Versican accumulation drives Nos2 induction and aortic disease in Marfan syndrome via Akt activation

Aortic aneurysm; Marfan syndrome; VersicanAneurisma aòrtic; Síndrome de Marfan; VersicanAneurisma aortico; Síndrome de Marfan; VersicanThoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition associated with Marfan syndrome (MFS), a disease caused by fibrillin-1 gene mutations. While various conditions causing TAAD exhibit aortic accumulation of the proteoglycans versican (Vcan) and aggrecan (Acan), it is unclear whether these ECM proteins are involved in aortic disease. Here, we find that Vcan, but not Acan, accumulated in Fbn1C1041G/+ aortas, a mouse model of MFS. Vcan haploinsufficiency protected MFS mice against aortic dilation, and its silencing reverted aortic disease by reducing Nos2 protein expression. Our results suggest that Acan is not an essential contributor to MFS aortopathy. We further demonstrate that Vcan triggers Akt activation and that pharmacological Akt pathway inhibition rapidly regresses aortic dilation and Nos2 expression in MFS mice. Analysis of aortic tissue from MFS human patients revealed accumulation of VCAN and elevated pAKT-S473 staining. Together, these findings reveal that Vcan plays a causative role in MFS aortic disease in vivo by inducing Nos2 via Akt activation and identify Akt signaling pathway components as candidate therapeutic targets.The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation), the CBMSO is supported by Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid. CBMSO and CNIC are Severo Ochoa Centers of Excellence (grants CEX2021-001154-S and CEX2020-001041-S, respectively) funded by MICIN/AEI/10.13039/501100011033. The project leading to these results has received funding from “La Caixa” Banking Foundation under project codes HR18-00068 (to MRC and JMR); Spanish Ministerio de Ciencia e Innovación grant RTI2018-099246-B-I00 (MICIU/AEI/FEDER, UE) to JMR, and grants PID2020-115217RB-100 and PID2021-122388OB-100 to MRC and JMR, respectively, funded by MCIN/AEI/10.13039/501100011033; Instituto de Salud Carlos III (CIBER-CV CB16/11/00264 and CB16/11/00479; and grants PI17/00381 to GT-T and PI21/00084 (co-funded by Fondo Europeo de Desarrollo Regional (FEDER)) to JFN); Fundacio La Marato TV3 (20151330 to JMR); Instituto de Investigación Sanitaria Marqués de Valdecilla (IDIVAL) (INNVAL 21/24) to JFN; The Marfan Foundation USA Faculty grant 2017 MRF/1701 (to JMR); Fundación MERCK-Fundación Española de Enfermedades Raras 2022 and V-Ayudas “Muévete por los que no pueden 2021” (to JO); and Spanish Ministerio de Ciencia e Innovación contracts FPI (BES-2016-077649) to MJR-R; Sara Borrell (CD18/00028) and Juan de la Cierva (IJC2020-044581-I) to MT; Ramón y Cajal (RYC2021-033343-I) to JO; and FPU (20/04814) to IA-R

Systematics of the Oswaldoi Complex (Anopheles, Nyssorhynchus) in South America

Abstract Background Effective malaria control relies on accurate identification of those Anopheles mosquitoes responsible for the transmission of Plasmodium parasites. Anopheles oswaldoi s.l. has been incriminated as a malaria vector in Colombia and some localities in Brazil, but not ubiquitously throughout its Neotropical range. This evidence together with variable morphological characters and genetic differences supports that An. oswaldoi s.l. compromises a species complex. The recent fully integrated redescription of An. oswaldoi s.s. provides a solid taxonomic foundation from which to molecularly determine other members of the complex.\ud \ud \ud \ud Methods\ud DNA sequences of the Second Internal Transcribed Spacer (ITS2 - rDNA) (n = 192) and the barcoding region of the Cytochrome Oxidase I gene (COI - mtDNA) (n = 110) were generated from 255 specimens of An. oswaldoi s.l. from 33 localities: Brazil (8 localities, including the lectotype series of An. oswaldoi), Ecuador (4), Colombia (17), Trinidad and Tobago (1), and Peru (3). COI sequences were analyzed employing the Kimura-two-parameter model (K2P), Bayesian analysis (MrBayes), Mixed Yule-Coalescent model (MYC, for delimitation of clusters) and TCS genealogies. Results\ud Separate and combined analysis of the COI and ITS2 data sets unequivocally supported four separate species: two previously determined (An. oswaldoi s.s. and An. oswaldoi B) and two newly designated species in the Oswaldoi Complex (An. oswaldoi A and An. sp. nr. konderi). The COI intra- and inter-specific genetic distances for the four taxa were non-overlapping, averaging 0.012 (0.007 to 0.020) and 0.052 (0.038 to 0.064), respectively. The concurring four clusters delineated by MrBayes and MYC, and four independent TCS networks, strongly confirmed their separate species status. In addition, An. konderi of Sallum should be regarded as unique with respect to the above. Despite initially being included as an outgroup taxon, this species falls well within the examined taxa, suggesting a combined analysis of these taxa would be most appropriate. Conclusions: Through novel data and retrospective comparison of available COI and ITS2 DNA sequences, evidence is shown to support the separate species status of An. oswaldoi s.s., An. oswaldoi A and An. oswaldoi B, and at least two species in the closely related An. konderi complex (An. sp. nr. konderi, An. konderi of Sallum). Although An. oswaldoi s.s. has never been implicated in malaria transmission, An. oswaldoi B is a confirmed vector and the new species An. oswaldoi A and An. sp. nr. konderi are circumstantially implicated, most likely acting as secondary vectors.This study formed part of the PhD study of FRL conducted at the Natural History Museum, London, and awarded from Canterbury Christ Church University, Canterbury, Kent, U.K. This investigation received financial support from the UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) (grant A50252 to YML), Canterbury Christ Church University (studentship to FRL). Additional funding was obtained through the Friends of the Natural History Museum, London to further the activities of the Mosquito Barcoding Initiative (to YML); the Consortium for the Barcode of Life (CBOL) (to YML and RCW) and the Sloane Foundation (to YML and RCW); the National Institute of Health (NIH), USA (grant 2R01AI054139 to Jan E. Conn) and COLCIENCIAS (grant 110134319196 to MLQ). We thank Dr. A. Papadopoulou for help with the MYC analysis and Dr. S. Mahamdallie for helpful suggestions and discussions during preparation of the manuscript.This manuscript was prepared in part whilst YML held a National Research Council Senior Research Associateship Award at the Walter Reed Army Institute of Research. This research was performed in part under a Memorandum of Understanding between the Walter Reed Army Institute of Research and the Smithsonian Institution, with institutional support provided by both organizations. The material to be published reflects the views of the authors and should not be construed to represent those of the Department of the Army or the Department of Defense

Electric dipole moments and the search for new physics

Static electric dipole moments of nondegenerate systems probe mass scales for physics beyond the Standard Model well beyond those reached directly at high energy colliders. Discrimination between different physics models, however, requires complementary searches in atomic-molecular-and-optical, nuclear and particle physics. In this report, we discuss the current status and prospects in the near future for a compelling suite of such experiments, along with developments needed in the encompassing theoretical framework.Comment: Contribution to Snowmass 2021; updated with community edits and endorsement

Advancements in synthetic biology-based bacterial cancer therapy: A modular design approach.

Synthetic biology aims to program living bacteria cells with artificial genetic circuits for user-defined functions, transforming them into powerful tools with numerous applications in various fields, including oncology. Cancer treatments have serious side effects on patients due to the systemic action of the drugs involved. To address this, new systems that provide localized antitumoral action while minimizing damage to healthy tissues are required. Bacteria, often considered pathogenic agents, have been used as cancer treatments since the early 20th century. Advances in genetic engineering, synthetic biology, microbiology, and oncology have improved bacterial therapies, making them safer and more effective. Here we propose six modules for a successful synthetic biology-based bacterial cancer therapy, the modules include Payload, Release, Tumor-targeting, Biocontainment, Memory, and Genetic Circuit Stability Module. These will ensure antitumor activity, safety for the environment and patient, prevent bacterial colonization, maintain cell stability, and prevent loss or defunctionalization of the genetic circuit.This research was funded by MCIN/AEI/10.13039/501100011033 Grant numbers PID2020-117271RB-C21 and TED2021-131049B-I00, Generalitat Valenciana GVA Grant CIAICO/2021/159, Centro de Investigacion ´ Biom´edica en Red de Cancer ´ (CIBERONC) Grant CB16-12- 00350, Instituto de Salud Carlos III (Grant PI22/01221), and GVA Grant AICO/2021/333. A Arboleda-García thanks the Grant PAID-01–21 Programa de Ayudas de Investigacion ´ y Desarrollo from Universitat Polit`ecnica de Val`encia, Spain. I Alarcon-Ruiz thanks the FPU grant (FPU20/04814) from the Spanish Government. L Boada-Acosta thanks the Grant Santiago Grisolía GRISOLIAP/2021/030 from Conselleria de Innovacion, ´ Universidades, Ciencia y Sociedad Digital and Generalitat Valenciana, Spain. Y Boada is thankful for the Grant PAID-10-21 Acceso al Sistema Espanol ˜ de Ciencia e Innovacion ´ from Universitat Polit`ecnica de Val`encia, Spain; and the Scholarship Convocatoria Abierta 2011 from Secretaría de Educacion ´ Superior, Ciencia, Tecnología e Innovacion, ´ Ecuador. The authors are grateful to Prof. Jesús Pico ´ for his guidance during the preparation of this manuscript. BioRender was used to illustrate the figures under a paid license for publication authorization.S

Systematics of the Oswaldoi Complex (Anopheles, Nyssorhynchus) in South America

Abstract Background Effective malaria control relies on accurate identification of those Anopheles mosquitoes responsible for the transmission of Plasmodium parasites. Anopheles oswaldoi s.l. has been incriminated as a malaria vector in Colombia and some localities in Brazil, but not ubiquitously throughout its Neotropical range. This evidence together with variable morphological characters and genetic differences supports that An. oswaldoi s.l. compromises a species complex. The recent fully integrated redescription of An. oswaldoi s.s. provides a solid taxonomic foundation from which to molecularly determine other members of the complex. Methods DNA sequences of the Second Internal Transcribed Spacer (ITS2 - rDNA) (n = 192) and the barcoding region of the Cytochrome Oxidase I gene (COI - mtDNA) (n = 110) were generated from 255 specimens of An. oswaldoi s.l. from 33 localities: Brazil (8 localities, including the lectotype series of An. oswaldoi), Ecuador (4), Colombia (17), Trinidad and Tobago (1), and Peru (3). COI sequences were analyzed employing the Kimura-two-parameter model (K2P), Bayesian analysis (MrBayes), Mixed Yule-Coalescent model (MYC, for delimitation of clusters) and TCS genealogies. Results Separate and combined analysis of the COI and ITS2 data sets unequivocally supported four separate species: two previously determined (An. oswaldoi s.s. and An. oswaldoi B) and two newly designated species in the Oswaldoi Complex (An. oswaldoi A and An. sp. nr. konderi). The COI intra- and inter-specific genetic distances for the four taxa were non-overlapping, averaging 0.012 (0.007 to 0.020) and 0.052 (0.038 to 0.064), respectively. The concurring four clusters delineated by MrBayes and MYC, and four independent TCS networks, strongly confirmed their separate species status. In addition, An. konderi of Sallum should be regarded as unique with respect to the above. Despite initially being included as an outgroup taxon, this species falls well within the examined taxa, suggesting a combined analysis of these taxa would be most appropriate. Conclusions Through novel data and retrospective comparison of available COI and ITS2 DNA sequences, evidence is shown to support the separate species status of An. oswaldoi s.s., An. oswaldoi A and An. oswaldoi B, and at least two species in the closely related An. konderi complex (An. sp. nr. konderi, An. konderi of Sallum). Although An. oswaldoi s.s. has never been implicated in malaria transmission, An. oswaldoi B is a confirmed vector and the new species An. oswaldoi A and An. sp. nr. konderi are circumstantially implicated, most likely acting as secondary vectors

International prevalence and risk factors evaluation for drug-resistant Streptococcus pneumoniae pneumonia

Objective: Streptococcus pneumoniae is the most frequent bacterial pathogen isolated in subjects with Community-acquired pneumonia (CAP) worldwide. Limited data are available regarding the current global burden and risk factors associated with drug-resistant Streptococcus pneumoniae (DRSP) in CAP subjects. We assessed the multinational prevalence and risk factors for DRSP-CAP in a multinational point-prevalence study. Design: The prevalence of DRSP-CAP was assessed by identification of DRSP in blood or respiratory samples among adults hospitalized with CAP in 54 countries. Prevalence and risk factors were compared among subjects that had microbiological testing and antibiotic susceptibility data. Multivariate logistic regressions were used to identify risk factors independently associated with DRSP-CAP. Results: 3,193 subjects were included in the study. The global prevalence of DRSP-CAP was 1.3% and continental prevalence rates were 7.0% in Africa, 1.2% in Asia, and 1.0% in South America, Europe, and North America, respectively. Macrolide resistance was most frequently identified in subjects with DRSP-CAP (0.6%) followed by penicillin resistance (0.5%). Subjects in Africa were more likely to have DRSP-CAP (OR: 7.6; 95% CI: 3.34-15.35, p < 0.001) when compared to centres representing other continents. Conclusions: This multinational point-prevalence study found a low global prevalence of DRSP-CAP that may impact guideline development and antimicrobial policies. Published by Elsevier Ltd on behalf of The British Infection Association

In COVID-19 health messaging, loss framing increases anxiety with little-to-no concomitant benefits: Experimental evidence from 84 countries

The COVID-19 pandemic (and its aftermath) highlights a critical need to communicate health information effectively to the global public. Given that subtle differences in information framing can have meaningful effects on behavior, behavioral science research highlights a pressing question: Is it more effective to frame COVID-19 health messages in terms of potential losses (e.g., “If you do not practice these steps, you can endanger yourself and others”) or potential gains (e.g., “If you practice these steps, you can protect yourself and others”)? Collecting data in 48 languages from 15,929 participants in 84 countries, we experimentally tested the effects of message framing on COVID-19-related judgments, intentions, and feelings. Loss- (vs. gain-) framed messages increased self-reported anxiety among participants cross-nationally with little-to-no impact on policy attitudes, behavioral intentions, or information seeking relevant to pandemic risks. These results were consistent across 84 countries, three variations of the message framing wording, and 560 data processing and analytic choices. Thus, results provide an empirical answer to a global communication question and highlight the emotional toll of loss-framed messages. Critically, this work demonstrates the importance of considering unintended affective consequences when evaluating nudge-style interventions