Phosphocreatine promotes epigenetic reprogramming to facilitate glioblastoma growth through stabilizing BRD2.

Glioblastoma (GBM) exhibits profound metabolic plasticity for survival and therapeutic resistance, while the underlying mechanisms remain unclear. Here, we show that GBM stem cells (GSCs) reprogram the epigenetic landscape by producing substantial amounts of phosphocreatine (PCr). This production is attributed to the elevated transcription of brain-type creatine kinase (CKB), mediated by Zinc finger E-box binding homeobox 1 (ZEB1). PCr inhibits the poly-ubiquitination of the chromatin regulator bromodomain containing protein 2 (BRD2) by outcompeting the E3 ubiquitin ligase SPOP for BRD2 binding. Pharmacological disruption of PCr biosynthesis by cyclocreatine leads to BRD2 degradation and a decrease in its targets' transcription, which inhibits chromosome segregation and cell proliferation. Notably, cyclocreatine treatment significantly impedes tumor growth and sensitizes tumors to a BRD2 inhibitor in mouse GBM models without detectable side effects. These findings highlight that high production of PCr is a druggable metabolic feature of GBM and a promising therapeutic target for GBM treatment.

Small intestinal CaSR-dependent and CaSR-independent protein sensing regulates feeding and glucose tolerance in rats.

Proteins activate small intestinal calcium sensing receptor (CaSR) and/or peptide transporter 1 (PepT1) to increase hormone secretion1-8, but the effect of small intestinal protein sensing and the mechanistic potential of CaSR and/or PepT1 in feeding and glucose regulation remain inconclusive. Here we show that, in male rats, CaSR in the upper small intestine is required for casein infusion to increase glucose tolerance and GLP1 and GIP secretion, which was also dependent on PepT1 (ref. 9). PepT1, but not CaSR, is required for casein infusion to lower feeding. Upper small intestine casein sensing fails to regulate feeding, but not glucose tolerance, in high-fat-fed rats with decreased PepT1 but increased CaSR expression. In the ileum, a CaSR-dependent but PepT1-independent pathway is required for casein infusion to lower feeding and increase glucose tolerance in chow-fed rats, in parallel with increased PYY and GLP1 release, respectively. High fat decreases ileal CaSR expression and disrupts casein sensing on feeding but not on glucose control, suggesting an ileal CaSR-independent, glucose-regulatory pathway. In summary, we discover small intestinal CaSR- and PepT1-dependent and -independent protein sensing mechanisms that regulate gut hormone release, feeding and glucose tolerance. Our findings highlight the potential of targeting small intestinal CaSR and/or PepT1 to regulate feeding and glucose tolerance.

Acute Activation of GFRAL in the Area Postrema Contributes to Glucose Regulation Independent of Weight.

GDF15 regulates energy balance and glucose homeostasis in rodents by activating its receptor GFRAL, expressed in the area postrema of the brain. However, whether GDF15-GFRAL signaling in the area postrema regulates glucose tolerance independent of changes in food intake and weight and contributes to the glucose-lowering effect of metformin remain unknown. Herein, we report that direct, acute GDF15 infusion into the area postrema of rats fed a high-fat diet increased intravenous glucose tolerance and insulin sensitivity to lower hepatic glucose production independent of changes in food intake, weight, and plasma insulin levels under conscious, unrestrained, and nonstressed conditions. In parallel, metformin infusion concurrently increased plasma GDF15 levels and glucose tolerance. Finally, a knockdown of GFRAL expression in the area postrema negated administration of GDF15, as well as metformin, to increase glucose tolerance independent of changes in food intake, weight, and plasma insulin levels. In summary, activation of GFRAL in the area postrema contributes to glucose regulation of GDF15 and metformin in vivo.

SGTR+: End-to-End Scene Graph Generation With Transformer.

Scene Graph Generation (SGG) remains a challenging visual understanding task due to its compositional property. Most previous works adopt a bottom-up, two-stage or point-based, one-stage approach, which often suffers from high time complexity or suboptimal designs. In this paper, we propose a novel SGG method to address the aforementioned issues, formulating the task as a bipartite graph construction problem. To address the issues above, we create a transformer-based end-to-end framework to generate the entity and entity-aware predicate proposal set, and infer directed edges to form relation triplets. Moreover, we design a graph assembling module to infer the connectivity of the bipartite scene graph based on our entity-aware structure, enabling us to generate the scene graph in an end-to-end manner. Based on bipartite graph assembling paradigm, we further propose a new technical design to address the efficacy of entity-aware modeling and optimization stability of graph assembling. Equipped with the enhanced entity-aware design, our method achieves optimal performance and time-complexity. Extensive experimental results show that our design is able to achieve the state-of-the-art or comparable performance on three challenging benchmarks, surpassing most of the existing approaches and enjoying higher efficiency in inference.

Current trends of clinical trials involving CRISPR/Cas systems.

The CRISPR/Cas9 system is a powerful genome editing tool that has made enormous impacts on next-generation molecular diagnostics and therapeutics, especially for genetic disorders that traditional therapies cannot cure. Currently, CRISPR-based gene editing is widely applied in basic, preclinical, and clinical studies. In this review, we attempt to identify trends in clinical studies involving CRISPR techniques to gain insights into the improvement and contribution of CRISPR/Cas technologies compared to traditional modified modalities. The review of clinical trials is focused on the applications of the CRISPR/Cas systems in the treatment of cancer, hematological, endocrine, and immune system diseases, as well as in diagnostics. The scientific basis underlined is analyzed. In addition, the challenges of CRISPR application in disease therapies and recent advances that expand and improve CRISPR applications in precision medicine are discussed.

The Impact of Informational Intervention on HPV Vaccination Intention among Heterosexual Men.

Human papillomavirus (HPV) is one of the most common sexually transmitted infections (STIs). However, despite widespread under-vaccination amongst men and the importance of vaccinating both sexes to curb the spread of HPV, research has focused on promoting HPV vaccination predominantly amongst women. Therefore, the current study examines the effectiveness of different informational interventions in promoting vaccination intentions amongst heterosexual men. In a preregistered study of 583 unvaccinated adult men, we randomly assigned participants to one of four informational interventions aimed at promoting awareness of HPV risks and vaccine uptake: (1) risks to oneself (n = 145), (2) risks to their female partner (n = 144), (3) risks to oneself and their female partner (n = 153), and (4) general vaccine information (n = 153). Amongst participants reporting a sexual history (67%), intentions to get vaccinated significantly increased by 10.75 points on a 100-point scale (p < 0.01) after they received information about the risks of HPV for both themselves and their female partner, compared to receiving information about only their own HPV risk. These findings provide valuable guidance for public health officials and policymakers into the effectiveness of different messaging strategies in promoting HPV vaccination amongst adult male populations to increase vaccination rates.

Machine-Learning-Enabled Framework in Engineering Plastics Discovery: A Case Study of Designing Polyimides with Desired Glass-Transition Temperature.

Great and continuous efforts have been made to discover high-performance engineering plastics with specific properties to replace traditional engineering materials in many fields. The utilization of machine learning (ML) has brought more opportunities for the discovery of high-performing engineering plastics. However, hindered by either the relatively small database or a lack of accurate structure descriptors with clear physical and chemical meanings relating to polymer properties, the current ML studies show some flaws in the accuracy and efficiency in polymer development. Herein, we collected a dataset of 878 polyimides (PI), one of the best engineering plastics, with experimentally measured glass-transition temperature (Tg) values, and developed a rapid and accurate ML approach to design PI candidates with the desired Tg value. After the conversion from PI structures into "mechanically identifiable" SMILES (Simplified molecular input line entry system) language, the eight most critical descriptors were ultimately obtained by multiple analysis methods. The physiochemical meaning of the key descriptors was further analyzed carefully to translate the implicit "machine language" to chemical knowledge. The artificial neural network (ANN)-based model gave the most accurate results with a root-mean-square error of ∼11 K among the studied ML methods. More importantly, three potential PI candidates with desired Tg (DPIs) were designed according to the chemical insight of the key descriptors, which were then verified by experiments. The experimental and predicted Tg values of DPIs have an acceptable average deviation of ca. 3.66%. This accuracy has reached the level of the traditional molecular simulation, but the time consumption and hold-up computing resource are tremendously reduced. Furthermore, the current ML approach could offer a scalable and adaptable framework in future engineer plastics innovation.

Metformin triggers a kidney GDF15-dependent area postrema axis to regulate food intake and body weight.

Metformin, the most widely prescribed medication for obesity-associated type 2 diabetes (T2D), lowers plasma glucose levels, food intake, and body weight in rodents and humans, but the mechanistic site(s) of action remain elusive. Metformin increases plasma growth/differentiation factor 15 (GDF15) levels to regulate energy balance, while GDF15 administration activates GDNF family receptor α-like (GFRAL) that is highly expressed in the area postrema (AP) and the nucleus of the solitary tract (NTS) of the hindbrain to lower food intake and body weight. However, the tissue-specific contribution of plasma GDF15 levels after metformin treatment is still under debate. Here, we found that metformin increased plasma GDF15 levels in high-fat (HF) fed male rats through the upregulation of GDF15 synthesis in the kidney. Importantly, the kidney-specific knockdown of GDF15 expression as well as the AP-specific knockdown of GFRAL expression negated the ability of metformin to lower food intake and body weight gain. Taken together, we unveil the kidney as a target of metformin to regulate energy homeostasis through a kidney GDF15-dependent AP axis.

A glucose-sensing mechanism with glucose transporter 1 and pyruvate kinase in the area postrema regulates hepatic glucose production in rats.

The area postrema (AP) of the brain is exposed to circulating metabolites and hormones. However, whether AP detects glucose changes to exert biological responses remains unknown. Its neighboring nuclei, the nucleus tractus solitarius (NTS), responds to acute glucose infusion by inhibiting hepatic glucose production, but the mechanism also remains elusive. Herein, we characterized AP and NTS glucose-sensing mechanisms. Infusion of glucose into the AP, like the NTS, of chow rats suppressed glucose production during the pancreatic (basal insulin)-euglycemic clamps. Glucose transporter 1 or pyruvate kinase lentiviral-mediated knockdown in the AP negated AP glucose infusion to lower glucose production, while the glucoregulatory effect of NTS glucose infusion was also negated by knocking down glucose transporter 1 or pyruvate kinase in the NTS. Furthermore, we determined that high-fat (HF) feeding disrupts glucose infusion to lower glucose production in association with a modest reduction in the expression of glucose transporter 1, but not pyruvate kinase, in the AP and NTS. However, pyruvate dehydrogenase activator dichloroacetate infusion into the AP or NTS that enhanced downstream pyruvate metabolism and recapitulated the glucoregulatory effect of glucose in chow rats still failed to lower glucose production in HF rats. We discovered that a glucose transporter 1- and pyruvate kinase-dependent glucose-sensing mechanism in the AP (as well as the NTS) lowers glucose production in chow rats and that HF disrupts the glucose-sensing mechanism that is downstream of pyruvate metabolism in the AP and NTS. These findings highlight the role of AP and NTS in mediating glucose to regulate hepatic glucose production.

Human gut microbiota after bariatric surgery alters intestinal morphology and glucose absorption in mice independently of obesity.

OBJECTIVE: Bariatric surgery is an effective treatment for type 2 diabetes (T2D) that changes gut microbial composition. We determined whether the gut microbiota in humans after restrictive or malabsorptive bariatric surgery was sufficient to lower blood glucose. DESIGN: Women with obesity and T2D had biliopancreatic diversion with duodenal switch (BPD-DS) or laparoscopic sleeve gastrectomy (LSG). Faecal samples from the same patient before and after each surgery were used to colonise rodents, and determinants of blood glucose control were assessed. RESULTS: Glucose tolerance was improved in germ-free mice orally colonised for 7 weeks with human microbiota after either BPD-DS or LSG, whereas food intake, fat mass, insulin resistance, secretion and clearance were unchanged. Mice colonised with microbiota post-BPD-DS had lower villus height/width and crypt depth in the distal jejunum and lower intestinal glucose absorption. Inhibition of sodium-glucose cotransporter (Sglt)1 abrogated microbiota-transmissible improvements in blood glucose control in mice. In specific pathogen-free (SPF) rats, intrajejunal colonisation for 4 weeks with microbiota post-BPD-DS was sufficient to improve blood glucose control, which was negated after intrajejunal Sglt-1 inhibition. Higher Parabacteroides and lower Blautia coincided with improvements in blood glucose control after colonisation with human bacteria post-BPD-DS and LSG. CONCLUSION: Exposure of rodents to human gut microbiota after restrictive or malabsorptive bariatric surgery improves glycaemic control. The gut microbiota after bariatric surgery is a standalone factor that alters upper gut intestinal morphology and lowers Sglt1-mediated intestinal glucose absorption, which improves blood glucose control independently from changes in obesity, insulin or insulin resistance.

Disruption of adipocyte HIF-1α improves atherosclerosis through the inhibition of ceramide generation.

Atherosclerosis is a chronic multifactorial cardiovascular disease. Western diets have been reported to affect atherosclerosis through regulating adipose function. In high cholesterol diet-fed ApoE -/- mice, adipocyte HIF-1α deficiency or direct inhibition of HIF-1α by the selective pharmacological HIF-1α inhibitor PX-478 alleviates high cholesterol diet-induced atherosclerosis by reducing adipose ceramide generation, which lowers cholesterol levels and reduces inflammatory responses, resulting in improved dyslipidemia and atherogenesis. Smpd3, the gene encoding neutral sphingomyelinase, is identified as a new target gene directly regulated by HIF-1α that is involved in ceramide generation. Injection of lentivirus-SMPD3 in epididymal adipose tissue reverses the decrease in ceramides in adipocytes and eliminates the improvements on atherosclerosis in the adipocyte HIF-1α-deficient mice. Therefore, HIF-1α inhibition may constitute a novel approach to slow atherosclerotic progression.

An Efficient Hypergraph Approach to Robust Point Cloud Resampling.

Efficient processing and feature extraction of large-scale point clouds are important in related computer vision and cyber-physical systems. This work investigates point cloud resampling based on hypergraph signal processing (HGSP) to better explore the underlying relationship among different points in the point cloud and to extract contour-enhanced features. Specifically, we design hypergraph spectral filters to capture multilateral interactions among the signal nodes of point clouds and to better preserve their surface outlines. Without the need and the computation to first construct the underlying hypergraph, our low complexity approach directly estimates hypergraph spectrum of point clouds by leveraging hypergraph stationary processes from the observed 3D coordinates. Evaluating the proposed resampling methods with several metrics, our test results validate the high efficacy of hypergraph characterization of point clouds and demonstrate the robustness of hypergraph-based resampling under noisy observations.

Multi-Scale 2D Temporal Adjacency Networks for Moment Localization With Natural Language.

We address the problem of retrieving a specific moment from an untrimmed video by natural language. It is a challenging problem because a target moment may take place in the context of other temporal moments in the untrimmed video. Existing methods cannot tackle this challenge well since they do not fully consider the temporal contexts between temporal moments. In this paper, we model the temporal context between video moments by a set of predefined two-dimensional maps under different temporal scales. For each map, one dimension indicates the starting time of a moment and the other indicates the duration. These 2D temporal maps can cover diverse video moments with different lengths, while representing their adjacent contexts at different temporal scales. Based on the 2D temporal maps, we propose a Multi-Scale Temporal Adjacency Network (MS-2D-TAN), a single-shot framework for moment localization. It is capable of encoding the adjacent temporal contexts at each scale, while learning discriminative features for matching video moments with referring expressions. We evaluate the proposed MS-2D-TAN on three challenging benchmarks, i.e., Charades-STA, ActivityNet Captions, and TACoS, where our MS-2D-TAN outperforms the state of the art.

Suppression of Ribosome Biogenesis by Targeting WD Repeat Domain 12 (WDR12) Inhibits Glioma Stem-Like Cell Growth.

Glioma stem-like cells (GSCs) are a subset of tumor cells that initiate malignant growth and promote the therapeutic resistance of glioblastoma, the most lethal primary brain tumor. Ribosome biogenesis is an essential cellular process to maintain cell growth, but its regulatory mechanism in GSCs remains largely unknown. Here, we show that WD repeat domain 12 (WDR12), a component of the Pes1-Bop1 complex (PeBoW), is required for ribosome biogenesis in GSCs. WDR12 is preferentially expressed in GSCs compared to non-stem tumor cells and normal brain cells. High levels of WDR12 are associated with glioblastoma progression and poor prognosis. Silencing WDR12 results in the degradation of PeBoW complex components and prevents the maturation of 28S rRNA, thereby inhibiting ribosome biogenesis in GSCs. Subsequently, WDR12 depletion compromises GSC proliferation, inhibits GSC-derived orthotopic tumor growth, and extends animal survival. Together, our results suggest that WDR12 is crucial for ribosome biogenesis in GSCs, and is thus a potential target for GSC-directed therapy of glioblastoma.

Suppression of mitochondrial ROS by prohibitin drives glioblastoma progression and therapeutic resistance.

Low levels of reactive oxygen species (ROS) are crucial for maintaining cancer stem cells (CSCs) and their ability to resist therapy, but the ROS regulatory mechanisms in CSCs remains to be explored. Here, we discover that prohibitin (PHB) specifically regulates mitochondrial ROS production in glioma stem-like cells (GSCs) and facilitates GSC radiotherapeutic resistance. We find that PHB is upregulated in GSCs and is associated with malignant gliomas progression and poor prognosis. PHB binds to peroxiredoxin3 (PRDX3), a mitochondrion-specific peroxidase, and stabilizes PRDX3 protein through the ubiquitin-proteasome pathway. Knockout of PHB dramatically elevates ROS levels, thereby inhibiting GSC self-renewal. Importantly, deletion or pharmacological inhibition of PHB potently slows tumor growth and sensitizes tumors to radiotherapy, thus providing significant survival benefits in GSC-derived orthotopic tumors and glioblastoma patient-derived xenografts. These results reveal a selective role of PHB in mitochondrial ROS regulation in GSCs and suggest that targeting PHB improves radiotherapeutic efficacy in glioblastoma.

Nutrient infusion in the dorsal vagal complex controls hepatic lipid and glucose metabolism in rats.

Hypothalamic regulation of lipid and glucose homeostasis is emerging, but whether the dorsal vagal complex (DVC) senses nutrients and regulates hepatic nutrient metabolism remains unclear. Here, we found in rats DVC oleic acid infusion suppressed hepatic secretion of triglyceride-rich very-low-density lipoprotein (VLDL-TG), which was disrupted by inhibiting DVC long-chain fatty acyl-CoA synthetase that in parallel disturbed lipid homeostasis during intravenous lipid infusion. DVC glucose infusion elevated local glucose levels similarly as intravenous glucose infusion and suppressed hepatic glucose production. This was independent of lactate metabolism as inhibiting lactate dehydrogenase failed to disrupt glucose sensing and neither could DVC lactate infusion recapitulate glucose effect. DVC oleic acid and glucose infusion failed to lower VLDL-TG secretion and glucose production in high-fat fed rats, while inhibiting DVC farnesoid X receptor enhanced oleic acid but not glucose sensing. Thus, an impairment of DVC nutrient sensing may lead to the disruption of lipid and glucose homeostasis in metabolic syndrome.

H19 gene polymorphisms and Wilms tumor risk in Chinese children: a four-center case-control study.

BACKGROUND: Wilms tumor is the most common pediatric renal cancer. However, genetic bases behind Wilms tumor remain largely unknown. H19 is a critical maternally imprinted gene. Previous studies indicated that single nucleotide polymorphisms (SNPs) in the H19 can modify the risk of several human malignancies. Epigenetic errors at the H19 locus lead to biallelic silencing in Wilms tumors. Genetic variations in the H19 may be related to Wilms tumor susceptibility. METHODS: We conducted a four-center study to investigate whether H19 SNP was a predisposing factor to Wilms tumor. Three polymorphisms in the H19 (rs2839698 G > A, rs3024270 C > G, rs217727 G > A) were genotyped in 355 cases and 1070 cancer-free controls, using Taqman method. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations. RESULTS: We found that all of these three polymorphisms were significantly associated with Wilms tumor risk alterations. The rs2839698 G > A polymorphism (AG vs. GG: adjusted OR = 0.74, 95% CI = 0.57-0.96, p = 0.024; AA vs. GG: adjusted OR = 1.52, 95% CI = 1.05-2.22, p = 0.027), the rs3024270 C > G polymorphism (CG vs. CC: adjusted OR = 0.61, 95% CI = 0.46-0.81, p = 0.0007; and the rs217727 polymorphism (AG vs. GG: adjusted OR = 0.76, 95% CI = 0.58-0.99, p = 0.035). The Carriers of 1, 2, and 1-2 risk genotypes were inclined to develop Wilms tumor compared with those without risk genotype (adjusted OR = 1.36, 95% CI = 1.02-1.80, p = 0.037; adjusted OR = 1.84, 95% CI = 1.27-2.67, p = 0.001; adjusted OR = 1.50, 95% CI = 1.17-1.92, p = 0.002, respectively). The stratified analysis further revealed that rs2839698 AA, rs217727 AA, and 1-2 risk genotypes could strongly increase Wilms tumor risk among children above 18 months of age, males, and with clinical stage I+II disease. CONCLUSION: Our findings indicate that genetic variations in the H19 may confer Wilms tumor risk.

FXR in the dorsal vagal complex is sufficient and necessary for upper small intestinal microbiome-mediated changes of TCDCA to alter insulin action in rats.

OBJECTIVE: Conjugated bile acids are metabolised by upper small intestinal microbiota, and serum levels of taurine-conjugated bile acids are elevated and correlated with insulin resistance in people with type 2 diabetes. However, whether changes in taurine-conjugated bile acids are necessary for small intestinal microbiome to alter insulin action remain unknown. DESIGN: We evaluated circulating and specifically brain insulin action using the pancreatic-euglycaemic clamps in high-fat (HF) versus chow fed rats with or without upper small intestinal healthy microbiome transplant. Chemical and molecular gain/loss-of-function experiments targeting specific taurine-conjugated bile acid-induced changes of farnesoid X receptor (FXR) in the brain were performed in parallel. RESULTS: We found that short-term HF feeding increased the levels of taurochenodeoxycholic acid (TCDCA, an FXR ligand) in the upper small intestine, ileum, plasma and dorsal vagal complex (DVC) of the brain. Transplantation of upper small intestinal healthy microbiome into the upper small intestine of HF rats not only reversed the rise of TCDCA in all reported tissues but also enhanced the ability of either circulating hyperinsulinaemia or DVC insulin action to lower glucose production. Further, DVC infusion of TCDCA or FXR agonist negated the enhancement of insulin action, while genetic knockdown or chemical inhibition of FXR in the DVC of HF rats reversed insulin resistance. CONCLUSION: Our findings indicate that FXR in the DVC is sufficient and necessary for upper small intestinal microbiome-mediated changes of TCDCA to alter insulin action in rats, and highlight a previously unappreciated TCDCA-FXR axis linking gut microbiome and host insulin action.

Small intestinal taurochenodeoxycholic acid-FXR axis alters local nutrient-sensing glucoregulatory pathways in rats.

OBJECTIVE: The mechanism of nutrient sensing in the upper small intestine (USI) and ileum that regulates glucose homeostasis remains elusive. Short-term high-fat (HF) feeding increases taurochenodeoxycholic acid (TCDCA; an agonist of farnesoid X receptor (FXR)) in the USI and ileum of rats, and the increase of TCDCA is prevented by transplantation of microbiota obtained from the USI of healthy donors into the USI of HF rats. However, whether changes of TCDCA-FXR axis in the USI and ileum alter nutrient sensing remains unknown. METHODS: Intravenous glucose tolerance test was performed in rats that received USI or ileal infusion of nutrients (i.e., oleic acids or glucose) via catheters placed toward the lumen of USI and/or ileum, while mechanistic gain- and loss-of-function studies targeting the TCDCA-FXR axis or bile salt hydrolase activity in USI and ileum were performed. RESULTS: USI or ileum infusion of nutrients increased glucose tolerance in healthy but not HF rats. Transplantation of healthy microbiome obtained from USI into the USI of HF rats restored nutrient sensing and inhibited FXR via a reduction of TCDCA in the USI and ileum. Further, inhibition of USI and ileal FXR enhanced nutrient sensing in HF rats, while inhibiting USI (but not ileal) bile salt hydrolase of HF rats transplanted with healthy microbiome activated FXR and disrupted nutrient sensing in the USI and ileum. CONCLUSIONS: We reveal a TCDCA-FXR axis in both the USI and ileum that is necessary for the upper small intestinal microbiome to govern local nutrient-sensing glucoregulatory pathways in rats.