Srcap haploinsufficiency induced autistic-like behaviors in mice through disruption of Satb2 expression.

Mutations in the SRCAP gene are among the genetic alterations identified in autism spectrum disorders (ASD). However, the pathogenic mechanisms remain unclear. In this study, we demonstrate that Srcap+/- mice manifest deficits in social novelty response, as well as increased repetitive behaviors, anxiety, and impairments in learning and memory. Notably, a reduction in parvalbumin-positive neurons is observed in the retrosplenial cortex (RSC) and dentate gyrus (DG) of these mice. Through RNA sequencing, we identify dysregulation in 27 ASD-related genes in Srcap+/- mice. Specifically, we find that Srcap regulates expression of Satb2 via H2A.z in the promoter. Therapeutic intervention via retro-orbital injection of adeno-associated virus (AAV)-Satb2 in neonatal Srcap+/- mice leads to amelioration of the neurodevelopmental and ASD-like abnormalities. Furthermore, the expression of Satb2 only in the RSC of adolescent mice rectifies social novelty impairments. These results underscore the pivotal role of Srcap in neurodevelopment, by regulating Satb2, providing valuable insights for the pathophysiology of ASD.

Mitophagy in neurodegenerative disease pathogenesis.

Mitochondria are critical cellular energy resources and are central to the life of the neuron. Mitophagy selectively clears damaged or dysfunctional mitochondria through autophagic machinery to maintain mitochondrial quality control and homeostasis. Mature neurons are postmitotic and consume substantial energy, thus require highly efficient mitophagy pathways to turn over damaged or dysfunctional mitochondria. Recent evidence indicates that mitophagy is pivotal to the pathogenesis of neurological diseases. However, more work is needed to study mitophagy pathway components as potential therapeutic targets. In this review, we briefly discuss the characteristics of nonselective autophagy and selective autophagy, including ERphagy, aggrephagy, and mitophagy. We then introduce the mechanisms of Parkin-dependent and Parkin-independent mitophagy pathways under physiological conditions. Next, we summarize the diverse repertoire of mitochondrial membrane receptors and phospholipids that mediate mitophagy. Importantly, we review the critical role of mitophagy in the pathogenesis of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Last, we discuss recent studies considering mitophagy as a potential therapeutic target for treating neurodegenerative diseases. Together, our review may provide novel views to better understand the roles of mitophagy in neurodegenerative disease pathogenesis.

Taok1 haploinsufficiency leads to autistic-like behaviors in mice via the dorsal raphe nucleus.

Strong evidence from human genetic studies associates the thousand and one amino acid kinase 1 (TAOK1) gene with autism spectrum disorder (ASD). In this work, we discovered a de novo frameshifting mutation in TAOK1 within a Chinese ASD cohort. We found that Taok1 haploinsufficiency induces autistic-like behaviors in mice. Importantly, we observed a significant enrichment of Taok1 in the dorsal raphe nucleus (DRN). The haploinsufficiency of Taok1 considerably restrained the activation of DRN neurons during social interactions, leading to the aberrant phosphorylation of numerous proteins. Intriguingly, the genetic deletion of Taok1 in VGlut3-positive neurons of DRN resulted in mice exhibiting autistic-like behaviors. Ultimately, reintroducing wild-type Taok1, but not its kinase-dead variant, into the DRN of adult mice effectively mitigated the autistic-like behaviors associated with Taok1 haploinsufficiency. This work suggests that Taok1, through its influence in the DRN, regulates social interaction behaviors, providing critical insights into the etiology of ASD.

Interventional hydrogel microsphere vaccine as an immune amplifier for activated antitumour immunity after ablation therapy.

The response rate of pancreatic cancer to chemotherapy or immunotherapy pancreatic cancer is low. Although minimally invasive irreversible electroporation (IRE) ablation is a promising option for irresectable pancreatic cancers, the immunosuppressive tumour microenvironment that characterizes this tumour type enables tumour recurrence. Thus, strengthening endogenous adaptive antitumour immunity is critical for improving the outcome of ablation therapy and post-ablation immune therapy. Here we present a hydrogel microsphere vaccine that amplifies post-ablation anti-cancer immune response via releasing its cargo of FLT3L and CD40L at the relatively lower pH of the tumour bed. The vaccine facilitates migration of the tumour-resident type 1 conventional dendritic cells (cDC1) to the tumour-draining lymph nodes (TdLN), thus initiating the cDC1-mediated antigen cross-presentation cascade, resulting in enhanced endogenous CD8+ T cell response. We show in an orthotopic pancreatic cancer model in male mice that the hydrogel microsphere vaccine transforms the immunologically cold tumour microenvironment into hot in a safe and efficient manner, thus significantly increasing survival and inhibiting the growth of distant metastases.

Sustainability assessment on paddy-upland crop rotations by carbon, nitrogen and water footprint integrated analysis: A field scale investigation.

Nutrients of carbon, nitrogen and water of farmland ecosystem are essential foundation to guarantee crop production, but also environmental flows associated greenhouse gas (GHG), reactive nitrogen (Nr) releases, and water consumption. Their flow characteristics serve as a crucial starting point for creating efficient management practices and mitigation measures. Therefore, the objectives of this study are to quantify the carbon footprint (CF), nitrogen footprint (NF), water footprint (WF), and comprehensive environmental footprint (ComF) of six paddy-upland rotation systems, including fallow-paddy rice (FA-PR), Chinese milk vetch-paddy rice (CMV-PR), wheat-paddy rice (WH-PR), rapeseed-paddy rice (RA-PR), green forage wheat-paddy rice (WF-PR), and vicia faba bean-paddy rice (FB-PR), as well as to analysis their relationships and define driving factors. Results showed that the lowest area-scaled CF of 3.74 t CO2-eq ha-1 were observed in the CMV-PR rotation, which were 41% lower than that for WH-PR (the highest CF, 9.13 t CO2-eq ha-1) when soil carbon change was taken into account. It is of importance that soil carbon sequestration in CMV-PR rotation could offset up to around 57% of its CF, while the WH-PR rotation only offset 25%. The RA-PR rotation had the highest area-scaled NF and WF, which was 1.8 and 1.9 times greater than those of the lowest rotation in FA-PR. In terms of comprehensive environmental effects, the six rotation systems showed the order of FA-PR < CMV-PR < FB-PR < RA-PR < WF-PR < WH-PR, with NH3 volatilization accounting 60.7%-66.7% and blue-green WF for 17.5%-26.6% of the total. Therefore, priority should be given to optimizing N fertilizer application and water consumption for paddy-upland rotation systems. The study also suggested that appropriate inter-annual adjustment of rotation system could contribute to achieving GHG mitigations and Nr losses.

Chromatin Remodeling Induced by ARID1A Loss in Lung Cancer Promotes Glycolysis and Confers JQ1 Vulnerability.

ARID1A is a key mammalian SWI/SNF complex subunit that is mutated in 5% to 11% of lung cancers. Although recent studies have elucidated the mechanism underlying dysregulation of the switch/sucrose non-fermentable (SWI/SNF) complexes in cancers, the significance of ARID1A loss and its implications in lung cancers remain poorly defined. This study investigates how ARID1A loss affects initiation and progression of lung cancer. In genetically engineered mouse models bearing mutant Kras and a deficient Trp53 allele (KP), ARID1A loss (KPA) promoted lung tumorigenesis. Analysis of the transcriptome profiles of KP and KPA tumors suggested enhanced glycolysis following ARID1A loss, and expression of the glycolytic regulators Pgam1, pyruvate kinase M (Pkm), and Pgk1 was significantly increased in ARID1A-deficient lung tumors. Furthermore, ARID1A loss increased chromatin accessibility and enhanced hypoxia-inducible factor-1α (HIF1α) binding to the promoter regions of Pgam1, Pkm, and Pgk1. Loss of ARID1A in lung adenocarcinoma also resulted in loss of histone deacetylase 1 (HDAC1) recruitment, increasing acetylation of histone-4 lysine at the promoters of Pgam1, Pkm, and Pgk1, and subsequently enhancing BRD4-driven transcription of these genes. Metabolic analyses confirmed that glycolysis is enhanced in ARID1A-deficient tumors, and genetic or pharmacologic inhibition of glycolysis inhibited lung tumorigenesis in KPA mice. Treatment with the small molecule bromodomain and extraterminal protein (BET) inhibitor JQ1 compromised both initiation and progression of ARID1A-deficient lung adenocarcinoma. ARID1A negatively correlated with glycolysis-related genes in human lung adenocarcinoma. Overall, ARID1A loss leads to metabolic reprogramming that supports tumorigenesis but also confers a therapeutic vulnerability that could be harnessed to improve the treatment of ARID1A-deficient lung cancer. SIGNIFICANCE: This study links ARID1A loss with enhanced glycolysis in lung cancer and demonstrates the preclinical efficacy of BET inhibitor therapy as a strategy to combat tumor growth.

The Protein Kinase Activity of NME7 Activates Wnt/ß-Catenin Signaling to Promote One-Carbon Metabolism in Hepatocellular Carcinoma.

Metabolic reprogramming by oncogenic signaling is a hallmark of cancer. Hyperactivation of Wnt/ß-catenin signaling has been reported in hepatocellular carcinoma (HCC). However, the mechanisms inducing hyperactivation of Wnt/ß-catenin signaling and strategies for targeting this pathway are incompletely understood. In this study, we find nucleoside diphosphate kinase 7 (NME7) to be a positive regulator of Wnt/ß-catenin signaling. Upregulation of NME7 positively correlated with the clinical features of HCC. Knockdown of NME7 inhibited HCC growth in vitro and in vivo, whereas overexpression of NME7 cooperated with c-Myc to drive tumorigenesis in a mouse model and to promote the growth of tumor-derived organoids. Mechanistically, NME7 bound and phosphorylated serine 9 of GSK3ß to promote ß-catenin activation. Furthermore, MTHFD2, the key enzyme in one-carbon metabolism, was a target gene of ß-catenin and mediated the effects of NME7. Tumor-derived organoids with NME7 overexpression exhibited increased sensitivity to MTHFD2 inhibition. In addition, expression levels of NME7, ß-catenin, and MTHFD2 correlated with each other and with poor prognosis in patients with HCC. Collectively, this study emphasizes the crucial roles of NME7 protein kinase activity in promoting Wnt/ß-catenin signaling and one-carbon metabolism, suggesting NME7 and MTHFD2 as potential therapeutic targets for HCC. SIGNIFICANCE: The identification of NME7 as an activator of Wnt/ß-catenin signaling and MTHFD2 expression in HCC reveals a mechanism regulating one-carbon metabolism and potential therapeutic strategies for treating this disease.

SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice.

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder, causing defects of social interaction and repetitive behaviors. Here, we identify a de novo heterozygous gene-truncating mutation of the Sentrin-specific peptidase1 (SENP1) gene in people with ASD without neurodevelopmental delay. We find that Senp1+/- mice exhibit core autistic-like symptoms such as social deficits and repetitive behaviors but normal learning and memory ability. Moreover, we find that inhibitory and excitatory synaptic functions are severely affected in the retrosplenial agranular (RSA) cortex of Senp1+/- mice. Lack of Senp1 leads to increased SUMOylation and degradation of fragile X mental retardation protein (FMRP), also implicated in syndromic ASD. Importantly, re-introducing SENP1 or FMRP specifically in RSA fully rescues the defects of synaptic function and autistic-like symptoms of Senp1+/- mice. Together, these results demonstrate that disruption of the SENP1-FMRP regulatory axis in the RSA causes autistic symptoms, providing a candidate region for ASD pathophysiology.

Effect of ZnO nanoparticles on the productivity, Zn biofortification, and nutritional quality of rice in a life cycle study.

Zinc oxide nanoparticles (ZnO NPs), have been commonly used in agriculture, and have attracted more attention for researchers. In this study, a 2-year experiment was conducted involving two Zn types (ZnO NPs and ZnSO4), two concentrations of Zn (25 and 100 mg kg-1), and three Zn application stages (basal stage, tillering stage, and panicle stage). This study comprehensively evaluated the effects of ZnO NPs on rice yield, nutrient uptake, Zn biofortification and grain nutritional quality. Our results showed that both ZnO NPs and Zn salt increased grain yield, NPK uptake, and grain Zn concentration. ZnO NPs application enhanced NPK content in rice, with subsequence increasing panicle number (3.8-10.3%), spikelet number per panicle (2.2-4.7%), and total biomass (6.8-7.6%), thereby promoting the rice yield. Compared with conventional fertilization, ZnO NPs enhanced Zn concentration of brown rice by 13.5-39.4%, this had no negative impact on human health. ZnO NPs application at panicle stage have a higher effectiveness in improving Zn concentration of brown rice than at basal and tillering stage. Furthermore, the application of ZnO NPs at panicle stage was more efficient in increasing Zn concentration of brown rice than for Zn salt. ZnO NPs application slightly altered the amino acids content of rice grains, but had no significant impact on total amino acids content. This study highlights that ZnO NPs could be used as a high performance and safe Zn fertilizer in rice production ecosystem.

Nitrogen fertilizer reduction in combination with Azolla cover for reducing ammonia volatilization and improving nitrogen use efficiency of rice.

BACKGROUND: Excessive nitrogen (N) application rate with low N use efficiency (NUE) caused a considerable amount of N losses, especially ammonia volatilization (AV). Proper N fertilizer reduction (RN) could significantly reduce AV. However, continuous RN led to a nutrient deficiency in the soil and therefore negatively impacted the NUE and rice yield. Paddy Azolla, a good green manure, is considered as a promising measure to decrease AV and improve NUE and grain yield of rice. However, there is limited information on the integrated effects of RN and Azolla cover on the AV, NUE, and rice yield, especially in the highly fertilized rice-growing systems. METHODS: The experiment was conducted including eight treatments: the control (without N fertilizer and Azolla cover), Azolla cover without N fertilizer (A), farmer's N application rate (FN), FN + Azolla cover (FNA), 15% RN from FN (RN15), RN15 + Azolla cover (RN15A). 30% RN from FN (RN30), RN30 + Azolla cover (RN30A). The integrated effects of N fertilizer reduction and Azolla cover on AV, NUE, and rice grain was evaluated. RESULTS: RN15A and RN30A substantially reduced total AV by 50.3 and 66.9% compared with FN, respectively, primarily due to the lower surface water ammonia concentrations and pH. RN improved the efficiency of Azolla cover on reducing AV, with 4.1-9.9% higher than for FN. Compared with the FN, RN15A and RN30A enhanced apparent N recovery efficiency (ANRE) by 46.5 and 39.1%, which might be responsible for the lower NH3 emission and the increased total N uptake / total chemical N applied. Furthermore, RN15A and RN30A reduced yield-scaled volatilization by 52.3 and 64.3% than for FN, respectively. Thus, combining 15-30% RN with Azolla cover may be a way to reduce AV and improve ANRE without decreasing rice grain yield.

Assessment of productivity, nutrient uptake and economic benefits of rice under different nitrogen management strategies.

BACKGROUND: Integrating a chemical nitrogen (N) fertilizer with an organic fertilizer and using slow-release mechanism are important N management strategies to increase the N utilization efficiency (NUE) and grain yield of rice. However, the performances of both N management strategies on the productivity, the nutrient absorption and utilization efficiency, and the economic benefits of rice have not yet been comprehensively evaluated. METHODS: A 2-year field experiment was conducted with seven N management strategies without fertilizer (control), 100% conventional N fertilizer (conventional compound fertilizer and urea) (N100), 75% conventional N fertilizer with 25% organic-inorganic compound fertilizer (N75+OICF25), 50% conventional N fertilizer with 50% organic-inorganic compound fertilizer (N50+OICF50), 100% organic-inorganic compound fertilizer (OICF100), slow-release compound fertilizer with urea (SRCF+U), compound fertilizer with sulfur-coated urea (CF+SCU). The responses of the productivity, the nutrient absorption and utilization efficiency, and the economic benefits of rice to the different N management strategies were evaluated. RESULTS: CF+SCU performed comparably or better than N100, judging by the grain yield (GY), the N, phosphate (P) and potassium (K) agronomic efficiency (NAE, PAE and KAE), and the apparent N, P and K recovery efficiency (ANRE, APRE and AKRE). SRCF+U significantly increased the GY by an average of 7.7%, the NAE and the ANRE by 23.8 and 26.7%, the PAE and the APRE by 90.6 and 109.3%, and the KAE and the AKRE by 74.2 and 57.7%. The higher GY and nutrient utilization efficiency when using SRCF+U were attributed to the higher total biomass and total nutrient absorption. N75+OICF25 and N50+OICF50 produced a comparable grain yield than N100, whereas a significant yield reduction was observed when using OICF100. Compared with N100, N75+OICF25 resulted in a comparable or higher fertilizer use efficiency (0.3 and 4.7% for NAE and ANRE, 0.3 and 3.2% for PAE and APRE, 0.3 and -2.8% for KAE and AKRE). However, the fertilizer use efficiency when using N50+OICF50 and OICF100 were lower than with N100. The highest net return (NR) (5,845.03 yuan ha-1) and benefit to cost (B:C) ratio (0.34) were obtained when using SRCF+U. The NR and the B:C ratio when using N75+OICF25 were slightly higher than when using N100. However, N50+OICF50 and OICF100 significantly decreased the NR and the B:C ratio compared with N100 by 14.5 and 12.1% and by 35.1 and 29.0%, respectively. CONCLUSIONS: SRCF+U and CF+SCU enhanced the crop productivity, the nutrient uptake and utilization efficiency, and the economic benefits compared with N100. The comprehensive performance of SRCF+U was better than that of CF+SCU. N75+OICF25 produced almost similar productivity, nutrient uptake and use efficiency compared with N100. It demonstrated that N75+OICF25 stabilized the grain yield production of rice and reduced the input of chemical N fertilizer.

Combining Azolla and urease inhibitor to reduce ammonia volatilization and increase nitrogen use efficiency and grain yield of rice.

Paddy Azolla is considered as a promising technical approach to reduce ammonia (NH3) volatilization and increase nitrogen use efficiency (NUE). However, it is not effective in highly fertilized paddy fields as the high ammonium N (NH4+-N) concentrations adversely inhibit the growth and N uptake of Azolla. Urease inhibitors could effectively decrease NH4+-N concentrations in surface water and NH3 volatilization. However, a lack of information still exists regarding the combined effects of Azolla and urease inhibitors on NH3 volatilization, NUE, and grain yield (GY) of rice. A two-year field experiment was conducted including five treatments (no urea application (control), urea (N), urea + Azolla (NA), urea + urease inhibitor (NUI), and urea + Azolla + urease inhibitor (NAUI)). Results showed that NA treatment (-25.2%) was not effective in reducing NH3 volatilization compared with NUI treatment (-43.3%). The NAUI treatment substantially reduced NH3 volatilization (-54.6%) more than that by NA and NUI treatments, primarily because of the lower NH4+-N concentrations, pH, and temperature in surface water. Furthermore, NAUI treatments significantly increased the grain yield (GY) and the apparent N recovery efficiency (ANRE) of rice by 9.0-9.7% and 66.0-71.3%, respectively. The significant increase in GY was mainly from the increased panicle number (4.0%), spikelet number per panicle (15.9%), and total biomass (22.9%), which caused by the enhanced total N uptake (35.8%). NAUI treatment also decreased the yield-scaled NH3 volatilization by 61.1-63.6%. Overall, the co-application of Azolla and urease inhibitor in the rice field substantially decreased NH3 volatilization, and increased NUE and rice yield.

Plants with lengthened phenophases increase their dominance under warming in an alpine plant community.

Predicting how shifts in plant phenology affect species dominance remains challenging, because plant phenology and species dominance have been largely investigated independently. Moreover, most phenological research has primarily focused on phenological firsts (leaf-out and first flower dates), leading to a lack of representation of phenological lasts (leaf senescence and last flower) and full phenological periods (growing season length and flower duration). Here, we simultaneously investigated the effects of experimental warming on different phenological events of various species and species dominance in an alpine meadow on the Tibetan Plateau. Warming significantly advanced phenological firsts for most species but had variable effects on phenological lasts. As a result, warming tended to extend species' full phenological periods, although this trend was not significant for all species. Experimental warming reduced community evenness and differentially impacted species dominance. Shifts in full phenological periods, rather than a single shift in phenological firsts or phenological lasts, were associated with changes in species dominance. Species with lengthened full phenological periods under warming increased their dominance. Our results advance the understanding of how altered species-specific phenophases relate to changes in community structure in response to climate change.

Reversal of Social Recognition Deficit in Adult Mice with MECP2 Duplication via Normalization of MeCP2 in the Medial Prefrontal Cortex.

Methyl-CpG binding protein 2 (MeCP2) is a basic nuclear protein involved in the regulation of gene expression and microRNA processing. Duplication of MECP2-containing genomic segments causes MECP2 duplication syndrome, a severe neurodevelopmental disorder characterized by intellectual disability, motor dysfunction, heightened anxiety, epilepsy, autistic phenotypes, and early death. Reversal of the abnormal phenotypes in adult mice with MECP2 duplication (MECP2-TG) by normalizing the MeCP2 levels across the whole brain has been demonstrated. However, whether different brain areas or neural circuits contribute to different aspects of the behavioral deficits is still unknown. Here, we found that MECP2-TG mice showed a significant social recognition deficit, and were prone to display aversive-like behaviors, including heightened anxiety-like behaviors and a fear generalization phenotype. In addition, reduced locomotor activity was observed in MECP2-TG mice. However, appetitive behaviors and learning and memory were comparable in MECP2-TG and wild-type mice. Functional magnetic resonance imaging illustrated that the differences between MECP2-TG and wild-type mice were mainly concentrated in brain areas regulating emotion and social behaviors. We used the CRISPR-Cas9 method to restore normal MeCP2 levels in the medial prefrontal cortex (mPFC) and bed nuclei of the stria terminalis (BST) of adult MECP2-TG mice, and found that normalization of MeCP2 levels in the mPFC but not in the BST reversed the social recognition deficit. These data indicate that the mPFC is responsible for the social recognition deficit in the transgenic mice, and provide new insight into potential therapies for MECP2 duplication syndrome.

Soil carbon loss with warming: New evidence from carbon-degrading enzymes.

Climate warming affects soil carbon (C) dynamics, with possible serious consequences for soil C stocks and atmospheric CO2 concentrations. However, the mechanisms underlying changes in soil C storage are not well understood, hampering long-term predictions of climate C-feedbacks. The activity of the extracellular enzymes ligninase and cellulase can be used to track changes in the predominant C sources of soil microbes and can thus provide mechanistic insights into soil C loss pathways. Here we show, using meta-analysis, that reductions in soil C stocks with warming are associated with increased ratios of ligninase to cellulase activity. Furthermore, whereas long-term (≥5 years) warming reduced the soil recalcitrant C pool by 14%, short-term warming had no significant effect. Together, these results suggest that warming stimulates microbial utilization of recalcitrant C pools, possibly exacerbating long-term climate-C feedbacks.

Direct seeding for rice production increased soil erosion and phosphorus runoff losses in subtropical China.

Estimating soil erosion and nutrient losses from surface runoff in paddy fields is essential for the assessment of sustainable rice (Oryza sativa L.) production and water quality protection. Different rice establishment methods have been used in the last three decades in Asia; however, it is still unclear how these methods influence sustainable agriculture and environmental protection in humid areas. The aim of this study was to evaluate the impacts of rice establishment method on soil erosion and phosphorus (P) losses from surface runoff in Hydragric Anthrosols under a subtropical monsoon climate. Total suspended solids (TSS), total P (TP), dissolved P (DP), and particulate P (PP) runoff losses were measured under four rice establishment treatments in 2013 and 2014, including traditional manual transplanting (TT), mechanical transplanting (MT), dry direct seeding (DD), and wet direct seeding (WD). The results showed that the seasonal TSS in the runoff varied from 59.9 to 829.8 kg ha-1 in the two years. Compared with TT, the DD significantly increased the TSS by 481% in 2013 and by 349% in 2014, while the WD significantly increased TSS by 783% in 2013 and by 571% in 2014. In the 2013 and 2014 rice seasons, the field-observed TP runoff losses were from 0.18 to 1.51 kg ha-1. Compared with TT, the DD significantly increased the TP lost by 222% in 2013 and by 197% in 2014, whereas the WD significantly increased the TP lost by 483% in 2013 and by 387% in 2014. However, the TSS and P losses from the MT and TT were similar in both years. The PP runoff losses accounted for 58-77% of the seasonal TP lost. These findings demonstrate that the conversion of traditional manual transplanting to direct seeding increased soil erosion and P runoff losses in subtropical China.

The critical role of ASD-related gene CNTNAP3 in regulating synaptic development and social behavior in mice.

Accumulated genetic evidences indicate that the contactin associated protein-like (CNTNAP) family is implicated in autism spectrum disorders (ASD). In this study, we identified genetic mutations in the CNTNAP3 gene from Chinese Han ASD cohorts and Simons Simplex Collections. We found that CNTNAP3 interacted with synaptic adhesion proteins Neuroligin1 and Neuroligin2, as well as scaffolding proteins PSD95 and Gephyrin. Significantly, we found that CNTNAP3 played an opposite role in controlling the development of excitatory and inhibitory synapses in vitro and in vivo, in which ASD mutants exhibited loss-of-function effects. In this study, we showed that the male Cntnap3-null mice exhibited deficits in social interaction， spatial learning and prominent repetitive behaviors. These evidences elucidate the pivotal role of CNTNAP3 in synapse development and social behaviors, providing mechanistic insights into ASD.

APPBP2 enhances non-small cell lung cancer proliferation and invasiveness through regulating PPM1D and SPOP.

BACKGROUND: The influence of amyloid protein-binding protein 2 (APPBP2) on lung cancer is unknown. METHODS: The function and mechanisms of APPBP2 were investigated in the NSCLC cell lines A549 and H1299. The ectopic expression of APPBP2, PPM1D and SPOP in NSCLS were examined in samples collected from ten pairs of human lung adenocarcinoma cancer tissues and adjacent normal lung tissues. shRNA vector was used for APPBP2 knockdown. Quantitative PCR and western blot assays quantified the mRNA and protein level of APPBP2, PPM1D, and SPOP. Cell proliferation was measured with BrdU, MTT, colony formation assays, and xenograft tumour growth experiments. Cell migration and invasion were analysed with transwell and wound healing assays. Co-Immunoprecipitation assay detected protein-protein interactions. FINDINGS: APPBP2 was upregulated in NSCLC tissues. Silencing APPBP2 in A549 and H1299 cells resulted in the inhibition of cell proliferation, migration, and invasion, enhancement of apoptosis, and a significant decrease in the expression of PPM1D and SPOP. Overexpression of PPM1D and SPOP attenuated the APPBP2-knockdown inhibition of NSCLC cells. Co-IP assay showed that PPM1D interacted with APPBP2. INTERPRETATION: The expression level of APPBP2 positively correlates with NSCLC cell proliferation, migration, and invasiveness. APPBP2 contributes to NSCLC progression through regulating the PPM1D and SPOP signalling pathway. This novel molecular mechanism, underlying NSCLC oncogenesis, suggests APPBP2 is a potential target for diagnosis and therapeutic intervention in NSCLC. FUND: Key Program of Natural Science Research of Higher Education of Anhui Province (No. KJ2017A241), the National Natural Science Foundation of China (No. 81772493).