Institute of Molecular Sciences

Ionic transition metal complexes (iTMCs) often suffer from low photoluminescence quantum yield, especially in the red to near‐infrared spectral region. Rational molecular design strategies unlock recovering the emission features efficiently. A potential solution is offered by bimetallic complexes, which are rapidly emerging as a valid and attractive class of emitters. In this work, the yet unexplored electrochemiluminescence (ECL) properties of a series of heterobimetallic complexes of general structure IrIII‐MI are investigated, where the formally neutral cyclometalated iridium complex provides efficient photo‐ and electro‐active properties to the molecular emitters. Whereas bulky MI (gold or copper) metalloligand increases structural rigidity and chemical stability of the architecture while enabling larger values for the radiative rate constant. The IrIII‐MI shows highly efficient red ECL at λem,max = 600 nm, which is stable in a wider range of applied potential. The activation is triggered at 0.45–0.65 V, ca. 0.3–0.5 V lower than that of tris‐(2,2′‐bipyridyl) ruthenium(II) complex, [Ru(bpy)3]²⁺. Remarkably, the ECL quantum yield relative to [Ru(bpy)3]²⁺ is up to six‐fold higher, thus positioning this new series of iTMCs amongst the brightest ECL‐active emitters to date and possibly offering a platform to develop novel and even more efficient ECL probes for biosensing and bioimaging applications.

The first total synthesis of the 2,3,5‐O‐(S,R)‐NonaHydroxyTriPhenoylated (NHTP) and 4,6‐O‐(S)‐HexaHydroxy‐DiPhenoylated (HHDP) C‐glucosidic ellagitannin (−)‐vescalagin was accomplished through a bioinspired route involving intramolecular atroposelective cupric‐diamine complex‐mediated phenolic couplings of gallates to forge its HHDP and NHTP units, and a methoxyamine‐driven opening of a glucopyranose intermediate followed by a phenolic aldol‐type reaction to form its C‐arylglucosidic bond. The minor epimer that resulted from this bond‐forming event was used to complete also a first total synthesis of the vescalagin epimer, (–)‐castalagin.

A chiral Brønsted acid‐catalyzed synthesis of axially chiral alkenes was developed via an enantioselective and para‐selective Friedel–Crafts reaction between phenols and 1‐alkynylnaphth‐2‐ols. This methodology features an efficient hydroarylation with high functional group tolerance, complete para‐selectivity, excellent yields (up to 99%), and enantioselectivities (up to 94% ee) in the presence of a N‐triflylphosphoramide catalyst. DFT calculations were performed to investigate para‐selectivity and results indicate that both kinetics and thermodynamics parameters are more favorable compared to ortho‐selectivity.

Mycoplasma pneumoniae causes atypical pneumonia in children and young adults. Its lack of a cell wall makes it resistant to beta-lactams, which are the first-line treatment for typical pneumonia. Current diagnostic tests are time-consuming and have low specificity, leading clinicians to administer empirical antibiotics. Using a LASSO regression simulation approach and blood microarray data from 107 children with pneumonia (including 30 M. pneumoniae) we identify eight different transcriptomic signatures, ranging from 3-10 transcripts, that differentiate mycoplasma pneumonia from other bacterial/viral pneumonias with high accuracy (AUC: 0.84–0.95). Additionally, we demonstrate that existing signatures for broadly distinguishing viral/bacterial infections and viral/bacterial pneumonias are ineffective in distinguishing M. pneumoniae from viral pneumonia. The new signatures are successfully validated in an independent RNAseq cohort of children with pneumonia, demonstrating their robustness. The high sensibility of these signatures presents a valuable opportunity to guide the treatment and management of M. pneumoniae pneumonia patients.

Various protecting groups have been developed for boronic acids, mostly based on diols. Alternatives include trifluoroborates and amine complexes, which offer easier synthesis and release under milder conditions. We present here a new strategy involving photocleavable protecting groups for boronic and borinic acids, based on the 2‐nitrobenzyl motif. A screening of several 1,2‐ and 1,3‐diols bearing a 2‐nitrobenzyl group led us to identify 1‐(2‐nitrophenyl)neopentyl glycol (npnp) for the protection of boronic acid derivatives. This diol is easily prepared in a single step on gram scale, and the corresponding npnp boronates are stable in wet acetonitrile at 90 °C for several days, and under under acidic conditions. Irradiation at 365 nm in acetonitrile allows for the controlled liberation of boronic acids in good to excellent yields, a method also applied to a dimesitylborinic ester bearing a 2‐nitrobenzylalcohol moiety. 1‐(2‐Nitrophenyl)neopentyl glycol boronates ArB(npnp) demonstrated their utility in light‐triggered siloxane crosslinking. We showed that catalysts incorporated into a polymer matrix, irradiated, and then incubated at 50 °C for 7 days resulted in efficient polymerization, forming solid materials in some cases.

Electrochemiluminescence (ECL) of the conventional system of [Ru(bpy)3]²⁺ luminophore and amine‐based coreactants is particularly inefficient on noble metal electrodes. This is due to the formation of a passivating oxide layer on the metal surface inhibiting the electro‐oxidation of amines like tri‐n‐propylamine (TPrA) coreactant. Herein, we demonstrated the enhancement of ECL emission on gold surface by hydroxyl radicals attack that are chemically generated with Cu‐Fenton reagent. These radicals selectively deactivate the gold active sites and knockout the metal surface asperities that counterintuitively led to an amplification of the ECL emission. Atomic force microscopy shows a massive smoothening of the surface. The electrochemical characterization proves that the involved ECL reaction mechanism switches from direct oxidation to catalytic route, where the kinetics of indirect TPrA oxidation is facilitated on deactivated gold surface. Besides, in situ smoothening of a rough electrode in presence of tandem [Ru(bpy)3]²⁺/TPrA enables Cu²⁺ sensing with good reliability and limit of detection. Such atomically smoothened and corrosion‐resistant gold surface readily tuned the ECL reactivity and opened new directions on influence of topography and reactivity on ECL mechanisms, thus will be extremely useful for the future development of ECL imaging strategies and highly sensitive ECL sensors.

Transthyretin (TTR), a homo‐tetrameric protein encoded by the TTR gene, can lead to amyloid diseases when destabilized by mutations. The TTR‐Ala97Ser (A97S) mutation is the predominant pathogenic variant found in Han‐Taiwanese patients and is associated with late‐onset familial amyloid polyneuropathy (FAP), which presents a rapid progression of symptoms affecting peripheral nerves and the heart. In this study, we combined nuclear magnetic resonance (NMR) spectroscopy and X‐ray crystallography to investigate how the A97S mutation impacts the structure and dynamics of TTR. Previous X‐ray analyses indicated that the FG loop exhibits increased flexibility due to the mutation, evidenced by missing electron density and a reduced number of hydrogen bonds. Our NMR hydrogen‐deuterium (H/D) exchange experiments provided additional insights, revealing that inter‐residue hydrogen bonds among the FG loop residues are unstable in both wild‐type (WT) and A97S TTR. Notably, the hydrogen bonds between G67 and S97 are unstable, influencing the stability of adjacent loops. This elongation of the FG loop is believed to contribute to increased flexibility and enhanced water‐protein proton exchange, as observed in NMR relaxation and chemical exchange experiments. Our findings offer a comprehensive understanding of how the A97S mutation affects TTR structure and dynamics, providing new insights into its amyloidogenicity.

Among strategies to limit ischemia/reperfusion (IR) injuries in transplantation, cell therapy using stem cells to condition/repair transplanted organs appears promising. We hypothesized that using a cell therapy based on extracellular vesicles (EVs) derived from urine progenitor cells (UPCs) during hypothermic and normothermic machine perfusion can prevent IR‐related kidney damage. We isolated and characterized porcine UPCs and their extracellular vesicles (EVs). Then these were used in an ex vivo porcine kidney preservation model. Kidneys were subjected to warm ischemia (32 min) and then preserved by hypothermic machine perfusion (HMP) for 24 h before 5 h of normothermic machine perfusion (NMP). Three groups were performed (n = 5–6): Group 1 (G1): HMP/vehicle + NMP/vehicle, Group 2 (G2): HMP/EVs + NMP/vehicle, Group 3 (G3): HMP/EVs + NMP/EVs. Porcine UPCs were successfully isolated from urine and fully characterized as well as their EVs which were found of expected size/phenotype. EVs injection during HMP alone, NMP alone, or both was feasible and safe and did not impact perfusion parameters. However, cell damage markers (LDH, ASAT) were decreased in G3 compared with G1, and G3 kidneys displayed a preserved tissue integrity with reduced tubular dilatation and inflammation notably. However, renal function indicators such as creatinine clearance measured for 5 h of normothermic perfusion or NGAL perfusate's level were not modified by EVs injection. Regarding perfusate analysis, metabolomic analyses and cytokine quantification showed an immunomodulation signature in G3 compared with G1 and highlighted potential metabolic targets. In vitro, EVs as well as perfusates from G3 partially recovered endothelial cell metabolic activity after hypoxia. Finally, RNA‐seq performed on kidney biopsies showed different profiles between G1 and G3 with regulation of potential IR targets of EVs therapy. We showed the feasibility/efficacy of UPC‐EVs for hypothermic/normothermic kidney conditioning before transplantation, paving the way for combining machine perfusion with EVs‐based cell therapy for organ conditioning. Highlights ·UPCs from porcine urine can be used to generate a cell therapy product based on extracellular vesicles (pUPC‐EVs). ·pUPC‐EVs injection during HMP and NMP decreases cell damage markers and has an immunomodulatory effect. ·pUPC‐EVs‐treated kidneys have distinct biochemical, metabolic, and transcriptomic profiles highlighting targets of interest. ·Our results pave the way for combining machine perfusion with EV‐based cell therapy for kidney conditioning.

The Cu‐glutathione (GSH) redox system, essential in biology, is designed here as a supramacromolecular assembly in which the tetrahedral 18e Cu(I) center loses a thiol ligand upon adsorption onto ZIF‐8, as shown by EXAFS and DFT calculation, to generate a very robust 16e planar trigonal single‐atom Cu(I) catalyst. Synergy between Cu(I) and ZIF‐8, revealed by catalytic experiments and DFT calculation, affords CO2 conversion into high‐value‐added chemicals with a wide scope of substrates by reaction with terminal alkynes or propargyl amines in excellent yields under mild conditions and reuse at least 10 times without significant decrease in catalytic efficiency.

The Ca2+-dependent activator protein for secretion (CAPS/CADPS) family protein facilitates catecholamine release through the dense-core vesicle exocytosis in model neuroendocrine cell lines. However, it remains unclear if it induces dopamine release in the central neurons. This study aimed to examine the expression and function of CADPS2, one of the two CADPS paralogs, in dopamine neurons of the mouse midbrain. This study shows that CADPS2 was expressed in tyrosine hydroxylase and the vesicular monoamine transporter 2 (VMAT2)-positive dopaminergic neurons of the midbrain samples and primary mesencephalic cell cultures. Subcellular fractions rich in dopamine were collected using immunoaffinity for CADPS2 from midbrain protein extracts. Cell imaging using fluorescent false neurotransmitter FFN511 as a substrate for VMAT2 showed decreased activity-dependent dopamine release in Cadps2-deficient cultures, compared to that in wild-type cultures. These results suggest that CADPS2 is involved in dopamine release from the central neurons, indicating its involvement in the central dopamine pathway.

Background Symptomatic hypermobility spectrum disorders (HSD) and hypermobile Ehlers Danlos syndromes (hEDS) are characterised by the presence, in addition to joint instability and skin fragility, of chronic pain, anxiety, depression, fatigue, a reduction or loss of functional independence and, as a result, an altered quality of life. Objectives We wanted to know to what extent functional independence could be affected in these two clinical entities, in what areas this impairment was manifested and what were the determinants of the severity of such patients. Methods As part of a study to evaluate the efficacy of compression garments (prospective multicentre study), we assessed functional independence (via the MIF score), pain level (VAS), anxiety-depression level (HAD scale) and quality of life (EQ-5D-3L scale) at inclusion. The MIF score is a hetero-administered scale used to assess activities of daily living (6 items), sphincter control (2 items), mobility (transfers) and locomotion (5 items), communication (2 items) and social cognitive activities (3 items). Each of the 18 items has a maximum score of 7, and a minimum of 1. The highest score is therefore 126, and the lowest 18. This is used to determine the determination and severity of the disability. A comparison of the two groups, HSD and hEDS, was followed by a principal component analysis. The search for homogeneous groups of patients was carried out using a hierarchical ascending analysis. This study was approved by the ethics committee and registered on ClinicalTrials.gov [NCT03330977]. Results 107 patients were included between December 2017 and March 2022 in 7 centres. There was no significant difference between the two groups of HSD and hEDS patients for any of the parameters studied. Three homogeneous groups of patients were identified: the first cluster (27 patients) was characterised by a more marked deterioration in quality of life (-0.05 [-0.17,-0.02]), a more marked level of depression, a more intense state of fatigue and a lower level of functional independence (MIF 100 [93-103]) with all components affected; cluster 2 (41 patients) had a slightly impaired level of MIF (MIF 124 [115-125]) and an intermediate QoL impairment (0. 25 [0.13-0.50]), cluster 3 (39 patients) was made up of subjects who also had a very slightly altered level of MIF (MIF 123 [116-126]), mainly in the motor domain, less fatigue and no depression, and a slightly altered QoL (0.58 [0.24, 0.64]). Conclusion This study assessed the functional independence of HSD and hEDS patients using the MIF score. The level of impairment of functional independence as determined by the MIF measurement, the patients’ quality of life and the presence of depression make it possible to characterise a sub-group of more severe HSD or hEDS patients. REFERENCES NIL Acknowledgements NIL Disclosure of Interests Roland JAUSSAUD: None declared, Jerôme Gagnoux Textile engineer at Novatex, Richard Amoretti: None declared, Violaine Laurant-Noel: None declared, amelie servettaz: None declared, Olivier Lidove: None declared, Bertrand Dussol: None declared, Boris Bienvenu: None declared, Elodie Vlamynck, Thomas MOULINET: None declared.

Background Joint hypermobility syndromes (hypermobile Ehlers Danlos syndrome, hEDS, and symptomatic hypermobility spectrum disorders, HSD) are characterised by the presence of a chronic pain syndrome, fatigue, a certain degree of anxiety and depression, with a consequent reduction in quality of life and functional independence. In France, medical compression garments are commonly used, but their long-term effectiveness has not yet been proven. Objectives Evaluate the effectiveness of compression garments in the therapeutic management of patients with hEDS on functional independence, pain, fatigue, quality of life (QoL) and anxiety-depression levels. Methods Prospective interventional clinical study with a duration of 2 years and a follow-up of 26 months, multicentre. Patients aged 15 to 60 years with a diagnosis of hEDS or symptomatic HSD who had not worn compression garments for at least 6 months. The use of compression garments was prescribed at 4 months. Functional independence (MIF scale), pain (VAS), fatigue (Pichot scale), anxiety-depression (HAD scale), quality of life (EQ-5D-3L), compliance and patient satisfaction were assessed at 5 follow-up visits. This study was approved by the ethics committee and registered on ClinicalTrials.gov [NCT03330977]. Results 107 patients (90% women) were included between December 2017 and March 2020. They included 83% with SED and 17% with HSD. The mean MIF score was relatively unchanged at inclusion (113.6 with a maximum of 126); 9.7% of patients had an increase in their score of at least 10% between 4 and 8 months; the score remained relatively constant between 4 and 26 months. At 26 months: 33.3% of patients improved their VAS pain score, 40% of patients improved their fatigue score, 35.3% of patients reduced their level of anxiety-depression on the HAD scale (with a more marked effect on the anxiety side) and 50% of patients increased their QoL score by more than 10%. 22% of patients had reduced their total daily dose of analgesics at 26 months.Mean compliance as assessed by the investigators was 9.4 hours per day at 26 months. VC use was daily in 45.5% of cases, frequent (more than 4 days a week) in 21.2%, infrequent (< 4 days a week) in 24.2%, and permanent (days and nights) in 9.1%. No serious adverse events related to clothing were reported. At 26 months, 93% of patients were satisfied or very satisfied. Conclusion First study to evaluate the long-term effects of compression garments in real life in patients with hEDS and HSD. It shows long-term improvements in pain, fatigue, anxiety, depression and quality of life. Compression garments are safe medical devices with high patient satisfaction. Further studies will be needed to determine the profile of patients who could benefit most from the use of compression garments. REFERENCES NIL Acknowledgements NIL Disclosure of Interests Roland JAUSSAUD: None declared, Thomas MOULINET: None declared, Violaine Laurant-Noel: None declared, Amélie Servettaz: None declared, Richard Amoretti: None declared, Olivier Lidove: None declared, Bertrand Dussol: None declared, Boris Bienvenu: None declared, Aranud Metlaine: None declared, Elodie Vlamynck, Jerôme Gagnoux.

Carbon-supported noble-metal-free single-atom catalysts (SACs) have aroused widespread interest due to their green chemistry aspects and excellent performances. Herein, we propose a “ligand regulation strategy” and achieve the successful fabrication of bifunctional SAC/MOF (MOF = metal–organic framework) nanocomposite (abbreviated NiSA/ZIF-300; ZIF = ZIF-8) with exceptional catalytic performance and robustness. The designed NiSA/ZIF-300 has a planar interfacial structure with the Ni atom, involving one S and three N atoms bonded to Ni(II), fabricated by controllable pyrolysis of volatile Ni-S fragments. For CO2 cycloaddition to styrene epoxide, NiSA/ZIF-300 exhibits ultrahigh activity (turnover number (TON) = 1.18 × 10⁵; turnover frequency (TOF) = 9830 molSC·molNi⁻¹·h⁻¹; SC = styrene carbonate) and durability at 70 °C under 1 atm CO2 pressure, which is much superior to Ni complex/ZIF, NiNP/ZIF-300, and most reported catalysts. This study offers a simple method of bifunctional SAC/MOF nanocomposite fabrication and usage, and provides guidance for the precise design of additional original SACs with unique catalytic properties.

Greenhouse-gas (GHG) reporting schemes for companies are increasingly part of climate-mitigation policies worldwide. Notably, the European Green Deal (2019) boosts new public regulations that oblige companies to compile GHG emission inventories, i.e., account for their emissions in a given system boundary. Along with this boost, the workload for companies increases; at the same time, the quality of reporting is questioned. Given the overarching goal to improve companies’ climate-mitigation performance, the quality of reporting is inseparably connected to the quality of the respective accounting. However, the literature discusses carbon accounting as a universal umbrella term focusing on managerial issues, thus disregarding the crucial role of accounting methodologies in the sense of calculation approaches. In this publication, we apply an analytical approach introducing a clear differentiation between the task of quantitatively accounting for GHG inventories and the task of reporting results from calculated inventories in response to stakeholder or policy expectations. We use this approach to investigate European GHG reporting schemes and related GHG accounting methodologies in detail. Our findings indicate that the current phase of the European Green Deal depicts a quantitative growth in reporting schemes and a significant qualitative change by shifting from formerly voluntary to mandatory reporting schemes, along with the application of accounting methodologies originally not intended for politically compulsory purposes. We analyze the consequences of this shift, which poses new challenges for companies and policymakers, i.e., data-management concepts and refined methodological frameworks.

Background The adoption of C-reactive protein point-of-care tests (CRP POCTs) in hospitals varies across Europe. We aimed to understand the factors that contribute to different levels of adoption of CRP POCTs for the management of acute childhood infections in two countries. Methods Comparative qualitative analysis of the implementation of CRP POCTs in the Netherlands and England. The study was informed by the non-adoption, abandonment, spread, scale-up, and sustainability (NASSS) framework. Data were collected through document analysis and qualitative interviews with stakeholders. Documents were identified by a scoping literature review, search of websites, and through the stakeholders. Stakeholders were sampled purposively initially, and then by snowballing. Data were analysed thematically. Results Forty-one documents resulted from the search and 46 interviews were conducted. Most hospital healthcare workers in the Netherlands were familiar with CRP POCTs as the tests were widely used and trusted in primary care. Moreover, although diagnostics were funded through similar Diagnosis Related Group reimbursement mechanisms in both countries, the actual funding for each hospital was more constrained in England. Compared to primary care, laboratory-based CRP tests were usually available in hospitals and their use was encouraged in both countries because they were cheaper. However, CRP POCTs were perceived as useful in some hospitals of the two countries in which the laboratory could not provide CRP measures 24/7 or within a short timeframe, and/or in emergency departments where expediting patient care was important. Conclusions CRP POCTs are more available in hospitals in the Netherlands because of the greater familiarity of Dutch healthcare workers with the tests which are widely used in primary care in their country and because there are more funding constraints in England. However, most hospitals in the Netherlands and England have not adopted CRP POCTs because the alternative CRP measurements from the hospital laboratory are available in a few hours and at a lower cost.

Protein–protein interactions (PPIs) offer great opportunities to expand the druggable proteome and therapeutically tackle various diseases, but remain challenging targets for drug discovery. Here, we provide a comprehensive pipeline that combines experimental and computational tools to identify and validate PPI targets and perform early-stage drug discovery. We have developed a machine learning approach that prioritizes interactions by analyzing quantitative data from binary PPI assays or AlphaFold-Multimer predictions. Using the quantitative assay LuTHy together with our machine learning algorithm, we identified high-confidence interactions among SARS-CoV-2 proteins for which we predicted three-dimensional structures using AlphaFold-Multimer. We employed VirtualFlow to target the contact interface of the NSP10-NSP16 SARS-CoV-2 methyltransferase complex by ultra-large virtual drug screening. Thereby, we identified a compound that binds to NSP10 and inhibits its interaction with NSP16, while also disrupting the methyltransferase activity of the complex, and SARS-CoV-2 replication. Overall, this pipeline will help to prioritize PPI targets to accelerate the discovery of early-stage drug candidates targeting protein complexes and pathways.

The rational design of efficient bimetallic nanoparticle (NP) catalysts is challenging due to the lack of theoretical understanding of active components and insights into the mechanisms of a specific reaction. Here, we report the rational design of nanoreactors comprising hollow carbon sphere‐confined PtNi bimetallic NPs (PtNi@HCS) as highly efficient catalysts for hydrogen generation via ammonia borane hydrolysis in water. Using both density functional theory calculations and molecular dynamics simulations, the effects of an active PtNi combination and the critical synergistic role of a hollow carbon shell on the molecule diffusion adsorption behaviors are explored. Kinetic isotope effects and theoretical calculations allow the clarification of the mechanism, with oxidative addition of an O–H bond of water to the catalyst surface being the rate‐determining step. The remarkable catalytic activity of the PtNi@HCS nanoreactor was also utilized for successful tandem catalytic hydrogenation reactions, using in situ‐generated H2 from ammonia borane with high efficiency. The concerted design, theoretical calculations, and experimental work presented here shed light on the rational elaboration of efficient nanocatalysts and contribute to the establishment of a circular carbon economy using green hydrogen.

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.