Recently, deep generative models have become increasingly popular in unsupervised anomaly detection. However, deep generative models aim at recovering the data distribution rather than detecting anomalies. Moreover, deep generative models have the risk of overfitting training samples, which has disastrous effects on anomaly detection performance. To solve the above two problems, we propose a self-adversarial variational autoencoder (adVAE) with a Gaussian anomaly prior assumption. We assume that both the anomalous and the normal prior distribution are Gaussian and have overlaps in the latent space. Therefore, a Gaussian transformer net T is trained to synthesize anomalous but near-normal latent variables. Keeping the original training objective of a variational autoencoder, a generator G tries to distinguish between the normal latent variables encoded by E and the anomalous latent variables synthesized by T, and the encoder E is trained to discriminate whether the output of G is real. These new objectives we added not only give both G and E the ability to discriminate, but also become an additional regularization mechanism to prevent overfitting. Compared with other competitive methods, the proposed model achieves significant improvements in extensive experiments. The employed datasets and our model are available in a Github repository.

This study was designed to investigate whether a non-protein nanostructured lipid carrier (NLC) resembling high-density lipoprotein (HDL) could deliver a hydrophobic anti-atherogenic drug, lovastatin, to foam cells. Lovastatin-loaded NLC (LT-NLC) was prepared by a nanoprecipitation/solvent diffusion method. The LT-NLC-apoprotein (LT-NLC-apo) was prepared by incubating LT-NLC with native HDL. The physicochemical parameters of LT-NLC were characterized in terms of particle size, zeta potential, morphology, entrapment efficiency, and crystallization behavior. Targeting behavior and mechanism were demonstrated by the incubation of LT-NLC-apo with a RAW 264.7 macrophage-derived foam cell model in the presence or absence of very-low-density lipoprotein (VLDL) and lipase. The results showed that LT-NLC was solid spherical or oval in shape with an average diameter of 13.8 ± 2.2 nm, zeta potential of −29.3 ± 0.2 mV and entrapment efficiency of 96.2 ± 1.3%. Phagocytosis studies showed that uptake of LT-NLC-apo by macrophages was significantly lower than LT-NLC (p < 0.01), suggesting that LT-NLC-apo could possibly escape recognition from macrophages in vivo. The uptake was increased twofold when LT-NLC-apo was incubated with transfected foam cells containing VLDL and lipase. These results indicated that non-protein NLC resembling HDL could be a useful tool to deliver lipophilic anti-atherogenic drugs to foam cells, and that uptake could be enhanced by the VLDL receptor pathway.

Chronic obstructive pulmonary disease (COPD) kills approximately 2.8 million people each year, and more than 80% of COPD cases can be attributed to smoking. Leukocytes recruited to the lung contribute to COPD pathology by releasing reactive oxygen metabolites and proteolytic enzymes. In this work, we investigated where leukocytes enter the lung in the early stages of COPD in order to better understand their effect as a contributor to the development of COPD. We simultaneously evaluated the parenchyma and airways for neutrophil accumulation, as well as increases in the adhesion molecules and chemokines that cause leukocyte recruitment in the early stages of tobacco smoke induced lung disease. We found neutrophil accumulation and increased expression of adhesion molecules and chemokines in the bronchial blood vessels that correlated with the accumulation of leukocytes recovered from the lung. The expression of adhesion molecules and chemokines in other vascular beds did not correlate with leukocytes recovered in bronchoalveolar lavage fluid (BALF). These data strongly suggest leukocytes are recruited in large measure through the bronchial circulation in response to tobacco smoke. Our findings have important implications for understanding the etiology of COPD and suggest that pharmaceuticals designed to reduce leukocyte recruitment through the bronchial circulation may be a potential therapy to treat COPD.

Trinucleotide repeat (TNR) sequences, which are responsible for several neurodegenerative genetic diseases, fold into hairpins that interfere with the protein machinery in replication or repair, thus leading to dynamic mutation -abnormal expansions of the genome. Despite their high thermodynamic stability, these hairpins can undergo configurational rearrangements, which may be crucial for continuous dynamic mutation. Here, we used CTG repeats as a model system to study their structural dynamics at the single-molecule level. A unique dynamic two-state configuration interchange was discovered over a wide range of odd-numbered CTG repeat sequences. Employing repeat-number-dependent kinetic analysis, we proposed a bulge translocation model, which is driven by the local instability and can be extended reasonably to longer (pathologically relevant) hairpins, implying the potential role in error accumulation in repeat expansion.

Increased growth and proliferation of distal pulmonary artery vascular smooth muscle cells (PAVSMC) is an important pathological component of pulmonary arterial hypertension (PAH). Transforming Growth Factor-β (TGF-β) superfamily plays a critical role in PAH, but relative impacts of self-secreted Activin A, Gremlin1, and TGF-β on PAH PAVSMC growth and proliferation are not studied. Here we report that hyper-proliferative human PAH PAVSMC have elevated secretion of TGF-β1 and, to a lesser extent, Activin A, but not Gremlin 1, and significantly reduced Ser465/467-Smad2 and Ser423/425-Smad3 phosphorylation compared to controls. Media, conditioned by PAH PAVSMC, markedly increased Ser465/467-Smad2, Ser423/425-Smad3, and Ser463/465-Smad1/5 phosphorylation, up-regulated Akt, ERK1/2, and p38 MAPK, and induced significant proliferation of non-diseased PAVSMC. Inhibitory anti-Activin A antibody reduced PAH PAVSMC growth without affecting canonical (Smads) or non-canonical (Akt, ERK1/2, p38 MAPK) effectors. Inhibitory anti-TGF-β antibody significantly reduced P-Smad3, P-ERK1/2 and proliferation of PAH PAVSMC, while anti-Gremlin 1 had no anti-proliferative effect. PDGF-BB diminished inhibitory effects of anti-Activin A and anti-TGF-β antibodies. None of the antibodies affected growth and proliferation of non-diseased PAVSMC induced by PAH PAVSMC-secreted factors. Together, these data demonstrate that human PAH PAVSMC have secretory, proliferative phenotype that could be targeted by anti-Activin A and anti-TGF-β antibodies; potential cross-talk with PDGF-BB should be considered while developing therapeutic interventions.