Striatal Proteomic Analysis Suggests that First L-Dopa Dose Equates to Chronic Exposure

L-3,4-dihydroxypheylalanine (L-dopa)-induced dyskinesia represent a debilitating complication of therapy for Parkinson's disease (PD) that result from a progressive sensitization through repeated L-dopa exposures. The MPTP macaque model was used to study the proteome in dopamine-depleted striatum with and without subsequent acute and chronic L-dopa treatment using two-dimensional difference in-gel electrophoresis (2D-DIGE) and mass spectrometry. The present data suggest that the dopamine-depleted striatum is so sensitive to de novo L-dopa treatment that the first ever administration alone would be able (i) to induce rapid post-translational modification-based proteomic changes that are specific to this first exposure and (ii), possibly, lead to irreversible protein level changes that would be not further modified by chronic L-dopa treatment. The apparent equivalence between first and chronic L-dopa administration suggests that priming would be the direct consequence of dopamine loss, the first L-dopa administrations only exacerbating the sensitization process but not inducing it

Revisiting the Effects of Gender Diversity in Small Groups on Divergent Thinking: A Large-Scale Study Using Synchronous Electronic Brainstorming

Numerous studies have examined the effects of gender diversity in groups on creative performance, and no clear effect has been identified. Findings depend on situational cues making gender diversity more or less salient in groups. A large-scale study on two cohorts (N = 2,261) was conducted among business students to examine the impact of the gender diversity in small groups on divergent thinking in an idea-generation task performed by synchronous electronic brainstorming. Participants were automatically randomized in three- or four-member groups to generate ideas during 10 min on a gendered or neutral task. Then, five categories of groups where the proportion of men/women in groups varied from three/four men to three/four women were compared to examine creative performance on three divergent thinking measures (fluency, flexibility, and originality). A Multivariate Generalized Linear Mixed Model (mGLMM) showed greater fluency in all-women groups than in other groups (except mixed-gender groups composed of two men and two women), and more specifically “solo” groups composed of a single woman/man among a majority of men/women. For flexibility and originality, the superiority of all-women groups was found only in comparison to “solo” groups composed of a single woman. As gender differences are more salient in “solo” groups than in other groups faultlines may appear in groups, leading to a deleterious impact on creative performance

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Ratiometric luminescence detection of copper(I) by a resonant system comprising two antenna/lanthanide pairs

International audienceSelective and sensitive detection of Cu(I) is an ongoing challenge due to its important role in biological systems, for example. Herein, we describe a photoluminescent molecular chemosensor integrating two lanthanide ions (Tb$^{3+}$ and Eu$^{3+}$) and respective tryptophan and naphthalene antennas onto a polypeptide backbone. The latter was structurally inspired from copper-regulating biomacromolecules in Gram-negative bacteria and was found to bind Cu$^+$ effectively under pseudobiological conditions (log K$_{Cu}$$^+$ = 9.7 ± 0.2). Ion regulated modulation of lanthanide luminescence in terms of intensity and long, millisecond lifetime offers perspectives in terms of ratiometric and time-gated detection of Cu$^+$. The role of the bound ion in determining the photophysical properties is discussed with the aid of additional model compounds

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

Impact of Multimeric Ferrocene‐containing Cyclodecapeptide Scaffold on Host‐Guest Interactions at a β‐Cyclodextrin Covered Surface

International audienceAmong non-covalent bonds, the host-guest interaction is an attractive way to attach biomolecules to solid surfaces since the binding strength can be tuned by the nature of host and guest partners or through the valency of the interaction. For that purpose, we synthesized cyclodecapeptide scaffolds exhibiting in a spatially controlled manner two independent domains enabling the multimeric presentation of guest molecules on one face and the other face enabling the potential grafting of a biomolecule of interest. In this work, we were interested in the β-cyclodextrin/ferrocene inclusion complex formed on β-CD monolayers functionalized surfaces. By using surface sensitive techniques such as quartz crystal microbalance and surface plasmon resonance, we quantified the influence of the guest valency on the stability of the inclusion complexes. The results show a drastic enhancement of the affinity with the gradual increase of guest valency. Considering that the sequential binding events are equal and independent, we applied the multivalent model developed by the Huskens group to extract intrinsic binding constants and an effective concentration of host

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