Mesenchyme Homeobox 2 Enhances Migration of Endothelial Colony Forming Cells Exposed to Intrauterine Diabetes Mellitus

Diabetes mellitus (DM) during pregnancy has long-lasting implications for the fetus, including cardiovascular morbidity. Previously, we showed that endothelial colony forming cells (ECFCs) from DM human pregnancies have decreased vasculogenic potential. Here, we evaluate whether the molecular mechanism responsible for this phenotype involves the transcription factor, Mesenchyme Homeobox 2 (MEOX2). In human umbilical vein endothelial cells, MEOX2 upregulates cyclin-dependent kinase inhibitor expression, resulting in increased senescence and decreased proliferation. We hypothesized that dysregulated MEOX2 expression in neonatal ECFCs from DM pregnancies decreases network formation through increased senescence and altered cell cycle progression. Our studies show that nuclear MEOX2 is increased in ECFCs from DM pregnancies. To determine if MEOX2 is sufficient and/or required to induce impaired network formation, MEOX2 was overexpressed and depleted in ECFCs from control and DM pregnancies, respectively. Surprisingly, MEOX2 overexpression in control ECFCs resulted in increased network formation, altered cell cycle progression, and increased senescence. In contrast, MEOX2 knockdown in ECFCs from DM pregnancies led to decreased network formation, while cell cycle progression and senescence were unaffected. Importantly, migration studies demonstrated that MEOX2 overexpression increased migration, while MEOX2 knockdown decreased migration. Taken together, these data suggest that altered migration may be mediating the impaired vasculogenesis of ECFCs from DM pregnancies. While initially believed to be maladaptive, these data suggest that MEOX2 may serve a protective role, enabling increased vessel formation despite exposure to a DM intrauterine environment. J. Cell. Physiol. 232: 1885-1892, 2017

Time-Weighted Average SPME Analysis for in Planta Determination of CVOCs

The Potential of Phytoscreening for Plume Delineation at Contaminated Sites Has Promoted Interest in Innovative, Sensitive Contaminant Sampling Techniques. Solid-Phase Microextraction (SPME) Methods Have Been Developed, Offering Quick, Undemanding, Noninvasive Sampling Without the Use of Solvents. in This Study, Time-Weighted Average SPME (TWA-SPME) Sampling Was Evaluated for in Planta Quantification of Chlorinated Solvents. TWA-SPME Was Found to Have Increased Sensitivity over Headspace and Equilibrium SPME Sampling. using a Variety of Chlorinated Solvents and a Polydimethylsiloxane/carboxen (PDMS/CAR) SPME Fiber, Most Compounds Exhibited Near Linear or Linear Uptake over the Sampling Period. Smaller, Less Hydrophobic Compounds Exhibited More Nonlinearity Than Larger, More Hydrophobic Molecules. using a Specifically Designed in Planta Sampler, Field Sampling Was Conducted at a Site Contaminated with Chlorinated Solvents. Sampling with TWA-SPME Produced Instrument Responses Ranging from 5 to over 200 Times Higher Than Headspace Tree Core Sampling. This Work Demonstrates that TWA-SPME Can Be Used for in Planta Detection of a Broad Range of Chlorinated Solvents and Methods Can Likely Be Applied to Other Volatile and Semivolatile Organic Compounds. © 2012 American Chemical Society

Epigenetic regulation in neonatal ECFCs following intrauterine exposure to gestational diabetes

poster abstractGestational diabetes (GDM) complicates up to 10% of pregnancies. In addition to acute risks, the children of diabetic mothers have an increased risk of obesity, diabetes, and hypertension, starting in childhood. While the causes of this increased risk are unknown, previous studies in our lab have identified functional deficits in endothelial colony forming cells (ECFCs) isolated from the cord blood of GDM pregnancies. This study focused on identifying genes that have altered epigenetic modifications that result in abnormal mRNA and protein expression in ECFCs from the cord blood GDM pregnancies. The objective of this study was to identify mRNA expression and DNA methylation alterations in ECFCs that may help identify the causes of ECFC dysfunction following intrauterine exposure to GDM. ECFCs were obtained from control and GDM pregnancies. DNA, RNA, and protein samples were isolated in parallel from ECFCs. RNA microarray analysis using the Affymetrix Human 1.0 Gene Array was used to identify gene expression alterations in GDM ECFCs compared to control ECFCs. Genome-wide DNA methylation was assessed using an Infinium 450K Methylation Array for DNA samples at >450,000 CpG sites. Correlation analysis was performed to identify possible sites that have altered CpG methylation and RNA expression. RNA expression results were validated using qRT-PCR and western blotting. Bisulfite sequencing of genomic DNA from the ECFCs was performed to identify additional sites with altered methylation for regions not included in the DNA methylation array. Of the 28,000 genetic loci tested, 596 mRNAs were altered between control and GDM ECFCs (p<0.01). More stringent criteria identified 38 genes for further investigation by limiting analysis to genes that exhibited increased or decreased expression by at least 50%, with a p<0.01. PLAC8 was identified as being increased 5-fold by microarray analysis, a result which was confirmed in two cohorts by qRT-PCR and western blotting. Analysis of the methylation array and bisulfite sequencing results revealed 3 regions surrounding the transcriptional start site of PLAC8 gene whose CpG methylation negatively correlate with RNA expression in samples from control and GDM ECFCs. In contrast, a CpG island is fully unmethylated in both control and GDM ECFCs. The discovery of CpG sites whose methylation correlates with PLAC8 mRNA expression in ECFCs is consistent with the hypothesis that intrauterine exposure to GDM results in epigenetic changes. Analysis of methylation at this site could be used as a biomarker for children of mothers with GDM who may be at risk for disease later in life. Using bisulfite pyrosequencing, we are currently developing assays to quickly determine if methylation of the PLAC8 putative promoter region is altered in cord blood mononuclear cells obtained from GDM or healthy control pregnancies. We are also investigating the role of methylation in regulating PLAC8 RNA expression, determining if there is altered histone modifications and transcription factor binding in these regions, and examining other genes that may comprise a molecular signature of ECFC dysfunction

On the benefits of the tryptophan metabolite 3-hydroxyanthranilic acid in Caenorhabditis elegans and mouse aging.

Tryptophan metabolism through the kynurenine pathway influences molecular processes critical to healthy aging including immune signaling, redox homeostasis, and energy production. Aberrant kynurenine metabolism occurs during normal aging and is implicated in many age-associated pathologies including chronic inflammation, atherosclerosis, neurodegeneration, and cancer. We and others previously identified three kynurenine pathway genes-tdo-2, kynu-1, and acsd-1-for which decreasing expression extends lifespan in invertebrates. Here we report that knockdown of haao-1, a fourth gene encoding the enzyme 3-hydroxyanthranilic acid (3HAA) dioxygenase (HAAO), extends lifespan by ~30% and delays age-associated health decline in Caenorhabditis elegans. Lifespan extension is mediated by increased physiological levels of the HAAO substrate 3HAA. 3HAA increases oxidative stress resistance and activates the Nrf2/SKN-1 oxidative stress response. In pilot studies, female Haao knockout mice or aging wild type male mice fed 3HAA supplemented diet were also long-lived. HAAO and 3HAA represent potential therapeutic targets for aging and age-associated disease

Genetic Disruption of Both Tryptophan Hydroxylase Genes Dramatically Reduces Serotonin and Affects Behavior in Models Sensitive to Antidepressants

The neurotransmitter serotonin (5-HT) plays an important role in both the peripheral and central nervous systems. The biosynthesis of serotonin is regulated by two rate-limiting enzymes, tryptophan hydroxylase-1 and -2 (TPH1 and TPH2). We used a gene-targeting approach to generate mice with selective and complete elimination of the two known TPH isoforms. This resulted in dramatically reduced central 5-HT levels in Tph2 knockout (TPH2KO) and Tph1/Tph2 double knockout (DKO) mice; and substantially reduced peripheral 5-HT levels in DKO, but not TPH2KO mice. Therefore, differential expression of the two isoforms of TPH was reflected in corresponding depletion of 5-HT content in the brain and periphery. Surprisingly, despite the prominent and evolutionarily ancient role that 5-HT plays in both vertebrate and invertebrate physiology, none of these mutations resulted in an overt phenotype. TPH2KO and DKO mice were viable and normal in appearance. Behavioral alterations in assays with predictive validity for antidepressants were among the very few phenotypes uncovered. These behavioral changes were subtle in the TPH2KO mice; they were enhanced in the DKO mice. Herein, we confirm findings from prior descriptions of TPH1 knockout mice and present the first reported phenotypic evaluations of Tph2 and Tph1/Tph2 knockout mice. The behavioral effects observed in the TPH2 KO and DKO mice strongly confirm the role of 5-HT and its synthetic enzymes in the etiology and treatment of affective disorders

The Rate, Amplitude, and Duration of Outbursts from Class 0 Protostars in Orion

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.At least half of a protostar's mass is accreted in the Class 0 phase, when the central protostar is deeply embedded in a dense, infalling envelope. We present the first systematic search for outbursts from Class 0 protostars in the Orion clouds. Using photometry from Spitzer/IRAC spanning 2004 to 2017, we detect three outbursts from Class 0 protostars with ≥2 mag changes at 3.6 or 4.5 μm. This is comparable to the magnitude change of a known protostellar FU Ori outburst. Two are newly detected bursts from the protostars HOPS 12 and 124. The number of detections implies that Class 0 protostars burst every 438 yr, with a 95% confidence interval of 161 to 1884 yr. Combining Spitzer and WISE/NEOWISE data spanning 2004–2019, we show that the bursts persist for more than nine years with significant variability during each burst. Finally, we use 19–100 μm photometry from SOFIA, Spitzer, and Herschel to measure the amplitudes of the bursts. Based on the burst interval, a duration of 15 yr, and the range of observed amplitudes, 3%–100% of the mass accretion during the Class 0 phase occurs during bursts. In total, we show that bursts from Class 0 protostars are as frequent, or even more frequent, than those from more evolved protostars. This is consistent with bursts being driven by instabilities in disks triggered by rapid mass infall. Furthermore, we find that bursts may be a significant, if not dominant, mode of mass accretion during the Class 0 phase. © 2022. The Author(s). Published by the American Astronomical Society.This work uses observations from the Spitzer Space Telescope, operated by JPL/Caltech under a contract with NASA. This paper also uses data from the Wide-field Infrared Survey Explorer, a joint project of the University of California, Los Angeles, and JPL/Caltech, funded by NASA. Observations were also made with the NASA/DLR Stratospheric Observatory for Infrared Astronomy (SOFIA). SOFIA is jointly operated by the Universities Space Research Association, Inc. (USRA), under NASA contract NNA17BF53C, and the Deutsches SOFIA Institut (DSI) under DLR contract 50 OK 0901 to the University of Stuttgart. Herschel is an ESA space observatory with science instruments provided by European-led Principal Investigator consortia and with important participation from NASA. Finally, this work makes use of the NASA/IPAC Infrared Science Archive, operated by JPL/Caltech under a contract with NASA. S.T.M. and R.A.G. were supported by the NASA ADAP grant 80NSSC19K0591, and S.T.M. was supported by the NASA ADAP grant 80NSSC20K0454. R.P. was supported by the NASA ADAP grant 80NSSC18K1564. Support for W.J.F. was provided by NASA through award #07_0200 issued by USRA. A.S. gratefully acknowledges funding support through Fondecyt Regular (project code 1180350), from the ANID BASAL project FB210003, and from the Chilean Centro de Excelencia en Astrofísica y Tecnologías Afines (CATA) BASAL grant AFB-170002. M.O. acknowledges support from the Spanish MINECO/AEI AYA2017-84390-C2-1-R (co-funded by FEDER) and MCIN/AEI/10.13039/501100011033 through the PID2020-114461GB-I00 grant, and from the State Agency for Research of the Spanish MCIU through the "Center of Excellence Severo Ochoa" award for the Instituto de Astrofísica de Andalucía (SEV-2017-0709). This work was completed while STM was a Fulbright Scholar hosted by AS at the Universidad de Concepcíon. The National Radio Astronomy Observatory is a facility of the National Science Foundation operated under cooperative agreement by Associated Universities, Inc.Peer reviewe

Low-intensity cognitive-behaviour therapy interventions for obsessive-compulsive disorder compared to waiting list for therapist-led cognitive-behaviour therapy: 3-arm randomised controlled trial of clinical effectiveness

Background Obsessive-compulsive disorder (OCD) is prevalent and without adequate treatment usually follows a chronic course. “High-intensity” cognitive-behaviour therapy (CBT) from a specialist therapist is current “best practice.” However, access is difficult because of limited numbers of therapists and because of the disabling effects of OCD symptoms. There is a potential role for “low-intensity” interventions as part of a stepped care model. Low-intensity interventions (written or web-based materials with limited therapist support) can be provided remotely, which has the potential to increase access. However, current evidence concerning low-intensity interventions is insufficient. We aimed to determine the clinical effectiveness of 2 forms of low-intensity CBT prior to high-intensity CBT, in adults meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for OCD. Methods and findings This study was approved by the National Research Ethics Service Committee North West–Lancaster (reference number 11/NW/0276). All participants provided informed consent to take part in the trial. We conducted a 3-arm, multicentre randomised controlled trial in primary- and secondary-care United Kingdom mental health services. All patients were on a waiting list for therapist-led CBT (treatment as usual). Four hundred and seventy-three eligible patients were recruited and randomised. Patients had a median age of 33 years, and 60% were female. The majority were experiencing severe OCD. Patients received 1 of 2 low-intensity interventions: computerised CBT (cCBT; web-based CBT materials and limited telephone support) through “OCFighter” or guided self-help (written CBT materials with limited telephone or face-to-face support). Primary comparisons concerned OCD symptoms, measured using the Yale-Brown Obsessive Compulsive Scale–Observer-Rated (Y-BOCS-OR) at 3, 6, and 12 months. Secondary outcomes included health-related quality of life, depression, anxiety, and functioning. At 3 months, guided self-help demonstrated modest benefits over the waiting list in reducing OCD symptoms (adjusted mean difference = −1.91, 95% CI −3.27 to −0.55). These effects did not reach a prespecified level of “clinically significant benefit.” cCBT did not demonstrate significant benefit (adjusted mean difference = −0.71, 95% CI −2.12 to 0.70). At 12 months, neither guided self-help nor cCBT led to differences in OCD symptoms. Early access to low-intensity interventions led to significant reductions in uptake of high-intensity CBT over 12 months; 86% of the patients allocated to the waiting list for high-intensity CBT started treatment by the end of the trial, compared to 62% in supported cCBT and 57% in guided self-help. These reductions did not compromise longer-term patient outcomes. Data suggested small differences in satisfaction at 3 months, with patients more satisfied with guided self-help than supported cCBT. A significant issue in the interpretation of the results concerns the level of access to high-intensity CBT before the primary outcome assessment. Conclusions We have demonstrated that providing low-intensity interventions does not lead to clinically significant benefits but may reduce uptake of therapist-led CBT

Dopamine and Glutamate in Antipsychotic-Responsive Compared With Antipsychotic-Nonresponsive Psychosis: A Multicenter Positron Emission Tomography and Magnetic Resonance Spectroscopy Study (STRATA)

The variability in the response to antipsychotic medication in schizophrenia may reflect between-patient differences in neurobiology. Recent cross-sectional neuroimaging studies suggest that a poorer therapeutic response is associated with relatively normal striatal dopamine synthesis capacity but elevated anterior cingulate cortex (ACC) glutamate levels. We sought to test whether these measures can differentiate patients with psychosis who are antipsychotic responsive from those who are antipsychotic nonresponsive in a multicenter cross-sectional study. 1H-magnetic resonance spectroscopy (1H-MRS) was used to measure glutamate levels (Glucorr) in the ACC and in the right striatum in 92 patients across 4 sites (48 responders [R] and 44 nonresponders [NR]). In 54 patients at 2 sites (25 R and 29 NR), we additionally acquired 3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine (18F-DOPA) positron emission tomography (PET) to index striatal dopamine function (Kicer, min−1). The mean ACC Glucorr was higher in the NR than the R group after adjustment for age and sex (F1,80 = 4.27; P = .04). This was associated with an area under the curve for the group discrimination of 0.59. There were no group differences in striatal dopamine function or striatal Glucorr. The results provide partial further support for a role of ACC glutamate, but not striatal dopamine synthesis, in determining the nature of the response to antipsychotic medication. The low discriminative accuracy might be improved in groups with greater clinical separation or increased in future studies that focus on the antipsychotic response at an earlier stage of the disorder and integrate other candidate predictive biomarkers. Greater harmonization of multicenter PET and 1H-MRS may also improve sensitivity

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe