Crocetin suppresses angiogenesis and metastasis through inhibiting sonic hedgehog signaling pathway in gastric cancer.

Gastric cancer (GC) is one of the major causes of cancer-related deaths and chemoresistance is a key obstacle to the treatment of GC, particularly in advanced GC. As an active component of saffron stigma, crocetin has important therapeutic effects on various diseases including tumors. However, the therapeutic potential of crocetin targeting GC is still unclear and the underlying mechanisms are remained to be further explored. In this study, crocetin significantly inhibited angiogenesis in GC, including tubes of HUVECs and vasculogenic mimicry (VM) formation of GC cells. Crocetin also suppressed cell proliferation, migration and invasion. To explore which signaling pathway involving in crocetin, HIF-1α, Notch1, Sonic hedgehog (SHH) and VEGF were examined with crocetin treatment and we found that SHH significantly decreased. Crocetin suppressed SHH signaling with SHH, PTCH2, Sufu and Gli1 protein level decreased in western blot assay. In addition, crocetin suppressed SHH secretion in GC and HUVEC cells. The promoted effects on cell migration induced by secreted SHH were also inhibited by crocetin in GC and HUVEC cell co-culture system. Furthermore, recombinant SHH promoted angiogenesis as well as cell migration and proliferation. However, these promoted effects were reversed by crocetin treatment. These results revealed that crocetin suppressed GC angiogenesis and metastasis through SHH signaling pathway, indicating that crocetin may function as an effective therapeutic drug against GC.

A dedicated eight-channel receive RF coil array for monkey brain MRI at 9.4 T.

The neuroimaging of nonhuman primates (NHPs) realised with magnetic resonance imaging (MRI) plays an important role in understanding brain structures and functions, as well as neurodegenerative diseases and pathological disorders. Theoretically, an ultrahigh field MRI (≥7 T) is capable of providing a higher signal-to-noise ratio (SNR) for better resolution; however, the lack of appropriate radiofrequency (RF) coils for 9.4 T monkey MRI undermines the benefits provided by a higher field strength. In particular, the standard volume birdcage coil at 9.4 T generates typical destructive interferences in the periphery of the brain, which reduces the SNR in the neuroscience-focused cortex region. Also, the standard birdcage coil is not capable of performing parallel imaging. Consequently, extended scan durations may cause unnecessary damage due to overlong anaesthesia. In this work, assisted by numerical simulations, an eight-channel receive RF coil array was specially designed and manufactured for imaging NHPs at 9.4 T. The structure and geometry of the proposed receive array was optimised with numerical simulations, so that the SNR enhancement region was particularly focused on monkey brain. Validated with rhesus monkey and cynomolgus monkey brain images acquired from a 9.4 T MRI scanner, the proposed receive array outperformed standard birdcage coil with higher SNR, mean diffusivity and fractional anisotropy values, as well as providing better capability for parallel imaging.

Effects of circadian rhythm disorder on the hippocampus of SHR and WKY rats.

The present study investigated the effects of circadian rhythm disorder (CRD) on the hippocampus of SHR and WKY rats. Male SHR rats (n = 27) and WKY rats (n = 27) were randomly divided into six groups: SHR and WKY normal (N)CR, SHR and WKY CRD 16/8 (CRD16/8), and SHR and WKY CRD 12/12 (CRD12/12). Activity patterns were adjusted using different photoperiods over 90 days and any changes were recorded. Rats were tested in the Morris water maze and in a novel object recognition experiment; serologic analysis, magnetic resonance imaging (diffusion tensor imaging + arterial spin labeling), hippocampal Nissl staining, Fluoro-Jade B staining, and immunohistochemistry were also performed. The results showed that both types of inverted photoperiod reduced CR amplitude and prolonged the circadian period. CRD and hypertension reduced memory performance and novel object recognition and preference. The decreases in memory and preference indices were greater in rats in the CRD12/12 group compared to the CRD16/8 group. CRD and hypertension decreased fractional anisotropy values, the number of neurons and astrocytes in the hippocampus, and the expression of brain-derived neurotrophic factor and synapsin 1; it also enhanced the degeneration of neurons and microglia and reduced blood flow in the hippocampus, and increased nuclear factor κB, caspase, neuron-specific enolase, and interleukin-6 levels. These findings reveal a biological basis for the link between CRD and cognitive decline, which has implications for CRD caused by shift work and other factors.

Characterization of miRNA profiles in the mammary tissue of dairy cattle in response to heat stress.

BACKGROUND: MicroRNAs (miRNAs) are a class of small noncoding RNAs that play important roles in the regulation of gene expression. However, the role of miRNAs in bovine mammary gland responses to heat stress is not well understood. RESULTS: In the present study, we performed a deep RNA sequencing analysis to identify miRNAs associated with the heat stress potential of the bovine mammary gland. We identified 27 miRNAs that were differentially expressed significantly between the mammary tissue of Holstein cattle heat stress and normal conditions. Twenty miRNAs had higher expression in the mammary tissue of heat-stressed Holstein cattle. The seven highest differentially expressed candidate miRNAs (bta-miR-21-5p, bta-miR-99a-5p, bta-miR-146b, bta-miR-145, bta-miR-2285 t, bta-miR-133a, and bta-miR-29c) identified by deep RNA sequencing were additionally evaluated by stem-loop qPCR. Enrichment analyses for targeted genes revealed that the major differences between miRNAs expression in the mammary gland of heat-stressed versus control were associated with the regulation of Wnt, TGF-ß, MAPK, Notch, and JAK-STAT. CONCLUSIONS: These data indicated that the differentially expressed miRNAs identified in this study may act as dominant regulators during heat stress. We might reduce heat stress damage of Holstein cows by up-regulating or down-regulating these differentially expressed miRNAs.

Decreased expression of long non-coding RNA WT1-AS promotes cell proliferation and invasion in gastric cancer.

Tumor recurrence and metastasis remain the major obstacles for the successful treatment of patients diagnosed with gastric cancer. In recent years, long non-coding RNAs (lncRNAs) have been considered as key regulators of tumor behavior. In this study, we investigated the expression and biological role of a newly-identified cancer-related lncRNA, WT1-AS. We found that WT1-AS expression was significantly down-regulated in tumor tissues compared to matched adjacent non-tumor tissues. The WT1-AS expression level was also associated with tumor size and the clinicopathological stage. Cell proliferation, migration, and invasion were inhibited, and the proportion of G0/G1 cells increased when WT1-AS was ectopically-expressed in gastric cancer cells. Furthermore, ectopic expression of WT1-AS was demonstrated to inhibit tumor growth and metastasis in vivo. Finally, we found that WT1-AS overexpression could decrease ERK protein phosphorylation. Our study indicates that WT1-AS is significantly down-regulated in gastric cancers and may be correlated with tumor progression.

Luteolin suppresses angiogenesis and vasculogenic mimicry formation through inhibiting Notch1-VEGF signaling in gastric cancer.

Gastric cancer is a great threat to the health of the people worldwide and lacks effective therapeutic regimens. Luteolin is one of Chinese herbs and presents in many fruits and green plants. In our previous study, we observed that luteolin inhibited cell migration and promoted cell apoptosis in gastric cancer. In the present study, luteolin significantly inhibited tube formation of human umbilical vein endothelial cells (HUVECs) through decreasing cell migration and proliferation of HUVECs in a dose-dependent manner. Vasculogenic mimicry (VM) tubes formed by gastric cancer cells were also inhibited with luteolin treatment. To explore how luteolin inhibited tubes formation, ELISA assay for VEGF was performed. Both of the VEGF secretion from Hs-746T cells and HUVECs were significantly decreased subsequent to luteolin treatment. In addition, cell migration was increased with the interaction between gastric cancer cells and HUVECs in co-culture assays. However, the promoting effects were abolished subsequent to luteolin treatment. Furthermore, luteolin inhibited VEGF secretion through suppressing Notch1 expression in gastric cancer. Overexpression of Notch1 in gastric cancer cells partially rescued the effects on cell migration, proliferation, HUVECs tube formation, and VM formation induced by luteolin treatment. In conclusion, luteolin inhibits angiogenesis and VM formation in gastric cancer through suppressing VEGF secretion dependent on Notch1 expression.

Diversity of crude oil-degrading bacteria and alkane hydroxylase (alkB) genes from the Qinghai-Tibet Plateau.

The aim of this study was to survey the response of the microbial community to crude oil and the diversity of alkane hydroxylase (alkB) genes in soil samples from the Qinghai-Tibet Plateau (QTP). The enrichment cultures and clone libraries were used. Finally, 53 isolates and 94 alkB sequences were obtained from 10 pristine soil samples after enrichment at 10 °C with crude oil as sole carbon source. The isolates fell into the phyla Proteobacteria, Actinobacteria, and Bacteroidetes, with the dominance of Pseudomonas and Acinetobacter. The composition of degraders was different from polar habitats where Acinetobacter sp. is not a predominant responder of alkane degradative microbial communities. Phylogenetic analysis showed that the alkB genes from isolates and enrichment communities formed eight clusters and mainly related with alkB genes of Pseudomonas, Rhodococcus, and Acinetobacter. The alkB gene diversity in the QTP was lower than marine environments and polar soil samples. In particular, a total of 10 isolates exhibiting vigorous growth with crude oil could detect no crude oil degradation-related gene sequences, such as alkB, P450, almA, ndoB, and xylE genes. The Shannon-Wiener index of the alkB clone libraries from the QTP ranged from 1.00 to 2.24 which is similar with polar pristine soil samples but lower than that of contaminated soils. These results indicated that the Pseudomonas, Acinetobacter, and Rhodococcus genera are the candidate for in situ bioremediation, and the environment of QTP may be still relatively uncontaminated by crude oil.

CEACAM6 promotes tumor angiogenesis and vasculogenic mimicry in gastric cancer via FAK signaling.

CEACAM6 is a member of glycosylphosphatidylinositol-linked immunoglobulin superfamily that is implicated in a variety of human cancers. In our previous study, we reported that CEACAM6 was overexpressed in gastric cancer tissues and promoted cancer metastasis. The purpose of this study is to determine the role of CEACAM6 in tumor angiogenesis and mimicry formation. We found that overexpressed CEACAM6 promoted tubule formation dependent on HUVEC cells and vasculogenic mimicry formation of gastric cancer cells; opposing results were achieved in CEACAM6-silenced groups. Moreover, we found that mosaic vessels formed by HUVEC cells and gastric cancer cells were observed in vitro by 3D-culture assay. Overexpressed CEACAM6 in gastric cancer cells promoted tumor growth, VEGF expression and vasculogenic mimicry structures formation in vivo. In accordance with these observations, we found that phosphorylation of FAK and phosphorylation of paxillin were up-regulated in CEACAM6-overexpressing gastric cancer cells, and FAK inhibitor Y15 could reduce tubule and vasculogenic mimicry formation. These findings suggest that CEACAM6 promotes tumor angiogenesis and vasculogenic mimicry formation via FAK signaling in gastric cancer and CEACAM6 may be a new target for cancer anti-vascular treatment.

Spatial Variations of Soil Microbial Activities in Saline Groundwater-Irrigated Soil Ecosystem.

Spatial variations of soil microbial activities and its relationship with environmental factors are very important for estimating regional soil ecosystem function. Based on field samplings in a typical saline groundwater-irrigated region, spatial variations of soil microbial metabolic activities were investigated. Combined with groundwater quality analysis, the relationship between microbial activities and water salinity was also studied. The results demonstrated that moderate spatial heterogeneity of soil microbial activities presented under the total dissolved solids (TDS) of groundwater ranging from 0.23 to 12.24 g L(-1). Groundwater salinity and microbial activities had almost opposite distribution characteristics: slight saline water was mainly distributed in west Baqu and south Quanshan, while severe saline and briny water were dominant in east Baqu and west Huqu; however, total AWCD was higher in the east-center and southwest of Baqu and east Huqu, while it was lower in east Baqu and northwest Huqu. The results of correlation analyses demonstrated that high-salinity groundwater irrigation had significantly adverse effects on soil microbial activities. Major ions Ca(2+), Mg(2+), Cl(-), and SO4(2-) in groundwater decisively influenced the results. Three carbon sources, carbohydrates, amines, and phenols, which had minor utilization rates in all irrigation districts, were extremely significantly affected by high-salinity groundwater irrigation. The results presented here offer an approach for diagnosing regional soil ecosystem function changes under saline water irrigation.

Betulinic acid arrests cell cycle at G2/M phase by up-regulating metallothionein 1G inhibiting proliferation of colon cancer cells.

Betulinic acid (BA) is a pentacyclic triterpene found in many plant species and has a broad-spectrum anti-tumor effect in various cancers, including colon cancer (CRC). However, its anticancer mechanism in CRC is no clear. RNA sequencing and bioinformatics analysis showed BA up-regulated 378 genes and down-regulated 137 genes in HT29 cells, while 2303 up-regulated and 1041 down-regulated genes were found in SW480 cells. KEGG enrichment analysis showed BA significantly stimulated the expression of metallothionein 1 (MT1) family genes in both HT29 and SW480 cells. Metallothionein 1G (MT1G) was the gene with the highest upregulation of MT1 family genes induced by BA dose-dependently. High MT1G expression enhanced the sensitivity of CRC cells to BA, whereas, MT1G knockdown had the opposite effect in vitro and in vivo. GSEA and GSCA showed genes affected by BA treatment were involved in cell cycle and G2/M checkpoint in CRC. Flow cytometry further exhibited BA reduced the percentage of G0/G1 cells and increased the percentage of G2/M cells in a dose-dependent manner, which could be rescued by MT1G knockdown. Moreover, MT1G also counteracted the BA-induced changes in cell cycle-related proteins (CDK2 and CDK4) and p-Rb. In summary, we have revealed a new anti-tumor mechanism that BA altered the cell cycle progression of CRC cells by upregulating MT1G gene, thereby inhibiting the proliferation of CRC cells.

Arachidonic acid released by PIK3CA mutant tumor cells triggers malignant transformation of colonic epithelium by inducing chromatin remodeling.

Key gene mutations are essential for colorectal cancer (CRC) development; however, how the mutated tumor cells impact the surrounding normal cells to promote tumor progression has not been well defined. Here, we report that PIK3CA mutant tumor cells transmit oncogenic signals and result in malignant transformation of intestinal epithelial cells (IECs) via paracrine exosomal arachidonic acid (AA)-induced H3K4 trimethylation. Mechanistically, PIK3CA mutations sustain SGK3-FBW7-mediated stability of the cPLA2 protein, leading to the synthetic increase in AA, which is transported through exosome and accumulated in IECs. Transferred AA directly binds Menin and strengthens the interactions of Menin and MLL1/2 methyltransferase. Finally, the combination of VTP50469, an inhibitor of the Menin-MLL interaction, and alpelisib synergistically represses PDX tumors harboring PIK3CA mutations. Together, these findings unveil the metabolic link between PIK3CA mutant tumor cells and the IECs, highlighting AA as the potential target for the treatment of patients with CRC harboring PIK3CA mutations.

Macaque Brainnetome Atlas: A multifaceted brain map with parcellation, connection, and histology.

The rhesus macaque (Macaca mulatta) is a crucial experimental animal that shares many genetic, brain organizational, and behavioral characteristics with humans. A macaque brain atlas is fundamental to biomedical and evolutionary research. However, even though connectivity is vital for understanding brain functions, a connectivity-based whole-brain atlas of the macaque has not previously been made. In this study, we created a new whole-brain map, the Macaque Brainnetome Atlas (MacBNA), based on the anatomical connectivity profiles provided by high angular and spatial resolution ex vivo diffusion MRI data. The new atlas consists of 248 cortical and 56 subcortical regions as well as their structural and functional connections. The parcellation and the diffusion-based tractography were evaluated with invasive neuronal-tracing and Nissl-stained images. As a demonstrative application, the structural connectivity divergence between macaque and human brains was mapped using the Brainnetome atlases of those two species to uncover the genetic underpinnings of the evolutionary changes in brain structure. The resulting resource includes: (1) the thoroughly delineated Macaque Brainnetome Atlas (MacBNA), (2) regional connectivity profiles, (3) the postmortem high-resolution macaque diffusion and T2-weighted MRI dataset (Brainnetome-8), and (4) multi-contrast MRI, neuronal-tracing, and histological images collected from a single macaque. MacBNA can serve as a common reference frame for mapping multifaceted features across modalities and spatial scales and for integrative investigation and characterization of brain organization and function. Therefore, it will enrich the collaborative resource platform for nonhuman primates and facilitate translational and comparative neuroscience research.

Sigmoid colon perforation with splenic abscess due to ulcerative colitis: A case report and review of the literature.

INTRODUCTION AND IMPORTANCE: The occurrence of abscesses in the spleen, a substantial abdominal organ with hematopoietic function, is relatively rare in clinical cases and mostly occurs in immunodeficient populations. The early symptoms of splenic abscess are not obvious, and the diagnosis is usually confirmed by a combination of patient symptoms, imaging manifestations and blood culture results. CASE PRESENTATION: A 36-year-old male patient was treated in the emergency room for severe lower abdominal pain and discomfort. An abdominal CT(Computed Tomography) examination initially suggested an acute bowel perforation and an enlarged and abnormally thick spleen. The patient first underwent a repair of the bowel perforation, which was followed by fever and no reduction in abdominal symptoms, while the patient's splenic abscess was then treated with a repeat splenectomy. CLINICAL DISCUSSION: Splenic abscesses mostly occur in immunocompromised patients. The treatment of splenic abscesses includes simple antibacterial medication, percutaneous puncture placement for drainage, and splenectomy for drainage. In our case, the treatment of this patient's splenic abscess was divided into several stages, and we finally used splenectomy for drainage because the patient's symptoms were not significantly better than before and combined with coagulation abnormalities. CONCLUSION: In patients with severe abdominal infection and relevant ancillary tests suggesting abnormal spleen size and density, it is also important to consider whether a splenic abscess has formed and to provide early diagnosis and treatment of splenic abscess while fighting abdominal infection.

Design and construction of an 8-channel transceiver coil array for rat imaging at 9.4 T.

Ultra-high field (UHF) small animal magnetic resonance imaging (MRI) is a crucial tool permitting investigation of metabolic diseases and identification of imaging biomarkers suitable for clinical diagnosis and translation. Radiofrequency (RF) coils are critical components in enabling acquisition of high-quality rat abdomen MRI data. However, efficient RF coils with high-channel count, capable of sensitive and accelerated rat abdomen imaging at 9.4 T, are not available commercially. The SNR of the commonly-used 9.4 T birdcage coil is relatively weak, particularly in the peripheral area of the subject. In addition, the birdcage is not readily to perform parallel imaging due to unavailability of the required multiple channels. Consequently, the extended scanning duration may cause unnecessary hazards to the rat. In this work, an 8-channel transceiver coil array was designed and constructed to provide good image quality and large coverage for rat abdomen imaging at 9.4 T. The structure and the performance of the developed array was optimized and evaluated by numerical electromagnetic simulations and bench tests, respectively. The MR imaging experiments in phantoms and rat models were also performed on a Bruker 9.4 T preclinical MRI system to validate the feasibility of the proposed design. The coil array supports a one-dimensional acceleration factor up to R = 4, providing good parallel imaging capabilities. These results demonstrated that the proposed 8-channel transceiver coil array for rat imaging has the ability to obtain high spatial resolution of rat abdomen anatomical structure images at 9.4 T.

The roles and molecular mechanisms of long non-coding RNA WT1-AS in the maintenance and development of gastric cancer stem cells.

It has been proposed that cancer stem cells (CSCs) are responsible for almost all malignant phenotypes of tumors. Long non-coding RNA WT1 antisense RNA (WT1-AS) has been found to be implicated in lung cancer cell stemness. However, the roles and molecular mechanisms of WT1-AS in the development of gastric cancer stem cells (GCSCs) remain unknown. Our present study showed that WT1-AS negatively regulated WT1 expression in GCSCs. WT1-AS knockdown or Wilms' tumor 1 (WT1) overexpression improved GCSC proliferative and migratory capacities, inhibited GCSC apoptosis, potentiated the resistance of GCSCs to 5-FU, promoted GCSC EMT, induced HUVEC angiogenesis, enhanced GCSC stemness, and facilitated in-vitro 3D GCSC aggregate formation. WT1-AS overexpression exerted reverse effects. WT1-AS ameliorated the malignant phenotypes of GCSCs by down-regulating WT1 in vitro. WT1-AS inhibited tumor growth and metastasis, and reduced tumor stemness in GCSCs-derived (s.c., i.p., and i.v.) xenografts in vivo. Moreover, XBP1 was identified as an upstream regulator of WT1-AS in GCSCs. Also, 4 potential WT1-AS downstream targets (i.e. PSPH, GSTO2, FYN, and PHGDH) in GCSCs were identified. Additionally, CACNA2D1 was demonstrated to be a downstream target of the WT1-AS/WT axis. XBP1 or CACNA2D1 knockdown exerted an adverse effect on the maintenance of stem cell-like behaviors and characteristics of GCSCs. In conclusion, WT1-AS weakened the stem cell-like behaviors and characteristics of GCSCs in vitro and in vivo by down-regulating WT1. Investigations into the molecular mechanisms underlying the complex phenotypes of GCSCs might contribute to the better management of gastric cancer.

Organic fertilizer and irrigation water are the primary sources of microplastics in the facility soil, Beijing.

The large-scale utilization of plastic products in agricultural facility production has resulted in considerable accumulation of microplastics in the soil. However, there is a lack of systematic research on the accumulation and distribution of microplastics in facility agriculture. This study examined the presence of microplastics in the 15 representatives of Beijing facility agriculture soil in five districts with different planting years, and assessed the potential pollution risks. The abundance of microplastics in soil layers at a depth of 0-10, 10-20, and 20-30 cm was 896.5 ± 80.0 (range, 160-2120), 630.6 ± 47.0 (180-1340), and 445.3 ± 47.0 (80-1480) items/kg, respectively. Overall, the microplastics were primarily fiber-shaped (72.2 %), white (75.9 %), 1-2 mm in size (37.9 %), and composed of polypropylene and polyethene. The risk assessment indices of the microplastics in the 0-10, 10-20, and 20-30 cm soil layers were 272.1, 289.5, and 291.6, respectively, representing a risk level of 4 in each case. Using the conditional fragmentation model, we found that the microplastics in facility soil featured low stability and small sizes, and their primary sources were organic fertilizer and irrigation water. The number of mulching years, irrigation method, and the amount of organic fertilizer applied, influenced the accumulation of microplastics in the facility soil. This study provides scientific evidence supporting the pollution levels and need for risk control related to microplastics in facility soils.

TNF+ regulatory T cells regulate the stemness of gastric cancer cells through the IL13/STAT3 pathway.

Regulatory T cells (Tregs) are an important component of the tumor microenvironment; however, the interaction between Tregs and gastric cancer cells is not completely understood. Recent studies have shown that Tregs participate in cancer cell stemness maintenance. In this study, we performed single-cell RNA sequencing of gastric cancer and adjacent tissues and found that Tregs with high TNF expression were recruited to gastric cancer tissues and were significantly correlated with patient survival. TNF+ Tregs significantly contribute to tumor growth and progression. Our studies have further demonstrated that TNF+ Tregs promote the stemness of gastric cancer cells through the IL13/STAT3 pathway. Therefore, blocking the interaction between TNF+ Tregs and gastric cancer cells may be a new approach in the treatment of gastric cancer.

Instantaneous antidepressant effect of lateral habenula deep brain stimulation in rats studied with functional MRI.

The available treatments for depression have substantial limitations, including low response rates and substantial lag time before a response is achieved. We applied deep brain stimulation (DBS) to the lateral habenula (LHb) of two rat models of depression (Wistar Kyoto rats and lipopolysaccharide-treated rats) and observed an immediate (within seconds to minutes) alleviation of depressive-like symptoms with a high-response rate. Simultaneous functional MRI (fMRI) conducted on the same sets of depressive rats used in behavioral tests revealed DBS-induced activation of multiple regions in afferent and efferent circuitry of the LHb. The activation levels of brain regions connected to the medial LHb (M-LHb) were correlated with the extent of behavioral improvements. Rats with more medial stimulation sites in the LHb exhibited greater antidepressant effects than those with more lateral stimulation sites. These results indicated that the antidromic activation of the limbic system and orthodromic activation of the monoaminergic systems connected to the M-LHb played a critical role in the rapid antidepressant effects of LHb-DBS. This study indicates that M-LHb-DBS might act as a valuable, rapid-acting antidepressant therapeutic strategy for treatment-resistant depression and demonstrates the potential of using fMRI activation of specific brain regions as biomarkers to predict and evaluate antidepressant efficacy.

CHD8 mutations increase gliogenesis to enlarge brain size in the nonhuman primate.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that affects social interaction and behavior. Mutations in the gene encoding chromodomain helicase DNA-binding protein 8 (CHD8) lead to autism symptoms and macrocephaly by a haploinsufficiency mechanism. However, studies of small animal models showed inconsistent findings about the mechanisms for CHD8 deficiency-mediated autism symptoms and macrocephaly. Using the nonhuman primate as a model system, we found that CRISPR/Cas9-mediated CHD8 mutations in the embryos of cynomolgus monkeys led to increased gliogenesis to cause macrocephaly in cynomolgus monkeys. Disrupting CHD8 in the fetal monkey brain prior to gliogenesis increased the number of glial cells in newborn monkeys. Moreover, knocking down CHD8 via CRISPR/Cas9 in organotypic monkey brain slices from newborn monkeys also enhanced the proliferation of glial cells. Our findings suggest that gliogenesis is critical for brain size in primates and that abnormal gliogenesis may contribute to ASD.

An App knock-in rat model for Alzheimer's disease exhibiting Aß and tau pathologies, neuronal death and cognitive impairments.

A major obstacle in Alzheimer's disease (AD) research is the lack of predictive and translatable animal models that reflect disease progression and drug efficacy. Transgenic mice overexpressing amyloid precursor protein (App) gene manifest non-physiological and ectopic expression of APP and its fragments in the brain, which is not observed in AD patients. The App knock-in mice circumvented some of these problems, but they do not exhibit tau pathology and neuronal death. We have generated a rat model, with three familiar App mutations and humanized Aß sequence knocked into the rat App gene. Without altering the levels of full-length APP and other APP fragments, this model exhibits pathologies and disease progression resembling those in human patients: deposit of Aß plaques in relevant brain regions, microglia activation and gliosis, progressive synaptic degeneration and AD-relevant cognitive deficits. Interestingly, we have observed tau pathology, neuronal apoptosis and necroptosis and brain atrophy, phenotypes rarely seen in other APP models. This App knock-in rat model may serve as a useful tool for AD research, identifying new drug targets and biomarkers, and testing therapeutics.