Metabotype analysis of Mthfd1l-null mouse embryos using desorption electrospray ionization mass spectrometry imaging.

Mammalian folate-dependent one-carbon (1C) metabolism provides the building blocks essential during development via amino acid interconversion, methyl-donor production, regeneration of redox factors, and de novo purine and thymidylate synthesis. Folate supplementation prevents many neural tube defects (NTDs) that occur during the embryonic process of neurulation. The mechanism by which folate functions during neurulation is not well understood, and not all NTDs are preventable by folate supplementation. Mthfd1l is a mitochondrial 1C metabolism enzyme that produces formate, a 1C donor that fuels biosynthesis and the methyl cycle in the cytoplasm. Homozygous deletion of the Mthfd1l gene in mice (Mthfd1lz/z) causes embryonic lethality, developmental delay, and folate-resistant NTDs. These mice also have defects in cranial mesenchyme formation. In this work, mass spectrometry imaging was used to obtain ion maps of the cranial mesenchyme that identified the spatial distribution and relative abundance of metabolites in wild-type and Mthfd1lz/z embryos. The relative abundances of purine and thymidylate derivatives, as well as amino acids, were diminished in the cranial mesenchyme of Mthfd1lz/z embryos. Loss of Mthfd1l activity in this region also led to abnormal levels of methionine and dysregulated energy metabolism. These alterations in metabolism suggest possible approaches to preventing NTDs in humans.

Deletion of neural tube defect-associated gene Mthfd1l causes reduced cranial mesenchyme density.

BACKGROUND: Periconceptional intake of supplemental folic acid can reduce the incidence of neural tube defects by as much as 70%, but the mechanisms by which folic acid supports cellular processes during neural tube closure are unknown. The mitochondrial 10-formyl-tetrahydrofolate synthetase MTHFD1L catalyzes production of formate, thus generating one-carbon units for cytoplasmic processes. Deletion of Mthfd1l causes embryonic lethality, developmental delay, and neural tube defects in mice. METHODS: To investigate the role of mitochondrial one-carbon metabolism during cranial neural tube closure, we have analyzed cellular morphology and function in neural tissues in Mthfd1l knockout embryos. RESULTS: The head mesenchyme showed significantly lower cellular density in Mthfd1l nullizygous embryos compared to wildtype embryos during the process of neural tube closure. Apoptosis and neural crest cell specification were not affected by deletion of Mthfd1l. Sections from the cranial region of Mthfd1l knockout embryos exhibited decreased cellular proliferation, but only after completion of neural tube closure. Supplementation of pregnant dams with formate improved mesenchymal density and corrected cell proliferation in the nullizygous embryos. CONCLUSIONS: Deletion of Mthfd1l causes decreased density in the cranial mesenchyme and this defect is improved with formate supplementation. This study reveals a mechanistic link between folate-dependent mitochondrially produced formate, head mesenchyme formation and neural tube defects.

The schizotypal ambivalence scale as a marker of schizotypy.

The present study examined the psychometric properties of the Schizotypal Ambivalence Scale (SAS) in a sample of 1798 young adults. The study also investigated the concurrent validity of the measure for identifying schizophrenic-like symptoms in a sample of 43 high scorers on the scale and 43 control participants. Previous findings indicated that high scores on the SAS were associated with schizophrenia-spectrum pathology in a sample of schizotypic young adults selected with other measures. However, this is the first study to assess schizophrenic-like psychopathology in a sample selected using the SAS. The SAS has good internal consistency (coefficient alpha = 0.84) and test-retest reliability (intraclass correlation = 0.74 across 9 weeks). As hypothesized, the ambivalence group exceeded the control group on interview ratings of schizotypal, schizoid, paranoid, psychotic-like, and negative symptoms, as well as exhibiting poorer overall functioning. The SAS seems to be a promising measure of schizotypy in young adults.

Plasma microRNAs to predict the response of radiotherapy in esophageal squamous cell carcinoma patients.

Although microRNAs (miRNAs) play an important role in esophageal squamous cell carcinoma (ESCC), their roles in radiotherapy response remain unexplored. Our study aims to investigate whether plasma miRNAs can be used as predictors of radiotherapy outcome in ESCC patients. We selected nine miRNAs, which were reported to be associated with carcinogenesis or radiobiology of ESCC, as the targets of our study. Plasma miRNA expression was investigated with 24 subjects (pre-, at the first week and post-radiotherapy). Tumor radiographic response and 3-year overall survival were used to evaluate the response. The results showed that the level of miR-16 in the patients with good outcome was significantly higher than that in the patients with poor outcome (P < 0.05, AUC: 0.762) at the post-radiotherapy. We also found that the variation tendency of miRNA expression were related to its radiotherapy response. Moreover, miR-16 levels increased by more than 2-fold following treatment, which were shown to be associated with longer OS (log-rank P = 0.009). In conclusion, miR-16 has considerable clinical value in predicting radiotherapy outcomes for ESCC patients.

Inhibition of non-small cell lung cancer (NSCLC) growth by a novel small molecular inhibitor of EGFR.

The epidermal growth factor receptor (EGFR) is a therapeutic target (oncotarget) in NSCLC. Using in vitro EGFR kinase activity system, we identified a novel small molecule, WB-308, as an inhibitor of EGFR. WB-308 decreased NSCLC cell proliferation and colony formation, by causing G2/M arrest and apoptosis. Furthermore, WB-308 inhibited the engraft tumor growths in two animal models in vivo (lung orthotopic transplantation model and patient-derived engraft mouse model). WB-308 impaired the phosphorylation of EGFR, AKT, and ERK1/2 protein. WB-308 was less cytotoxic than Gefitinib. Our study suggests that WB-308 is a novel EGFR-TKI and may be considered to substitute for Gefitinib in clinical therapy for NSCLC.

Mesoporous bioactive glass surface modified poly(lactic-co-glycolic acid) electrospun fibrous scaffold for bone regeneration.

A mesoporous bioactive glass (MBG) surface modified with poly(lactic-co-glycolic acid) (PLGA) electrospun fibrous scaffold for bone regeneration was prepared by dip-coating a PLGA electrospun fibrous scaffold into MBG precursor solution. Different surface structures and properties were acquired by different coating times. Surface morphology, chemical composition, microstructure, pore size distribution, and hydrophilicity of the PLGA-MBG scaffold were characterized. Results of scanning electron microscopy indicated that MBG surface coating made the scaffold rougher with the increase of MBG content. Scaffolds after MBG modification possessed mesoporous architecture on the surface. The measurements of the water contact angles suggested that the incorporation of MBG into the PLGA scaffold improved the surface hydrophilicity. An energy dispersive spectrometer evidenced that calcium-deficient carbonated hydroxyapatite formed on the PLGA-MBG scaffolds after a 7-day immersion in simulated body fluid. In vitro studies showed that the incorporation of MBG favored cell proliferation and osteogenic differentiation of human mesenchymal stem cells on the PLGA scaffolds. Moreover, the MBG surface-modified PLGA (PLGA-MBG) scaffolds were shown to be capable of providing the improved adsorption/release behaviors of bone morphogenetic protein-2 (BMP-2). It is very significant that PLGA-MBG scaffolds could be effective for BMP-2 delivery and bone regeneration.

Relationships between knee valgus, hip-muscle strength, and hip-muscle recruitment during a single-limb step-down.

CONTEXT: Reduced strength and activation of hip muscles might correlate with increased weight-bearing knee valgus. OBJECTIVE: To describe relationships among frontal-plane hip and knee angles, hip-muscle strength, and electromyographic (EMG) recruitment in women during a step-down. DESIGN: Exploratory study. SETTING: Laboratory. PARTICIPANTS: 20 healthy women 20 to 30 years of age. INTERVENTIONS: Frontal-plane hip and knee angles were measured. Gluteus maximus and medius recruitment were examined with surface EMG. Hip-abduction and -external-rotation strength were quantified with handheld dynamometry. MAIN OUTCOME MEASUREMENTS: The authors analyzed correlation coefficients between knee and hip angles, gluteus maximus and medius EMG, and hip-abduction and -external-rotation strength. RESULTS: Hip-adduction angles (r = .755, P = .001), gluteus maximus EMG (r = -.451, P = .026), and hip-abduction strength (r = .455, P = .022) correlated with frontal-plane projections of knee valgus. CONCLUSIONS: Gluteus maximus recruitment might have greater association with reduced knee valgus in women than does external-rotation strength during step-down tasks. Gluteus medius strength might be associated with increased knee valgus.

Effects of search efficiency on surround suppression during visual selection in frontal eye field.

Previous research has shown that visually responsive neurons in the frontal eye field of macaque monkeys select the target for a saccade during efficient, pop-out visual search through suppression of the representation of the nontarget distractors. For a fraction of these neurons, the magnitude of this distractor suppression varied with the proximity of the target to the receptive field, exhibiting more suppression of the distractor representation when the target was nearby than when the target was distant. The purpose of this study was to determine whether the variation of distractor suppression related to target proximity varied with target-distractor feature similarity. The effect of target proximity on distractor suppression did not vary with target-distractor similarity and therefore may be an endogenous property of the selection process.