A novel mutation in the UBAP1 gene causing hereditary spastic paraplegia: A case report and overview of the genotype-phenotype correlation

Hereditary Spastic Paraplegia (HSP) is considered to be one of the common neurodegenerative diseases with marked genetic heterogeneity. Recently, the mutations in ubiquitin-associated protein 1 (UBAP1) have been described in patients with HSP, known as spastic paraplegias 80 (SPG80). Here, we reported a Chinese HSP family presenting a frameshift mutation in the UBAP1 gene leading to complex HSP. Their clinical features encompassed spastic paraparetic gait, exaggerated patellar tendon reflexes, bilateral Babinski signs, and hyperactive Achilles tendon reflex. The proband also had severe urinary incontinence and a dermoid cyst at the lumbar 4–5 spinal cord, which rarely occurs in HSP patients. Following whole-exome sequencing, a novel heterozygous mutation (c.437dupG, NM_016,525) was identified in the UBAP1 that segregated with the family’s phenotype and resulted in truncating UBAP1 protein (p.Ser146ArgfsTer13). Moreover, we reviewed the genotypes of UBAP1 and the phenotypic variability in 90 HSP patients reported in the literature. We found that the age of onset in UBAP1-related patients was juvenile, and there were population differences in the age of onset. The main complications were lower extremity spasticity, hyperreflexia, and the Babinski sign. Exon 4 of UBAP1 was identified as a mutation hotspot region. Our study expands the knowledge of UBAP1 mutations, which will aid in HSP patient counseling. Further molecular biological research is needed to explore the genotype-phenotype correlations of UBAP1-related HSP

Adiponectin-Mediated Promotion of CD44 Suppresses Diabetic Vascular Inflammatory Effects

While adiponectin (APN) was known to significantly abolish the diabetic endothelial inflammatory response, the specific mechanisms have yet to be elucidated. Aortic vascular tissues from mice fed normal and high-fat diets (HFD) were analyzed by transcriptome analysis. GO functional annotation showed that APN inhibited vascular endothelial inflammation in an APPL1-dependent manner. We confirmed that activation of the Wnt/β-catenin signaling plays a key role in APN-mediated anti-inflammation. Mechanistically, APN promoted APPL1/reptin complex formation and β-catenin nuclear translocation. Simultaneously, we identified APN promoted the expression of CD44 by activating TCF/LEF in an APPL1-mediated manner. Clinically, the serum levels of APN and CD44 were decreased in diabetes; the levels of these two proteins were positively correlated. Functionally, treatment with CD44 C-terminal polypeptides protected diabetes-induced vascular endothelial inflammation in vivo. Collectively, we provided a roadmap for APN-inhibited vascular inflammatory effects and CD44 might represent potential targets against the diabetic endothelial inflammatory effect

Loss of Cannabinoid Receptor CB1 Induces Preterm Birth

Preterm birth accounting approximate 10% of pregnancies in women is a tremendous social, clinical and economic burden. However, its underlying causes remain largely unknown. Emerging evidence suggests that endocannabinoid signaling via cannabinoid receptor CB1 play critical roles in multiple early pregnancy events in both animals and humans. Since our previous studies demonstrated that loss of CB1 defers the normal implantation window in mice, we surmised that CB1 deficiency would influence parturition events.Exploiting mouse models with targeted deletion of Cnr1, Cnr2 and Ptgs1 encoding CB1, CB2 and cyclooxygenase-1, respectively, we examined consequences of CB1 or CB2 silencing on the onset of parturition. We observed that genetic or pharmacological inactivation of CB1, but not CB2, induced preterm labor in mice. Radioimmunoassay analysis of circulating levels of ovarian steroid hormones revealed that premature birth resulting from CB1 inactivation is correlated with altered progesterone/estrogen ratios prior to parturition. More strikingly, the phenotypic defects of prolonged pregnancy length and parturition failure in mice missing Ptgs1 were corrected by introducing CB1 deficiency into Ptgs1 null mice. In addition, loss of CB1 resulted in aberrant secretions of corticotrophin-releasing hormone and corticosterone during late gestation. The pathophysiological significance of this altered corticotrophin-releasing hormone-driven endocrine activity in the absence of CB1 was evident from our subsequent findings that a selective corticotrophin-releasing hormone antagonist was able to restore the normal parturition timing in Cnr1 deficient mice. In contrast, wild-type females receiving excessive levels of corticosterone induced preterm birth.CB1 deficiency altering normal progesterone and estrogen levels induces preterm birth in mice. This defect is independent of prostaglandins produced by cyclooxygenase-1. Moreover, CB1 inactivation resulted in aberrant corticotrophin-releasing hormone and corticosterone activities prior to parturition, suggesting that CB1 regulates labor by interacting with the corticotrophin-releasing hormone-driven endocrine axis

Construction of a novel circRNA-miRNA-ferroptosis related mRNA network in ischemic stroke

Abstract Molecule alterations are important to explore the pathological mechanism of ischemic stroke (IS). Ferroptosis, a newly recognized type of regulated cell death, is related to IS. Identification of the interactions between circular RNA (circRNA), microRNA (miRNA) and ferroptosis related mRNA may be useful to understand the molecular mechanism of IS. The circRNA, miRNA and mRNA transcriptome data in IS, downloaded from the Gene Expression Omnibus (GEO) database, was used for differential expression analysis. Ferroptosis related mRNAs were identified from the FerrDb database, followed by construction of circRNA-miRNA-ferroptosis related mRNA network. Enrichment and protein–protein interaction analysis of mRNAs in circRNA-miRNA-mRNA network was performed, followed by expression validation by reverse transcriptase polymerase chain reaction and online dataset. A total of 694, 41 and 104 differentially expressed circRNAs, miRNAs and mRNAs were respectively identified in IS. Among which, dual specificity phosphatase 1 (DUSP1), nuclear receptor coactivator 4 (NCOA4) and solute carrier family 2 member 3 (SLC2A3) were the only three up-regulated ferroptosis related mRNAs. Moreover, DUSP1, NCOA4 and SLC2A3 were significantly up-regulated in IS after 3, 5 and 24 h of the attack. Based on these three ferroptosis related mRNAs, 4 circRNA-miRNA-ferroptosis related mRNA regulatory relationship pairs were identified in IS, including hsa_circ_0071036/hsa_circ_0039365/hsa_circ_0079347/hsa_circ_0008857-hsa-miR-122-5p-DUSP1, hsa_circ_0067717/hsa_circ_0003956/hsa_circ_0013729-hsa-miR-4446-3p-SLC2A3, hsa_circ_0059347/hsa_circ_0001414/hsa_circ_0049637-hsa-miR-885-3p-SLC2A3, and hsa_circ_0005633/hsa_circ_0004479-hsa-miR-4435-NCOA4. In addition, DUSP1 is involved in the signaling pathway of fluid shear stress and atherosclerosis. Relationship of regulatory action between circRNAs, miRNAs and ferroptosis related mRNAs may be associated with the development of IS

Synthesis and characterization of tungsten and barium co-doped La2Mo2O9 by sol-gel process for solid oxide fuel cells

Herein, we demonstrate the synthesis of W and Ba co-doped La2Mo2O9 (LBMWO) nanocrystalline powder by a sol-gel process. In all the compositions have general formulae La1.9Ba0.1Mo2–xWxO8.95 (x = 0–0.40). The crystal structure, microstructure and conductivity of LBMWO were characterized by X-ray diffraction, scanning electron microscopy and electrical impedance spectroscopy. In addition, the thermal and decomposition properties of the LBMWO gel were analyzed by differential scanning calorimetry - thermogravimetric. The results reveal that all LBMWO powders calcined at 700 °C have a cubic structure; the average crystallite size is about 48 nm. The unit cell parameter of LBMWO powders increases with increase in W content. The as-synthesized nanocrystalline LBMWO samples exhibit excellent sinterability and a relatively lower sintering temperature of 900 °C. A high relative density of ∼96% is achieved after sintering at 900 °C which is in good agreement with the results of the SEM. Moreover, W and Ba co-doping suppresses the phase transition and effectively stabilizes the β-phase at low temperature. At the same time, La1.9Ba0.1Mo1.85W0.15O8.95 exhibits high ionic conductivity, 3.07 × 10−2 S/cm at 800 °C. It is therefore concluded that co-doping can improve the properties of La2Mo2O9 electrolytes.Hefei Universit

Clinical characteristics of peripherally inserted central catheter-related complications in cancer patients undergoing chemotherapy: a prospective and observational study

Abstract Purpose The incidence of peripherally inserted central catheter (PICC)-related complications is higher in cancer patients than in noncancer patients. However, the pattern of specific complication occurrence over time remains unclear. The purpose of this study was to investigate the clinical characteristics of PICC-related complications in cancer patients undergoing chemotherapy. Methods This prospective, observational study was conducted at a university-affiliated hospital in Western China. Cancer patients undergoing PICC insertion for anticancer treatment were recruited and followed up until the first week after catheter removal. Any complications, including occurrence time and outcomes, were recorded. The trajectory of specific PICC-related complications over time were identify based on the Kaplan‒Meier curve analysis. Results Of the 233 patients analyzed, nearly half (n = 112/233, 48.1%) developed 150 PICC-related complication events. The most common were symptomatic catheter-related thrombosis (CRT) (n = 37/233, 15.9%), medical adhesive-related skin injury (MARSI) (n = 27/233, 11.6%), and catheter dislodgement (n = 17/233, 7.3%), accounting for 54.0% (n = 81/150, 54.0%) of total complications events. According to Kaplan‒Meier curve analysis, symptomatic CRT, pain, phlebitis, and insertion site bleeding were classified as the “early onset” group mainly occurring within the first month post-insertion. Catheter fracture and catheter-related bloodstream infection were classified as the “late onset” group occurring after the second month post-insertion. MARSI, catheter dislodgement, occlusion, and insertion site infection were classified as the “persistent onset” group persistently occurring during the whole catheter-dwelling period. Among the 112 patients with PICC-related complications, 50 (44.6%) patients had their catheters removed due to complications, and 62 (55.4%) patients successfully retained their catheters until treatment completion through conventional interventions. The major reasons for unplanned catheter removal were catheter dislodgement (n = 12/233, 5.2%), symptomatic CRT (n = 10/233, 4.3%), and MARSI (n = 7/233, 3.0%), accounting for 58.0% (n = 29/50, 58.0%) of the total unplanned catheter removal cases. Catheter dwelling times between patients with complications under successful interventions (130.5 ± 32.1 days) and patients with no complications (138.2 ± 46.4 days) were not significantly different (t = 1.306, p = 0.194; log-rank test = 2.610, p = 0.106). Conclusions PICC-related complications were pretty common in cancer patients undergoing chemotherapy. The time distribution of PICC-related complications varied, and medical staff should develop time-specific protocols for prevention. Because more than half of the patients with PICC-related complications could be managed with conventional interventions, PICCs remain a priority for cancer patients undergoing short-term chemotherapy. The study was registered in 02/08/2019 at Chinese Clinical Trial Registry (registration number: ChiCTR1900024890)

Mouse models of GNAO1-associated movement disorder: Allele- and sex-specific differences in phenotypes.

BackgroundInfants and children with dominant de novo mutations in GNAO1 exhibit movement disorders, epilepsy, or both. Children with loss-of-function (LOF) mutations exhibit Epileptiform Encephalopathy 17 (EIEE17). Gain-of-function (GOF) mutations or those with normal function are found in patients with Neurodevelopmental Disorder with Involuntary Movements (NEDIM). There is no animal model with a human mutant GNAO1 allele.ObjectivesHere we develop a mouse model carrying a human GNAO1 mutation (G203R) and determine whether the clinical features of patients with this GNAO1 mutation, which includes both epilepsy and movement disorder, would be evident in the mouse model.MethodsA mouse Gnao1 knock-in GOF mutation (G203R) was created by CRISPR/Cas9 methods. The resulting offspring and littermate controls were subjected to a battery of behavioral tests. A previously reported GOF mutant mouse knock-in (Gnao1+/G184S), which has not been found in patients, was also studied for comparison.ResultsGnao1+/G203R mutant mice are viable and gain weight comparably to controls. Homozygotes are non-viable. Grip strength was decreased in both males and females. Male Gnao1+/G203R mice were strongly affected in movement assays (RotaRod and DigiGait) while females were not. Male Gnao1+/G203R mice also showed enhanced seizure propensity in the pentylenetetrazole kindling test. Mice with a G184S GOF knock-in also showed movement-related behavioral phenotypes but females were more strongly affected than males.ConclusionsGnao1+/G203R mice phenocopy children with heterozygous GNAO1 G203R mutations, showing both movement disorder and a relatively mild epilepsy pattern. This mouse model should be useful in mechanistic and preclinical studies of GNAO1-related movement disorders