Differential expressions and potential clinical values of lncRNAs in the plasma exosomes of rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a common autoimmune disease with unclear pathogenesis. Progress in its clinical diagnosis and treatment mainly depends on the elucidation of its pathogenesis and the exploration of new biomarkers. Exosomes contain various biomolecules, including long non-coding ribonucleic acids (lncRNAs). lncRNAs may participate in the regulation of autoimmune and inflammatory processes during RA pathogenesis by transmitting these biomolecules via exosomes among different cells. Therefore, the investigation of lncRNAs in RA exosomes may be a feasible pathway to elucidate RA pathogenesis, identify new diagnostic biomarkers, and identify potential therapeutic targets. METHODS: In the first phase of exosomal non-coding RNAs screening, exosomes were isolated from the peripheral blood of six patients with RA and healthy controls (HC). High-throughput RNA sequencing was performed to obtain lncRNA expression profiles, and 15 lncRNAs with the highest differential expression were selected as candidate lncRNAs. In the second phase of validation using real-time quantitative polymerase chain reaction (qRT-PCR), differential expression of the 15 candidate lncRNAs was verified in 42 patients with RA and their matched HC. Their potential value as RA diagnostic biomarkers was assessed using receiver operating characteristic (ROC) curve analysis. Their relationships with common clinical indices of RA were explored using Spearman's rank correlation and linear regression analyses. RESULT: Compared to HC, patients with RA had 206 upregulated and 2,332 downregulated lncRNAs. Fifteen candidate lncRNAs were validated by qRT-PCR, of which 12 (SNHG6, RPS18P9, RPL21P28, EBLN3P, FAM153CP, RPL23P8, SNHG31, NORAD, H3P6, DLEU2, TUG1, and OIP5-AS1) were upregulated, and three (CXXC4-AS1, OLMALINC, and NPHP3-AS1) were downregulated. In the ROC analysis of the 15 candidate lncRNAs, the area under the curve (AUC) ranged from 0.847 (0.767, 0.927) for OLMALINC to 0.994 (0.984, 1.000) for CXXC4-AS1. Spearman rank correlation analysis revealed erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and disease activity score of 28 (DAS28) were correlated with seven, six, and five lncRNAs, respectively. Further linear regression analysis revealed a negative relationship between exosomal SNHG6 and ESR (B = -0.384, P = 0.006), and a positive relationship between SNHG31 and ESR (B = 0.381, P = 0.007). Exosomal SNHG6 also showed a negative relationship with CRP (B = -0.361, P = 0.019). Moreover, exosomal RPS18P9 and SNGH31 had a negative effect and a positive effect on DAS28, respectively (B = -0.463, P < 0.001; B = 0.586, P < 0.001), implying novel exosomal lncRNAs were the independent influencing factors of the main RA-related clinical indices. CONCLUSIONS: lncRNAs in RA plasma exosomes have characteristic expression profiles, including some lncRNAs with potential as diagnostic biomarkers and therapeutic targets for RA.

Impaired Lactate Release in Dorsal CA1 Astrocytes Contributed to Nociceptive Sensitization and Comorbid Memory Deficits in Rodents.

BACKGROUND: Memory deficits are a common comorbid disorder in patients suffering from neuropathic pain. The mechanisms underlying the comorbidities remain elusive. The hypothesis of this study was that impaired lactate release from dysfunctional astrocytes in dorsal hippocampal CA1 contributed to memory deficits. METHODS: A spared nerve injury model was established to induce both pain and memory deficits in rats and mice of both sexes. von Frey tests, novel object recognition, and conditioned place preference tests were applied to evaluate the behaviors. Whole-cell recording, fiber photometry, Western blotting, and immunohistochemistry combined with intracranial injections were used to explore the underlying mechanisms. RESULTS: Animals with spared sciatic nerve injury that had displayed nociception sensitization or memory deficit comorbidities demonstrated a reduction in the intrinsic excitability of pyramidal neurons, accompanied by reduced Ca2+ activation in astrocytes (ΔF/F, sham: 6 ± 2%; comorbidity: 2 ± 0.4%) and a decrease in the expression of glial fibrillary acidic protein and lactate levels in the dorsal CA1. Exogenous lactate supply or increasing endogenous lactate release by chemogenetic activation of astrocytes alleviated this comorbidity by enhancing the cell excitability (129 ± 4 vs. 88 ± 10 for 3.5 mM lactate) and potentiating N-methyl-d-aspartate receptor-mediated excitatory postsynaptic potentials of pyramidal neurons. In contrast, inhibition of lactate synthesis, blocking lactate transporters, or chemogenetic inhibition of astrocytes resulted in comorbidity-like behaviors in naive animals. Notably, ß2-adrenergic receptors in astrocytes but not neurons were downregulated in dorsal CA1 after spared nerve injury. Microinjection of a ß2 receptor agonist into dorsal CA1 or activation of the noradrenergic projections onto the hippocampus from the locus coeruleus alleviated the comorbidity, possibly by increasing lactate release. CONCLUSIONS: Impaired lactate release from dysfunctional astrocytes, which could be rescued by activation of the locus coeruleus, led to nociception and memory deficits after peripheral nerve injury.

Deactivation of dorsal CA1 pyramidal neurons projecting to medial prefrontal cortex contributes to neuropathic pain and short-term memory impairment.

ABSTRACT: Neuropathic pain after peripheral nerve injury is a multidimensional experience that includes sensory, affective, and cognitive components that interact with one another. Hypoexcitation of the medial prefrontal cortex (mPFC) was observed in mice with peripheral nerve injury, but the changes in neural inputs onto the mPFC have not been completely explored. Here, we report that the neural terminals from the dorsal hippocampus CA1 (dCA1) form excitatory connection with layer 5 pyramidal neurons in the prelimbic area (PrL) of the mPFC. Spared nerve injury (SNI) induced a reduction in the intrinsic excitability of dCA1 pyramidal neurons innervating the PrL and impairment in excitatory synaptic transmission onto dCA1 pyramidal cells. Specifically, activating the neural circuit from dCA1 to mPFC alleviated neuropathic pain behaviors and improved novel object recognition ability in SNI mice, whereas deactivating this pathway in naïve animals recapitulated tactile allodynia and memory deficits. These results indicated that hypoactivity in dCA1 pyramidal cells after SNI in turn deactivated layer 5 pyramidal neurons in PrL and ultimately caused pain hypersensitivity and memory deficits.

Anisotropic charge transfer and gate tuning for p-SnS/n-MoS2 vertical van der Waals diodes.

2D-material-based van der Waals heterostructures (vdWhs) have shown great potential in next-generation multi-functional microelectronic devices. Thanks to their sharp interface and ultrathin thickness, 2D p-n junctions with high rectification properties have been established by combining p-type monochalcogenides with n-type transition metal dichalcogenides. However, the anisotropic rectification together with the charge transfer and gate effect has not been clarified. Herein, the electrical anisotropy of p-SnS/n-MoS2 diodes was studied. Optimum ideality factors within 1.08-1.18 have been achieved for the diode with 6.6 nm thick SnS on monolayer MoS2, and a high rectification ratio of 3.1 × 104 with strong in-plane anisotropy is observed along the zigzag direction of SnS. A strong gate effect on the anisotropic series resistance has been verified and an effective tuning over the transport length of the SnS channel can be established through adjustment of the current orientation and gate voltage. A thickness-dependent minority carrier transport mechanism has also been demonstrated for the reverse drain current, and Fowler-Nordheim tunneling and direct tunneling are proposed for the increase of the reverse current of the thicker and thinner diodes, respectively. This work will provide another strategy for high-performance diodes based on vdWhs via the control of the current orientation and the gate effect.

A Transformer-Based Neural Network for Gait Prediction in Lower Limb Exoskeleton Robots Using Plantar Force.

Lower limb exoskeleton robots have shown significant research value due to their capabilities of providing assistance to wearers and improving physical motion functions. As a type of robotic technology, wearable robots are directly in contact with the wearer's limbs during operation, necessitating a high level of human-robot collaboration to ensure safety and efficacy. Furthermore, gait prediction for the wearer, which helps to compensate for sensor delays and provide references for controller design, is crucial for improving the the human-robot collaboration capability. For gait prediction, the plantar force intrinsically reflects crucial gait patterns regardless of individual differences. To be exact, the plantar force encompasses a doubled three-axis force, which varies over time concerning the two feet, which also reflects the gait patterns indistinctly. In this paper, we developed a transformer-based neural network (TFSformer) comprising convolution and variational mode decomposition (VMD) to predict bilateral hip and knee joint angles utilizing the plantar pressure. Given the distinct information contained in the temporal and the force-space dimensions of plantar pressure, the encoder uses 1D convolution to obtain the integrated features in the two dimensions. As for the decoder, it utilizes a multi-channel attention mechanism to simultaneously focus on both dimensions and a deep multi-channel attention structure to reduce the computational and memory consumption. Furthermore, VMD is applied to networks to better distinguish the trends and changes in data. The model is trained and tested on a self-constructed dataset that consists of data from 35 volunteers. The experimental results show that FTSformer reduces the mean absolute error (MAE) up to 10.83%, 15.04% and 8.05% and the mean squared error (MSE) by 20.40%, 29.90% and 12.60% compared to the CNN model, the transformer model and the CNN transformer model, respectively.

Tail nerve electrical stimulation promoted the efficiency of transplanted spinal cord-like tissue as a neuronal relay to repair the motor function of rats with transected spinal cord injury.

Following transected spinal cord injury (SCI), there is a critical need to restore nerve conduction at the injury site and activate the silent neural circuits caudal to the injury to promote the recovery of voluntary movement. In this study, we generated a rat model of SCI, constructed neural stem cell (NSC)-derived spinal cord-like tissue (SCLT), and evaluated its ability to replace injured spinal cord and repair nerve conduction in the spinal cord as a neuronal relay. The lumbosacral spinal cord was further activated with tail nerve electrical stimulation (TNES) as a synergistic electrical stimulation to better receive the neural information transmitted by the SCLT. Next, we investigated the neuromodulatory mechanism underlying the action of TNES and its synergism with SCLT in SCI repair. TNES promoted the regeneration and remyelination of axons and increased the proportion of glutamatergic neurons in SCLT to transmit brain-derived neural information more efficiently to the caudal spinal cord. TNES also increased the innervation of motor neurons to hindlimb muscle and improved the microenvironment of muscle tissue, resulting in effective prevention of hindlimb muscle atrophy and enhanced muscle mitochondrial energy metabolism. Tracing of the neural circuits of the sciatic nerve and tail nerve identified the mechanisms responsible for the synergistic effects of SCLT transplantation and TNES in activating central pattern generator (CPG) neural circuits and promoting voluntary motor function recovery in rats. The combination of SCLT and TNES is expected to provide a new breakthrough for patients with SCI to restore voluntary movement and control their muscles.

Bisphenol A exposure induces testicular oxidative damage via FTO/m6A/Nrf2 axis during postnatal development in mice.

Bisphenol A (BPA), a commonly used plasticizer in the production of polycarbonate plastics and epoxy resins, has been shown to induce male reproductive toxicity. However, the effects of BPA exposure on early testicular development have not been thoroughly studied, and the underlying mechanism is yet to be elucidated. In the current study, neonatal male mice were exposed to BPA at 0, 0.1, and 5 mg/kg, respectively, by daily subcutaneous injection during postnatal day (PND) 1-35 to explore its effects on testicular development at PND 36 (the end of the first round of spermatogenesis). Morphological analyses showed that BPA exposure significantly induced apoptosis of testicular cells (p < 0.01 and p < 0.001) and reduced the thickness of seminiferous epithelium (p < 0.01). In addition, BPA exposure significantly decreased the total antioxidant capacity of testes and levels of transcription factor Nrf2 as well as its downstream antioxidant molecules of NQO1 and GPx-1 (p < 0.05 and p < 0.01). Furthermore, global m6A modifications of mRNAs were upregulated accompanied by declined m6A demethylase (FTO) in the testes of BPA groups (p < 0.05 and p < 0.01). MeRIP-quantitative real-time polymerase chain reaction (qPCR) demonstrated that BPA exposure markedly increased the m6A modification of Nrf2 mRNA (p < 0.05 and p < 0.01). These findings suggest that upregulation of m6A induced by inhibited FTO may be involved in BPA-induced testicular oxidative stress and developmental injury during postnatal development, which provides a new idea to reveal the mechanism underlying BPA interfering with testicular development.

Histone methyltransferase WHSC1 loss dampens MHC-I antigen presentation pathway to impair IFN-γ-stimulated antitumor immunity.

IFN-γ-stimulated MHC class I (MHC-I) antigen presentation underlies the core of antitumor immunity. However, sustained IFN-γ signaling also enhances the programmed death ligand 1 (PD-L1) checkpoint pathway to dampen antitumor immunity. It remains unclear how these opposing effects of IFN-γ are regulated. Here, we report that loss of the histone dimethyltransferase WHSC1 impaired the antitumor effect of IFN-γ signaling by transcriptional downregulation of the MHC-I machinery without affecting PD-L1 expression in colorectal cancer (CRC) cells. Whsc1 loss promoted tumorigenesis via a non-cell-autonomous mechanism in an Apcmin/+ mouse model, CRC organoids, and xenografts. Mechanistically, we found that the IFN-γ/STAT1 signaling axis stimulated WHSC1 expression and, in turn, that WHSC1 directly interacted with NLRC5 to promote MHC-I gene expression, but not that of PD-L1. Concordantly, silencing Whsc1 diminished MHC-I levels, impaired antitumor immunity, and blunted the effect of immune checkpoint blockade. Patient cohort analysis revealed that WHSC1 expression positively correlated with enhanced MHC-I expression, tumor-infiltrating T cells, and favorable disease outcomes. Together, our findings establish a tumor-suppressive function of WHSC1 that relays IFN-γ signaling to promote antigen presentation on CRC cells and provide a rationale for boosting WHSC1 activity in immunotherapy.

Governor Vessel Electro-Acupuncture Promotes the Intrinsic Growth Ability of Spinal Neurons through Activating Calcitonin Gene-Related Peptide/α-Calcium/Calmodulin-Dependent Protein Kinase/Neurotrophin-3 Pathway after Spinal Cord Injury.

Spinal cord injury (SCI) invariably results in neuronal death and failure of axonal regeneration. This is attributed mainly to the hostile microenvironment and the poor intrinsic regrowth capacity of the injured spinal neurons. We have reported previously that electro-acupuncture on Governor Vessel acupoints (GV-EA) can promote neuronal survival and axonal regeneration of injured spinal cord. However, the underlying mechanism for this has remained uncertain. The present study aimed to explore the neural afferent pathway of GV-EA stimulation and the possible mechanism by which GV-EA can activate the intrinsic growth ability of injured spinal neurons. By cholera toxin B (CTB) retrograde labeling, immunostaining, and enzyme-linked immunosorbent assay (ELISA), we showed here that GV-EA could stimulate the spinal nerve branches of the dorsal root ganglion cells. This would then increase the release of calcitonin gene-related peptide (CGRP) from the afferent terminals in the spinal cord. It is of note that the effect was abrogated after dorsal rhizotomy. Additionally, both in vivo and in vitro results showed that CGRP would act on the post-synaptic spinal cord neurons and triggered the synthesis and secretion of neurotrophin-3 (NT-3) by activating the calcitonin gene-related peptide (CGRP)/ receptor activity-modifying protein (RAMP)1/calcium/calmodulin-dependent protein kinase (αCaMKII) pathway. Remarkably, the observed effect was prevented by the dorsal rhizotomy and the blockers of the CGRP/RAMP1/αCaMKII pathway. More importantly, increase in NT-3 promoted the survival, axonal regrowth, and synaptic maintenance of spinal cord neurons in the injured spinal cord. Therefore, it is concluded that increase in NT-3 production is one of the mechanisms by which GV-EA can activate the intrinsic growth ability of spinal neurons after SCI. The experimental results have reinforced the theoretical basis of GV-EA for its clinical efficacy in patients with SCI.

Circulating apelin, chemerin and omentin levels in patients with gestational diabetes mellitus: a systematic review and meta-analysis.

BACKGROUND: The available data on the significance of circulating apelin, chemerin and omentin in women with gestational diabetes mellitus (GDM) are inconsistent. This analysis includes a systematic review of the evidence associating the serum concentrations of these adipokines with GDM. METHODS: Publications through December 2019 were retrieved from PubMed, Embase, the Cochrane Library, and Web of Science. Subgroup analysis and meta-regression were conducted to evaluate sources of heterogeneity. RESULTS: Analysis of 20 studies, including 1493 GDM patients and 1488 normal pregnant women did not find significant differences in circulating apelin and chemerin levels (apelin standardized mean difference [SMD] = 0.43, 95% confidence interval (CI): - 0.40 to 1.26, P = 0.31; chemerin SMD = 0.77, 95% CI - 0.07 to 1.61, P = 0.07). Circulating omentin was significantly lower in women with GDM than in healthy controls (SMD = - 0.72, 95% CI - 1.26 to - 0.19, P = 0.007). Publication bias was not found; sensitivity analysis confirmed the robustness of the pooled results. CONCLUSIONS: Circulating omentin was decreased in GDM patients, but apelin and chemerin levels were not changed. The results suggest that omentin has potential as a novel biomarker for the prediction and early diagnosis of GDM.

Associations of serum citrate levels with knee structural changes and cartilage enzymes in patients with knee osteoarthritis.

OBJECTIVE: The aim of this study was to investigate cross-sectional associations between serum levels of citrate and knee structural changes and cartilage enzymes in patients with knee osteoarthritis (OA). METHOD: A total of 137 subjects with symptomatic knee OA (mean age 55.0 years, range 34-74, 84% female) were included. Knee radiography was used to assess knee osteophytes, joint space narrowing (JSN) and radiographic OA assessed by Kellgren-Lawrence (K-L) grading system. T2-weighted fat-suppressed fast spin echo magnetic resonance imaging (MRI) was used to determine knee cartilage defects, bone marrow lesions (BMLs) and infrapatellar fat pad (IPFP) signal intensity alternations. Colorimetric fluorescence was used to measure the serum levels of citrate. Enzyme-linked immunosorbent assay was used to measure the serum cartilage enzymes including matrix metalloproteinase (MMP)-3 and MMP-13. RESULTS: After adjustment for potential confounders (age, sex, body mass index), serum citrate was negatively associated with knee osteophytes at the femoral site, cartilage defects at medial femoral site, total cartilage defects, and total BMLs (odds ratio [OR] 0.17-0.30, all P < .05). Meanwhile, serum citrate was negatively associated with IPFP signal intensity alteration (OR 0.30, P = .05) in multivariable analyses. Serum citrate was significantly and negatively associated with MMP-13 (ß -3106.37, P < .05) after adjustment for potential confounders. However, citrate was not significantly associated with MMP-3 in patients with knee OA. CONCLUSION: Serum citrate was negatively associated with knee structural changes including femoral osteophytes, cartilage defects, and BMLs and also serum MMP-13 in patients with knee OA, suggesting that low serum citrate may be a potential indicator for advanced knee OA.

Associations between circulating adipokines and bone mineral density in patients with knee osteoarthritis: a cross-sectional study.

BACKGROUND: Associations between adipokines and bone mineral density (BMD) in knee osteoarthritis (OA) remain indistinct. The aim of this study was to investigate the cross-sectional associations between serum levels of adipokines and BMD in patients with knee OA. METHODS: This study included 164 patients with symptomatic knee OA from the Anhui Osteoarthritis study. Serum levels of leptin, adiponectin, and resistin were measured using an enzyme-linked immunosorbent assay (ELISA). BMD at total body, spine, hip, and femur were measured by dual-energy X-ray absorptiometry (DXA). RESULTS: In multivariable analyses, serum levels of leptin were significantly associated with reduced BMD at total body, hip, total femur, femoral neck, and femoral shaft (ß = - 0.019, 95% CI -0.034 to - 0.005; ß = - 0.018, 95% CI -0.034 to - 0.003; ß = - 0.018, 95% CI -0.034 to - 0.002; ß = - 0.016, 95% CI -0.032 to 0.000; ß = - 0.026, 95% CI -0.046 to - 0.006; respectively). Serum levels of adiponectin were significantly and negatively associated with BMD at total femur and femoral shaft (ß = - 0.007, 95% CI -0.013 to 0.000; ß = - 0.011, 95% CI -0.018 to - 0.003; respectively). However, no significant associations were found between serum levels of resistin and BMD at any site measured. CONCLUSIONS: Serum levels of leptin and adiponectin were significantly and negatively associated with BMD, suggesting potentially detrimental effects of leptin and adiponectin on BMD in knee OA patients.

Associations between systemic bone mineral density, knee cartilage defects and bone marrow lesions in patients with knee osteoarthritis.

AIM: The relationship between bone mineral density (BMD) and osteoarthritis (OA) remains controversial. This study aimed to explore the cross-sectional associations between BMD at the total body, hip and spine and joint structural abnormalities including cartilage defects and bone marrow lesions (BMLs) in patients with knee OA. METHOD: One hundred and eight-five subjects with symptomatic knee OA were included in this study. T2-weighted fast spin echo magnetic resonance imaging was used to assess knee cartilage defects and BMLs. Total body, hip and spine BMD were measured using dual-energy X-ray absorptiometry. RESULTS: After adjustment for potential confounders, total hip BMD was negatively associated with medial tibial cartilage defects, lateral femoral cartilage defects, medial tibial BMLs and lateral tibial BMLs. Spine and total body BMD were negatively associated with lateral femoral cartilage defects, but not with BMLs. CONCLUSION: We concluded that BMD particularly at the hip was negatively associated with knee cartilage defects and BMLs.

Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis.

The histone H3K36 methyltransferase SETD2 is frequently mutated or deleted in a variety of human tumors. Nevertheless, the role of SETD2 loss in oncogenesis remains largely undefined. Here, we found that SETD2 counteracts Wnt signaling and its inactivation promotes intestinal tumorigenesis in mouse models of colorectal cancer (CRC). SETD2 was not required for intestinal homeostasis under steady state; however, upon irradiation, genetic inactivation of Setd2 in mouse intestinal epithelium facilitated the self-renewal of intestinal stem/progenitor cells as well as tissue regeneration. Furthermore, depletion of SETD2 enhanced the susceptibility to tumorigenesis in the context of dysregulated Wnt signaling. Mechanistic characterizations indicated that SETD2 downregulation affects the alternative splicing of a subset of genes implicated in tumorigenesis. Importantly, we uncovered that SETD2 ablation reduces intron retention of dishevelled segment polarity protein 2 (DVL2) pre-mRNA, which would otherwise be degraded by nonsense-mediated decay, thereby augmenting Wnt signaling. The signaling cascades mediated by SETD2 were further substantiated by a CRC patient cohort analysis. Together, our studies highlight SETD2 as an integral regulator of Wnt signaling through epigenetic regulation of RNA processing during tissue regeneration and tumorigenesis.

Epithelial EZH2 serves as an epigenetic determinant in experimental colitis by inhibiting TNFα-mediated inflammation and apoptosis.

Epithelial barrier disruption is a major cause of inflammatory bowel disease (IBD); however, the mechanism through which epigenetic regulation modulates intestinal epithelial integrity remains largely undefined. Here we show that EZH2, the catalytic subunit of polycomb repressive complex (PRC2), is indispensable for maintaining epithelial cell barrier integrity and homeostasis under inflammatory conditions. In accordance with reduced EZH2 expression in patients, the inactivation of EZH2 in IECs sensitizes mice to DSS- and TNBS-induced experimental colitis. Conversely, EZH2 overexpression in the intestinal epithelium renders mice more resistant to colitis. Mechanistically, the genes encoding TRAF2/5 are held in a finely tuned bivalent status under inflammatory conditions. EZH2 deficiency potentiates the expression of these genes to enhance TNFα-induced NF-κB signaling, thereby leading to uncontrolled inflammation. More importantly, we show that EZH2 depletion compromises the protective role of NF-κB signaling in cell survival by directly up-regulating ITCH, a well-known E3 ligase that degrades the c-FLIP protein. Thus, our findings highlight an epigenetic mechanism by which EZH2 integrates the multifaceted effects of TNFα signaling to promote the inflammatory response and apoptosis in colitis.

AKT-mediated stabilization of histone methyltransferase WHSC1 promotes prostate cancer metastasis.

Loss of phosphatase and tensin homolog (PTEN) and activation of the PI3K/AKT signaling pathway are hallmarks of prostate cancer (PCa). However, these alterations alone are insufficient for cells to acquire metastatic traits. Here, we have shown that the histone dimethyl transferase WHSC1 critically drives indolent PTEN-null tumors to become metastatic PCa. In a PTEN-null murine PCa model, WHSC1 overexpression in prostate epithelium cooperated with Pten deletion to produce a metastasis-prone tumor. Conversely, genetic ablation of Whsc1 prevented tumor progression in PTEN-null mice. Molecular characterization revealed that increased AKT activity due to PTEN loss directly phosphorylates WHSC1 at S172, preventing WHSC1 degradation by CRL4Cdt2 E3 ligase. Increased WHSC1 expression transcriptionally upregulates expression of RICTOR, a pivotal component of mTOR complex 2 (mTORC2), to further enhance AKT activity. Therefore, the AKT/WHSC1/mTORC2 signaling cascade represents a vicious feedback loop that elicits unrestrained AKT signaling. Furthermore, we determined that WHSC1 positively regulates Rac1 transcription to increase tumor cell motility. The biological importance of a WHSC1-mediated signaling cascade is substantiated by patient sample analysis in which WHSC1 signaling is tightly correlated with disease progression and recurrence. Taken together, our findings highlight a pivotal link between an epigenetic regulator, WHSC1, and key intracellular signaling molecules, AKT, RICTOR, and Rac1, to drive PCa metastasis.

Domain-confined catalytic soot combustion over Co3O4 anchored on a TiO2 nanotube array catalyst prepared by mercaptoacetic acid induced surface-grafting.

Herein, we introduce a specially designed domain-confined macroporous catalyst, namely, the Co3O4 nanocrystals anchored on a TiO2 nanotube array catalyst, which was synthesized by using the mercaptoacetic acid induced surface-grafting method. This catalyst exhibits much better performance for catalytic soot combustion than the conventional TiO2 powder supported one in gravitational contact mode (GMC).