Secretin-dependent signals in the ventromedial hypothalamus regulate energy metabolism and bone homeostasis in mice.

Secretin, though originally discovered as a gut-derived hormone, is recently found to be abundantly expressed in the ventromedial hypothalamus, from which the central neural system controls satiety, energy metabolism, and bone homeostasis. However, the functional significance of secretin in the ventromedial hypothalamus remains unclear. Here we show that the loss of ventromedial hypothalamus-derived secretin leads to osteopenia in male and female mice, which is primarily induced by diminished cAMP response element-binding protein phosphorylation and upregulation in peripheral sympathetic activity. Moreover, the ventromedial hypothalamus-secretin inhibition also contributes to hyperphagia, dysregulated lipogenesis, and impaired thermogenesis, resulting in obesity in male and female mice. Conversely, overexpression of secretin in the ventromedial hypothalamus promotes bone mass accrual in mice of both sexes. Collectively, our findings identify an unappreciated secretin signaling in the central neural system for the regulation of energy and bone metabolism, which may serve as a new target for the clinical management of obesity and osteoporosis.

The transcription factor PtoMYB142 enhances drought tolerance in Populus tomentosa by regulating gibberellin catabolism.

Drought stress caused by global warming has resulted in significant tree mortality, driving the evolution of water conservation strategies in trees. Although phytohormones have been implicated in morphological adaptations to water deficits, the molecular mechanisms underlying these processes in woody plants remain unclear. Here, we report that overexpression of PtoMYB142 in Populus tomentosa results in a dwarfism phenotype with reduced leaf cell size, vessel lumen area, and vessel density in the stem xylem, leading to significantly enhanced drought resistance. We found that PtoMYB142 modulates gibberellin catabolism in response to drought stress by binding directly to the promoter of PtoGA2ox4, a GA2-oxidase gene induced under drought stress. Conversely, knockout of PtoMYB142 by the CRISPR/Cas9 system reduced drought resistance. Our results show that the reduced leaf size and vessel area, as well as the increased vessel density, improve leaf relative water content and stem water potential under drought stress. Furthermore, exogenous GA3 application rescued GA-deficient phenotypes in PtoMYB142-overexpressing plants and reversed their drought resistance. By suppressing the expression of PtoGA2ox4, the manifestation of GA-deficient characteristics, as well as the conferred resistance to drought in PtoMYB142-overexpressing poplars, was impeded. Our study provides insights into the molecular mechanisms underlying tree drought resistance, potentially offering novel transgenic strategies to enhance tree resistance to drought.

Nanopore long-read RNA sequencing reveals functional alternative splicing variants in human vascular smooth muscle cells.

Vascular smooth muscle cells (VSMCs) are the major contributor to vascular repair and remodeling, which showed high level of phenotypic plasticity. Abnormalities in VSMC plasticity can lead to multiple cardiovascular diseases, wherein alternative splicing plays important roles. However, alternative splicing variants in VSMC plasticity are not fully understood. Here we systematically characterized the long-read transcriptome and their dysregulation in  human aortic smooth muscle cells (HASMCs) by employing the Oxford Nanopore Technologies long-read RNA sequencing in HASMCs that are separately treated with platelet-derived growth factor, transforming growth factor, and hsa-miR-221-3P transfection. Our analysis reveals frequent alternative splicing events and thousands of unannotated transcripts generated from alternative splicing. HASMCs treated with different factors exhibit distinct transcriptional reprogramming modulated by alternative splicing. We also found that unannotated transcripts produce different open reading frames compared to the annotated transcripts. Finally, we experimentally validated the unannotated transcript derived from gene CISD1, namely CISD1-u, which plays a role in the phenotypic switch of HASMCs. Our study characterizes the phenotypic modulation of HASMCs from an insight of long-read transcriptome, which would promote the understanding and the manipulation of HASMC plasticity in cardiovascular diseases.

The AP2/ERF transcription factor PtoERF15 confers drought tolerance via JA-mediated signaling in Populus.

Drought stress is one of the major limiting factors for the growth and development of perennial trees. Xylem vessels act as the center of water conduction in woody species, but the underlying mechanism of its development and morphogenesis under water-deficient conditions remains elucidation. Here, we identified and characterized an osmotic stress-induced ETHYLENE RESPONSE FACTOR 15 (PtoERF15) and its target, PtoMYC2b, which was involved in mediating vessel size, density, and cell wall thickness in response to drought in Populus tomentosa. PtoERF15 is preferentially expressed in differentiating xylem of poplar stems. Overexpression of PtoERF15 contributed to stem water potential maintaining, thus promoting drought tolerance. RNA-Seq and biochemical analysis further revealed that PtoERF15 directly regulated PtoMYC2b, encoding a switch of JA signaling pathway. Additionally, our findings verify that three sets of homologous genes from NAC (NAM, ATAF1/2, and CUC2) gene family: PtoSND1-A1/A2, PtoVND7-1/7-2, and PtoNAC118/120, as the targets of PtoMYC2b, are involved in the regulation of vessel morphology in poplar. Collectively, our study provides molecular evidence for the involvement of the PtoERF15-PtoMYC2b transcription cascade in maintaining stem water potential through the regulation of xylem vessel development, ultimately improving drought tolerance in poplar.

Time-Series Expression Profile Analysis of Post-Traumatic Joint Contracture in Rats at the Early Stages of the Healing Process.

Objective: This study aimed to characterize the gene expression profile at the early stages of the healing process of post-traumatic joint contracture (PTJC). Methods: Twelve rats were used for PTJC model establishment and were divided into four groups according to the sampling time: S0d, S3d, S7d and S2w. Transcriptome sequencing was performed on fibrotic joint capsule samples in four groups followed by bioinformatics analyses including differentially expressed genes (DEGs) screening, Short Time-series Expression Miner (STEM) analysis, network construction, and pathway analysis. Five important genes were validated by qRT-PCR. Results: A total of 1171, 1052 and 793 DEGs were screened in S3d vs S0d, S7d vs S0d, and S2w vs S0d comparison groups, respectively. A total of 383 overlapping genes were screened out, which were significantly enriched in some inflammatory functions and pathways. Through STEM analysis, three clusters were identified, including 105, 57 and 57 DEGs, respectively. Then, based on the cluster genes, 10 genes, such as Il6, Timp1, Cxcl1, Cxcr4 and Mmp3, were further selected after PPI and pathway analyses. The expression levels of Il6, Timp1, Cxcl1, Cxcr4 and Mmp3 were validated by qRT-PCR. Conclusion: The present study screened out several genes with significant changes in expression levels at the early stages of the healing process in PTJC, such as Il6, Timp1, Cxcl1, Cxcr4 and Mmp3. Our study offers a valuable contribution to the understanding pathomechanism of PTJC.

Cadmium modulates steatosis, fibrosis, and oncogenic signaling in liver cancer cells by activating notch and AKT/mTOR pathways.

Cadmium (Cd) is an environmental pollutant that increases hepatotoxicity and the risk of liver diseases. In the current study, we investigated the effect of a physiologically relevant, low concentration of Cd on the regulation of liver cancer cell proliferation, steatosis, and fibrogenic/oncogenic signaling. Exposure to low concentrations of Cd increased endogenous reactive oxygen species (ROS) production and enhanced cell proliferation in a human bipotent progenitor cell line HepaRG and hepatocellular carcinoma (HCC) cell lines. Acute exposure of Cd increased Jagged-1 expression and activated Notch signaling in HepaRG and HCC cells HepG2 and SK-Hep1. Cd activated AKT/mTOR signaling by increasing phosphorylation of AKT-S473 and mTOR-S-4448 residues. Moreover, a low concentration of Cd also promoted cell steatosis and induced fibrogenic signaling in HCC cells. Chronic exposure to low concentrations of Cd-activated Notch and AKT/mTOR signaling induced the expression of pro-inflammatory cytokines tumor necrosis factor-alpha (TNFα) and its downstream target TNF-α-Induced Protein 8 (TNFAIP8). RNA-Seq data revealed that chronic exposure to low concentrations of Cd modulated the expression of several fatty liver disease-related genes involved in cell steatosis/fibrosis in HepaRG and HepG2 cells. Collectively, our data suggest that low concentrations of Cd modulate steatosis along with fibrogenic and oncogenic signaling in HCC cells by activating Notch and AKT/mTOR pathways.

Sex bias in social deficits, neural circuits and nutrient demand in Cttnbp2 autism models.

Autism spectrum disorders caused by both genetic and environmental factors are strongly male-biased neuropsychiatric conditions. However, the mechanism underlying the sex bias of autism spectrum disorders remains elusive. Here, we use a mouse model in which the autism-linked gene Cttnbp2 is mutated to explore the potential mechanism underlying the autism sex bias. Autism-like features of Cttnbp2 mutant mice were assessed via behavioural assays. C-FOS staining identified sex-biased brain regions critical to social interaction, with their roles and connectivity then validated by chemogenetic manipulation. Proteomic and bioinformatic analyses established sex-biased molecular deficits at synapses, prompting our hypothesis that male-biased nutrient demand magnifies Cttnbp2 deficiency. Accordingly, intakes of branched-chain amino acids (BCAA) and zinc were experimentally altered to assess their effect on autism-like behaviours. Both deletion and autism-linked mutation of Cttnbp2 result in male-biased social deficits. Seven brain regions, including the infralimbic area of the medial prefrontal cortex (ILA), exhibit reduced neural activity in male mutant mice but not in females upon social stimulation. ILA activation by chemogenetic manipulation is sufficient to activate four of those brain regions susceptible to Cttnbp2 deficiency and consequently to ameliorate social deficits in male mice, implying an ILA-regulated neural circuit is critical to male-biased social deficits. Proteomics analysis reveals male-specific downregulated proteins (including SHANK2 and PSD-95, two synaptic zinc-binding proteins) and female-specific upregulated proteins (including RRAGC) linked to neuropsychiatric disorders, which are likely relevant to male-biased deficits and a female protective effect observed in Cttnbp2 mutant mice. Notably, RRAGC is an upstream regulator of mTOR that senses BCAA, suggesting that mTOR exerts a beneficial effect on females. Indeed, increased BCAA intake activates the mTOR pathway and rescues neuronal responses and social behaviours of male Cttnbp2 mutant mice. Moreover, mutant males exhibit greatly increased zinc demand to display normal social behaviours. Mice carrying an autism-linked Cttnbp2 mutation exhibit male-biased social deficits linked to specific brain regions, differential synaptic proteomes and higher demand for BCAA and zinc. We postulate that lower demand for zinc and BCAA are relevant to the female protective effect. Our study reveals a mechanism underlying sex-biased social defects and also suggests a potential therapeutic approach for autism spectrum disorders.

Tumor immunosuppressive microenvironment modulating hydrogels for second near-infrared photothermal-immunotherapy of cancer.

Immunotherapy has recently been seen as a hopeful therapeutic device to inhibit tumor growth and metastasis, while the curative efficacy is limited by intrinsic immunosuppressive tumor microenvironment. Herein, we reported a tumor immunosuppressive microenvironment modulating hydrogel (TIMmH) platform to achieve second near-infrared (NIR-II) photothermal therapy (PTT) combined immunotherapy for durable inhibition of breast cancer. This TIMmH platform was synthesized through co-loading of NIR-II photothermal nanoagent and an immunoadjuvant cytosine-phosphateguanosine oligodeoxynucleotides (CpG ODNs) into the alginate hydrogel (ALG). Upon the administration of ALG into the tumor, the TIMmH was in situ formed via the coordination effect with Ca2+, locally encapsulating the semiconducting polymer nanoparticles (SPIIN) and CpG in the colloid, achieving to prolong the accumulation time and prevent the premature damage and release of immunotherapeutic agents. Upon 1064-nm photoirradiation, the TIMmHSD was able to elevate the intratumoral temperature for the ablation of tumors, which could induce the apoptosis of tumor cells and achieve thermal immune activation by regulating of an immunosuppressive microenvironment. The TIMmH-mediated combined treatment effectively suppressed the growths of breast cancers, and even acquired a sustained inhibition of the lung metastasis. This study provides a novel tumor immunosuppressive microenvironment modulating hydrogel platform with NIR-II photoexcited capacity for the safe, effective and durable lung metastasis-inhibiting breast cancer treatment.

Surgical Management of Hirschsprung's Disease: A Comparative Study Between Conventional Laparoscopic Surgery, Transumbilical Single-Site Laparoscopic Surgery, and Robotic Surgery.

Background: Hirschsprung's disease (HD) is a commonly digestive malformation in children that usually requires surgery. This study aims to evaluate the short-term efficacy of conventional laparoscopic surgery (CLS), transumbilical single-hole laparoscopic surgery (TU-LESS), and robotic surgery (RS) in the treatment of Hirschsprung's disease. Methods: 90 patients with Hirschsprung's disease undergone laparoscopic surgery at our center between 2015 and 2019, divided into three groups (group CLS, TU-LESS and RS), were retrospectively analysed. Results: CLS and TU-LESS group showed no significant difference in operation duration (P > 0.05) but shorter operation duration than the RS group (P < 0.05). RS group had highest overall SCAR scores, while TU-LESS group had the lowest one (P < 0.05). Other parameters such as operative blood loss, hospital stays, recovery time of digestive function, postoperative complications had no significant difference among the three groups (P > 0.05). Conclusion: The three surgical methods for HD revealed similar efficacy, where TU-LESS and CLS spent less time than RS; TU-LESS led to the most aesthetic effect, followed by CLS and RS.

Expression Level of Keratin 7 in Epithelial Ovarian Cancer and Malignant Metastasis of Benign Epithelial Ovarian Tumors.

It was to investigate the diagnostic value of keratin 7 (KRT7) in malignant metastasis of epithelial ovarian cancer and benign epithelial ovarian tumors. From January 2018 to January 2019, 30 fresh tissues of benign epithelial ovarian tumors, 30 fresh tissues of borderline tumors, 30 fresh tissues of metastatic ovarian were collected in The First Affiliated Hospital of Fujian Medical University, and 30 fresh tissues of normal ovarian tissues were collected as the control group. Federation of gynecology and obstetrics (FIGO) staging criteria: 25 cases of stage I, 26 cases of stage II, 16 cases of stage III, and 23 cases of stage IV. The relative expression of KRT7 was detected by real-time fluorescence quantitative PCR, and the relationship between KRT7 expression and epithelial ovarian cancer grading was analyzed. The results showed that the positive expression rate of KRT7 was 12.1% in normal ovarian tissues, 28.4% in benign epithelial ovarian tumors, 53.5% in borderline tumors, and 24.2% in metastatic ovarian cancer. With the increase of tumor stage malignancy, the relative expression of KRT7 decreased significantly, but there was no significant difference between stage I and stage II, stage III and stage IV (P > 0.05). The difference between stage I and stage III, and stage IV was significant (P < 0.05). Patients with epithelial ovarian cancer had a significant difference compared with the control group (P < 0.05). In summary, compared with the control group, the expression of KRT7 in patients with benign epithelial ovarian tumors and borderline tumors was significantly decreased. The expression level of KRT7 in benign epithelial ovarian tumors was lower than that in borderline tumors. The expression of KRT7 was related to the occurrence, development, and deterioration of ovarian cancer, which provided a basis for targeted therapy of tumors.

Ion beam-induced bending of TiO2 nanowires with bead-like and prismatic shapes.

Ion beam irradiation is a promising method to manipulate the composition and shape of nanowires. It causes the formation of crystal defects like vacancies and dislocations, and consequently, a volume expansion within the irradiated region, giving rise to the nanowire bending. The bending effect has been extensively discussed within nanowires with different diameters under ion beams with varying energies and ion fluences. However, the behaviors of nanowires with complicated shapes, which may have non-uniform irradiated regions due to the changing angle of incidence and shadowing effect, have remained largely unknown. Herein, the structural changes and bending of TiO2 nanowires with both bead-like and prismatic shapes are investigated under a Ga+ ion beam. The multi-faceted morphology, and consequently, varying angles of incidence, result in inhomogeneous irradiation and volume expansion. As a result, significant bending is only observed in prismatic nanowires. Since irradiation is confined within the half of nanowires facing the ion beam, the bending of nanowires is reversible by changing the direction of the ion beam. In order to provide insights into the tailoring composition and morphology of nanowires, we anticipate that this finding can establish the beam analog at the nanoscale, the bending of which can be tuned by ion irradiation.

Sulfur transformation and bacterial community dynamics in both desulfurization-denitrification biofilm and suspended activated sludge.

Types of microbial aggregates have essential effects on bacterial communities' characteristics, thus affecting the pollutants removal. An up-flow biofilm reactor was used to study the different performances of S2-/NO2- removal and functional genes in suspended sludge and biofilms. The metabolic pathways of sulfurous and nitrogenous pollutants in the desulfurization-denitrification process were proposed. The results showed that S0 formation dominated the reactor with a high S2- concentration. Autotrophic Sulfurovum responsible for S2-/S0 oxidation was the only dominant bacteria in suspended sludge. Heterotrophic Desulfocapsa responsible for SO42- reduction coexisted with Sulfurovum and dominated in biofilms. S2- oxidation to S0 was catalyzed via fccA/B and sqr genes in suspended sludge. S32-/S0 oxidation to SO42- was catalyzed via dsrA/B gene in biofilms. SO42- and NO2- were removed via the dissimilatory sulfate reduction and denitrification pathway, respectively. This work provides a fundamental and practical basis for optimizing suspended sludge/biofilm systems for S2-/NO2- removal.

Whole-genome resequencing and bisulfite sequencing provide new insights into the feeding habit domestication in mandarin fish (Siniperca chuatsi).

Mandarin fish (Siniperca chuatsi) is one of the most economically important fish in China. However, it has the peculiar feeding habit that it feeds solely on live prey fish since first-feeding, while refuses dead prey fish or artificial diets. After the specific training procedure, partial individuals could accept dead prey fish and artificial diets. The genetic basis of individual difference in artificial diet feeding habit is still unknown. In the present study, the resequencing was performed between 10 individuals which could be domesticated to accept artificial diets and 10 individuals which could not. Through the selective sweep analysis based on heterozygosity (Hp) and population differentiation coefficient (Fst), 57 candidate windows were identified as the putative selected regions for feeding habit domestication of mandarin fish, involved in 149 genes. These genes were related to memory, vision and olfaction function, which could be potential targets of molecular marker assistant breeding of artificial diet feeding trait. Beside of the DNA sequence, we also explored the potential role of DNA methylation in feeding habit domestication in mandarin fish. Whole-genome bisulfite sequencing was performed between the individuals which could be domesticated to accept artificial diets and those could not. 5,976 differentially methylated regions were identified, referring to 3,522 genes, such as the genes involved in cAMP signaling pathway. The DNA methylation changes of these genes might contribute to the adaption of artificial diets in mandarin fish. In conclusion, the putative selected regions and the differentially methylated regions were identified in the whole genome, providing new insights into the feeding habit domestication from live prey fish to artificial diets in mandarin fish. And the involved genes were identified as the candidate genes for molecular breeding of artificial diet utilization in mandarin fish.

Role of Autophagy in Cadmium-Induced Hepatotoxicity and Liver Diseases.

Cadmium (Cd) is a toxic pollutant that is associated with several severe human diseases. Cd can be easily absorbed in significant quantities from air contamination/industrial pollution, cigarette smoke, food, and water and primarily affects the liver, kidney, and lungs. Toxic effects of Cd include hepatotoxicity, nephrotoxicity, pulmonary toxicity, and the development of various human cancers. Cd is also involved in the development and progression of fatty liver diseases and hepatocellular carcinoma. Cd affects liver function via modulation of cell survival/proliferation, differentiation, and apoptosis. Moreover, Cd dysregulates hepatic autophagy, an endogenous catabolic process that detoxifies damaged cell organelles or dysfunctional cytosolic proteins through vacuole-mediated sequestration and lysosomal degradation. In this article, we review recent developments and findings regarding the role of Cd in the modulation of hepatotoxicity, autophagic function, and liver diseases at the molecular level.

Emerging Roles of Impaired Autophagy in Fatty Liver Disease and Hepatocellular Carcinoma.

Autophagy is a conserved catabolic process that eliminates dysfunctional cytosolic biomolecules through vacuole-mediated sequestration and lysosomal degradation. Although the molecular mechanisms that regulate autophagy are not fully understood, recent work indicates that dysfunctional/impaired autophagic functions are associated with the development and progression of nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), and hepatocellular carcinoma (HCC). Autophagy prevents NAFLD and AFLD progression through enhanced lipid catabolism and decreasing hepatic steatosis, which is characterized by the accumulation of triglycerides and increased inflammation. However, as both diseases progress, autophagy can become impaired leading to exacerbation of both pathological conditions and progression into HCC. Due to the significance of impaired autophagy in these diseases, there is increased interest in studying pathways and targets involved in maintaining efficient autophagic functions as potential therapeutic targets. In this review, we summarize how impaired autophagy affects liver function and contributes to NAFLD, AFLD, and HCC progression. We will also explore how recent discoveries could provide novel therapeutic opportunities to effectively treat these diseases.

Perivenous Stellate Cells Are the Main Source of Myofibroblasts and Cancer-Associated Fibroblasts Formed After Chronic Liver Injuries.

BACKGROUND AND AIMS: Studies of the identity and pathophysiology of fibrogenic HSCs have been hampered by a lack of genetic tools that permit specific and inducible fate-mapping of these cells in vivo. Here, by single-cell RNA sequencing of nonparenchymal cells from mouse liver, we identified transcription factor 21 (Tcf21) as a unique marker that restricted its expression to quiescent HSCs. APPROACH AND RESULTS: Tracing Tcf21+ cells by Tcf21-CreER (Cre-Estrogen Receptor fusion protein under the control of Tcf21 gene promoter) targeted ~10% of all HSCs, most of which were located at periportal and pericentral zones. These HSCs were quiescent under steady state but became activated on injuries, generating 62%-67% of all myofibroblasts in fibrotic livers and ~85% of all cancer-associated fibroblasts (CAFs) in liver tumors. Conditional deletion of Transforming Growth Factor Beta Receptor 2 (Tgfbr2) by Tcf21-CreER blocked HSC activation, compromised liver fibrosis, and inhibited liver tumor progression. CONCLUSIONS: In conclusion, Tcf21-CreER-targeted perivenous stellate cells are the main source of myofibroblasts and CAFs in chronically injured livers. TGF-ß signaling links HSC activation to liver fibrosis and tumorigenesis.

MicroRNA-205-5p inhibits skin cancer cell proliferation and increase drug sensitivity by targeting TNFAIP8.

Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is a member of the TIPE/TNFAIP8 family which regulates tumor growth and survival. Our goal is to delineate the detailed oncogenic role of TNFAIP8 in skin cancer development and progression. Here we demonstrated that higher expression of TNFAIP8 is associated with basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma development in patient tissues. Induction of TNFAIP8 expression by TNFα or by ectopic expression of TNFAIP8 in SCC or melanoma cell lines resulted in increased cell growth/proliferation. Conversely, silencing of TNFAIP8 decreased cell survival/cell migration in skin cancer cells. We also showed that miR-205-5p targets the 3'UTR of TNFAIP8 and inhibits TNFAIP8 expression. Moreover, miR-205-5p downregulates TNFAIP8 mediated cellular autophagy, increased sensitivity towards the B-RAFV600E mutant kinase inhibitor vemurafenib, and induced cell apoptosis in melanoma cells. Collectively our data indicate that miR-205-5p acts as a tumor suppressor in skin cancer by targeting TNFAIP8.

TNFAIP8 drives metabolic reprogramming to promote prostate cancer cell proliferation.

Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is a member of TIPE/TNFAIP8 family, has been involved in the development and progression of various human cancers. We hypothesized that TNFAIP8 promotes prostate cancer (PCa) progression via regulation of oxidative phosphorylation (OXPHOS) and glycolysis. Ectopic expression of TNFAIP8 increased PCa cell proliferation/migration/spheroid formation by enhancing cell metabolic activities. Mechanistically, TNFAIP8 activated the PI3K-AKT pathway and up-regulated PCa cell survival. TNFAIP8 was also found to regulate the expression of glucose metabolizing enzymes, enhancing glucose consumption, and endogenous ATP production. Treatment with a glycolysis inhibitor, 2-deoxyglucose (2-DG), reduced TNFAIP8 mediated glucose consumption, ATP production, spheroid formation, and PCa cell migration. By maintaining mitochondrial membrane potential, TNFAIP8 increased OXPHOS and glycolysis. Moreover, TNFAIP8 modulates the production of glycolytic metabolites in PCa cells. Collectively, our data suggest that TNFAIP8 exerts its oncogenic effects by enhancing glucose metabolism and by facilitating metabolic reprogramming in PCa cells. Therefore, TNFAIP8 may be a biomarker associated with prostate cancer and indicate a potential therapeutic target.

CTTNBP2 Controls Synaptic Expression of Zinc-Related Autism-Associated Proteins and Regulates Synapse Formation and Autism-like Behaviors.

Synaptic dysregulation is a critical feature of autism spectrum disorders (ASDs). Among various autism-associated genes, cortactin binding protein 2 (CTTNBP2) is a cytoskeleton regulator predominantly expressed in neurons and highly enriched at dendritic spines. Here, using Cttnbp2 knockout and ASD-linked mutant mice, we demonstrate that Cttnbp2 deficiency reduces zinc levels in the brain, alters synaptic protein targeting, impairs dendritic spine formation and ultrastructure of postsynaptic density, and influences neuronal activation and autism-like behaviors. A link to autism, the NMDAR-SHANK pathway, and zinc-related regulation are three features shared by CTTNBP2-regulated synaptic proteins. Zinc supplementation rescues the synaptic expression of CTTNBP2-regulated proteins. Moreover, zinc supplementation and administration of D-cycloserine, an NMDAR coagonist, improve the social behaviors of Cttnbp2-deficient mice. We suggest that CTTNBP2 controls the synaptic expression of a set of zinc-regulated autism-associated genes and influences NMDAR function and signaling, providing an example of how genetic and environmental factor crosstalk controls social behaviors.