Transcriptome profiling reveals significant changes in the gastric muscularis externa with obesity that partially overlap those that occur with idiopathic gastroparesis

BACKGROUND: Gastric emptying is impaired in patients with gastroparesis whereas it is either unchanged or accelerated in obese individuals. The goal of the current study was to identify changes in gene expression in the stomach muscularis that may be contributing to altered gastric motility in idiopathic gastroparesis and obesity. METHODS: Quantitative real time RT-PCR and whole transcriptome sequencing were used to compare the transcriptomes of lean individuals, obese individuals and either lean or obese individuals with idiopathic gastroparesis. RESULTS: Obesity leads to an increase in mRNAs associated with muscle contractility whereas idiopathic gastroparesis leads to a decrease in mRNAs associated with PDGF BB signaling. Both obesity and idiopathic gastroparesis were also associated with similar alterations in pathways associated with inflammation. CONCLUSIONS: Our findings show that obesity and idiopathic gastroparesis result in overlapping but distinct changes in the gastric muscularis transcriptome. Increased expression of mRNAs encoding smooth muscle contractile proteins may be contributing to the increased gastric motility observed in obese subjects, whereas decreased PDGF BB signaling may be contributing to the impaired motility seen in subjects with idiopathic gastroparesis

Patient Characteristics, Length of Stay, and Functional Improvement for Schizophrenia Spectrum Disorders: A Population Study of Inpatient Care in Ontario 2005 to 2015

Objectives: Schizophrenia and associated illnesses account for a large proportion of mental illness burden and health care expenditures, with the majority of expense involving inpatient care. To date, the literature exploring factors associated with length of stay (LOS) and functional improvement during inpatient care is underdeveloped. In response, this study examined the association between patient characteristics, LOS, and functional improvement using Ontario Mental Health Reporting System (OMHRS) data from 2005 to 2015. Methods: The associations of patient characteristics (including key demographics, psychosocial variables, reasons for admission, and service use history) and 2 outcome measures (LOS and Global Assessment of Functioning [GAF]) were analysed with generalised linear mixed modelling (GLMM). From 2005 to 2015, a total of 48,498 episodes for distinct patients from 18 psychiatric hospitals and 57 general hospitals in Ontario were included. Results: For psychiatric and general hospitals, mean LOS was 96.6 and 20.5 days, and mean GAF improvement was 14.8 and 16.1, respectively. The majority of associations probed demonstrated a high degree of significance with similar patterns across general and tertiary facility contexts. Older age and more recent readmission following a psychiatric discharge were associated with longer LOS and less GAF improvement. Recent experience of adverse life events and substance misuse were associated with shorter LOS. Conclusions: While the findings of this exploratory cross-sectional analysis will require further inquiry with respect to validity and reliability, they suggest that a different service pathway is likely required for individuals with greater psychosocial challenge and extensive service use histories

The impact of a mobile phone-delivered digital financial education program on financial behavior among Hispanics

We explored the potential of digital financial education programs among Hispanic populations, through the design and evaluation of a mobile phone delivered digital program called Mind Your Money (MYM). This program sought to improve financial knowledge and behavior among low- to-moderate income Hispanics residing in the Greater Los Angeles area. We assessed the program through a randomized controlled trial with a wait-list control group. Our digital financial education program had a higher retention rate than comparable in-person financial coaching programs. We found that our program had a positive statistical significant effect on financial capability. Participants who completed program activities were more likely to have a budget/spending plan and felt more confident about their ability to pay for unexpected expenses

Discovery of macrocyclic inhibitors of apurinic/apyrimidinic endonuclease 1

Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential base excision repair enzyme that is upregulated in a number of cancers, contributes to resistance of tumors treated with DNA-alkylating or -oxidizing agents, and has recently been identified as an important therapeutic target. In this work, we identified hot spots for binding of small organic molecules experimentally in high resolution crystal structures of APE1 and computationally through the use of FTMAP analysis (http://ftmap.bu.edu/). Guided by these hot spots, a library of drug-like macrocycles was docked and then screened for inhibition of APE1 endonuclease activity. In an iterative process, hot-spot-guided docking, characterization of inhibition of APE1 endonuclease, and cytotoxicity of cancer cells were used to design next generation macrocycles. To assess target selectivity in cells, selected macrocycles were analyzed for modulation of DNA damage. Taken together, our studies suggest that macrocycles represent a promising class of compounds for inhibition of APE1 in cancer cells.This work was supported by grants from the National Institutes of Health (Grant R01CA205166 to M.R.K. and M.M.G. and Grant R01CA167291 to M.R.K.) and by the Earl and Betty Herr Professor in Pediatric Oncology Research, Jeff Gordon Children's Foundation, and the Riley Children's Foundation (M.R.K.). Work at the BU-CMD (J.A.P., L.E.B., R.T.) is supported by the National Institutes of Health, Grant R24 GM111625. D.B. and S.V. were supported by the National Institutes of Health, Grant R35 GM118078. (R35 GM118078 - National Institutes of Health; R01CA205166 - National Institutes of Health; R01CA167291 - National Institutes of Health; R24 GM111625 - National Institutes of Health; Earl and Betty Herr Professor in Pediatric Oncology Research; Jeff Gordon Children's Foundation; Riley Children's Foundation)Accepted manuscriptSupporting documentatio

Applying latent tree analysis to classify Traditional Chinese Medicine syndromes (Zheng) in patients with psoriasis vulgari

OBJECTIVE To treat patients with psoriasis vulgaris using Traditional Chinese Medicine (TCM), one must stratify patients into subtypes (known as TCM syndromes or Zheng) and apply appropriate TCM treatments to different subtypes. However, no unified symptom-based classification scheme of subtypes (Zheng) exists for psoriasis vulgaris. The present paper aims to classify patients with psoriasis vulgaris into different subtypes via the analysis of clinical TCM symptom and sign data. METHODS A cross-sectional survey was carried out in Beijing from 2005-2008, collecting clinical TCM symptom and sign data from 2764 patients with psoriasis vulgaris. Roughly 108 symptoms and signs were initially analyzed using latent tree analysis, with a selection of the resulting latent variables then used as features to cluster patients into subtypes. RESULTS The initial latent tree analysis yielded a model with 43 latent variables. The second phase of the analysis divided patients into three subtype groups with clear TCM Zheng connotations: 'blood deficiency and wind dryness'; 'blood heat'; and 'blood stasis'. CONCLUSIONS Via two-phase analysis of clinic symptom and sign data, three different Zheng subtypes were identified for psoriasis vulgaris. Statistical characteristics of the three subtypes are presented. This constitutes an evidence-based solution to the syndromedifferentiation problem that exists with psoriasis vulgaris

International Reverse Transfer Students: A Critical Analysis Based on Field, Habitus, and Social and Cultural Capital

Objective: International reverse transfer students are international students who begin their postsecondary journey at a four-year institution but subsequently transfer to a community college. In this qualitative study, we examine the lived experiences of international reverse transfers to understand the reasons for reverse-transfer and to understand the students’ learning experiences. Methods: Using a phenomenological approach, we recruited 10 international reverse transfer students attending one four-year university or one of the two community colleges. We conducted individual interviews with all participants and analyzed transcript data through Bourdieu’s sociological theory of field, habitus, and social and cultural capital. Results: We identified three types of international reverse transfer students: undergraduate reverse transfers, temporary reverse transfers, and postbaccalaureate reverse transfers. Each type reported different reasons for reverse transfer but shared similar influential factors of the reverse transfer process as well as the learning experiences while enrolled at the community colleges. Contributions: This study helps to fill an information and research gap regarding international reverse transfer students. We present the academic, social, and cultural challenges faced by international students and offer practical implications for higher education practitioners for improved understandings and better processes to serve international students from diverse cultural backgrounds

Endothelial Cell-Specific Deletion of P2Y2 Receptor Promotes Plaque Stability in Atherosclerosis-Susceptible ApoE-Null Mice

OBJECTIVE: Nucleotide P2Y2 receptor (P2Y2R) contributes to vascular inflammation by increasing vascular cell adhesion molecule-1 expression in endothelial cells (EC), and global P2Y2R deficiency prevents fatty streak formation in apolipoprotein E null (ApoE-/-) mice. Because P2Y2R is ubiquitously expressed in vascular cells, we investigated the contribution of endothelial P2Y2R in the pathogenesis of atherosclerosis. APPROACH AND RESULTS: EC-specific P2Y2R-deficient mice were generated by breeding VEcadherin5-Cre mice with the P2Y2R floxed mice. Endothelial P2Y2R deficiency reduced endothelial nitric oxide synthase activity and significantly altered ATP- and UTP (uridine 5'-triphosphate)-induced vasorelaxation without affecting vasodilatory responses to acetylcholine. Telemetric blood pressure and echocardiography measurements indicated that EC-specific P2Y2R-deficient mice did not develop hypertension. We investigated the role of endothelial P2Y2R in the development of atherosclerotic lesions by crossing the EC-specific P2Y2R knockout mice onto an ApoE-/- background and evaluated lesion development after feeding a standard chow diet for 25 weeks. Histopathologic examination demonstrated reduced atherosclerotic lesions in the aortic sinus and entire aorta, decreased macrophage infiltration, and increased smooth muscle cell and collagen content, leading to the formation of a subendothelial fibrous cap in EC-specific P2Y2R-deficient ApoE-/- mice. Expression and proteolytic activity of matrix metalloproteinase-2 was significantly reduced in atherosclerotic lesions from EC-specific P2Y2R-deficient ApoE-/- mice. Furthermore, EC-specific P2Y2R deficiency inhibited nitric oxide production, leading to significant increase in smooth muscle cell migration out of aortic explants. CONCLUSIONS: EC-specific P2Y2R deficiency reduces atherosclerotic burden and promotes plaque stability in ApoE-/- mice through impaired macrophage infiltration acting together with reduced matrix metalloproteinase-2 activity and increased smooth muscle cell migration

Small molecule activation of apurinic/apyrimidinic endonuclease 1 reduces DNA damage induced by cisplatin in cultured sensory neurons

Although chemotherapy-induced peripheral neuropathy (CIPN) affects approximately 5-60% of cancer patients, there are currently no treatments available in part due to the fact that the underlying causes of CIPN are not well understood. One contributing factor in CIPN may be persistence of DNA lesions resulting from treatment with platinum-based agents such as cisplatin. In support of this hypothesis, overexpression of the base excision repair (BER) enzyme, apurinic/apyrimidinic endonuclease 1 (APE1), reduces DNA damage and protects cultured sensory neurons treated with cisplatin. Here, we address stimulation of APE1's endonuclease through a small molecule, nicorandil, as a means of mimicking the beneficial effects observed for overexpression of APE1. Nicorandil, was identified through high-throughput screening of small molecule libraries and found to stimulate APE1 endonuclease activity by increasing catalytic efficiency approximately 2-fold. This stimulation is primarily due to an increase in kcat. To prevent metabolism of nicorandil, an approved drug in Europe for the treatment of angina, cultured sensory neurons were pretreated with nicorandil and daidzin, an aldehyde dehydrogenase 2 inhibitor, resulting in decreased DNA damage but not altered transmitter release by cisplatin. This finding suggests that activation of APE1 by nicorandil in cisplatin-treated cultured sensory neurons does not imbalance the BER pathway in contrast to overexpression of the kinetically faster R177A APE1. Taken together, our results suggest that APE1 activators can be used to reduce DNA damage induced by cisplatin in cultured sensory neurons, although further studies will be required to fully assess their protective effects

Regulation of 130kDa smooth muscle myosin light chain kinase expression by an intronic CArG element

The mylk1 gene encodes a 220-kDa nonmuscle myosin light chain kinase (MLCK), a 130-kDa smooth muscle MLCK (smMLCK), as well as the non-catalytic product telokin. Together, these proteins play critical roles in regulating smooth muscle contractility. Changes in their expression are associated with many pathological conditions; thus, it is important to understand the mechanisms regulating expression of mylk1 gene transcripts. Previously, we reported a highly conserved CArG box, which binds serum response factor, in intron 15 of mylk1. Because this CArG element is near the promoter that drives transcription of the 130-kDa smMLCK, we examined its role in regulating expression of this transcript. Results show that deletion of the intronic CArG region from a β-galactosidase reporter gene abolished transgene expression in mice in vivo. Deletion of the CArG region from the endogenous mylk1 gene, specifically in smooth muscle cells, decreased expression of the 130-kDa smMLCK by 40% without affecting expression of the 220-kDa MLCK or telokin. This reduction in 130-kDa smMLCK expression resulted in decreased phosphorylation of myosin light chains, attenuated smooth muscle contractility, and a 24% decrease in small intestine length that was associated with a significant reduction of Ki67-positive smooth muscle cells. Overall, these data show that the CArG element in intron 15 of the mylk1 gene is necessary for maximal expression of the 130-kDa smMLCK and that the 130-kDa smMLCK isoform is specifically required to regulate smooth muscle contractility and small intestine smooth muscle cell proliferation

Fairness-Aware Graph Neural Networks: A Survey

Graph Neural Networks (GNNs) have become increasingly important due to their representational power and state-of-the-art predictive performance on many fundamental learning tasks. Despite this success, GNNs suffer from fairness issues that arise as a result of the underlying graph data and the fundamental aggregation mechanism that lies at the heart of the large class of GNN models. In this article, we examine and categorize fairness techniques for improving the fairness of GNNs. Previous work on fair GNN models and techniques are discussed in terms of whether they focus on improving fairness during a preprocessing step, during training, or in a post-processing phase. Furthermore, we discuss how such techniques can be used together whenever appropriate, and highlight the advantages and intuition as well. We also introduce an intuitive taxonomy for fairness evaluation metrics including graph-level fairness, neighborhood-level fairness, embedding-level fairness, and prediction-level fairness metrics. In addition, graph datasets that are useful for benchmarking the fairness of GNN models are summarized succinctly. Finally, we highlight key open problems and challenges that remain to be addressed