A novel DOTA-like building block with a picolinate arm for the synthesis of lanthanide complex-peptide conjugates with improved luminescence properties

International audienceCombination of complexes of trivalent lanthanide cations (Ln 3+) for their luminescent properties and peptides for their recognition properties or folding abilities is interesting in view of designing responsive luminescent probes. The octadentate DOTA chelate is the most popular chelate to design luminescent Ln 3+ complex-peptide conjugates. In this article, we describe a novel building block, DO3Apic-tris(allyl)ester, which provides access to peptides with a conjugated nonadentate chelate, namely DO3Apic, featuring a cyclen macrocycle functionalized by three acetate and one picolinamide arms, for improved luminescence properties. This building block, with allyl protecting groups, is readily obtained by solid phase synthesis. We show that it is superior to its analogue with tBu protecting groups for the preparation of peptide conjugates because of the difficult removal of the tBu protecting groups for the latter. Then, two Zn 2+-responsive luminescent probes, which rely on (i) a zinc finger scaffold for selective Zn 2+ binding, (ii) a Eu 3+ complex and (iii) an acridone antenna for long-wavelength sensitization of Eu 3+ luminescence, are compared. One of these probes, LZF3 ACD|Eu , incorporates a DOTA chelate whereas the other, LZF4 ACD|Eu , incorporates a DO3Apic chelate. We show that changing the octadentate DOTA for the nonadentate DO3Apic ligand results in a higher Eu 3+ luminescence lifetime and in a doubling of the quantum yield, confirming the interest of the DO3Apic chelate and the DO3Apic(tris(allyl)ester building block for the preparation of Ln 3+ complex-peptide conjugates. Additionally, the DO3Apic chelate provides self-calibration for LZF4 ACD|Eu luminescence upon excitation of its picolinamide chromophore, making LZF4 ACD|Eu a ratiometric sensor for Zn 2+ detection

Using Native Chemical Ligation for Site-specific Synthesis of Hetero- bis-lanthanide Peptide Conjugates: Application to Ratiometric Visible or Near-infrared Detection of Zn 2+

International audienceThe interest for ratiometric luminescent probes that detect and quantify a specific analyte is growing. Due to their special luminescence properties, lanthanide(III) cations offer attractive opportunities for the design of dual-color ratiometric probes. Here, we describe the design principle of hetero-bis-lanthanide peptide conjugates using native chemical ligation for a perfect control of the localization of each lanthanide cation within the molecule. Two zinc-responsive probes, r-LZF1 Tb|Cs124|Eu and r-LZF1 Eu|Cs124|Tb are described on the basis of a zinc finger peptide and two DOTA complexes of terbium and europium. Both display dual-color ratiometric emission responding to the presence of Zn 2+. Using a screening approach, anthracene was identified for the sensitization of the luminescence of two near infrared-emitting lanthanides, Yb 3+ and Nd 3+. Thus, two novel zinc-responsive hetero-bis-lanthanide probes, r-LZF3 Yb|Anthra|Nd and r-LZF3 Nd|Anthra|Yb were assembled, the former offering a neat ratiometric response to Zn 2+ with emission in the near-infrared around 1000 nm, which is unprecedented

Molecular prevalence of bovine noroviruses and neboviruses in newborn calves in Iran

International audienceIn this study, bovine enteric caliciviruses (BECs) were detected in 49.4% of a total of 253 stool specimens for diarrheic calves collected from 42 industrial dairy farms from March 2010 to February 2012. Genogroup III norovirus (NoVsGIII) were more prevalent (39.5%) than neboviruses (NBs) (15%), and coinfections were observed in 5.1% of the samples tested. Sequence analysis of the partial polymerase gene from 13 NoVsGIII samples indicated the circulation of both genotype 1 and genotype 2 strains. Among the six NB strains sequenced, five were related to the Bo/Nebraska/80/US strain, while one was related to the Bo/Newbury1/76/UK strai

The molecular epidemiology of bovine rotaviruses circulating in Iran: a two-year study

International audienceBovine group A rotavirus (bovine RVA) is recognized as a major cause of severe gastroenteritis in newborn calves. The purpose of this study was to estimate the prevalence and identify the genotypes of circulating bovine RVA in newborn diarrheic calves. Two hundred fifty-three stool samples of diarrheic calves up to 1 month old were collected from 42 industrial dairy farms in two Iranian provinces during March 2010 to February 2012. All collected samples were screened for the presence of bovine RVA by RT-PCR, and the G and P genotypes were determined by semi-nested multiplex RT-PCR assay. The results of RT-PCR indicated that 49.4 % (125 out of 253) of the samples were positive for bovine RVA. The G and P genotyping of a subset of positive samples (n = 85) by semi-nested multiplex RT-PCR revealed that G6 (55.3 %) and G10 (43.5 %) and P[5] (51.8 %) and P[11] (27 %) were the most prevalent G and P genotypes, respectively. G6P[5] was the dominant genotype (35.3 %), followed by G10P[5], G10P[11] and G6P[11], with prevalence rates of 16.5 %, 15.3 % and 10.6 %, respectively. Sequence analysis of 20 VP7 and four VP4 genes showed highest nucleotide sequence identity with the corresponding genes of strains RVA/Cow-tc/GBR/UK/1973/G6P7[5] and RVA/Cow-tc/USA/B223/XXXX/G10P[11]. The results of this study reveal the diversity of G and P genotypes in bovine RVA samples from diarrheic Iranian calves and expands our knowledge of bovine RVA infections in the Middle East. These results also highlight the importance of producing of an effective rotavirus vaccine and its inclusion in the national cattle immunization program

Type 1 Diabetes in People Hospitalized for COVID-19: New Insights From the CORONADO Study

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The association between macrovascular complications and intensive care admission, invasive mechanical ventilation, and mortality in people with diabetes hospitalized for coronavirus disease-2019 (COVID-19)

International audienceAbstract Background It is not clear whether pre-existing macrovascular complications (ischemic heart disease, stroke or peripheral artery disease) are associated with health outcomes in people with diabetes mellitus hospitalized for COVID-19. Methods We conducted cohort studies of adults with pre-existing diabetes hospitalized for COVID-19 infection in the UK, France, and Spain during the early phase of the pandemic (between March 2020—October 2020). Logistic regression models adjusted for demographic factors and other comorbidities were used to determine associations between previous macrovascular disease and relevant clinical outcomes: mortality, intensive care unit (ICU) admission and use of invasive mechanical ventilation (IMV) during the hospitalization. Output from individual logistic regression models for each cohort was combined in a meta-analysis. Results Complete data were available for 4,106 (60.4%) individuals. Of these, 1,652 (40.2%) had any prior macrovascular disease of whom 28.5% of patients died. Mortality was higher for people with compared to those without previous macrovascular disease (37.7% vs 22.4%). The combined crude odds ratio (OR) for previous macrovascular disease and mortality for all four cohorts was 2.12 (95% CI 1.83–2.45 with an I 2 of 60%, reduced after adjustments for age, sex, type of diabetes, hypertension, microvascular disease, ethnicity, and BMI to adjusted OR 1.53 [95% CI 1.29–1.81]) for the three cohorts. Further analysis revealed that ischemic heart disease and cerebrovascular disease were the main contributors of adverse outcomes. However, proportions of people admitted to ICU (adjOR 0.48 [95% CI 0.31–0.75], I 2 60%) and the use of IMV during hospitalization (adjOR 0.52 [95% CI 0.40–0.68], I 2 37%) were significantly lower for people with previous macrovascular disease. Conclusions This large multinational study of people with diabetes mellitus hospitalized for COVID-19 demonstrates that previous macrovascular disease is associated with higher mortality and lower proportions admitted to ICU and treated with IMV during hospitalization suggesting selective admission criteria. Our findings highlight the importance correctly assess the prognosis and intensive monitoring in this high-risk group of patients and emphasize the need to design specific public health programs aimed to prevent SARS-CoV-2 infection in this subgroup