High-Resolution Structures and Orientations of Antimicrobial Peptides Piscidin 1 and Piscidin 3 in Fluid Bilayers Reveal Tilting, Kinking, and Bilayer Immersion

While antimicrobial peptides (AMPs) have been widely investigated as potential therapeutics, high-resolution structures obtained under biologically relevant conditions are lacking. Here, the high-resolution structures of the homologous 22-residue long AMPs piscidin 1 (p1) and piscidin 3 (p3) are determined in fluid-phase 3:1 phosphatidylcholine/phosphatidylglycerol (PC/PG) and 1:1 phosphatidylethanolamine/phosphatidylglycerol (PE/PG) bilayers to identify molecular features important for membrane destabilization in bacterial cell membrane mimics. Structural refinement of 1H–15N dipolar couplings and 15N chemical shifts measured by oriented sample solid-state NMR and all-atom molecular dynamics (MD) simulations provide structural and orientational information of high precision and accuracy about these interfacially bound α-helical peptides. The tilt of the helical axis, τ, is between 83° and 93° with respect to the bilayer normal for all systems and analysis methods. The average azimuthal rotation, ρ, is 235°, which results in burial of hydrophobic residues in the bilayer. The refined NMR and MD structures reveal a slight kink at G13 that delineates two helical segments characterized by a small difference in their τ angles (<10°) and significant difference in their ρ angles (∼25°). Remarkably, the kink, at the end of a G(X)4G motif highly conserved among members of the piscidin family, allows p1 and p3 to adopt ρ angles that maximize their hydrophobic moments. Two structural features differentiate the more potent p1 from p3: p1 has a larger ρ angle and less N-terminal fraying. The peptides have comparable depths of insertion in PC/PG, but p3 is 1.2 Å more deeply inserted than p1 in PE/PG. In contrast to the ideal α-helical structures typically assumed in mechanistic models of AMPs, p1 and p3 adopt disrupted α-helical backbones that correct for differences in the amphipathicity of their N- and C-ends, and their centers of mass lie ∼1.2–3.6 Å below the plane defined by the C2 atoms of the lipid acyl chains

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Millennial landscape and tourist development in China. The case of the Hani rice terraces in Yunnan

Between 1995 and 2015, I conducted fieldwork in a rice-growing village in southwest China as an artist-researcher. In this text, I examine the profound changes taking place in rural border areas inhabited by non-Han minorities, and particularly those of the Hani in the Yunnan Red River Valley. What future is there for the Hani ancestral model of irrigated rice terraces, and what are the stakes? My work combines a sensitive approach through diverse artistic representations of landscapes – from classical Chinese art to the works of contemporary artists, including mine – and examines landscape planning and patrimonial policies. The conservation stakes are not only environmental – biodiversity, sustainable development – but also identity-based through vernacular and minority cultures. I will point out the limits of this landscape planning and outline its future

Desarrollo turístico y paisaje milenario en China. El caso de las terrazas de los Hani en Yunnan

En base a unos trabajos de campo desarrollados entre 1995 y 2015 en un pueblo de arroceros en el suroeste de China como artista-investigador, examino en este texto los cambios profundos que afectan a los territorios fronterizos rurales habitados por las minorías nacionales no-Han y, en particular, la de los Hani en el valle del río Rojo en Yunnan. ¿Cuál es el futuro para su modelo ancestral de cultivo del arroz en terrazas y cuáles son los retos a los que debe hacer frente? Mi trabajo toma un enfoque sensible a través de la fotografía, el paisaje pintado, hasta las obras de artistas chinos de arte contemporáneo, y examina las políticas patrimoniales de planificación del paisaje. Los retos de la preservación no son sólo medioambientales -biodiversidad, desarrollo sostenible-, son también identitarios -culturas vernaculares y minoritarias. Señalaré los límites y expondré el futuro

Desenvolupament turístic i paisatge mil·lenari a la Xina. El cas de les terrasses dels Hani a Yunnan

En base a uns treballs de camp desenvolupats entre 1995 i 2015 en un poble d’arrossaires al sud-oest de la Xina com a artista-investigador, examino en aquest text els canvis profunds que afecten els territoris fronterers rurals habitats per les minories nacionals no-Han i, en particular, la dels Hani a la vall del riu Vermell a Yunnan. Quin és el futur per al seu model ancestral de cultiu de l’arròs en terrasses i quins són els reptes als quals ha de fer front? El meu treball pren un enfocament sensible a través de la fotografia, el paisatge pintat, fins a les obres d’artistes xinesos d’art contemporani, i examina les polítiques patrimonials de planificació del paisatge. Els reptes de la preservació no són només mediambientals -biodiversitat, desenvolupament sostenible-, són també identitaris -cultures vernaculars i minoritàries. Assenyalaré els límits i exposaré el futur

Paysage millénaire et développement touristique en Chine. Le cas des rizières en terrasses des Hani du Yunnan

Suite à un travail de terrain entre 1995 et 2015, dans un village de riziculteurs du Sud-Ouest de la Chine, en tant qu’artiste-chercheuse, j’examine dans ce texte les profondes mutations qui traversent les territoires frontaliers ruraux habités par les minorités nationales non-Han et en particulier ceux des Hani de la vallée du fleuve Rouge au Yunnan. Quel devenir pour leur modèle ancestral de riziculture irriguée en terrasse et quels sont les enjeux auxquels ils font face ? Mon travail croise une approche sensible par la photographie, le paysage peint, jusqu’aux œuvres des artistes chinois de l’art contemporain, et examine les politiques patrimoniales d’aménagement du paysage. Les enjeux de la préservation ne sont pas seulement environnementaux - biodiversité, développement durable, ils sont identitaires - cultures vernaculaires et minoritaires. J’en pointerai les limites et esquisserai le devenir

The blockade of cannabinoid receptor type 1 : a new therapeutic perspective in chronic kidney disease

La modulation du système endocannabinoïde, en particulier le blocage de son récepteur de type 1 (CB1R), pourrait être un outil thérapeutique dans la prise en charge de la maladie rénale chronique (MRC). Notre hypothèse principale était que CB1R favorise la fibrogenèse rénale, indépendamment de sa cause. Son blocage, génétique ou pharmacologique, pourrait protéger le rein contre la progression de la MRC. Nous avons étayé notre hypothèse par une triple approche : translationnelle, expérimentale chez la souris et in vitro avec des lignées de cellules épithéliales tubulaires proximales et de myofibroblastes. Dans une étude translationnelle chez l’homme, nous avons montré que l’expression de CB1R augmentait fortement au cours de la dysfonction chronique de l’allogreffe et était corrélée avec la fibrose interstitielle 3 mois après la greffe. In vitro, le blocage pharmacologique de CB1R réduisait la synthèse de collagène par les cellules épithéliales tubulaires. Dans un modèle expérimental murin de MRC après ischémie-reperfusion (I/R-CKD), le blocage génétique global ou pharmacologique de CB1R prévenait la MRC et réduisait significativement la fibrose interstitielle. In vitro, l’inhibition pharmacologique de CB1R réduisait la synthèse de collagène par les myofibroblastes. De façon inattendue, la délétion de CB1R restreinte aux cellules tubulaires rénales aggravait la MRC dans l’I/R-CKD. L’effet protecteur du blocage global de CB1R est donc probablement lié à un effet prépondérant sur les myofibroblastes. Ainsi, le blocage pharmacologique de CB1R pourrait constituer un nouvel outil dans la prise en charge thérapeutique de la MRC, indépendamment de son origine.Some studies suggest that the cannabinoid receptor type 1 (CB1R) inhibition could be a new therapeutic toolbox in chronic kidney disease (CKD), especially in metabolic nephropathies. We aimed that CB1R promotes renal fibrogenesis, regardless of its cause. Its inhibition, genetic or pharmacological, could protect the kidney against the progression of CKD. We supported our hypothesis by a threefold approach: translational, experimental in mice and in vitro with culture cells of proximal tubular epithelial cells and myofibroblasts. Whereas CB1R expression was low in normal kidney grafts, it was highly expressed during chronic allograft dysfunction, especially in tubular cells. CB1R expression significantly increased early on after transplantation and correlated with renal fibrosis at M3. In vitro, we found that rimonabant, a CB1R antagonist, blunted collagen synthesis by tubular cells. We performed an experimental mouse model of CKD induced by ischemia-reperfusion (I/R-CKD). In this model, the global genetic or pharmacological inhibition of CB1R prevented CKD and significantly reduced interstitial fibrosis. In vitro, pharmacological inhibition of CB1R reduced collagen synthesis by myofibroblasts. Unexpectedly, the deletion of CB1R restricted to renal tubular cells worsened CKD in I/R-CKD. The protective effect of the global inhibition of CB1R is therefore probably mediated by a predominant effect on myofibroblasts.Thus, we demonstrated that the pharmacological blockade of CB1R could be a new therapeutic toolbox in CKD, regardless of its origin

Cannabinoid Receptor 1 Inhibition in Chronic Kidney Disease: A New Therapeutic Toolbox

International audienceChronic kidney disease (CKD) concerns millions of individuals worldwide, with few therapeutic strategies available to date. Recent evidence suggests that the endocannabinoid system (ECS) could be a new therapeutic target to prevent CKD. ECS combines receptors, cannabinoid receptor type 1 (CB1R) and type 2 (CB2R), and ligands. The most prominent receptor within the kidney is CB1R, its endogenous local ligands being anandamide and 2-arachidonoylglycerol. Therefore, the present review focuses on the therapeutic potential of CB1R and not CB2R. In the normal kidney, CB1R is expressed in many cell types, especially in the vasculature where it contributes to the regulation of renal hemodynamics. CB1R could also participate to water and sodium balance and to blood pressure regulation but its precise role remains to decipher. CB1R promotes renal fibrosis in both metabolic and non-metabolic nephropathies. In metabolic syndrome, obesity and diabetes, CB1R inhibition not only improves metabolic parameters, but also exerts a direct role in preventing renal fibrosis. In non-metabolic nephropathies, its inhibition reduces the development of renal fibrosis. There is a growing interest of the industry to develop new CB1R antagonists without central nervous side-effects. Experimental data on renal fibrosis are encouraging and some molecules are currently under early-stage clinical phases (phases I and IIa studies). In the present review, we will first describe the role of the endocannabinoid receptors, especially CB1R, in renal physiology. We will next explore the role of endocannabinoid receptors in both metabolic and non-metabolic CKD and renal fibrosis. Finally, we will discuss the therapeutic potential of CB1R inhibition using the new pharmacological approaches. Overall, the new pharmacological blockers of CB1R could provide an additional therapeutic toolbox in the management of CKD and renal fibrosis from both metabolic and non-metabolic origin