University of Strasbourg

The catalytic deoxyamination of readily available 2‐arylethanols offers an appealing, simple, and straightforward means of accessing β‐(hetero)arylethylamines of biological interest. Yet, it currently represents a great challenge to synthetic chemistry. In most cases, the alcohol has to be either pre‐activated in situ or converted into a reactive carbonyl intermediate, limiting the substrate scope for some methods. Examples of direct dehydrative amination of 2‐arylethanols are thus still scarce. Here, we describe a catalytic protocol based on the synergy of triflic acid and hexafluoroisopropanol, which enables the direct and stereospecific amination of a broad array of 2‐arylethanols, and does not require any pre‐activation of the alcohol. This approach yields high value‐added products incorporating sulfonamide, amide, urea, and aniline functionalities. In addition, this approach was applied to the sulfidation of 2‐arylethanols. Mechanistic experiments and DFT computations indicate the formation of phenonium ions as key intermediates in the reaction.

Numerous reactions within metabolic pathways have been reported to occur nonenzymatically, supporting the hypothesis that life arose upon a primitive nonenzymatic precursor to metabolism. However, most of those studies reproduce individual transformations or segments of pathways without providing a common set of conditions for classes of reactions that span multiple pathways. In this study, we search across pathways for common nonenzymatic conditions for a recurring chemical transformation in metabolism: alkene hydration. The mild conditions that we identify (Fe oxides such as green rust) apply to all hydration reactions of the rTCA cycle and gluconeogenesis, including the hydration of phosphoenolpyruvate (PEP) to 2‐phosphoglycerate (2PGA), which had not previously been reported under nonenzymatic conditions. Mechanistic insights were obtained by studying analogous substrates and through anoxic and radical trapping experiments. Searching for nonenzymatic conditions across pathways provides a complementary strategy to triangulate conditions conducive to the nonenzymatic emergence of a protometabolism.

Background The prognosis for patients with relapse of localized rhabdomyosarcoma (RMS) remains poor, with limited evidence for optimal second‐line therapy. This study describes the management and outcomes of relapsed RMS patients in France. Methods We retrospectively reviewed all nonmetastatic RMS patients enrolled in France in the RMS 2005 study who relapsed between 2006 and 2019 after achieving complete local control, defined as complete remission or stable residue ≥ 6 months after treatment completion. Data were extracted from the RMS 2005 database and medical records. Results Ninety‐five patients relapsed at a median age of 6.0 years (range: 1.0–27.0). The median time from diagnosis to relapse was 17.5 months (range: 7.4–82.0). Most patients had embryonal RMS (65.3%) and local/locoregional relapses (71.6%). The first relapse treatment included chemotherapy (all except two patients), radiotherapy (52.6%), and surgery (48.4%). Second‐line chemotherapy yielded a 58.5% objective response rate after 3 ± 1 cycles. Fifty‐five patients achieved second complete remission. With a median follow‐up of 7.2 years from the first relapse (range: 0.3–11.3), 5‐year progression‐free survival was 26% (95% CI: 18–36), and 5‐year overall survival was 35% (95% CI: 25–45). Importantly, no patient survived relapse without receiving locoregional treatment (surgery and/or radiotherapy). Conclusion This study confirmed the inconsistencies in therapy and the poor prognosis for relapsed RMS but highlighted the potential for long‐term survival in patients who received surgery and/or radiotherapy, emphasizing the crucial role of achieving local control in improving outcomes at relapse.

Protein synthesis begins with the formation of a ribosome-messenger RNA (mRNA) complex. In bacteria, the small ribosomal subunit (30 S ) is recruited to many mRNAs through base pairing with the Shine-Dalgarno (SD) sequence and RNA binding by ribosomal protein bS1. Translation can initiate on nascent mRNAs, and RNA polymerase (RNAP) can promote the recruitment of the pioneering 30 S . Here, we examined 30 S recruitment to nascent mRNAs using cryo–electron microscopy, single-molecule fluorescence colocalization, and in-cell cross-linking mass spectrometry. We show that bS1 delivers the mRNA to the ribosome for SD duplex formation and 30 S activation. Additionally, bS1 and RNAP stimulate translation initiation. Our work provides a mechanistic framework for how the SD duplex, ribosomal proteins, and RNAP cooperate in 30 S recruitment to mRNAs and establish transcription-translation coupling.

The Groundwater Module within the Sustainability Nexus Analytics, Informatics, and Data (AID) Programme of the United Nations University (UNU) addresses critical challenges in sustainable groundwater management. Groundwater resources around the world are under increasing stress from overextraction and pollution, threatening water and food security for billions. Groundwater governance is not one-dimensional but multi-faceted, and central to the management of environmental, social, and economic systems worldwide. In line with the Nexus Approach, the goal of the UNU Sustainability Nexus AID Programme's Groundwater Module is improving access to data and information tools that help scientists and decision-makers address interdisciplinary groundwater problems that affect humans and nature. Here, we describe the critical need for a Nexus Approach to groundwater-related issues and highlight current challenges involving data and information gaps and data-model operability. The Groundwater Module can help address these challenges by offering a central hub for data, analytics, and informatics for addressing groundwater-related issues. By integrating dispersed datasets and modeling tools, this module aims to enable analysis and new insights. We showcase some of the tools in the Groundwater Module and discuss future opportunities in the global pursuit to fulfill the UN Sustainable Development Goals (SDGs).

The use of water as a solvent to facilitate supramolecular polymerization is well documented, however, it is rare that water acts as a monomer that undergoes polymerization. We report the copolymerization of water with a saddle-shaped porphyrinoid macrocycle, carpyridine, which allows for linearly stacked, eclipsed columns within formed 2D nanosheets. Self-assembling carpyridine monomers from solutions with different extents of wetness allow for the formation of nanosheets on surface that appear identical by microscopy. Structural analysis through electron diffrac-tion reveals fundamental changes in the local organization. Under dry conditions, carpyridine stacks are formed through π–π interactions between curved surfaces whereas in solutions containing greater quantities of water, a hy-drogen-bonded water-to-carpyridine-core network is propagated throughout perfectly linear columns. The observed wet phase can be interconverted to a dry one through vapor annealing, indicating an accessible energy surface of polymorphism.

The lipid cis‐trans isomerase (Cti) is a periplasmic heme‐c enzyme found in several bacteria including Pseudomonas aeruginosa, a pathogen known for causing nosocomial infections. This metalloenzyme catalyzes the cis‐trans isomerization of unsaturated fatty acids in order to rapidly modulate membrane fluidity in response to stresses that impede bacterial growth. As a consequence, breakthrough in the elucidation of the mechanism of this metalloenzyme might lead to new strategies to combat bacterial antibiotic resistance. We report the first comprehensive biochemical, electrochemical and spectroscopic characterization of a Cti enzyme. This has been possible by the successful purification of Cti from P. aeruginosa (Pa‐Cti) in favorable yields with enzyme activity of 0.41 μmol/min/mg when tested with palmitoleic acid. Through a synergistic approach involving enzymology, site‐directed mutagenesis, Raman spectroscopy, Mössbauer spectroscopy and electrochemistry, we identified the heme coordination and redox state, pinpointing Met163 as the sixth ligand of the FeII of heme‐c in Pa‐Cti. Significantly, the development of an innovative assay based on liposomes demonstrated for the first time that Cti catalyzes cis‐trans isomerization directly using phospholipids as substrates without the need of protein partners, answering the important question about the substrate of Cti within the bacterial membrane.

Objective Intravascular lymphoma is a rare subtype of B‐cell lymphoma characterized by a clonal proliferation restricted to the lumen of small vessels. Over 50% of patients exhibit central nervous system (CNS) involvement, but diagnosis is often delayed due to the lack of distinctive features. We aimed to identify key phenotypic features for early diagnosis of intravascular lymphoma with CNS involvement through an in‐depth cohort study. Methods We built up a multicenter retrospective cohort of 17 patients recruited in collaboration with the French Expert Network for Oculo‐Cerebral Lymphomas (LOC network), and retrospectively analyzed data from medical records. Results In this cohort, 15 of 17 (88%) patients developed focal neurological episodes, often fluctuating and/or recurrent, with a sudden onset in 68% of episodes, suggesting a vascular origin. Rapid cognitive deterioration occurred in 15 of 17 (88%) patients, psychiatric manifestations in 8 of 17 (47%), and “B signs” in 14 of 17 (82%). Brain MRI showed polymorphic FLAIR hyperintensities in 14 of 16 (87%) patients, and DWI‐positive lesions in 13 of 16 (81%) of patients, which accumulated over time and had unusual characteristics for ischemic lesions (progressive growth, persistent DWI‐hyperintensity over 1 month, surrounded by a wider FLAIR hyperintensity). Early‐onset inflammatory syndrome, and elevated lactate dehydrogenase (LDH) levels were observed in over 90% of cases. Mild and inconsistent meningitis contrasted with a nearly‐constant hyperproteinorachia. An increased interleukin 10/6 ratio over 0,7 was found in 4 of 7 (57%) patients, and skin biopsy led to a pathological diagnosis in 3 of 6 (50%) patients. Interpretation The results of this study highlight “red flags” that could help accelerate the diagnosis of intravascular lymphoma involving the CNS. ANN NEUROL 2024

Glioblastoma multiforme (GBM) is the most common adult primary brain tumor. The standard of care involves maximal surgery followed by radiotherapy and concomitant chemotherapy with temozolomide (TMZ), in addition to adjuvant TMZ. However, the recurrence rate of GBM within 1–2 years post-diagnosis is still elevated and has been attributed to the accumulation of multiple factors including the heterogeneity of GBM, genomic instability, angiogenesis, and chronic tumor hypoxia. Tumor hypoxia activates downstream signaling pathways involved in the adaptation of GBM to the newly oxygen-deprived environment, thereby contributing to the resistance and recurrence phenomena, despite the multimodal therapeutic approach used to eradicate the tumor. Therefore, in this review, we will focus on the development and implication of chronic or limited-diffusion hypoxia in tumor persistence through genetic and epigenetic modifications. Then, we will detail the hypoxia-induced activation of vital biological pathways and mechanisms that contribute to GBM resistance. Finally, we will discuss a proteomics-based approach to encourage the implication of personalized GBM treatments based on a hypoxia signature.

In this review, the difference between π‐mers (pimers) and π‐dimers (pi‐dimers) will be discussed. Often interchanged or confused in the literature, these two radical interactions lead to different or even opposite physico‐chemical behaviors. This review aims at clarifying the terms π‐mers and π‐dimers and at describing their main physico‐chemical properties to address their differences. Finally, selected literature examples exhibiting the successive formation of π‐mers and π‐dimers within the same systems will be detailed to emphasize the physico‐chemical changes occurring upon conversion.

The use of VIV and CuII spins to design weakly coupled and dissymmetric spin systems has been examined. Such systems were synthesized using porphyrin‐based complexes, with external coordination sites allowing for the formation of dimers via a PdII linker ion. Continuous‐wave (CW) Electron Paramagnetic Resonance (EPR) spectroscopy allowed the unequivocal magnetic characterization of the mononuclear precursors VO and Cu. The porphyrin dimer (VO)PdCu presented a broad and overlapped spectrum that was more pronounced than for the previously reported (VO)Pd(VO), hinting at the effect of weak interspin interactions between dissimilar spins. Pulsed EPR experiments on VO, (VO)Pd(VO) and (VO)PdCu samples diluted in a diamagnetic matrix confirmed that this complication is also present in the Field‐Swept Echo‐Detected (FSED) spectra of the heterometallic (VO)PdCu system. Despite the strongly overlapped field‐swept spectra, spin nutation experiments revealed two distinct oscillations in the case of (VO)PdCu, which are assigned to transitions with different spin characters. Remarkably, coherence is retained above liquid nitrogen temperatures for all complexes, in particular up to 295 K for VO and (VO)Pd(VO) and 150 K for (VO)PdCu.

The development of hard carbon (HC) electrodes using biobased binders, formulated in water solvent, is of great interest for Na-ion batteries. Five Na-carboxymethyl cellulose (CMC) binders with different molecular weights and degrees of substitution were investigated. The increase in the CMC molecular weight led to an increase in the volume of water necessary for slurry preparation and a decrease in the electrode mass loading. Moreover, the adhesion of the slurry was strongly impacted by the aluminum current collector properties. A high initial Coulombic efficiency, iCE (up to ∼90%), and reversible capacity (up to 334 mAh g–1 at C/10) were obtained in Na half-cells. Post-mortem XPS analyses performed on several electrodes under various conditions allowed a better understanding of the formation and composition of the solid electrolyte interphase (SEI) layer. The genesis of SEI was initially chemically driven: to a small extent, by HC and to a greater extent, by the Na metal. However, SEI formation was mainly governed by the electrochemical-driven degradation of the electrolyte salt and solvent. The SEI layer composed of an inorganic-rich core and an organic-rich shell significantly decreased the resistance of the HC electrode, allowing superior iCE while maintaining high capacity retention (96.2%), after 100 cycles at 1C.

Today, companies are competing to improve the innovation cycle time in order to gain pioneering advantages in the market. To achieve this goal, these companies could apply the TRIZ-based systematic approaches such as Inventive the Design Methodology (IDM). Nevertheless, one of the criticisms often leveled is that these approaches are time-consuming due to the demands for building a complete map to clarify a problem situation in the initial analysis phase of the inventive design process. As a result, the Inverse Problem Graph (IPG) method has been proposed to increase the agility of the process by starting the problem formulation from an initial problem located in the lower level of a problem situation. The application of the IPG method decreases problem formulation time by identifying a limited number of problems. However, this method does not provide any tool for prioritizing the initial problems in the process. The purpose of this article is to integrate a Failure Mode Effect Analysis (FMEA)—Analytic Hierarchy Process (AHP) based method into the IPG method to prioritize the initial problems in the first phase of the design process. The proposal capability is finally tested through its application in a case study on the Lattice Structure.

The ribosome maturation factor Rea1 (or Midasin) catalyses the removal of assembly factors from large ribosomal subunit precursors and promotes their export from the nucleus to the cytosol. Rea1 consists of nearly 5000 amino-acid residues and belongs to the AAA+ protein family. It consists of a ring of six AAA+ domains from which the ≈1700 amino-acid residue linker emerges that is subdivided into stem, middle and top domains. A flexible and unstructured D/E rich region connects the linker top to a MIDAS (metal ion dependent adhesion site) domain, which is able to bind the assembly factor substrates. Despite its key importance for ribosome maturation, the mechanism driving assembly factor removal by Rea1 is still poorly understood. Here we demonstrate that the Rea1 linker is essential for assembly factor removal. It rotates and swings towards the AAA+ ring following a complex remodelling scheme involving nucleotide independent as well as nucleotide dependent steps. ATP-hydrolysis is required to engage the linker with the AAA+ ring and ultimately with the AAA+ ring docked MIDAS domain. The interaction between the linker top and the MIDAS domain allows direct force transmission for assembly factor removal.

We propose a three-dimensional macroscopic continuum model designed to predict the remodeling phenomenon of bone tissue. In the proposed model, we focus on the evolution of two crucial stiffness parameters: the bulk and shear moduli. These parameters independently adapt to the mechanical demands to which bone tissue is subjected, mainly to withstand hydrostatic and deviatoric deformations. These mechanical stimulations influence the activity of bone cells, leading to changes in bone structure and strength and, in turn, the above-mentioned moduli. The formulation is simplified, serving as an initial step towards a more comprehensive modeling approach. The evolution of these stiffness parameters is proposed based on an energetic argument to describe the functional adaptation process. Numerical experiments, conducted on a cylindrical specimen resembling a femur, demonstrate the feasibility of modeling the bone remodeling process with distinct evolutions for multiple material parameters, in contrast to the conventional approach that permits only one-parameter evolution.

Purpose The intraperitoneal leak of urine is considered as a major cause of peritoneal inflammatory reaction that could lead to paralytic ileus. Our aim was to document the effect of urine on the peritoneal surface. Methods Seven white minipigs (one control-six tests) underwent standardized general anaesthesia. In three test pigs urine was aspirated from the bladder and instilled in the peritoneal cavity. In the remaining three pigs a continuous urine leak was created through section of the ureter. At 4 and 10 h laparoscopic harvesting of slices of the parietal peritoneum at the level of the Douglas pouch, lateral pelvic wall and subdiaphragmatic area was performed. Ileum slices were also obtained at 10 h. The slices were microscopically evaluated for inflammatory infiltrate (INI) of the peritoneum according to the Sydney system classification. Results The presence of urine in the peritoneum induces distention of the ileum. At 4 h, a light-moderate INI was observed to two pigs of both test groups but not to the control pig. At 10 h a light-moderate INI appeared in the peritoneal slices of the control pig. Moreover, three out of six pigs of both test groups showed some degree of INI of the parietal peritoneum. The histologic evaluation of the slices of the distended ileum did not reveal INI. Conclusions The intraperitoneal urine induces distention of the bowel but no inflammation of the visceral peritoneum in the short term (10 h). Other than inflammation mechanisms through which the urine induces small ileum distention should be investigated.