Fulin Liu

Rôle de PPARγ dans le développement placentaire normal et pathologique: Dans la première partie, nous avons extrait les ensembles de données d'expression génique qui combinaient le génome du placenta humain pendant la grossesse de 4 à 40 semaines de gestation. Nos résultats ont montré un total de 5173 gènes impliqués dans différentes périodes de placentation avec la voie de signalisation du récepteur activé par les proliférateurs de peroxysomes (PPAR) confirmée comme médiateur de la diminution constante des lipides placentaires tout au long de la grossesse. Dans la deuxième partie, nous avons étudié l'un des PPAR, PPARγ, dans les trophoblastes, les cellules qui constituent la partie principale du placenta. La recherche a été menée sur les cytotrophoblastes extravilleux (EVCT) et les cytotrophoblastes villeux (VCT), où PPARγ est exprimé. Nous avons exploré les effets à l'échelle du génome de PPARγ activé sur les EVCT et les VCT. À partir de nos données de puces à ADN, nous avons fourni une large perspective des processus biologiques activés par PPARγ dans les trophoblastes. Dans la troisième partie, nous avons tenté de comprendre la relation entre les cibles du PPARγ et du facteur inductible par l'hypoxie (HIF) dans le transcriptome placentaire humain du premier trimestre en réponse à l'augmentation des niveaux d'oxygène dans l'environnement. En comparant les transcriptomes de placentas humains à 8-10 semaines de gestation et 12-14 semaines de gestation, nous avons caractérisé les similitudes et les différences entre les schémas d'enrichissement, ainsi que ceux associés aux cibles HIF. Cependant, une intersection entre les cibles de PPARγ et HIF n'a montré aucun élément chevauchant. Dans la quatrième partie, nous avons exploré la relation entre les polymorphismes de PPARγ et la susceptibilité à la prééclampsie, une maladie gravide. Avec des caractéristiques cliniques et des polymorphismes génotypés de PPARγ d'un total de 1648 femmes, nous avons appliqué huit algorithmes d'apprentissage automatique pour optimiser les modèles prédictifs. L'arbre décisif avec la plus haute performance de précision et la zone sous la courbe caractéristique de fonctionnement du récepteur (AUC) a été sélectionné et affiché pour montrer la procédure de prédiction de la prééclampsie. Pour résumer, nos résultats soutiennent que PPARγ médie la diminution constante des lipides placentaires tout au long de la grossesse via la voie de signalisation PPAR, fournit une large perspective des processus biologiques activés par PPARγ dans les EVCT et les VCT grâce à l'analyse des signatures transcriptomiques, et développe un modèle pragmatique pour clinique avec les polymorphismes de PPARγ.

Bladder cancer ranks among the most prevalent malignancies affecting the urinary system worldwide. Despite advances in treatment, poor drug penetration and uncontrolled release continue to impede the effectiveness of chemotherapy for this disease. To overcome these obstacles, we have developed a self-driven electrical triggering system, which leverages intravesical pressure to produce electricity. This electronic trigger system can rapidly transport hydroxycamptothecin through tunneling nanotubes, acting as a high-speed channel, thereby enhancing the drug absorption by tumor cells. Additionally, the voltage generated by this system effectively induces reactive oxygen species (ROS), further promoting the eradication of bladder cancer cells. In orthotopic female animal models of bladder cancer, our results indicate that an intravesical pressure-driven system in the bladder generates electricity to facilitate drug release and rapid diffusion through a tunneling nanotube highway, while also effectively generating ROS to eliminate bladder cancer cells. This self-driven electrical trigger system, coupled with a tunneling nanotube highway to transport drugs, offers renewed hope for bladder cancer treatment. With its potential to transform current therapeutic approaches, this system is poised for deeper exploration in research and clinical settings.

The increasing incidence of central nervous system lymphoma (CNSL) is hindered by the blood-brain barrier and costly prolonged drug development. To overcome these obstacles, we developed a carboplatin lock-designed MOF (Pt-MOFs@Glu) targeting intestinal macrophages for brain-directed drug transport. Single-cell RNA sequencing analyses revealed that intestinal macrophages migrate to the brain in response to chemokines. Building on this insight, Pt-MOFs@Glu was designed to engage these cells for precise delivery. Comprising carboplatin, pyrazine-quinoxaline, and β-glucan, the system induces an “avalanche effect” in the CNSL microenvironment, promoting tumor apoptosis and inhibiting metastasis. Combining pyrazine-quinoxaline to lock carboplatin and β-glucan to boost targeting, immunity, and oral absorption, the system enables ROS-triggered drug release, efficiently crosses the gastrointestinal tract and BBB, and synergizes chemo-immunotherapy to enhance therapeutic efficacy. This approach redefines CNSL treatment by harnessing the gut-brain axis, offering a transformative pathway to overcoming therapeutic barriers and improving patient outcomes.

Background: The regulatory molecule Human Leukocyte Antigen F (HLA-F) has been implicated in trophoblast proliferation during pregnancy, and reduced levels of this antigen have been identified in trophoblast cells of patients with preeclampsia. This study aimed to analyze the effect and mechanism of HLA-F on the proliferation of trophoblast and the underlying mechanism of reduced HLA-F involved in preeclampsia. Methods: q-PCR, Western blot (WB), and Immunohistochemistry (IHC) were used to detect the expression of HLA-F and Pyruvate Kinase Muscle isoform 2 (PKM2) in placenta tissues. Jar cells were transfected with overexpression lentivirus, specific siRNA, and shRNA to regulate corresponding genes. Immunofluorescence was used to analyze the expression and distribution of HLA-F and PKM2. Extracellular and intracellular lactate, pyruvate, and enzymatic activity of PKM2 were measured using the corresponding assay kits. Cell proliferation was measured by CCK8, MTT, colony formation assay, and Mini patient-derived xenograft (Mini-PDX). Chromatin Immunoprecipitation and deep sequencing (ChIP-seq) and 4-dimensional label-free quantitative proteomics (4D-LFQP-LA) were used to analyze the HLA-F-binding DNA sequences and the differential lactylation proteins in HLA-F-overexpression Jar and its control. Results: The expression of HLA-F is reduced in extravillous trophoblast and villous cytotrophoblast from patients with preeclampsia. Over-expression of HLA-F promoted proliferation while under-expression inhibited it. Further experiments demonstrated that over-expression of HLA-F promoted expression of the PKM2 protein and its enzymatic activity, resulting in enhanced glycolysis in Jar cells. Specifically, we determined that HLA-F regulated the expression of PKM2 by binding the promoter of PKM, and promoted PKM2 enzyme activity by down-regulating the lactylation of residue K305. Moreover, silencing PKM2 with siRNA reduced HLA-F–mediated glycolysis and proliferation in HLA-F–overexpressing Jar cells. Finally, we corroborated these results using a MiniPDX model, with which we confirmed that the PKM2 agonist TEPP-46 promoted the proliferation of ShHLA-F Jar cells. Conclusions: The reduced expression of HLA-F in placental trophoblast cells resulted in the downregulation of both PKM2 transcription and protein expression. Concurrently, the relative upregulation of lactylation at PKM2 K305 contributed to a decline in enzyme activity, further exacerbating glycolysis dysfunction. Collectively, these alterations led to a suppression of trophoblast proliferation capacity and involvement in the pathogenesis of preeclampsia. Graphical

Noninvasive prenatal testing (NIPT) has been widely used in various monogenic recessive disorders based on relative haplotype dosage (RHDO) analysis. We accepted a congenital adrenal hyperplasia (CAH) pedigree with highly similar parental pathogenic haplotypes. The initial monogenic NIPT attempt was unsuccessful due to a paucity of informative single‐nucleotide polymorphisms (SNPs), prompting improvement of the current method. With a refined algorithm that deduces the fetal genotype based on dosage changes at SNPs located on a specific parental haplotype, while also effectively sidestepping allele bias introduced by hybrid capture, monogenic NIPT was successfully carried out in this family, yielding results consistent with invasive prenatal diagnosis. Theoretically, this algorithm can be employed in scenarios involving consanguineous marriages or when parents share a highly homologous haplotype, thereby broadening its applicability. Detailed methodology is described, and the advantages of our algorithm are discussed.

Background Spinocerebellar ataxia-36 (SCA36) is an inherited neurodegenerative disorder caused by the heterozygous expansion of an intronic GGCCTG hexanucleotide repeat in the NOP56 gene on chromosome 20p13. Unaffected individuals typically carry 3 to 14 repeats, whereas affected individuals carry 650 to 2,500. However, based on a single study, this pathogenic range was conservatively established, limiting its extended clinical applicability such as preimplantation genetic testing (PGT). In this study, we propose a novel methodology to recalibrate the pathogenic range of SCA36 repeat expansion. Methods We conducted a comprehensive literature review and collected examination data from 2012 onward. We used the gamma distribution to describe the data distribution and applied Bayesian methods to update the prior distribution with data from recent publications. Based on the recalibrated distribution, the 95% confidence interval (CI) was used to determine the new lower boundary of the pathogenic range. A pedigree was collected to validate the proposal with long-read sequencing (LRS) applied to detect the high GC content and long length of repeat expansions. Results Our results, based on 2 studies, indicate that the data distribution is well-described by gamma distribution. The prior, likelihood and posterior distributions within the 95% CI for the integrated research of SCA36 pathogenic repeat expansions were [446, +∞), [124, +∞), and [484, +∞), respectively. These recalibrated pathogenic ranges were validated by an authentic case: a proband diagnosed with SCA36 carrying 418 repeats and her daughter with 499 repeats, under the detection of LRS. Conclusions Therefore, we proposed a novel methodology that integrates updated data, 95% CI using Bayesian methods and LRS for accurate detection of repeat expansions of dynamic mutations to present an up-to-date pathogenic range of SCA36, as well as other similar diseases.

Aim: Fetal growth restriction (FGR) can lead to short‐term and long‐term impairments in the fetus. The placenta functions as an exchanger for substance transport, playing a critical role in fetal growth. However, the mechanism from the placental standpoint is still not fully understood. In this study, we aimed to investigate the pathophysiological mechanisms in the placenta that mediated the development of FGR and sex differences.Methods: We analyzed the gene expression profiles of GSE100415 containing specific normotensive FGR placental samples and GSE114691 with canonical samples using three different methods, differentially expressed gene analysis, weighted gene co‐expression network analysis, and gene set enrichment analysis. Gene enrichment was performed, including the gene ontology and pathway from the Kyoto Encyclopedia of Genes and Genomes. The important process was then validated in pregnant Wistar rats subcutaneously administered dexamethasone (0.2 mg/kg/d) or saline from gestation Day 9 to 21.Results: Our results revealed little difference between the comparison of normal and normotensive FGR placental samples but confirmed the sex difference. Further analyses of the canonical samples identified the occurrence of vascular dysfunction, which was validated by the calculation of the vascular lumen area, showing that the vascular lumen in the FGR group was more than in the control. We also discovered 17 significantly expressed genes from the involved eigengenes.Conclusion: Our study provides an important theoretical and experimental basis to reevaluate the development of FGR from the placental standpoint and suggests a series of biomarkers for future clinical use.

Although there are millions of left-behind children in China, the researches on brain structure and functions in left-behind children are not sufficient at the brain imaging level. This study aimed to explore whether there is decreased prefrontal synchronization during joint attention in left-behind children. Sixty children (65.12 ± 6.54 months, 29 males) with 34 left-behind children were recruited. The functional near-infrared spectroscopy (fNIRS) imaging data from the prefrontal cortex during joint attention, as well as behavioral measures (associated with family income, intelligence, language, and social-emotional abilities), were collected. Results verified that brain imaging data and behavioral measures are correlative and support that left-behind children have deficits in social-emotional abilities. More importantly, left-behind children showed decreased synchronization strength and asymmetry in the right middle frontal gyrus during joint attention. The findings suggest that decreased right prefrontal synchronization strength and asymmetry during joint attention might be vulnerability factors in the development of left-behind children.