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Abstract Background Extrapolation of human absorbed doses (ADs) from biodistribution experiments on laboratory animals is used to predict the efficacy and toxicity profiles of new radiopharmaceuticals. Comparative studies between available animal-to-human dosimetry extrapolation methods are missing. We compared five computational methods for mice-to-human AD extrapolations, using two different radiopharmaceuticals, namely [111In]CHX-DTPA-scFv78-Fc and [68Ga]NODAGA-RGDyK. Human organ-specific time-integrated activity coefficients (TIACs) were derived from biodistribution studies previously conducted in our centre. The five computational methods adopted are based on simple direct application of mice TIACs to human organs (M1), relative mass scaling (M2), metabolic time scaling (M3), combined mass and time scaling (M4), and organ-specific allometric scaling (M5), respectively. For [68Ga]NODAGA-RGDyK, these methods for mice-to-human extrapolations were tested against the ADs obtained on patients, previously published by our group. Lastly, an average [68Ga]NODAGA-RGDyK-specific allometric parameter αnew was calculated from the organ-specific biological half-lives in mouse and humans and retrospectively applied to M3 and M4 to assess differences in human AD predictions with the α = 0.25 recommended by previous studies. Results For both radiopharmaceuticals, the five extrapolation methods showed significantly different AD results (p

In response to the current worldwide amphibian extinction crisis, conservation instances have encouraged the establishment of ex-situ collections for endangered species. The resulting assurance populations are managed under strict biosecure protocols, often involving artificial cycles of temperature and humidity to induce active and overwintering phases, which likely affect the bacterial symbionts living on the amphibian skin. However, the skin microbiota is an important first line of defense against pathogens that can cause amphibian declines, such as the chytrid Batrachochytrium dendrobatidis (Bd). Determining whether current husbandry practices for assurance populations might deplete amphibians from their symbionts is therefore essential to conservation success. Here, we characterize the effect of the transitions from the wild to captivity, and between aquatic and overwintering phases, on the skin microbiota of two newt species. While our results confirm differential selectivity of skin microbiota between species, they underscore that captivity and phase-shifts similarly affect their community structure. More specifically, the translocation ex-situ is associated with rapid impoverishment, decrease in alpha diversity and strong species turnover of bacterial communities. Shifts between active and overwintering phases also cause changes in the diversity and composition of the microbiota, and on the prevalence of Bd-inhibitory phylotypes. Altogether, our results suggest that current husbandry practices strongly restructure the amphibian skin microbiota. Although it remains to be determined whether these changes are reversible or have deleterious effects on their hosts, we discuss methods to limit microbial diversity loss ex-situ and emphasize the importance of integrating bacterial communities to applied amphibian conservation.

Abstract Background The role played by large-scale repetitive SARS-CoV-2 screening programs within university populations interacting continuously with an urban environment, is unknown. Our objective was to develop a model capable of predicting the dispersion of viral contamination among university populations dividing their time between social and academic environments. Methods Data was collected through real, large-scale testing developed at the University of Liège, Belgium, during the period Sept. 28th-Oct. 29th 2020. The screening, offered to students and staff (n = 30,000), began 2 weeks after the re-opening of the campus but had to be halted after 5 weeks due to an imposed general lockdown. The data was then used to feed a two-population model (University + surrounding environment) implementing a generalized susceptible-exposed-infected-removed compartmental modeling framework. Results The considered two-population model was sufficiently versatile to capture the known dynamics of the pandemic. The reproduction number was estimated to be significantly larger on campus than in the urban population, with a net difference of 0.5 in the most severe conditions. The low adhesion rate for screening (22.6% on average) and the large reproduction number meant the pandemic could not be contained. However, the weekly screening could have prevented 1393 cases (i.e. 4.6% of the university population; 95% CI: 4.4–4.8%) compared to a modeled situation without testing. Conclusion In a real life setting in a University campus, periodic screening could contribute to limiting the SARS-CoV-2 pandemic cycle but is highly dependent on its environment.

Fish introduction into fishless high-altitude lakes has detrimental effects on biodiversity. Removal of alien fish through intensive fishing is cost-intensive and difficult to achieve in productive lakes. Lake Sulzkarsee is the only lake in the National Park Gesäuse, Austria, and was an important breeding site for amphibians until the lake was stocked with fish in the late 1970s. Salmonids were eradicated in 2005, but the lake remained degraded by the introduced minnows (Phoxinus sp.). In 2018, the lake was drained through a siphon pipe and then by pumping out water with dirt water pumps. The deepest part was treated with slaked lime, but several hundred adult minnows survived in sediment crevices and reproduced in the following season. After drainage, the phytoplankton biomass increased. Indicator species, such as Daphnia longispina and amphibians, showed signs of recovery, but they went back to an impacted state when minnows recovered after the failed eradication attempt. Purse seines proved to be the most efficient gear to catch minnows. These results indicate that deep mountain lakes are difficult to drain efficiently. Sediment treatment is required to eliminate all fish.

The 6th century Codex Sinopensis or Sinope Gospels (Paris, Bibliothèque nationale de France) is one of the most precious purple codices that survive from the Late Antique period. Together with the Vienna Genesis (Wien, Österreichische Nationalbibliothek) and the Rossano Gospels (Rossano Calabro, Museo Diocesano), it has an unusually rich decorative apparatus with scenes representing biblical episodes. It can be, therefore, considered one of the most important preserved artistic productions of the early medieval era. The manuscript has been subjected to a non-invasive diagnostic campaign to evaluate the quality of the colourants used in its decoration, to understand how the parchment was coloured, and to carry out a comparison with the Vienna Genesis and the Rossano Gospels. The techniques used were UV-visible diffuse reflectance spectrophotometry with optical fibres (FORS), X-ray fluorescence spectrometry (XRF), spectrofluorimetry, and optical microscopy. Analyses highlighted the presence of ultramarine blue, which, besides the use of pure gold for the ink and paint, certifies the high value of the manuscript. In addition, this must be seen as one of the earliest examples of its use in paintings. The purple colour of the parchment was identified as orchil, a dye extracted from lichens, similar to the results of analytical investigations carried out on other purple codices, and not the expected Tyrian purple dye.

Abstract Background In species with complex life cycles, size at metamorphosis is a key life-history trait which reflects the complex interactions between costs and benefits of life in the aquatic and terrestrial environments. Whereas the effects of a deteriorating larval habitat (e.g. pond desiccation) on triggering an early metamorphosis have been extensively investigated in amphibians, the consequences of the resulting reduced size at metamorphosis on fitness in the post-metamorphic terrestrial stage remain poorly understood. We tested the hypothesis that a smaller size at metamorphosis negatively affects performance and survival in the ensuing terrestrial stage. Using as model a tropical amphibian (Ceratophrys stolzmanni) showing a large phenotypic plasticity in metamorphosing traits, we evaluated the effects of size at metamorphosis on fitness-related trophic and locomotor performance traits, as well as on growth and survival rates. Results Our results support the hypothesis that a larger size at metamorphosis is correlated with better survival and performance. The survival rate of large metamorphosing individuals was 95%, compared to 60% for those completing metamorphosis at a small size. Locomotor performance and gape size were positively correlated with body size, larger animals being more mobile and capable to ingest larger prey. However, smaller individuals achieved higher growth rates, thus reducing the size gap. Conclusions Overall, size at metamorphosis affected profoundly the chances of survival in the short term, but smaller surviving individuals partly compensated their initial disadvantages by increasing growth rates.

Platelet-rich plasma (PRP) is increasingly used in the treatment of musculoskeletal diseases. Its preservation by freezing it for the realization of multiple injections in clinical use has never been discussed. Calcaneal tendons of rats were surgically sectioned. Platelet concentration of the PRP was 2.5 x 106/µl with autologous plasma of rats. Frozen-thawed PRP was prepared by performing two cycles of freezing and thawing on PRP aliquots. Both platelet preparations were injected in the lesion. Biomechanical and histological evaluations were carried out after 7, 20 or 40 days post surgery. After 7 and 40 days, no significant difference was observed between the PRP and the frozen-thawed PRP group. There is however a difference 20 days after surgery: the ultimate tensile strength (UTS) was greater in the fresh PRP group. No obvious difference with histological aspect was observed between the two groups. In conclusion, fresh PRP and frozen-thawed PRP injections can lead to similar results in the healing process of section calcaneal tendons of rats. Improvements with fresh PRP are slight. PRP could thus be frozen to be preserved if multiple injections are needed (e.g. osteoarthritis).

The genomic era contributes to update the taxonomy of many debated terrestrial vertebrates. In an accompanying work, we provided a comprehensive molecular assessment of spadefoot toads (Pelobates) using genomic data. Our results call for taxonomic updates in this group. First, nuclear phylogenomics confirmed the species-level divergence between the Iberian P. cultripes and its Moroccan relative P. varaldii. Second, we inferred that P. fuscus and P. vespertinus, considered subspecies until recently, feature partial reproductive isolation and thus deserve a specific level. Third, we evidenced cryptic speciation and diversification among deeply diverged lineages collectively known as Pelobates syriacus. Populations from the Near East correspond to the Eastern spadefoot toad P. syriacus sensu stricto, which is represented by two subspecies, one in the Levant (P. s. syriacus) and the other in the rest of the range (P. s. boettgeri). Populations from southeastern Europe correspond to the Balkan spadefoot toad, P. balcanicus. Based on genetic evidence, this species is also polytypic: the nominal P. b. balcanicus inhabits the Balkan Peninsula; a new subspecies P. b. chloeae ssp. nov. appears endemic to the Peloponnese. In this paper, we provide an updated overview of the taxonomy and distribution of all extant Pelobates taxa and describe P. b. chloeae ssp. nov.

Abstract Background Biodistribution studies based on organ harvesting represent the gold standard pre-clinical technique for dose extrapolations. However, sequential imaging is becoming increasingly popular as it allows the extraction of longitudinal data from single animals, and a direct correlation with deterministic radiation effects. We assessed the feasibility of mouse-specific, microPET-based dosimetry of an antibody fragment labeled with the positron emitter 152Tb [(T 1/2 = 17.5 h, Eβ+mean = 1140 keV (20.3%)]. Image-based absorbed dose estimates were compared with those obtained from the extrapolation to 152Tb of a classical biodistribution experiment using the same antibody fragment labeled with 111In. 152Tb was produced by proton-induced spallation in a tantalum target, followed by mass separation and cation exchange chromatography. The endosialin-targeting scFv78-Fc fusion protein was conjugated with the chelator p-SCN-Bn-CHX-A”-DTPA, followed by labeling with either 152Tb or 111In. Micro-PET images of four immunodeficient female mice bearing RD-ES tumor xenografts were acquired 4, 24, and 48 h after the i.v. injection of 152Tb-CHX-DTPA-scFv78-Fc. After count/activity camera calibration, time-integrated activity coefficients (TIACs) were obtained for the following compartments: heart, lungs, liver, kidneys, intestines, tumor, and whole body, manually segmented on CT. For comparison, radiation dose estimates of 152Tb-CHX-DTPA-scFv78-Fc were extrapolated from mice dissected 4, 24, 48, and 96 h after the injection of 111In-CHX-DTPA-scFv78-Fc (3–5 mice per group). Imaging-derived and biodistribution-derived organ TIACs were used as input in the 25 g mouse model of OLINDA/EXM® 2.0, after appropriate mass rescaling. Tumor absorbed doses were obtained using the OLINDA2 sphere model. Finally, the relative percent difference (RD%) between absorbed doses obtained from imaging and biodistribution were calculated. Results RD% between microPET-based dosimetry and biodistribution-based dose extrapolations were + 12, − 14, and + 17 for the liver, the kidneys, and the tumors, respectively. Compared to biodistribution, the imaging method significantly overestimates the absorbed doses to the heart and the lungs (+ 89 and + 117% dose difference, respectively). Conclusions MicroPET-based dosimetry of 152Tb is feasible, and the comparison with organ harvesting resulted in acceptable dose discrepancies for body districts that can be segmented on CT. These encouraging results warrant additional validation using radiolabeled biomolecules with a different biodistribution pattern.

The Argentine province of San Juan is considered as an emblematic case given that the authorities’ speech underlines its character of “mining model province”. By analysing the reconfiguration of public and private agents’ system as well as the power relationships which develop in various scales, it seems that the local socio-spatial translations of the relations of dependence thus woven are the expression of political choices linked to the mining activity and the fragility of the model.

This essay addresses historiographical and methodological issues about the very beginnings of the scholarship on early medieval manuscript illumination during the eighteenth and nineteenth centuries. The enduring importance of Greek art and the development of national or ethnic approaches have profoundly shaped our appreciation and interpretation of early medieval illumination, and the latter is still relevant today. By putting into perspective the deep history of early medieval manuscript illumination studies, I seek to show how this area of research connects with other fields such as history or archaeology and why it occupied a long marginalized position within art historical scholarship.

Divergence in ecological niche offers organisms the opportunity of exploiting different food and habitat resources, scaling down competition and predation both among species, and within different age or size-classes of the same species. In harsh environments, where abiotic factors determine a clustering of resources during short timespans, competition and predation between organisms is likely to be enhanced. This is the case in tropical dry forests, where amphibians have limited opportunities to feed, their activity being restricted to the short rainy season. One way to maximize resource exploitation while avoiding predation risk is by adopting different diel activity patterns. We tested this hypothesis by comparing activity patterns in adults and recently metamorphosed juveniles of Pacific horned frogs (Ceratophrys stolzmanni) during field surveys and in an experimental study. Field surveys showed that the adults are strictly nocturnal, whereas freshly metamorphosed juveniles can be found active above ground at all hours, with a peak activity during daytime. The average body condition index of juveniles found active during the night was higher than that of juveniles found active during the day, suggesting that the weaker individuals may be constrained to being active during the day. On the other hand, in a laboratory experiment, juveniles that were visually exposed to adults moved less than those in the absence of adults. Both field and experimental observations indicate a temporal niche divergence between life stages. The results of the experiment offer support to the hypothesis that the juveniles in this species display an inverse activity pattern compared to adults, which can reduce competitive interactions and predation pressure from the larger conspecifics.

Abstract Comparing information from the ancient texts about the illumination of the manuscripts to the analysis of the components used to create colour in illuminations sheds interesting light. Our research team studied several manuscripts from the Carolingian era issued from different sources including: the Gospels of St Riquier kept in the library of Abbeville (ms. 4), two Theodulphe’s Bibles, (Orléans-Fleury, BnF lat.11937 and BnF lat.9380), the Godescalc Evangelistary (BnF NAL 1203), the Gospels of St Denis (BnF lat.9387) and the Gospels of St Médard de Soissons (BnF lat.8850), the last three from the court of Charlemagne, and all preserved at the French National Library. These most luxurious manuscripts were written and illuminated between the late eighth century and the first quarter of the ninth century. Through non-destructive portable visual and spectrometric analysis, our research team was able to identify the palette of materials used in scripts and illuminations and especially highlighted the amazing use of Egyptian blue in a very specific part of the illumination in the Godescalc Evangelistary. Our team also found that some substitutes including folium had been used instead of Tyrian purple for the decoration and to dye the parchment. These manuscripts, produced at the initiative of various patrons during Charlemagne’s reign, reveal in the light of the material analysis and the reconstitutions’ experiments by professional illuminators their differences and, beyond, the artistic diversity of this very particular period called the Carolingian Renaissance.

Anurans have been introduced in many parts of the world and have often become invasive over large geographic areas. Although predation is involved in the declines of invaded amphibian populations, there is a lack of quantitative assessments evaluating the potential risk posed to native species. This is particularly true for Pelophylax water frogs, which have invaded large parts of western Europe, but no studies to date have examined their predation on other amphibians in their invaded range. Predation of native amphibians by marsh frogs (Pelophylax ridibundus) was assessed by stomach flushing once a month over four months in 21 ponds in southern France. Nine percent of stomachs contained amphibians. Seasonality was a major determinant of amphibian consumption. This effect was mediated by body size, with the largest invaders ingesting bigger natives, such as tree frogs. These results show that invasive marsh frogs represent a threat through their ability to forage on natives, particularly at the adult stage. The results also indicate that large numbers of native amphibians are predated. More broadly, the fact that predation was site- and time-specific highlights the need for repeated samplings across habitats and key periods for a clear understanding of the impact of invaders.

Abstract The genetic era has revolutionized our perception of biological invasions. Yet, it is usually too late to understand their genesis for efficient management. Here, we take the rare opportunity to reconstruct the scenario of an uprising invasion of the famous water frogs (Pelophylax) in southern France, through a fine-scale genetic survey. We identified three different taxa over less than 200 km2: the autochthonous P. perezi, along with the alien P. ridibundus and P. kurtmuelleri, which have suddenly become invasive. As a consequence, the latter hybridizes and may now form a novel hybridogenetic complex with P. perezi, which could actively promote its replacement. This exceptional situation makes a textbook application of genetics to early-detect, monitor and understand the onset of biological invasions before they pose a continental-wide threat. It further emphasizes the alarming rate of amphibian translocations, both at global and local scales, as well as the outstanding invasive potential of Pelophylax aliens.

The use of protein antigens able to protect against the majority of Streptococcus pneumoniae serotypes is envisaged as stand-alone and/or complement to the current capsular polysaccharide-based pneumococcal vaccines. Pneumolysin (Ply) is a key virulence factor that is highly conserved in amino acid sequence across pneumococcal serotypes, and therefore may be considered as a vaccine target. However, native Ply cannot be used in vaccines due to its intrinsic cytolytic activity. In the present work a completely, irreversibly detoxified pneumolysin (dPly) has been generated using an optimized formaldehyde treatment. Detoxi-fication was confirmed by dPly challenge in mice and histological analysis of the injection site in rats. Immunization with dPly elicited Ply-specific functional antibodies that were able to inhibit Ply activity in a hemolysis assay. In addition, immunization with dPly protected mice against lethal intranasal challenge with Ply, and intranasal immunization inhibited nasopharyngeal colonization after intranasal challenge with homologous or heterologous pneumococcal strain. Our findings supported dPly as a valid candidate antigen for further pneumococcal vaccine development.

The Pyrenees represent a natural laboratory for biogeographic, evolutionary and ecological research of mountain fauna as a result of the high variety of habitats and the profound effect of the glacial and interglacial periods. There is a paucity of studies providing a detailed insight into genetic processes and better knowledge on the patterns of genetic diversity and how they are maintained under high altitude conditions. This is of particular interest when considering the course of past climate conditions and glaciations in a species which is considered site tenacious, with long generation times. Here we analyzed the genetic patterns of diversity and structure of the endemic Pyrenean brook newt (Calotriton asper) along its distribution range, with special emphasis on the distinct habitat types (caves, streams, and lakes), and the altitudinal and geographical ranges, using a total set of 900 individuals from 44 different localities across the Pyrenean mountain range genotyped for 19 microsatellite loci. We found evidence for a negative longitudinal and positive altitudinal gradient of genetic diversity in C. asper populations. The fact that genetic diversity was markedly higher westwards is in accordance with other Pyrenean species. However, the impact of altitudinal gradient on the genetic diversity seems to differ from other species, and mostly from other amphibians. We found that lower altitudes can act as a barrier probably because the lowlands do not provide a suitable habitat for C. asper. Regarding the distinct habitat types, caves had significantly lower values of genetic diversity compared to streams or lakes. The mean FST value was relatively high (0.304) with maximum values as high as 0.771, suggesting a highly structured total population. Indeed, populations were grouped into five subclusters, the eastern populations (cluster 1) remained grouped into two subclusters and the central-western Pyrenees (cluster 2) into three subclusters. The increase of isolation with geographical distance is consistent with the population structure detected. In conclusion, C. asper seems to be adapted to high altitude mountain habitats, and its genetic diversity is higher in the western Pyrenees. In terms of conservation priority, we consider more relevant the populations that represent a reservoir of genetic diversity.

Mycobacterium avium subsp. hominissuis (Mah) represents a health concern for humans and to a lesser extent for pigs, but its zoonotic potential remains elusive. Using multispacer sequence typing (MST) we previously identified 49 different genotypes of Mah among Belgian clinical and porcine isolates, with 5 MSTs shared by both hosts. Using experimental intranasal infection of BALB/c mice, we compared the virulence and immunogenicity of porcine and clinical human isolates with shared genotype or with a genotype only found in humans or pigs. Bacterial replication was monitored for 20 weeks in lungs, spleen and liver and mycobacteria specific spleen cell IFN-γ, IL-10 and IL-17 production as well as serum antibody responses were analyzed. Isolates varied in virulence, with human and porcine isolates sharing MST22 genotype showing a thousand fold higher bacterial replication in lungs and more dissemination to spleen and liver than the human and porcine MST91 isolates. Virulent MST22 type was also associated with progressive suppression of IFN-γ and IL-17 responses, and increased IL-10 production. Whole genome sequencing of the two virulent isolates with MST22 genotype and two avirulent isolates of genotype MST91 and comparison with two well-studied M. avium subsp. hominissuis reference strains i.e. Mah 104 and Mah TH135, identified in the two MST22 isolates nine specific virulence factors of the mammalian cell entry family, that were identical with Mah 104 strain. Despite the obvious limitations of the mouse model, a striking link of virulence and identity at the genome level of porcine and human isolates with the same multisequence type, for which no correlation of place of residence (humans) or farm of origin (pigs) was observed, seems to point to the existence in the environment of certain genotypes of Mah which may be more infectious both for humans and pigs than other genotypes.

Alternative reproductive strategies are widespread in caudate amphibians. Among them, fire salamanders (Salamandra salamandra) usually rely on streams to give birth to aquatic larvae but also use ponds, whereas palmate newt larvae (Lissotriton helveticus) typically metamorphose into terrestrial juveniles, but can also reproduce in retaining their gills, a process known as paedomorphosis. Here we report repeated observations of an unusual case of coexistence of these two alternative traits in the same pond (Larzac, France). The prevalence of fire salamanders in Southern Larzac was very low (pond occupancy: 0.36%). The observed abundance of fire salamander larvae and paedomorphic newts was also low in the studied pond. On one hand, the rarity of this coexistence pattern may suggest that habitat characteristics may not be optimal or that competition or predation processes might be operating. However, these hypotheses remain to be tested. On the other hand, as this is the only known case of breeding in Southern Larzac, it could be considered to be at a high risk of extirpation.

Several studies have reported underprescription of anticoagulants in atrial fibrillation (AF). We conducted an observational study on 142 out of a total of 995 consecutive ≥75 years old patients presenting AF (14%) when admitted in an emergency unit of a general hospital, in search of geriatric characteristics that might be associated with the underprescription of anticoagulation therapy (mostly antivitamin K at the time of the study). The following data was collected from patients presenting AF: medical history including treatment and comorbidities, CHADS2 score, ISAR scale (frailty), Lawton’s scale (ADL), GDS scale (mood status), MUST (nutrition), and blood analysis (INR, kidney function, and albumin). Among those patients for who anticoagulation treatment was recommended (73%), only 61% were treated with it. In the group with anticoagulation therapy, the following characteristics were observed more often than in the group without such therapy: a recent (≤6 months) hospitalization and medical treatment including digoxin or based on >3 different drugs. Neither the value of the CHADS2 score, nor the geriatric characteristics could be correlated with the presence or the absence of an anticoagulation therapy. More research is thus required to identify and clarify the relative importance of patient-, physician-, and health care system-related hurdles for the prescription of oral anticoagulation therapy in older patients with AF.

With the development of conjugate vaccines, Neisseria meningitidis serogroup B (MenB) will remain the major cause of meningitis, as it is not covered by vaccination. In order to develop a vaccine able to confer a broad cross-protection against invasive MenB strains, we have developed a new generation of outer-membrane vesicles (OMVs) based on the over-expression of well conserved minor outer membrane proteins (OMPs) and the presence of high percentage of detoxified LOS.