Cell & Bioscience

Homologous recombination deficiency (HRD) testing has been approved by FDA for selecting epithelial ovarian cancer (EOC) patients who may benefit from the first-line poly (ADP-ribose) polymerase inhibitor (PARPi) maintenance therapy. However, the effects of HRD on the clinical outcomes of first-line chemotherapy and first-line PARPi maintenance therapy have not been rigorously evaluated in Chinese EOC patients. Here, we developed an HRD assay and applied it to two large Chinese EOC patient cohorts. In the first-line adjuvant chemotherapy cohort (FACT, N = 380), HRD status significantly improved PFS (median, 15.6 months vs. 9.4 months; HR, 0.688; 95% CI, 0.526 to 0.899; P = 0.003) and OS (median, 89.5 months vs. 60.9 months; HR, 0.636; 95% CI, 0.423 to 0.955; P = 0.008). In the first-line PARPi maintenance therapy cohort (FPMT, N = 83), HRD status significantly improved PFS (median, NA vs 12 months; HR, 0.438; 95% CI, 0.201 to 0.957; P = 0.033) and OS (median, NA vs NA months; HR, 0.12; 95% CI, 0.029 to 0.505; P = 0.001). Our results demonstrate that HRD status is a significant predictor for PFS and OS in both first-line chemotherapy and first-line PARPi maintenance therapy, providing strong real-world evidence for conducting genetic testing and improving clinical recommendations for Chinese EOC patients.

Papillary thyroid cancer (PTC) is the most common thyroid malignancy. Although PTC usually has a favorable prognosis, some aggressive PTC subtypes and lymph node (LN) metastasis contribute to high rates of recurrence and poor clinical outcomes. We analyzed single-cell RNA sequencing (scRNA-seq) data from 15 samples, including primary tumors of PTC, metastatic LNs, and paracancerous tissues. After quality filtering, 28,205 cells were detected. Of these, 13,390 cells originated from 7 tumor tissues, 2,869 cells from 2 metastatic LNs, and 11,945 cells from 6 paracancerous tissues. The increase in the proportion of CD4+ Tregs may be a key factor responsible for the immunosuppressive property of PTC. A novel cell type was identified, named Protective EGR1+CD4+ T cell, which might be antagonistic to the CD4+ Tregs and inhibit the formation of the immunosuppressive microenvironment and tumor immune evasion. Inhibitory checkpoints TIGIT and CD96 were found to be better targets than PD-1 for immune therapy in PTC patients with LN metastasis. For PTC patients without LN metastasis, however, PD-1, TIGIT, and CD96 could be suitable targets of immunotherapy. These findings would contribute to the further understanding of molecular mechanisms resulting in occurrence and development of PTC, and provide a theoretical rationale for targeted therapy and immunotherapy.

BackgroundTesticular aging is known to cause male age-related fertility decline and hypogonadism, but the underlying molecular mechanisms remain unclear. MethodsWe survey the single-cell transcriptomic landscape of testes from young and old men and examine age-related changes in germline and somatic niche cells. ResultsIn-depth evaluation of the gene expression dynamics of germline cells reveals that disturbance of base-excision repair pathway is a major feature of aging spermatogonial stem cells (SSCs), suggesting that defective DNA repair of SSCs may serve as a potential driver for increased de novo germline mutations with age. Further analysis of aging-associated transcriptional changes shows that stress-related changes and apoptotic signaling pathway accumulate in aged somatic cells. We identify age-related impairment of redox homeostasis in aged Leydig cells and find that pharmacological treatment with antioxidants alleviate this cellular dysfunction of Leydig cells and promote testosterone production. Lastly, our results reveal that decreased pleiotrophin (PTN) signaling is a contributing factor for testicular aging. ConclusionsThese findings provide a comprehensive understanding of the cell-type-specific mechanisms underlying human testicular aging at a single-cell resolution, and suggest potential therapeutic targets that may be leveraged to address age-related male fertility decline and hypogonadism. FundingThis work was supported by the National Key Research and Development Program of China (2018YFA0107200, 2018YFA0801404), the National Natural Science Foundation of China (32130046, 82171564, 82101669, 81871110, 81971759), the Key Research and Development Program of Guangdong Province (2019B020234001), the Natural Science Foundation of Guangdong Province, China (2022A1515010371), the Major Project of Medical Science and Technology Development Research Center of National Health Planning Commission, China (HDSL202001000), the Open Project of NHC Key Laboratory of Male Reproduction and Genetics (Family Planning Research Institute of Guangdong Province) (KF202001), the Guangdong Province Regional Joint Fund-Youth Fund Project (2021A1515110921), the China Postdoctoral Science Foundation (2021M703736).

To elucidate the molecular basis of multiple system atrophy (MSA), a neurodegenerative disease, we conducted a genome-wide association study (GWAS) in a Japanese MSA case/control series followed by replication studies in Japanese, Korean, Chinese, European and North American samples. In the GWAS stage rs2303744 on chromosome 19 showed a suggestive association (P = 6.5 x 10-7) that was replicated in additional Japanese samples (P = 2.9 x 10-6. OR = 1.58; 95% confidence interval, 1.30 to 1.91), and then confirmed as highly significant in a meta-analysis of East Asian population data (P = 5.0 x 10-15. Odds ratio= 1.49; 95% CI 1.35 to 1.72). The association of rs2303744 with MSA remained significant in combined European/North American samples (P =0.023. Odds ratio=1.14; 95% CI 1.02 to 1.28) despite allele frequencies being quite different between these populations. rs2303744 leads to an amino acid substitution in PLA2G4C that encodes the cPLA2{gamma} lysophospholipase/transacylase. The cPLA2{gamma}-Ile143 isoform encoded by the MSA risk allele has significantly decreased transacylase activity compared with the alternate cPLA2{gamma}-Val143 isoform that may perturb membrane phospholipids and -synuclein biology.

Leucine rich repeat and fibronectin type III domain containing 4(LRFN4) has been reported to be upregulated in multiple tumors and related to prognosis and survival of patients. However, the function of LRFN4 in LUAD is still unclear. Herein, bioinformatic approach was used for the first time to elucidate the relationship between LRFN4 and LUAD. In LUAD tissues, we discovered that LRFN4 mRNA expression was considerably higher. Higher LRFN4 expression was associated with poorer prognosis and higher clinical stage of LUAD patients. Paraffin pathology sections (12 samples including LUAD tissues and paired normal tissues from the Second Affiliated Hospital of Chongqing Medical University) were used to verify the expression of LRFN4 at the protein level by immunohistochemical staining. On the other hand, we identified that LRFN4 expression was related to multiple immune cells that constitute tumor immune microenvironment. Pathway enrichment analysis also suggested the enrichment of several tumor- and immune-related pathways, such as: Hippo pathway, NOD-like pathway, TNF pathway and P53 pathway. Finally, we constructed an 8-gene prognostic risk signature based on 35 LRFN4-related immunomodulators using the Cox regression model, and obtained reasonably good accuracy through Receiver Operating Characteristic curve (ROC curve) validation. The risk signature was further identified as an independent risk factor - was linked with worse survival of LUAD patients. Furthermore, a prognostic risk profile based on LRFN4-related immunomodulators was constructed. Meanwhile, other clinical features were integrated together as prognostic markers to construct a nomogram to predict the long-term survival probability of LUAD patients, and fairly high credibility was obtained by validation of calibration curves.

Clear cell renal cell carcinoma (ccRCC) accounts for the highest number of renal malignancies and 3% of all adult cancers. The incidence of ccRCC is increasing worldwide, and its prognosis is poor. Approximately 30% of the patients are diagnosed at a late stage and are frequently asymptomatic. Cuproptosis is a new type of cell death that is regulated by Cu ions. As cuproptosis is associated with cancer development, we hypothesized that changes in the expression of cuproptosis-related genes (CRGs) are associated with the prognosis of ccRCC, and that CRGs can serve as biomarkers for the diagnosis and prognosis of ccRCC. In the present study, we explored the correlation between CRGs and ccRCC prognosis by analyzing publicly available data. We analyzed the clinical information and RNA-sequencing data in The Cancer Genome Atlas using bioinformatics tools. Dihydrolipoamide S-succinyltransferase (DLST) was identified as a novel gene with predictive and diagnostic potential. CRGs were under-expressed in ccRCC samples, and downregulation of DLST was highly associated with poor prognosis. Cox univariate and multivariate regression analyses revealed that DLST could serve as an independent prognostic factor for ccRCC. Further, functional enrichment analysis indicated that low expression of DLST may affect immune function. Our results strongly indicate that DLST plays an important role in ccRCC progression and may serve as an independent diagnostic and prognostic biomarker for ccRCC. Therefore, DLST is a potential therapeutic target for patients with ccRCC.

Sry on the Y chromosome is the master switch in sex determination in mammals. It has been well established that Sry encodes a transcription factor that is transiently expressed in somatic cells of male gonad, inducing a series of events that lead to the formation of testes. In the testis of adult mice, Sry is expressed as a circular RNA (circRNA) transcript, a type of noncoding RNA that forms a covalently linked continuous loop. However, the physiological function of this Sry circRNA (circSry) remains unknown since its discovery in 1993. Here we show that circSry is mainly expressed in the spermatocytes, but not in mature sperms and Sertoli cells. Loss of circSry led to the reduction of sperm number and the defect of germ cell development. The expression of {gamma}H2AX was decreased and failure of XY body formation was noted in circSry KO germ cells. Further study demonstrates that circSry regulates H2AX mRNA indirectly in pachytene spermatocytes through sponging miR-138-5p. Our study demonstrates that, in addition to its well-known sex-determination function, Sry also plays important role in spermatogenesis as a circRNA.

This study investigated the human papillomavirus (HPV) infection status, genotype distribution, and associated risk factors among women in Suzhou to provide a theoretical basis for controlling cervical cancer and guiding vaccine development. From November 2022 to April 2023, 566 qualified participants undergoing health examinations at Suzhou Municipal Hospital were enrolled. Cervical exfoliated cells were tested for 21 HPV genotypes using fluorescence quantitative PCR, and data on general information, lifestyle, and clinical history were collected via questionnaire. The overall HPV infection rate was 11.31% (64/566). The most prevalent genotypes were HPV16, HPV52, and HPV58, each with an infection rate of 1.77%. Single infections predominated (8.83%, 50/566), with HPV16 (18%), HPV58 (14%), HPV51 (12%), and HPV81 (12%) being the most common. Multiple infections accounted for 2.47%, primarily dual infections (78.57%). Infection rates varied significantly by age, with the highest prevalence in women aged [&ge;]50 years (24.37%), followed by those aged 40-49 (8.42%) and [&le;]39 (7.35%). Significant risk factors for HPV infection included older age (OR=1.075, P<0.01), secondhand smoke exposure (OR=2.126, P<0.05), a history of underlying diseases, and a history of cervical surgery. In conclusion, the HPV infection rate in Suzhou remains considerable, with genotypes 16, 52, and 58 being predominant and single infections most common. Older age, secondhand smoke exposure, underlying diseases, and cervical surgery history are key risk factors, highlighting the need for targeted prevention and comprehensive control strategies.

Telomeres protect chromosomal integrity, and telomere length (TL) is influenced by environmental and genetic factors. While short-telomeres are linked to rare telomeropathies, this study explored the hypothesis that a "long-telomeropathy" is associated with a cancer-predisposing syndrome. Using genomic and health data from 113,861 individuals, a trans-ancestry polygenic risk score for TL (PRSTL) was developed. A phenome-wide association study (PheWAS) identified 65 tumor traits linked to elevated PRSTL. Using this result, a trans-ancestry phenotype risk score for a long-TL (PheRSLTL) was develop and validated. Rare variant analyses revealed 13 genes associated with PheRSLTL. Individuals who were carriers of these rare variants had a predisposition for long-TL validating original hypothesis. Most of these genes were new to both cancer and telomere biology. In conclusion, this study identified a novel tumor-predisposing syndrome shaped by both common and rare genetic variants, broadening the understanding of telomeropathies to those with a predisposition for long telomeres.

Incidence and severity of prostate cancer (PrCa) substantially varies across ancestries. American men of African ancestry (AA) are more likely to be diagnosed with and die from PrCa than the those of European ancestry (EA). Published polygenic risk scores for developing prostate cancer, even those based on multi-ancestry genome-wide association studies, do not address population-specific genetic mechanisms underlying PrCa risk in men of African ancestry. Specifically, the role of non-coding regulatory polymorphisms in driving inter-ancestry variation in PrCa has not been sufficiently explored. Here, by employing a sequence-based deep learning model of prostate regulatory enhancers, we identified [~]2,000 SNPs with higher alternate allele frequency in AA men that potentially affect enhancer function associated with PrCa susceptibility, as supported by our experimental validation. The identified enhancer SNPs (eSNPs) may influence PrCa development through two complementary mechanisms: 1) the alternate allele that increase enhancer activity result in immune suppression and telomere elongation, and 2) the alternate alleles that decrease enhancer activity, lead to de-differentiation and inhibition of apoptosis. Notably, the eSNPs tend to disrupt the binding of known prostate transcription factors including FOX, AR and HOX families. Lastly, the identified eSNPs can be combined into a polygenic risk score that adds value to current GWAS-based risk variants in assessing PrCa risk in independent cohorts.

The genetic cause of Huntington disease (HD) is attributed to the N-terminal polyglutamine expansion of huntingtin (mHTT). mHTT, which is a ubiquitously expressed protein, induces noticeable damage to the striatum, which affects motor, psychiatric, and cognitive functions in HD individuals. Although inflammatory responses apparently precede striatal damage and an overall progression of HD, the molecular mechanisms at work remain unclear (1-6). In this study, we found that cyclic GMP-AMP synthase (cGAS), a DNA sensor, which regulates inflammation, autophagy, and cellular senescence (7-9), plays a critical role in the inflammatory responses of HD. Ribosome profiling analysis reveals that cGAS mRNA has a high ribosome occupancy at exon 1 and codon-specific pauses at positions 171 (CCG) and 172 (CGT) in HD cells, compared to the control, indicating an altered cGAS expression. Accordingly, cGAS protein levels and activity, as measured by phosphorylation of stimulator of interferon genes (STING) or TANK-binding kinase 1 (TBK1), are increased in HD striatal cells, mouse Q175HD striatum and human postmortem HD striatum, compared to the healthy control. Furthermore, cGAS-dependent inflammatory genes such as Cxcl10 and Ccl5 show enhanced ribosome occupancy at exon 3 and exon 1, respectively and are upregulated in HD cells. Depletion of cGAS via CRISPR/Cas-9 diminishes cGAS activity and decreases expression of inflammatory genes while suppressing the autophagy upregulation in HD cells. We additionally detected the presence of numerous micronuclei, a known inducer of cGAS, in the cytoplasm of HD cells. Overall, the data indicates that cGAS is highly upregulated in HD and mediates inflammatory and autophagy responses. Thus, targeting cGAS may offer therapeutic benefits in HD.

Testicular homeostasis requires the balanced interplay between specific molecules in Sertoli cells, Leydig cells, germ cells. Loss of this coordination can lead to the disruption of spermatogenesis, even male infertility. By operating the upregulation and downregulation of Sirt3 in our male subfertility rats model and two testicular cells models, we indicated that Sirt3 overexpression and activator ameliorated cholesterol metabolism via P450scc deacetylation in Leydig cells, and cytoskeleton assembly via PDLIM1 with SOD2 deacetylation in Sertoli cells and elongating spermatids. In terms of the upstream regulator of Sirt3, the phosphorylation of NF-{kappa}B p65Ser536 stimulated the nuclear translocation of NF-{kappa}B subunits (p50, p65, RelB), which bound to TFBS1 and TFBS2 synchronously in the promoter of Sirt3, repressing Sirt3 transcription. This study demonstrates that NF-{kappa}B-repressed SIRT3 acts directly on cholesterol metabolism of Leydig cells and cytoskeleton assembly of Sertoli cells via P450scc/SOD2 deacetylation to regulate sperm differentiation, influencing spermatogenesis, even male fertility. Research organism: Rat, mouse

Aging usually suppresses the renewal and regeneration of intestinal epithelium. The imbalance of intestinal epithelial homeostasis may also be a promoter for aging. JWA responds to oxidative stress and repairs damaged DNA; it participates in multiple cellular processes like cell proliferation and differentiation. Here we identified JWA as a new aging-associated gene, whose deletion-accelerated aging in mice was related to intestinal epithelium atrophy. We further knocked out intestinal epithelial JWA and found it disrupted intestinal epithelial homeostasis, thus promoting aging in mice. Mechanistically, we discovered that JWA deficiency promoted Notch1 ubiquitination degradation via ERK/Fbxw7 cascade and interfered with the PPAR{gamma}/Stat5 signal axis. This reduced the intestinal stem cell function and altered the intestinal epithelial cell lineage distribution, finally suppressing the renewal and regeneration of intestinal epithelium. Our results demonstrated that JWA is a new aging-associated gene essential for the renewal and regeneration of intestinal epithelium. We also provide a new idea that maintaining intestinal epithelial homeostasis may be a potential anti-aging strategy in humans or mammals.

BackgroundDespite chemo-immunotherapy has been applied to the neoadjuvant treatment of non-small cell lung cancer (NSCLC), the impacts of dosage and the order of medication on treatment efficacy and safety remain largely unexplored. We originally designed an exploratory study to investigate the efficacy and safety of reduced-dose chemotherapy combined with delayed immunotherapy as well as the dynamic changes of circulating tumor DNA (ctDNA) and T cell receptor (TCR) during the therapy. MethodsPatients with clinical stage IIA to IIIA resectable NSCLC were treated with 2 cycles of reduced-dose platinum-based chemotherapy on day 1 combined with immunotherapy on day 5. The same postoperative modified adjuvant therapy regimen was administered for 2 cycles. Plasma samples at different time-points were collected and performed with T cell receptor (TCR) and circulating tumor DNA (ctDNA) sequencing. Results38 patients received modified chemo-immunotherapy. The proportion of patients exhibiting complete response and partial response was 5.3% and 68.4%, respectively. The confirmed objective response rate was 73.7%. Radiological downstaging was achieved in 39.5%. Major pathologic response and complete pathologic response were observed in 47.4% and 31.6% of patients, respectively. Only one patient experienced grade 3 adverse event. Further analyses revealed that this modified chemo-immunotherapy led to the expansion of predominant TCR clones and reduction of tumor burden after the first cycle of chemotherapy. ConclusionThe promising clinical efficacy and low side effects of modified neoadjuvant chemo-immunotherapy position it as a prospective and innovative strategy for NSCLC. Trial registration: Registration Number: ChiCTR2000033092

IntroThe molecular mechanisms of chronic fatigue syndrome (CFS, or Myalgic encephalomyelitis), a disease defined by extreme, long-term fatigue, remain largely uncharacterized, and presently no molecular diagnostic test and no specific treatments exist to diagnose and treat CFS patients. While CFS has historically had an estimated prevalence of 0.1-0.5% [1], concerns of a "long hauler" version of Coronavirus disease 2019 (COVID-19) that symptomatically overlaps CFS to a significant degree (Supplemental Table-1) and appears to occur in 10% of COVID-19 patients[2], has raised concerns of a larger spike in CFS [3]. Here, we established molecular signatures of CFS and a corresponding network-based disease context from RNA-sequencing data generated on whole blood and FACs sorted specific peripheral blood mononuclear cells (PBMCs) isolated from CFS cases and non-CFS controls. The immune cell type specific molecular signatures of CFS we identified, overlapped molecular signatures from other fatiguing illnesses, demonstrating a common molecular etiology. Further, after constructing a probabilistic causal model of the CFS gene expression data, we identified master regulator genes modulating network states associated with CFS, suggesting potential therapeutic targets for CFS.

Coronaviruses remodel intracellular membranes to form specialized viral replication compartments, such as double-membrane vesicles where viral RNA genome replication takes place. Understanding the factors affecting host response is instrumental to design of therapeutics to prevent or ameliorate the course of infection. As part of explorative tests in hospitalized patients with confirmed COVID-19 infection participating in ODYSSEY trial, we obtained samples for whole genome sequencing analysis as well as for viral genome sequencing. Based on our data, we confirm one of the strongest severity susceptibility locus thus far reported in association with severe COVID-19: 3p21.31 locus with lead variant rs73064425. We further examine the associated region. Interestingly based on LD analysis we report 3 coding mutations within one gene in the region of FYVE and Coiled-Coil Domain Autophagy Adaptor 1 (FYCO1). We specifically focus on the role of FYCO1 modifiers and gain-of-function variants. We report the associations between the region and clinical characteristics in this severe set of COVID-19 patients. We next analyzed expression profiles of FYCO1 across all 466 compounds tested. We selected only those results that showed a significant reduction of expression of FYCO1. The most significant candidate was indomethacin - an anti-inflammatory that could potentially downregulate FYCO1. We hypothesize that via its direct effects on efficiency of viral egress, it may serve as a potent therapeutic decreasing the replication and infectivity of the virus. Clinical studies will be needed to examine the therapeutic utility of indomethacin and other compounds downregulating FYCO1 in COVID-19 infection and other strains of betacoronaviruses.

BackgroundThe involvement of the androgen and androgen receptor (AR) pathway in the development of epithelial ovarian cancer is increasingly recognized. However, the specific mechanisms by which anti-androgen agents, such as flutamide, may prevent ovarian cancer and their efficacy remain unknown. We examined the effects of flutamide on the miRNA expression profile found in women at high risk (HR) for ovarian cancer. MethodsOvarian and tubal tissues, free from ovarian, tubal, peritoneal cancers, and serous tubal intraepithelial carcinoma (STIC), were collected from untreated and flutamide-treated HR women. Low-risk (LR) women served as controls. Transcriptomic miRNA sequencing was performed on these 3 sample cohorts. The miRNAs that showed the most notable differential expression were subjected to functional assays in primary ovarian epithelial cells and ovarian cancer cells. ResultsFlutamide treatment demonstrated a normalization effect on diminished miRNA levels in HR tissues compared to LR tissues. Particularly, the miR-449 family was significantly upregulated in HR ovarian tissues following flutamide treatment, reaching levels comparable to those in LR tissues. MiR-449a and miR-449b-5p, members of the miR-449 family, were computationally predicted to target the mRNAs of AR and colony-stimulating factor 1 receptor (CSF1R, also known as c-fms), both of which are known contributors to ovarian cancer progression, with emerging evidence also supporting their roles in ovarian cancer initiation. These findings were experimentally validated in primary ovarian epithelial cells and ovarian cancer cell lines (SKOV3 and Hey): flutamide treatment resulted in elevated levels of miR-449a and miR-449b-5p, and introducing mimics of these miRNAs reduced the mRNA and protein levels of CSF1R and AR. Furthermore, introducing miR-449a and miR-449b-5p mimics showed inhibitory effects on the migration and proliferation of ovarian cancer cells. ConclusionFlutamide treatment restored the reduced expression of miR-449a and miR-449b-5p in HR tissues, thereby decreasing the expression of CSF1R and AR, functional biomarkers associated with an increased risk of ovarian cancer. In addition to the known direct binding of flutamide to the AR, we found that flutamide also suppresses AR expression via miR-449a and miR-449b-5p upregulation, revealing a novel dual-inhibitory mechanism on the AR pathway. Taken together, our study highlights mechanisms supporting the chemopreventive potential of flutamide in ovarian cancer, particularly in HR patients with reduced miR-449 expression.

Alzheimers disease (AD), the leading cause of dementia, imposes a significant societal and economic burden; however, its complex molecular mechanisms remain unclear. This study integrates multi-omics data with advanced artificial intelligence (AI) methods to uncover the molecular basis underlying AD phenotype regulation and explore personalized drug repositioning strategies based on individual genetic backgrounds. First, we applied the PrediXcan method to identify candidate genes closely associated with AD cognitive diagnosis, selecting from 61 brain-related traits. We validated these findings through individual-level analysis using gene expression and genotype data from 553 dorsolateral prefrontal cortex samples in the ROSMAP database. Simultaneously, we constructed a deep, multi-layer information fusion model (AD-MIF) by integrating genotype and gene expression data and employing autoencoders as well as graph autoencoders for multi-modal feature extraction. The results revealed a 10-20% improvement in the Area Under the Curve (AUC) for predicting AD-related phenotypes. Both approaches showed high consistency across cellular structures, brain regions, and neurobiological pathways, demonstrating their complementary advantages. Gene enrichment analysis indicated that APOE and its interacting gene APOC1 play a central role in cholesterol metabolism, lipid transport, and immune regulation, while genes such as SCIMP and KAT8 are involved in immune signaling, epigenetic regulation, and neuroprotection. After incorporating attention mechanisms, AD-MIF highlighted the importance of key genes, such as POLR2C and TRAPPC4, in regulating neuronal function. Based on predictive results and enrichment analysis, we further identified candidate drugs, including sirolimus, dasatinib, and MGCD-265. In vivo experiments confirmed that MGCD-265, also known as Glesatinib, and dasatinib significantly improve cognitive deficits in the SAMP8 AD model mice by inhibiting neuroinflammation, pathological tau phosphorylation, and A{beta} deposition. This study demonstrates the complementary advantages of bioinformatics pipelines and AI-based multi-modal fusion methods in elucidating the complex pathological mechanisms of AD and enhancing phenotype prediction accuracy. It also provides new theoretical support for personalized drug interventions based on individual genetic characteristics, laying a solid foundation for optimizing early screening, prediction, and personalized treatment strategies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/25319880v2_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@156b7c1org.highwire.dtl.DTLVardef@3a1e23org.highwire.dtl.DTLVardef@190a284org.highwire.dtl.DTLVardef@9d963f_HPS_FORMAT_FIGEXP M_FIG C_FIG

In mammals, the transcription of transposable elements (TEs) is important for maintaining early embryonic development. Here, we systematically analyzed the expression characteristics of TE-derived transcripts in early embryos by constructing a database of TEs and transcriptome data from goats and using it to study the function of endogenous retroviruses (ERVs) in regulating early embryo development. We found that ERV1 made up the highest proportion of TE sequences and exhibited a stage-specific expression pattern during early embryonic development. Among ERV elements, ERV1 had the potential to encode the Gag protein domain to form virus-like particles (VLPs) in early goat embryos. Knockdown of ERV1_1_574 significantly reduced the embryo development rate and the number of trophoblast cells (P< 0.05). Transcriptome sequencing analysis of morula embryos showed that ERV1_1_574 mainly regulated the expression of genes related to embryo compaction and trophoblast cell differentiation, such as CX43 and CDX2. In summary, we found that ERV1 expression was essential for early embryonic development in goats through regulation of trophoblast cell differentiation.

Both the canonical Wnt signaling and androgen signaling are important factors regulating prostate organogenesis. How these two pathways crosstalk to regulate prostate stem cell functions remain unclear. Here, we show that while canonical Wnt activity is required for prostate basal stem cell multipotency in vivo, ectopic Wnt activity does not promote basal-to-luminal cell differentiation. We provide evidence that androgen signaling may keep Wnt activity in check. In prostate organoid culture from basal cells, dihydrotestosterone (DHT) antagonizes R-spondin-stimulated organoid growth in a concentration-dependent manner. Molecular analyses of organoids under different treatment conditions showed that androgen signaling down-regulated the expressions of a Wnt reporter as well as many Wnt target genes. Pathway analysis and gene set enrichment analysis of organoid RNA-seq data also revealed the canonical Wnt signaling as a key pathway distinguishing organoids treated with or without DHT. Notably, DHT treatment enhanced AR and {beta}-catenin binding in the nuclei of prostate organoids, providing possible mechanistic clues. Our results reveal a critical role of AR signaling in modulating canonical Wnt activity in prostate basal cells to regulate their multipotency.