricated and characterized.