Biology subjects

Zhao, X.

Publications and source records attributed to Zhao, X..

At least 379 records · Page 21Linked to original sources

bioRxiv2022

Temporally integrated transcriptome analysis reveals ASFV pathology and host response dynamics

African swine fever virus (ASFV) causes a lethal swine hemorrhagic disease and is currently responsible for widespread damage to the pig industry. The molecular mechanisms of ASFV pathogenicity and its interaction with host responses remain poorly understood. In this study, we profiled the temporal viral and host transcriptomes in porcine alveolar macrophages (PAMs) infected at 6, 12, 24 and 48 hours with highly virulent (SY18) and low virulent (HuB20) ASFV strains. We first identified profound differences in the virus expression programs between SY18 and HuB20, while the transcriptome dynamics in host cells were dominated by infection time. Through integrated computational analysis and experimental validation, we identified differentially expressed genes and related biological processes, and elaborated differential usage of the NF-kappaB related pathways by the two virus strains. In addition, we observed that compared to the highly virulent SY18 strain, HuB20 infection quickly activates expression of receptors, sensors, regulators, as well as downstream effectors, including cGAS, STAT1/2, IRF9, MX1/2, suggesting rapid induction of a strong immune response. Lastly, we constructed a host-virus coexpression network, which shed light on pathogenic functions of several ASFV genes. Taken together, these results will provide a basis for further mechanistic studies on the functions of both viral and cellular genes that are involved in different responses. Author SummarySince it was first described in Kenya in 1921, ASF has spread across sub-Saharan Africa, the Caribbean, the Western Europe, the Trans-Caucasus region, and the Russian Federation. Recent outbreaks have also been reported in Asia, which has devastated the pig industry, resulting in an approximately 40% reduction in pork worldwide. In the absence of effective vaccine or treatment, the mortality for infections with highly virulent strains approaches 100%, while low virulent strains causing less mortality spreads fast recently. Nevertheless, the mechanisms of ASFV pathogenicity, especially the differences between highly and low virulent strains remain poorly understood. Here, we used RNA-seq to analyze the viral and host transcriptome changes in PAMs infected with a virulent strain (SY18) or an attenuated strain (HuB20) at different stages. We found that the presence of ASFV significantly affected the cellular transcriptome profile. In addition, we did temporal and described the dynamic expression programs induced in the host cells by ASFV infection of different virulence strains. In particular, we identified differential gene expression patterns in host innate immune responses and expressed cytokines and chemokines between ASFV strains of different virulence. Our study provides new insights into ASFV pathogenicity research and novel drug or vaccine targets.

microbiology↗

bioRxiv2022

Trophoblast and blood vessel organoid cultures recapitulate the role of WNT2B in promoting intravillous vascularization in human intrauterine and ectopic pregnancy

Tubal ectopic pregnancy (TEP), a pregnancy complication caused by aberrant implantation in fallopian tubes, accounts for 9-13% pregnancy-related deaths. The lack of models for human TEP hampers the understanding of its pathological mechanisms. Here, we employed multiple models to investigate the crosstalk between human trophoblast development and intravillous vascularization. We found that the severity of TEP, the size of placental villi, and the depth of trophoblast invasion are correlated with the extent of intravillous vascularization. We identified a key pro-angiogenic factor secreted by trophoblasts, WNT2B, that promotes villous vasculogenesis, angiogenesis, and vascular network expansion. In an organoid coculture model consisting of trophoblast organoids and blood vessel organoids, knockdown of WNT2B in trophoblast organoids compromises their pro-angiogenic effect on the development of blood vessel organoids. These organoid-based models reveal an important role for WNT-mediated angiogenesis in pregnancies and could be employed to investigate the commutations between trophoblasts and endothelial/endothelial progenitor cells.

cell biology↗

bioRxiv2022

Population genomics unravels the Holocene history of Triticum-Aegilops species

Deep knowledge of crop biodiversity is essential to improve global food security. Despite bread wheat serving as a keystone crop worldwide, the population history of bread wheat and its wild relatives (a.k.a. wheats) remains elusive. By analyzing whole-genome sequences of 795 wheats, we found that bread wheat originated southwest of the Caspian Sea [~]11,700 years ago and underwent a slow speciation process, lasting [~]3,300 years due to persistent gene flow from wild relatives. Soon after, bread wheat spread across Eurasia and reached Europe, South Asia, and East Asia [~]7,000 to [~]5,000 years ago, shaping a diversified but occasionally convergent adaptive landscape of bread wheat in novel environments. Opposite to cultivated wheat, wild wheat populations have declined by [~]82% in the past [~]2,000 years due to the food choice shift of humans, and likely continue to drop because of the changing climate. These findings will guide future efforts in protecting and utilizing wheat biodiversity to improve global food security.

genetics↗

bioRxiv2022

Pan-cancer quantification of neoantigen-mediated immunoediting in cancer evolution

Immunoediting, which includes three temporally distinct stages, termed elimination, equilibrium, and escape, has been proposed to explain the interactions between cancer cells and the immune system during the evolution of cancer. However the status of immunoediting in cancer remains unclear, and the existence of neoantigen depletion signal in untreated cancer has been debated. Here we developed a distribution pattern based method for quantifying neoantigen mediated negative selection in cancer evolution. Our method provides a robust and reliable quantification for immunoediting signal in an individual cancer patient. The prevalence of immunoediting signal in immunotherapy untreated cancer genome has been demonstrated with this method. Importantly, the elimination and escape stages of immunoediting can be quantified separately, tumor types with strong immunoediting-elimination tend to have weak immunoediting-escape signal, and vice versa. Quantified immunoediting-elimination signal predicts cancer immunotherapy clinical response. Immunoediting quantification provides an evolutional perspective for evaluating the antigenicity of neoantigen, and reveals a potential biomarker for cancer precision immunotherapy.

cancer biology↗

bioRxiv2022

Antibody Resistance of SARS-CoV-2 Omicron BA.1, BA.1.1, BA.2 and BA.3 Sub-lineages

The SARS-CoV-2 Omicron variant has been partitioned into four sub-lineages designated BA.1, BA.1.1, BA.2 and BA.3, with BA.2 becoming dominant worldwide recently by outcompeting BA.1 and BA.1.1. We and others have reported the striking antibody evasion of BA.1 and BA.2, but side-by-side comparison of susceptibility of all the major Omicron sub-lineages to vaccine-elicited or monoclonal antibody (mAb)-mediated neutralization are urgently needed. Using VSV-based pseudovirus, we found that sera from individuals vaccinated by two doses of inactivated whole-virion vaccines (BBIBP-CorV) showed very weak to no neutralization activity, while a homologous inactivated vaccine booster or a heterologous booster with protein subunit vaccine (ZF2001) markedly improved the neutralization titers against all Omicron variants. The comparison between sub-lineages indicated that BA.1.1, BA.2 and BA.3 had comparable or even greater antibody resistance than BA.1. We further evaluated the neutralization profile of a panel of 20 mAbs, including 10 already authorized or approved, against these Omicron sub-lineages as well as viruses with different Omicron spike single or combined mutations. Most mAbs lost their neutralizing activity completely or substantially, while some demonstrated distinct neutralization patterns among Omicron sub-lineages, reflecting their antigenic difference. Taken together, our results suggest all four Omicron sub-lineages threaten the efficacies of current vaccines and antibody therapeutics, highlighting the importance of vaccine boosters to combat the emerging SARS-CoV-2 variants.

microbiology↗

bioRxiv2022

Extended longevity geometrically-inverted proximal tubule organoids for protein uptake studies

While some in vitro platforms have been adapted to study proteinuric kidney disease, organoids have been challenging to study the disease. This is because apical access is historically difficult, and this is the surface on which megalin (LRP2), an endocytic receptor responsible for tubular reabsorption of filtered plasma proteins, resides. Based on our previous geometrically-inverted organoids, this study established high-throughput basal-in and apical-out proximal tubule organoids to study proteinuric kidney disease in a more physiologically consistent manner. Organoids successfully formed around a minimal Matrigel scaffold, and were maintained in culture for 90+ days, the longest reported hanging drop culture to date. The proximal tubule organoids exhibited good polarization, showed upregulation of maturity markers, such as aquaporin-1 and megalin, and experienced less epithelial-to-mesenchymal (EMT) transition compared to 2D cells. To assess protein uptake, fluorescent albumin was placed in the surrounding media, facing the apical surface, and organoids demonstrated functional protein uptake even at 90 days. To mimic proteinuric conditions, organoids were exposed to human serum albumin and released kidney injury molecule-1 (KIM-1), a common biomarker for kidney injury, in both dose- and time-dependent manners. While this study focuses on applications for modeling proteinuric kidney disease conditions, these organoids are envisioned to have broad utility where apical proximal tubule cell access is required.

bioengineering↗

bioRxiv2022

Anti-phasic oscillatory development for speech and noise processing in cochlear implanted toddlers

Human brain demonstrates amazing readiness for speech and language learning at birth, but the auditory development preceding such readiness remains unknown. Cochlear implanted (CI) children with prelingual deafness provide a unique opportunity to study this developmental stage. Using functional near-infrared spectroscopy, we revealed that the brain of CI children was nearly irresponsive to sounds at CI hearing onset. With increasing CI experiences up to 32 months, the brain demonstrated function, region and hemisphere specific development. Most strikingly, the left anterior temporal lobe showed an oscillatory trajectory, changing in opposite phases for speech and noise. In addition, speech responses increased linearly in left sylvian parieto-temporal area and right inferior frontal gyrus, and noise responses changed in U shape in right supramarginal gyrus. Such cortical development predicted behavioral improvement. The study provides the first longitudinal brain imaging evidence for early auditory development preceding speech acquisition in the human brain. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/483211v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@d84974org.highwire.dtl.DTLVardef@1be9ba0org.highwire.dtl.DTLVardef@db5fb7org.highwire.dtl.DTLVardef@68f420_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIThe brain of cochlear implanted toddlers is functionally inferior to neonates C_LIO_LIHearing experiences drive functional development in auditory related cortical areas C_LIO_LISpeech and noise processing develop in anti-phasic oscillatory trajectories C_LIO_LIAuditory cortical development predicts post-implantation behavioral improvement C_LI

neuroscience↗

bioRxiv2022

The ITPRIPL1- CD3ϵ axis: a novel immune checkpoint controlling T cells activation

The immune system is critical to fighting infections and disease. The molecular recognition of harmful entities takes place when antigen-presenting cells (APC) harboring major histocompatibility complex (MHC) molecules bound to peptides derived from harmful antigens (ligand) dock on specific T cell receptor (TCR)-CD3 complex (receptor) at the surface of CD8+ T cells. The discovery of a general immune checkpoint mechanism to avoid the harmful impact of T cell hyperactivation provoked a paradigm shift. The clinical relevance of this mechanism is highlighted by the fact that PD-1 and PD-L1 inhibitors are very effective at boosting immune reactions. Still, immune evasion frequently happens. The observation that some PD-1/PD-L1 negative tumors have a poor immune response opens the door to identifying a novel immune checkpoint mechanism. Here, we discovered that ITPRIPL1, a gene with unknown function, impairs T cell activation. Surprisingly, we found that CD3{varepsilon} is the direct receptor of ITPRIPL1. This novel immune checkpoint was validated as a drug target using ITPRIPL1 KO mice and monoclonal antibodies. Thus, targeting the ITPRIPL1-CD3e axis, especially in PD-1 - PDL-1 negative patients, is a promising therapeutic strategy to reduce immune evasion.

immunology↗

bioRxiv2022

Dual species transcriptomics reveals core metabolic and immunologic processes in the interaction between primary human neutrophils and Neisseria gonorrhoeae strains

Neisseria gonorrhoeae (the gonococcus, Gc) is the causative agent of the sexually transmitted infection gonorrhea. Gc is a prominent threat to human health by causing severe and lifelong clinical sequelae, including infertility and chronic pelvic pain, which is amplified by the emergence of "superbug" strains that are resistant to all current antibiotics. Gc is highly adapted to colonize human mucosal surfaces, where it survives despite initiating a robust inflammatory response and influx of polymorphonuclear leukocytes (PMNs or neutrophils) that typically clear bacteria. Here, dual-species RNA-sequencing (RNA-seq) was used to define Gc and PMN transcriptional profiles alone and after infection. Three strains of Gc and three human donors transcriptional responses were assessed to characterize core host and bacterial responses. Comparative analysis of Gc transcripts revealed major overlap between the Gc response to PMNs, iron, and hydrogen peroxide; specifically, the TonB system and TonB dependent transporters (TDT) were upregulated in response to PMNs. We experimentally confirmed that induction of the iron-dependent TDT TbpB is responsive to the presence of PMNs and that tonB is required for Gc survival from PMNs. Pathway analysis of PMN transcripts induced by Gc infection revealed differential expression of genes driving pathways involved in cell adhesion and migration, inflammatory responses, and inflammation resolution. Production of pro-inflammatory cytokines, including IL1B and IL8, the adhesion factor ICAM1, and the anti-inflammatory prostaglandin PGE2 was confirmed to be induced in PMNs in response to Gc. Together, this study represents a comprehensive and experimentally validated dual-species transcriptomic analysis of three isolates of Gc and primary human PMNs that gives insight into how this bacterium survives innate immune onslaught to cause disease in humans.

genomics↗

bioRxiv2022

Extrachromosomal DNA is associated with decreased immune cell infiltration and antigen presentation, represents a potential cancer immune evasion mechanism

Extrachromosomal DNA (ecDNA) is a type of circular and tumor specific genetic element. EcDNA has been reported to display open chromatin structure, facilitate oncogene amplification and genetic material unequal segregation, and is associated with poor cancer patients prognosis. The ability of immune evasion is a typical feature for cancer progression, however the tumor intrinsic factors that determine immune evasion remain poorly understood. Here we show that the presence of ecDNA is associated with markers of tumor immune evasion, and obtaining ecDNA could be one of the mechanisms employed by tumor cells to escape immune surveillance. Tumors with ecDNA usually have comparable TMB and neoantigen load, however they have lower immune cell infiltration and lower cytotoxic T cell activity. The microenvironment of tumors with ecDNA shows increased immune desert, decreased immune enriched fibrotic types. Both MHC class I and class II antigen presentation genes expression are decreased in tumors with ecDNA, and this could be the underlying mechanism for ecDNA associated immune evasion. This study provides evidence that the presence of ecDNA is an immune escape mechanism for cancer cells.

cancer biology↗

bioRxiv2022

Rtt105 configurationally staples RPA and blocks facilitated exchange and interactions with RPA-interacting proteins

Replication Protein A (RPA) binds to single-stranded DNA (ssDNA) and recruits over three dozen RPA-interacting proteins (RIPs) to coordinate multiple aspects of DNA metabolism including DNA replication, repair, and recombination. Rtt105 is a molecular chaperone that regulates nuclear localization of RPA. Whether and how Rtt105 regulates the activities of RPA is poorly understood. Here, we show that Rtt105 binds to multiple DNA binding and protein-interaction domains of RPA and configurationally staples the complex. In the absence of ssDNA, Rtt105 inhibits RPA binding to Rad52, thus preventing spurious binding to RPA-interacting proteins (RIPs). When ssDNA is available, Rtt105 promotes formation of high-density RPA nucleoprotein filaments and dissociates during this process. Free Rtt105 further stabilizes the RPA-ssDNA filaments by inhibiting RPA facilitated exchange. Collectively, our data suggest that Rtt105 sequesters free RPA in the nucleus to prevent untimely RIP interaction, while stabilizing RPA-ssDNA filaments at DNA lesion sites.

biochemistry↗

bioRxiv2022

3D Printable High Performance Conducting Polymer Hydrogel for All-Hydrogel Bioelectronics

Owing to the unique combination of electrical conductivity and tissue-like mechanical properties, conducting polymer hydrogels have emerged as a promising candidate for bioelectronic interfacing with biological systems. However, despite the recent advances, the development of hydrogels with both excellent electrical and mechanical properties in physiological environments remains a lingering challenge. Here, we report a bi-continuous conducting polymer hydrogel (BC-CPH) that simultaneously achieves high electrical conductivity (over 11 S cm-1), stretchability (over 400%) and fracture toughness (over 3,300 J m-2) in physiological environments, and is readily applicable to advanced fabrication methods including 3D printing. Enabled by the BC-CPH, we further demonstrate multi-material 3D printing of monolithic all-hydrogel bioelectronic interfaces for long-term electrophysiological recording and stimulation of various organs. This study may offer promising materials and a platform for future bioelectronic interfacing.

bioengineering↗

bioRxiv2022

Transcription factor determines the sources of extracellular vesicle DNA

Extracellular vesicle DNAs (evDNAs) possess the important diagnostic value for multiple diseases and play roles for horizontally transferring genetic materials among cells. In this study, we have found that transcription factor FOXM1 can mediate the loading of certain chromatin genes or DNA fragments (named FOXM1-chDNAs) to extracellular vesicles (EVs). FOXM1 interacts with LC3 in nucleus and FOXM1-chDNAs (such as DUX4 gene and Telomere DNA) are specified by FOXM1 and translocated to cytoplasm. These DNAs are released to EVs through the process of an LC3-involved autophagosome-multivesicular body (MVB) transport. The roles of FOXM1 on loading FOXM1-chDNAs to EVs are further confirmed by DNA-FISH experiments, tracing the translocation of selected chromatin loci with the TetO/TetR-GFP method, and PCR analysis of the DNA samples from MVBs and EVs. Furthermore, disrupting the expression of FOXM1 or the process of autophagosome-MVB transport impairs the loading of FOXM1-chDNAs to EVs. This discovery suggests that transcription factor FOXM1 contributes the constitution of evDNAs from nuclear chromatin, providing the first example to explain how chromatin DNA fragments are specified and loaded to EVs. It also provide a foundation to further explore the roles of evDNAs in biological processes such as the horizontal gene transfer.

cell biology↗

bioRxiv2022

Marine Bacteria Chemotaxis to Crude Oil Components with Opposing Effects

Marine microorganisms were critical to hydrocarbon removal from the Gulf of Mexico oil spill. Chemotaxis, a process attracting motile bacteria toward higher hydrocarbon concentrations, can increase biodegradation efficiency. However, crude oil also contains heavy metal ions that repel bacteria. Will bacteria migrate toward hydrocarbons or away from heavy metals? We exposed a marine isolate Halomonas sp. to decane and copper ions in a microfluidic device that maintained a constant concentration gradient across a channel. Bacterial distributions were used to quantify parameters in a mathematical model capturing bacteria motility and chemotaxis. This multi-scale model was adapted from the signal transduction mechanism of E. coli. For Halomonas sp., we used independent receptors for sensing attractant or repellent and chemotaxis parameter values were assessed. Predictions based on the multi-scale model correctly estimated the net attraction or repulsion responses of bacteria to the stimuli mixture. In some cases, the model yielded a stronger repulsion than what was observed experimentally, but still captured the general trends of bacteria distribution. Understanding how marine bacteria integrate information from multiple inputs to yield net migration toward or away from oil will improve predictions of hydrocarbon degradation rates.

bioengineering↗

bioRxiv2022

A reference single-cell regulomic and transcriptomic map of cynomolgus monkeys

Non-human primates (NHP) are attractive laboratory animal models that accurately reflect both developmental and pathological features of humans. Here we present a compendium of cell types from the cynomolgus monkey Macaca fascicularis (denoted as Monkey Atlas) using both single-cell chromatin accessibility (scATAC-seq) and RNA sequencing (scRNA-seq) data at the organism-wide level. The integrated cell map enables in-depth dissection and comparison of molecular dynamics, cell-type composition and cellular heterogeneity across multiple tissues and organs. Using single-cell transcriptomic data, we inferred pseudotime cell trajectories and cell-cell communications to uncover key molecular signatures underlying their cellular processes. Furthermore, we identified various cell-specific cis-regulatory elements and constructed organ-specific gene regulatory networks at the single-cell level. Finally, we performed a comparative analysis of single-cell landscapes among mouse, cynomolgus monkey and human, and we showed that cynomolgus monkey has significantly higher degree of cell-type similarity to human than mouse. Taken together, our study provides a valuable resource for NHP cell biology.

bioinformatics↗

bioRxiv2022

ASGR1 is a candidate receptor for SARS-CoV-2 that promotes infection of liver cells

Backgroud & AimsCurrently, the COVID-19 pandemic, caused by SARS-CoV-2 infection, represents a serious public health problem worldwide. Although it has been shown that ACE2 serves as the main receptor for SARS-CoV-2 entry into host cells, studies have shown that ACE2 is expressed at extremely low levels in various tissues, especially in some organs where virus particles have been found, such as the heart and liver. Therefore, these organs potentially express additional SARS-CoV-2 receptors that have not yet been discovered. Methods & ResultsHere, by a genome-wide CRISPR-Cas9 activation library screening, we found that ASGR1 promoted SARS-CoV-2 infection of 293T cells. In Huh-7 and HepG2 cell lines, simultaneous knock out of ACE2 and ASGR1 prevented SARS-CoV-2 pseudovirus infection. In the immortalized THLE-2 hepatocyte cell line and primary liver parenchymal cells, both of which hardly express ACE2, SARS-CoV-2 could successfully establish an infection. After treatment with ASGR1 antibody, the infection rate significantly reduced. This suggests that SARS-CoV-2 infects liver cells mainly through an ASGR1-dependent mechanism. Finally, we also found that the soluble ASGR1 could not only prevent the SARS-CoV-2 pseudovirus, which binds to the ASGR1 receptors, from infecting host liver cells, but also had a protective effect on those expressing ACE2, indicating that administration of soluble ASGR1 protein may represent a new treatment approach. ConclusionsColletively, these findings indicate that ASGR1 is a candidate receptor for SARS-CoV-2 that promotes infection of liver cells. Lay SummaryWe show that ASGR1 is a candidate receptor for SARS-CoV-2 to infect liver cells.

microbiology↗

bioRxiv2022

Maternal immune activation accelerates puberty initiation and alters mechanical allodynia in male and female C57BL6/J mice.

The mechanisms that link maternal immune activation (MIA) with the onset of neurodevelopmental disorders remain largely unclear. Accelerated puberty is also associated with a heightened risk for psychopathology in later life but there is a dearth of evidence on the impacts of maternal infection on pubertal timing. We examined the effects of MIA on reproductive development, mechanical allodynia, and sensorimotor gating in juvenile, adolescent, and adult male and female mice. Moreover, we investigated hypothalamic neural markers associated with the reproductive and stress axes. Finally, we tested the mitigating effects of environmental enrichment (EE), which has clinical relevancy in human rehabilitation settings. Our results show that administration of polyinosinic-polycytidylic acid (poly(I:C)) on gestational day 12.5 led to early preputial separation, vaginal openings, and age of first estrus in offspring. MIA exposure altered pain sensitivity across development and modestly altered prepulse inhibition. The downregulation of Nr3c1 and Oprk mRNA in the hypothalamus of juvenile mice suggests that MIAs effects may be mediated through disruption of hypothalamic-pituitary-adrenal axis activity. In contrast, life-long housing with EE rescued many of these MIA-induced consequences. Overall, our findings suggest that accelerated puberty may be associated with the deleterious effects of infection during pregnancy and the onset of psychopathology.

neuroscience↗

bioRxiv2022

Sustained correction of hippocampal neurogenic and cognitive deficits after a brief treatment by Nutlin-3 in a mouse model of Fragile X Syndrome

BackgroundFragile X syndrome (FXS), the most prevalent inherited intellectual disability and one of the most common monogenic form of autism, is caused by a loss of FMRP translational regulator 1 (FMR1). We have previously shown that FMR1 represses the levels and activities of ubiquitin ligase MDM2 in young adult FMR1-deficient mice and treatment by a MDM2 inhibitor Nutlin-3 rescues both hippocampal neurogenic and cognitive deficits in FMR1-deficient mice when analyzed shortly after the administration. However, it is unknown whether Nutlin-3 treatment can have long-lasting therapeutic effects. MethodsWe treated 2-month-old young adult FMR1-deficient mice with Nutlin-3 for 10 days and then assessed the persistent effect of Nutlin-3 on both cognitive functions and adult neurogenesis when mice were 6-month-old mature adults. To investigate the mechanisms underlying persistent effects of Nutlin-3, we analyzed proliferation and differentiation of neural stem cells isolated from these mice and assessed the transcriptome of the hippocampal tissues of treated mice. ResultsWe found that transient treatment with Nutlin-3 of 2-month-old young adult FMR1-deficient mice prevents the emergence of neurogenic and cognitive deficits in mature adult FXS mice at 6-month of age. We further found that the long-lasting restoration of neurogenesis and cognitive function might not be mediated by changing intrinsic properties of adult neural stem cells. Transcriptomic analysis of the hippocampal tissue demonstrated that transient Nultin-3 treatment leads to significant expression changes in genes related to extracellular matrix, secreted factors, and cell membrane proteins in FMR1-deficient hippocampus. ConclusionsOur data indicates that transient Nutlin-3 treatment in young adults leads to long-lasting neurogenic and behavioral changes through modulating adult neurogenic niche rather than intrinsic properties of adult neural stem cells. Our results demonstrate that cognitive impairments in FXS may be prevented by an early intervention through Nutlin-3 treatment.

neuroscience↗