University of Montpellier

Alzheimer's disease (AD) remains an incurable neurodegenerative disorder, requiring novel therapeutic strategies. We developed multitarget-directed ligands designed to inhibit human butyrylcholinesterase (hBChE) and activate the sigma-1 receptor (S1R), addressing both cholinergic dysfunction and neuroinflammation, the latter being reduced through action on both targets. The (pseudo-)irreversible carbamate inhibitor 18c emerged as the most promising compound, exhibiting potent and selective hBChE inhibition (IC50 = 3.3 nM, 45-fold selectivity over human acetylcholinesterase) and strong S1R agonistic activity (IC50 = 25 nM, EC50 = 99nM) determined in a radioligand binding assay and by S1R-BiP dissociation, respectively. Its cleavage product 14c (after carbamate hydrolysis by hBChE) retained dual activity (IC50(hBChE) = 269 nM, IC50(S1R) = 20 nM, and EC50(S1R) = 279nM). Both compounds reduced the lipopolysaccharide-induced pro-inflammatory activation profile in microglial N9 cells while preserving anti-inflammatory marker expression, thereby indicating an overall immunomodulatory effect. In vivo, inhibitor 18c improved cognitive deficits in a mouse model with Aβ25-35-induced neurotoxicity, enhancing short- and long-term memory in Y-maze and passive avoidance tests at dosages as low as 0.1-1 mg/kg. These findings highlight the potential of dual-targeting hBChE/S1R strategies for AD therapy.

ABSTRACT The white grub Cochliotis melolonthoides (Gerstaecker) (Scarabaeidae: Melolonthinae) is a pest of sugarcane fields in northern Tanzania. Larvae damage root systems and, in severe infestations, reduce sugarcane yields by up to 45%, with long‐lasting effects as the dead stools do not produce new stalks and create gaps in succeeding ratoon crops. Because of their economic importance in sugarcane, white grubs (Dynastidae, Melolonthinae, Rutelinae) have been extensively studied worldwide; however, their management is species‐dependent. This study aims to determine which parameters create C. melolonthoides grub infestation hotspots by focusing on soil health factors and agricultural practices. A spatiotemporal statistical analysis of 928 locations in TPC Limited (Tanzania, Arusha chini) with two white grub counts and soil analysis per location from 2022 to 2024 showed that alkaline and sodic soils had significantly higher grub density than neutral or solely alkaline soils. The presence of trash cover did not influence white grub density, nor did the irrigation method. Sugarcane varieties were a less important variable than pH and sodicity interaction in predicting white grub infestation. Pest management strategies based on changing soil conditions and agricultural practices are discussed.

Notochordal cells (NCs), abundantly found in the developing nucleus pulposus (NP), show potential for intervertebral disc regeneration because of their unique instructive and healthy matrix-producing capacity. However, NCs are lost early in life, and attempts at in vitro expansion have failed because they lose their specific phenotype. Therefore, much effort is focused on the generation of cells resembling the properties of healthy matrix-producing NP-like cells from human induced pluripotent stem cells (hiPSCs). They are considered a promising alternative for employing native NCs. Given the ongoing challenges in the field to fine-tune the differentiation protocol and obtain a high yield of mature matrix-producing cells, this study aims to build on the epigenetic memory and instructive capacity of healthy NP tissue. For this, we employed the epigenetic memory of tissue-specific hiPSCs derived from TIE2+ NP progenitor cells (NPPCs) and microenvironmental cues of decellularized porcine NC-derived matrix (dNCM), consisting of matrix components and bioactive factors to differentiate hiPSC into mature, healthy matrix-producing cells for NP repair. As a comparison, donor-matched minimally invasive peripheral blood mononuclear cell-derived hiPSCs were used. The results show that employing NPPC-derived hiPSCs instructed by natural cues provided by dNCM resulted in an increased expression of healthy phenotypic and matrisome-related NP markers. Furthermore, within this in vitro environment, differentiation of blood-derived hiPSC lines led to augmented differentiation into the hematopoietic and neural cell lineage. In conclusion, we demonstrate that hiPSCs derived from NPPCs achieve enhanced differentiation outcomes in the presence of dNCM, highlighting the potential impact of the epigenetic memory.

The 3D folding of the genome is tightly linked to its epigenetic state which maintains gene expression programmes. Although the relationship between gene expression and genome organisation is highly context dependent, 3D genome organisation is emerging as a novel epigenetic layer to reinforce and stabilise transcriptional states. Whether regulatory information carried in genome folding could be transmitted through mitosis is an area of active investigation. In this review, we discuss the relationship between epigenetic state and nuclear organisation, as well as the interplay between transcriptional regulation and epigenetic genome folding. We also consider the architectural remodelling of nuclei as cells enter and exit mitosis, and evaluate the potential of the 3D genome to contribute to cellular memory.

Phoenix dactylifera L. is an economically, nutritionally, and culturally important fruit crop in the arid and semi-arid regions of the Middle East and North Africa. Here, we present a gap-free, telomere-to-telomere reference genome of the variety Ajwa, along with 19 additional high-quality assemblies (18 female and 1 male). These assemblies reveal novel chromosomal structures validated through cytogenetics, Hi-C, optical mapping, and synteny analyses with other palm genomes. Chromosome names were revised based on average lengths across all sequenced genomes. The Sex Determination Region (SDR) on chromosome 14 was confirmed through male-specific k-mer analysis, spanning approximately 14.7 Mb. Nucleolar organizing regions (NORs) were localized on chromosome 10, where a large 45S rDNA locus displayed unique repeat spacer motifs containing transposon-like sequences. In some accessions, a second NOR was identified on the female sex chromosome. This collection of date palm assemblies, anchored by the Ajwa reference genome, provides a critical resource for advancing breeding strategies aimed at enhancing the genetic resilience and productivity of date palm.

Rare diseases (RD) have progressively emerged as public health priority in many countries. Epidemiological data are still lacking and the extraction of data from the public health system remains insufficient. In France, RD database set up in 2013 as Banque Nationale de Données de Maladies Rares (BNDMR). Patients’ information is provided by physician at each consultation and RD are classified according ORPHAcode. The status of each diagnosis can be entered as ‘confirmed’, ‘probable’ or ‘under investigation’, as well as related families. We aimed to test the reliability and quality of data for epidemiology by analyzing the data from a RD caused by autosomal dominant inheritance and with a univocal genetic diagnosis: TNF receptor-associated periodic syndrome (TRAPS). Patients were extracted on January 2023 and genetic files were retrieved from January to march 2023. All patients registered with a diagnosis of TRAPS were included. We identified 132 patients who fulfilled inclusion criteria, among which 31 were excluded (missing data and duplicates). We analyzed 101 patients and their sequences of TNFSRSF1A gene. Pathogenic and likely pathogenic variants were found in 69% of patients, while the remaining 31% may rather represent undetermined systemic autoinflammatory disease. The main pathogenic variant found was T50M (c.236 G > T) while the main VUS was R92Q (c.362 G > A). For the patients entered as ‘confirmed’, only 44% of them had a pathogenic/likely pathogenic variant. We identified eight different families. We therefore estimated the minimum prevalence of TRAPS in France: 1/1 156 711. In the French National Rare Disease Registry, the quality of data remains a challenge, especially in monogenic diseases where the knowledge of the pathogenicity of variants and the number of gene involved is constantly increasing. Our study suggests that the data exported from the BNDMR needs important data correction to allow reliable epidemiologic studies in these diseases.

The life expectancy of patients with diffuse IDH-mutant low-grade gliomas (IDHmt LGG) ranges from 5 to over 20 years. Tumor behavior, including spontaneous growth rate, varies even within homogeneously classified subtypes of oligodendroglioma and astrocytoma. Risk-adjusted treatment strategies are needed to avoid therapy-related toxicities without compromising outcome. The spontaneous tumor volume growth rate (TVGR) serves as a prognostic marker and predicts response to therapy. Accurate prediction of TVGR through biomarkers would enable improved evidence-based risk management. A cohort of 77 patients treated in Montpellier, France, for IDHmt LGG grade II (WHO 2016) (29 oligodendrogliomas and 48 astrocytomas) was constituted (age >18 years; MRI scans, frozen tumor tissue). The DNA methylome (Illumina, EPIC array) and transcriptome (RNAseq) were established. TVGR was determined based on serial MRIs collected over the "watch & wait" period before the first treatment beyond surgery. Transcriptomic and methylome data were analyzed for signatures associated with TVGR using rank-rank regression followed by preranked gene set enrichment analysis. The median TVGR was lower in IDHmt codeleted compared to non-codeleted LGG (0.241 year-1 range 0.082-0.366 vs. 0.424 year-1 range 0.264-0.609, P < .001). In codeleted IDHmt LGG, TVGR was associated with upregulated gene signatures for neuronal systems, synaptic activity, and activation of repressed or poised signatures of neural progenitor cells, while the TVGR in non-codeleted IDHmt LGG was dominated by upregulated proliferation-related signatures, including DNA replication and repair. Spontaneous TVGR of codeleted and non-codeleted IDHmt LGG involves distinct biological processes, suggesting possible differences in response to therapies.

Enhancing the catalytic stability of Fe-N-C catalysts for cathodic oxygen reduction in proton-exchange membrane fuel cells (PEMFCs) necessitates an in-depth understanding of their degradation mechanisms. This study identifies key stressors affecting the stability of Fe-N-C catalysts, specifically acidic environment, oxygen (O2), and reactive oxygen species (ROS). Through ex situ/operando experiments, we show that the oxidation of local carbon by acidic environment + O2 + ROS, along with the demetalation of catalytic FeNxCy sites by O2 or O2 + ROS, is the primary factor responsible for the initial fast degradation of Fe-N-C catalysts. The demetalation of FeNxCy sites, influenced by O2, in particular by O2 + ROS, leads to the subsequent gradual degradation of Fe-N-C. Notably, FeN4C12-type active sites are more susceptible to demetalation than FeN4C10-type sites in O2 or O2 + ROS. Our findings indicate that, besides constructing more stable FeNxCy sites, preventing local carbon oxidation and scavenging of ROS are all critical for maintaining the stability of Fe-N-C catalysts.