HSP90 inhibitors stimulate DNAJB4 protein expression through a mechanism involving N6-methyladenosine.

Small-molecule inhibitors for the 90-kDa heat shock protein (HSP90) have been extensively exploited in preclinical studies for the therapeutic interventions of human diseases accompanied with proteotoxic stress. By using an unbiased quantitative proteomic method, we uncover that treatment with three HSP90 inhibitors results in elevated expression of a large number of heat shock proteins. We also demonstrate that the HSP90 inhibitor-mediated increase in expression of DNAJB4 protein occurs partly through an epitranscriptomic mechanism, and is substantially modulated by the writer, eraser, and reader proteins of N6-methyladenosine (m6A). Furthermore, exposure to ganetespib leads to elevated modification levels at m6A motif sites in the 5'-UTR of DNAJB4 mRNA, and the methylation at adenosine 114 site in the 5'-UTR promotes the translation of the reporter gene mRNA. This m6A-mediated mechanism is also at play upon heat shock treatment. Cumulatively, we unveil that HSP90 inhibitors stimulate the translation of DNAJB4 through an epitranscriptomic mechanism

A Dimension-Augmented Physics-Informed Neural Network (DaPINN) with High Level Accuracy and Efficiency

Physics-informed neural networks (PINNs) have been widely applied in different fields due to their effectiveness in solving partial differential equations (PDEs). However, the accuracy and efficiency of PINNs need to be considerably improved for scientific and commercial use. To address this issue, we systematically propose a novel dimension-augmented physics-informed neural network (DaPINN), which simultaneously and significantly improves the accuracy and efficiency of the PINN. In the DaPINN model, we introduce inductive bias in the neural network to enhance network generalizability by adding a special regularization term to the loss function. Furthermore, we manipulate the network input dimension by inserting additional sample features and incorporating the expanded dimensionality in the loss function. Moreover, we verify the effectiveness of power series augmentation, Fourier series augmentation and replica augmentation, in both forward and backward problems. In most experiments, the error of DaPINN is 1$\sim$2 orders of magnitude lower than that of PINN. The results show that the DaPINN outperforms the original PINN in terms of both accuracy and efficiency with a reduced dependence on the number of sample points. We also discuss the complexity of the DaPINN and its compatibility with other methods.Comment: 33 pages, 12 figure

Effective Image Restorations Using a Novel Spatial Adaptive Prior

Bayesian or Maximum a posteriori (MAP) approaches can effectively overcome the ill-posed problems of image restoration or deconvolution through incorporating a priori image information. Many restoration methods, such as nonquadratic prior Bayesian restoration and total variation regularization, have been proposed with edge-preserving and noise-removing properties. However, these methods are often inefficient in restoring continuous variation region and suppressing block artifacts. To handle this, this paper proposes a Bayesian restoration approach with a novel spatial adaptive (SA) prior. Through selectively and adaptively incorporating the nonlocal image information into the SA prior model, the proposed method effectively suppress the negative disturbance from irrelevant neighbor pixels, and utilizes the positive regularization from the relevant ones. A two-step restoration algorithm for the proposed approach is also given. Comparative experimentation and analysis demonstrate that, bearing high-quality edge-preserving and noise-removing properties, the proposed restoration also has good deblocking property

Low-Level Saturated Fatty Acid Palmitate Benefits Liver Cells by Boosting Mitochondrial Metabolism via CDK1-SIRT3-CPT2 Cascade.

Saturated fatty acids (SFAs) (the "bad" fat), especially palmitate (PA), in the human diet are blamed for potential health risks such as obesity and cancer because of SFA-induced lipotoxicity. However, epidemiological results demonstrate a latent benefit of SFAs, and it remains elusive whether a certain low level of SFAs is physiologically essential for maintaining cell metabolic hemostasis. Here, we demonstrate that although high-level PA (HPA) indeed induces lipotoxic effects in liver cells, low-level PA (LPA) increases mitochondrial functions and alleviates the injuries induced by HPA or hepatoxic agent carbon tetrachloride (CCl4). LPA treatment in mice enhanced liver mitochondrial activity and reduced CCl4 hepatotoxicity with improved blood levels of aspartate aminotransferase (AST), alanine transaminase (ALT), and mitochondrial aspartate transaminase (m-AST). LPA-mediated mitochondrial homeostasis is regulated by CDK1-mediated SIRT3 phosphorylation, which in turn deacetylates and dimerizes CPT2 to enhance fatty acid oxidation. Thus, an advantageous effect is suggested by the consumption of LPA that augments mitochondrial metabolic homeostasis via CDK1-SIRT3-CPT2 cascade

Third-order nonlinearity in Ge–Sb–Se glasses at mid-infrared wavelengths

International audienceThe optical properties of Ge–Sb–Se glasses have been extensively studied at telecom wavelengths in recent years. However, the understanding of nonlinearity in Ge–Sb–Se glasses at mid-infrared wavelengths still remains limited. In this work, a series of Ge20SbxSe80−x (x = 0, 5, 10) glasses were prepared by conventional melt–quenching method. The absorption spectra and the refractive index of glasses were recorded. The third order nonlinearity, n2, and nonlinear absorption coefficient were measured for Ge–Sb–Se glass samples at the wavelengths of 1550, 2000 and 2500 nm by Z-scan technique, respectively. With the increasing of Sb contents, the linear refractive index of glass increased. Among the three operating wavelengths, all the three glass samples have a highest n2 at 2000 nm. By using the figure of merit (FOM) to evaluate the studied three glasses, the Ge20Sb10Se70 glass shows the greatest potential for mid-IR all optical switching device

Structural basis for DNMT3A-mediated de novo DNA methylation.

DNA methylation by de novo DNA methyltransferases 3A (DNMT3A) and 3B (DNMT3B) at cytosines is essential for genome regulation and development. Dysregulation of this process is implicated in various diseases, notably cancer. However, the mechanisms underlying DNMT3 substrate recognition and enzymatic specificity remain elusive. Here we report a 2.65-ångström crystal structure of the DNMT3A-DNMT3L-DNA complex in which two DNMT3A monomers simultaneously attack two cytosine-phosphate-guanine (CpG) dinucleotides, with the target sites separated by 14 base pairs within the same DNA duplex. The DNMT3A-DNA interaction involves a target recognition domain, a catalytic loop, and DNMT3A homodimeric interface. Arg836 of the target recognition domain makes crucial contacts with CpG, ensuring DNMT3A enzymatic preference towards CpG sites in cells. Haematological cancer-associated somatic mutations of the substrate-binding residues decrease DNMT3A activity, induce CpG hypomethylation, and promote transformation of haematopoietic cells. Together, our study reveals the mechanistic basis for DNMT3A-mediated DNA methylation and establishes its aetiological link to human disease

Thoracic low-dose CT image processing using an artifact suppressed large-scale nonlocal means.

International audienceThe x-ray exposure to patients has become a major concern in computed tomography (CT) and minimizing the radiation exposure has been one of the major efforts in the CT field. Due to plenty high-attenuation tissues in the human chest, under low-dose scan protocols, thoracic low-dose CT (LDCT) images tend to be severely degraded by excessive mottled noise and non-stationary streak artifacts. Their removal is rather a challenging task because the streak artifacts with directional prominence are often hard to discriminate from the attenuation information of normal tissues. This paper describes a two-step processing scheme called 'artifact suppressed large-scale nonlocal means' for suppressing both noise and artifacts in thoracic LDCT images. Specific scale and direction properties were exploited to discriminate the noise and artifacts from image structures. Parallel implementation has been introduced to speed up the whole processing by more than 100 times. Phantom and patient CT images were both acquired for evaluation purpose. Comparative qualitative and quantitative analyses were both performed that allows conclusion on the efficacy of our method in improving thoracic LDCT data

Pomegranate (Punica granatum) extract and its polyphenols reduce the formation of methylglyoxal-DNA adducts and protect human keratinocytes against methylglyoxal-induced oxidative stress

Pomegranate extract (PE) and its polyphenols have been reported to show skin protective effects but their cytoprotective effects against methylglyoxal (MGO)-induced DNA damage and cell dysfunctions are unclear. Herein, we evaluated whether PE, punicalagin (PA), ellagic acid (EA), and urolithin A (UA), can alleviate MGO-induced DNA damage in human keratinocytes. PE (50 µg/mL) and PA (50 µM) protected DNA integrity and reduced the formation of MGO-DNA adducts and tailed DNA by 60.2 and 49.7%, respectively, in HaCaT cells. PE and PA reduced MGO-induced cytotoxicity by increasing the cell viability (by 17.5 and 15.0%) and decreasing reactive oxygen species (by 28.3 and 30.0%), respectively. PE and PA also ameliorated MGO-induced cell dysfunction by restoring cell adhesion, migration, and wound healing capacity. Findings from this study provide insights into the skin protective effects of PE and its polyphenols supporting their applications as potential bioactive ingredients for cosmeceuticals

Exploring potential genes and mechanisms linking erectile dysfunction and depression

BackgroundThe clinical correlation between erectile dysfunction (ED) and depression has been revealed in cumulative studies. However, the evidence of shared mechanisms between them was insufficient. This study aimed to explore common transcriptomic alterations associated with ED and depression.Materials and methodsThe gene sets associated with ED and depression were collected from the Gene Expression Omnibus (GEO) database. Comparative analysis was conducted to obtain common genes. Using R software and other appropriate tools, we conducted a range of analyses, including function enrichment, interactive network creation, gene cluster analysis, and transcriptional and post-transcriptional signature profiling. Candidate hub crosslinks between ED and depression were selected after external validation and molecular experiments. Furthermore, subpopulation location and disease association of hub genes were explored.ResultsA total of 85 common genes were identified between ED and depression. These genes strongly correlate with cell adhesion, redox homeostasis, reactive oxygen species metabolic process, and neuronal cell body. An interactive network consisting of 80 proteins and 216 interactions was thereby developed. Analysis of the proteomic signature of common genes highlighted eight major shared genes: CLDN5, COL7A1, LDHA, MAP2K2, RETSAT, SEMA3A, TAGLN, and TBC1D1. These genes were involved in blood vessel morphogenesis and muscle cell activity. A subsequent transcription factor (TF)–miRNA network showed 47 TFs and 88 miRNAs relevant to shared genes. Finally, CLDN5 and TBC1D1 were well-validated and identified as the hub crosslinks between ED and depression. These genes had specific subpopulation locations in the corpus cavernosum and brain tissue, respectively.ConclusionOur study is the first to investigate common transcriptomic alterations and the shared biological roles of ED and depression. The findings of this study provide insights into the referential molecular mechanisms underlying the co-existence between depression and ED