Bipolar disorder and schizophrenia are highly heritable conditions that are associated with structural brain abnormalities. Although brain abnormalities are found in the well relatives of people with schizophrenia, the extent to which genetic liability relates to brain structure in either disorder is still unclear. This study sought to ascertain the effects of genetic liability to schizophrenia and bipolar disorder on white and grey matter volume in patients with these diagnoses and their well relatives. Seventy-one patients and 72 unaffected relatives were recruited for the study. Patients included those with schizophrenia from families affected by schizophrenia alone, those with bipolar disorder from families affected by bipolar disorder alone and those with bipolar disorder from families affected by both bipolar disorder and schizophrenia. Samples of unaffected relatives of each patient group were also recruited. Subjects underwent an MRI scan of the brain, which was analysed using optimised voxel-based morphometry (VBM). Grey and white matter volume was then related to a continuous measure of genetic liability based on a threshold-liability model. Genetic liability to schizophrenia was associated with decreased grey matter volume in dorso- (DLPFC) and ventrolateral prefrontal (VLPFC) cortices. The relationship remained after diagnostic status had been taken into account. Complementary white matter changes were also demonstrated. No relationship was demonstrated between a genetic liability to bipolar disorder and either white or grey matter volume. Genes that raise the likelihood of developing schizophrenia may exert their effects by diminishing grey matter volume in the DLPFC and VLPFC and their associated white matter connections. Genes for bipolar illness might have subtle effects on brain structure, which may need particularly large samples to detect.

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Objective: The recessive disease arterial calcification due to deficiency of CD73 (ACDC) presents with extensive nonatherosclerotic medial layer calcification in lower extremity arteries. Lack of CD73 induces a concomitant increase in TNAP (tissue nonspecific alkaline phosphatase; ALPL ), a key enzyme in ectopic mineralization. Our aim was to investigate how loss of CD73 activity leads to increased ALPL expression and calcification in CD73-deficient patients and assess whether this mechanism may apply to peripheral artery disease calcification. Approach and Results: We previously developed a patient-specific disease model using ACDC primary dermal fibroblasts that recapitulates the calcification phenotype in vitro. We found that lack of CD73-mediated adenosine signaling reduced cAMP production and resulted in increased activation of AKT. The AKT/mTOR (mammalian target of rapamycin) axis blocks autophagy and inducing autophagy prevented calcification; however, we did not observe autophagy defects in ACDC cells. In silico analysis identified a putative FOXO1 (forkhead box O1 protein) binding site in the human ALPL promoter. Exogenous AMP induced FOXO1 nuclear localization in ACDC but not in control cells, and this was prevented with a cAMP analogue or activation of A2a/2b adenosine receptors. Inhibiting FOXO1 reduced ALPL expression and TNAP activity and prevented calcification. Mutating the FOXO1 binding site reduced ALPL promoter activation. Importantly, we provide evidence that non-ACDC calcified femoropopliteal arteries exhibit decreased CD73 and increased FOXO1 levels compared with control arteries. Conclusions: These data show that lack of CD73-mediated cAMP signaling promotes expression of the human ALPL gene via a FOXO1-dependent mechanism. Decreased CD73 and increased FOXO1 was also observed in more common peripheral artery disease calcification.

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With increasing population and an uncertainty in the long-term sustainability of reliable potable water sources, many cities have decided to investigate water reuse as a means to compliment water supply demand. The City of Anaheim (California) recently completed construction of a 100,000 gpd decentralized water recycling facility that produces Title 22 disinfected tertiary effluent. The process equipment including fine screen, MBR, ozone, UV, carbon adsorbers for odor control and recycled water pumps along with associated appurtenances were all housed in a small footprint (1800 ft 2 ) next to the City Hall. The facility was designed to blend in with existing surrounding structures and architectural styles, and look aesthetically appealing. The project team faced significant challenges during the design and startup, which included 1) accommodating equipment in a small footprint 2) obtaining permits from regulatory agencies for these relatively newer treatment processes, and 3) optimizing plant operation to meet end user demand. Despite these challenges, the startup was completed successfully. During the performance testing, the effluent produced from the facility had average BOD, COD and TOC concentrations of 5, 22 and 6 mg/L, respectively. The WRF achieved complete nitrification and partial denitrification with average ammonia and nitrate concentrations of 0.3 and 8.0 mg/L-N, respectively. The bioassay validation and 14-day coliform testing performed on the ozone system demonstrated that the ozone system achieved greater than 5-log removal of seeded MS-2 bacteriophage and total coliform bacterial concentration of less than 1 CFU/100 mL.

BackgroundCalcific aortic valve disease (CAVD) is the pathological remodeling of the valve leaflets which leads to heart failure and high stroke risk. While several mechanisms are known to drive cardiovascular calcification, the initial steps orchestrating the osteogenic reprogramming of cells are not fully understood. Non-canonical functions of telomerase reverse transcriptase (TERT) include service as a cofactor to stimulate gene transcription, and TERT overexpression primes mesenchymal stem cells to differentiate into osteoblasts. We investigated whether TERT contributes to osteogenic reprogramming of valve interstitial cells.MethodsBaseline transcription of TERT and osteogenic markers, senescence, DNA damage, and telomere length in valve tissue and primary aortic valve interstitial cells (VICs) from control and CAVD patients were assessed. TERT expression was depleted in cells using lentiviral vectors. Cells from Tert+/+ and Tert-/- mice were used to validate human findings. Immunofluorescence staining, proximity ligation assay, and chromatin immunoprecipitation assay were used in mechanistic experiments.ResultsTERT protein was highly expressed in calcified valve leaflets, without changes in telomere length, DNA damage, or senescence. These phenotypic features were retained in primary VICs isolated and cultured from those diseased tissues. TERT levels were increased with osteogenic or inflammatory stimuli, and genetic deletion or reduction of TERT prevented calcification of VICs isolated from humans and mice. Similar results were seen in smooth muscle cells (SMCs) and mesenchymal stem cells (MSCs). TERT and Signal Transducer and Activator of Transcription 5A/B (STAT5) colocalize and bind to the Runt-Related Transcription Factor 2 (RUNX2) gene promoter, and TERT and STAT5 co-localized in calcified valve tissues. Pharmacological inhibition of STAT5A prevented calcification in vitro.ConclusionsThese data show that non-canonical TERT activity is required for the calcification of VICs. TERT partners with STAT5A to bind to and activate the RUNX2 gene promoter. These data identify a novel therapeutic target to abate vascular calcification.Novelty and SignificanceWhat Is Known?Calcific aortic valve disease (CAVD) is the most prevalent form of aortic valve pathology. CAVD strongly correlates with age and leads to heart failure and a high risk of stroke. Currently, the only therapeutic option is valve replacement, which comes with significant healthcare costs and additional risks to patients.Runt-related transcription factor 2 (RUNX2) is the master transcription factor required for osteogenic differentiation of osteoblasts and osteogenic reprogramming of vascular cells, yet the early events driving its transcription in valve cells are not well defined.Overexpression of TERT primes mesenchymal stem cells to differentiate down the osteoblast lineage, suggesting that TERT signaling plays an important role in cell differentiation and phenotype.What New Information Does This Article Contribute?TERT protein is highly expressed in calcified aortic leaflets and valve interstitial cells, independent of changes in telomere length.Genetic loss or depletion of TERT blocks calcification in valve interstitial cells, coronary smooth muscle cells, and mesenchymal stem cells.TERT co-localizes with STAT5 in the cytosol and on the RUNX2 gene promoter, the master regulator of osteogenic transcriptional programs.Pharmacological inhibition of STAT5 prevents calcification of human valve interstitial cells, coronary smooth muscle cells, and mesenchymal stem cells.What are the clinical implications?We have identified TERT/STAT5 as novel signaling axis that promotes the early transcriptional reprogramming in cardiovascular cells. Inhibiting TERT and STAT5 interaction and activity can be leveraged for the development of pharmacological or biological therapeutic strategies to halt or prevent calcification in the aortic valve and perhaps other cardiovascular tissues.Surgical procedures are currently the only treatment option for patients with CAVD. Discovering the early events driving vascular calcification identifies novel and druggable targets for the development of non-surgical therapies.