16p11.2 CNV gene Doc2α functions in neurodevelopment and social behaviors through interaction with Secretagogin.

Copy-number variations (CNVs) of the human 16p11.2 genetic locus are associated with neurodevelopmental disorders, including autism spectrum disorders (ASDs) and schizophrenia. However, it remains largely unclear how this locus is involved in the disease pathogenesis. Doc2α is localized within this locus. Here, using in vivo and ex vivo electrophysiological and morphological approaches, we show that Doc2α-deficient mice have neuronal morphological abnormalities and defects in neural activity. Moreover, the Doc2α-deficient mice exhibit social and repetitive behavioral deficits. Furthermore, we demonstrate that Doc2α functions in behavioral and neural phenotypes through interaction with Secretagogin (SCGN). Finally, we demonstrate that SCGN functions in social/repetitive behaviors, glutamate release, and neuronal morphology of the mice through its Doc2α-interacting activity. Therefore, Doc2α likely contributes to neurodevelopmental disorders through its interaction with SCGN.

Analysis of Potato Physiological and Molecular Adaptation in Response to Different Water and Nitrogen Combined Regimes.

Water and nitrogen are essential for potato growth and development. We aim to understand how potato adapts to changes in soil water and nitrogen content. Potato plant adaptations to changes in soil moisture and nitrogen levels were analyzed at the physiological and transcriptomic levels in four treatment groups: adequate nitrogen under drought, adequate nitrogen under sufficient irrigation, limited nitrogen under drought, and limited nitrogen under sufficient irrigation. Many light-capture pigment complex genes and oxygen release complex genes were differentially expressed in leaves when nitrogen levels were increased under drought conditions, and several genes encoding rate-limiting enzymes in the Calvin-Benson-Bassham cycle were up-regulated; furthermore, leaf stomatal conductance decreased, whereas the saturated vapor pressure difference and relative chlorophyll content in the chloroplasts increased. StSP6A, a key gene in potato tuber formation, was down-regulated in response to increased nitrogen application, and the stolon growth time was prolonged. Genes related to root nitrogen metabolism were highly expressed, and protein content in the tuber increased. Weighted gene co-expression network analysis (WGCNA) revealed 32 gene expression modules that responded to changes in water and nitrogen levels. A total of 34 key candidate genes were identified, and a preliminary molecular model of potato responses to alterations in soil water and nitrogen content was constructed.

SCGN deficiency is a risk factor for autism spectrum disorder.

Autism spectrum disorder (ASD) affects 1-2% of all children and poses a great social and economic challenge for the globe. As a highly heterogeneous neurodevelopmental disorder, the development of its treatment is extremely challenging. Multiple pathways have been linked to the pathogenesis of ASD, including signaling involved in synaptic function, oxytocinergic activities, immune homeostasis, chromatin modifications, and mitochondrial functions. Here, we identify secretagogin (SCGN), a regulator of synaptic transmission, as a new risk gene for ASD. Two heterozygous loss-of-function mutations in SCGN are presented in ASD probands. Deletion of Scgn in zebrafish or mice leads to autism-like behaviors and impairs brain development. Mechanistically, Scgn deficiency disrupts the oxytocin signaling and abnormally activates inflammation in both animal models. Both ASD probands carrying Scgn mutations also show reduced oxytocin levels. Importantly, we demonstrate that the administration of oxytocin and anti-inflammatory drugs can attenuate ASD-associated defects caused by SCGN deficiency. Altogether, we identify a convergence between a potential autism genetic risk factor SCGN, and the pathological deregulation in oxytocinergic signaling and immune responses, providing potential treatment for ASD patients suffering from SCGN deficiency. Our study also indicates that it is critical to identify and stratify ASD patient populations based on their disease mechanisms, which could greatly enhance therapeutic success.

Effects of different rotation cropping systems on potato yield, rhizosphere microbial community and soil biochemical properties.

Continuous potato cropping systems cause yield reduction, soil-borne disease aggravation, and soil degradation, but crop rotation can alleviate these negative effects. However, there are limited studies on the relationships between microbial community and other soil biochemical properties of continuous potato cropping at both pre-planting and harvest in North China. A 4-year study was conducted to explore the effects of different rotation system on soil biochemical properties, microbial community at pre-planting and harvest, and potato yield, tuber number and black scurf incidence at harvest in 2020 and 2021, which included 4 treatments vis. potato-potato-potato-potato (PC), potato-oat-faba bean-potato (PR), oat-faba bean-potato-oat (O), and faba bean-potato-oat-faba bean (B). The results showed that soil biochemical properties and microbial community among all treatments showed no significant difference at pre-planting after a long cold winter generally. At harvest, PC reduced tuber yield and number and significantly increased black scurf incidence relative to potato rotation systems. PC also reduced soil enzyme activities, the content of soil nutrients, and fungal community diversity, and increased bacterial community diversity compared with the other treatments, insignificantly when compared with PR. Relative abundance of microorganisms related to the degradation of organic residues, soil nitrogen cycling, and disease suppression, such as the genera Devosia, Aeromicrobium, Paraphoma, and Papiliotrema, were significantly higher in O or B than in PC and PR, while microorganisms related to disease infection such as the genera Pseudomonas, Colletotrichum, Plectosphaerella, Fusarium, and Verticillium exhibited increased in PC and PR. Principal Coordinates Analysis (PCoA) showed that there were significant differences in the microbial community structure of PC and PR at harvest compared with that of O and B. Redundancy analysis (RDA) revealed that soil available potassium (AK), acid phosphatase (ACP), available phosphorus (AP), sucrase (SUC) and pH were the dominant factors that significantly affected bacterial and fungal community structure. Partial least squares structural equation model indicated rotation system had significant negative effect on fungal community. It was concluded that growing oat or faba bean after potato can increase soil beneficial microorganisms and maintain the ecosystem healthy, thus reducing the incidence of tuber black scurf and increasing potato yield.

Global multi-environment resistance QTL for foliar late blight resistance in tetraploid potato with tropical adaptation.

The identification of environmentally stable and globally predictable resistance to potato late blight is challenged by the clonal and polyploid nature of the crop and the rapid evolution of the pathogen. A diversity panel of tetraploid potato germplasm bred for multiple resistance and quality traits was genotyped by genotyping by sequencing (GBS) and evaluated for late blight resistance in three countries where the International Potato Center (CIP) has established breeding work. Health-indexed, in vitro plants of 380 clones and varieties were distributed from CIP headquarters and tuber seed was produced centrally in Peru, China, and Ethiopia. Phenotypes were recorded following field exposure to local isolates of Phytophthora infestans. QTL explaining resistance in four experiments conducted across the three countries were identified in chromosome IX, and environment-specific QTL were found in chromosomes III, V, and X. Different genetic models were evaluated for prediction ability to identify best performing germplasm in each and all environments. The best prediction ability (0.868) was identified with the genomic best linear unbiased predictors (GBLUPs) when using the diploid marker data and QTL-linked markers as fixed effects. Genotypes with high levels of resistance in all environments were identified from the B3, LBHT, and B3-LTVR populations. The results show that many of the advanced clones bred in Peru for high levels of late blight resistance maintain their resistance in Ethiopia and China, suggesting that the centralized selection strategy has been largely successful.

Silencing of circHIPK3 hampers platelet-derived growth factor-induced proliferation and migration in airway smooth muscle cells through the miR-375/MMP-16 axis.

Emerging evidence has suggested a pivotal role of circular RNAs (circRNAs) in the progression of asthma. In this paper, we explored the mechanisms underlying the modulation of circRNA homeodomain interacting protein kinase 3 (circHIPK3, circ_0000284) in airway smooth muscle cell (AMSC) migration and proliferation induced by platelet-derived growth factor (PDGF). The stability of circHIPK3 was gauged by Ribonuclease R (RNase R) and Actinomycin D assays. Relative expression levels of circHIPK3, microRNA (miR)-375 and matrix metallopeptidase 16 (MMP-16) were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Cell proliferation, invasion, and apoptosis were evaluated by Cell Counting Kit-8 (CCK-8) assay, transwell assay, and flow cytometry, respectively. Cell migration was detected by wound-healing and transwell assays. Direct relationship between miR-375 and circHIPK3 or MMP-16 was verified by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Our results indicated that PDGF induced the expression of circHIPK3 in human AMSCs (HAMSCs). CircHIPK3 silencing impeded proliferation, migration, invasion and promoted apoptosis of PDGF-treated HAMSCs. Mechanistically, circHIPK3 targeted miR-375 by directly binding to miR-375. MiR-375 was a downstream effector of circHIPK3 in controlling PDGF-induced proliferation, invasion and migration. MMP-16 was directly targeted and inhibited by miR-375, and circHIPK3 functioned as a post-transcriptional modulator of MMP-16 expression through miR-375. Moreover, miR-375-mediated inhibition of MMP-16 impacted HAMSC proliferation, invasion and migration induced by PDGF. Our findings identified the miR-375/MMP-16 axis as a novel mechanism for the modulation of circHIPK3 in PDGF-induced migration and proliferation in HASMCs.

Allosteric inhibitors of the STAT3 signaling pathway.

Over-expression and/or hyperactivation of signal transducer and activator of transcription 3 (STAT3) signaling are found in various human diseases, including cancer, autoimmune disorders, and inflammatory diseases. Therefore, STAT3 represents a highly promising therapeutic target for the treatment of these diseases. However, the traditional orthosteric inhibitors of STAT3 exhibit limited clinical efficacy, with low selectivity, numerous side effects, and emerging acquired resistance. Allosteric inhibitors targeting STAT3 or its upstream molecules have emerged as a promising approach to overcome these barriers. In this review, we summarize the recent advances in the development of these inhibitors as well as their applications.