Discovery of a Potent α ‑ Galactosidase Inhibitor by in Situ Analysis of a Library of Pyrrolizidine − (Thio)urea Hybrid Molecules Generated via Click Chemistry

The parallel synthesis of a 26-membered-library of aromatic/aliphatic-(thio)urea-linked pyrrolizidines followed by in situ biological evaluation toward α -galactosidases has been carried out. The combination of the (thio)urea-forming click reaction and the in situ screening is pioneer in the search for glycosidase inhibitors and has allowed the discovery of a potent co ff ee bean α -galactosidase inhibitor (IC 50 = 0.37 μ M, K i = 0.12 μ M) that has also showed inhibition against human lysosomal α -galactosidase ( α -Gal A, IC 50 = 5.3 μ M, K i = 4.2 μ M).Ministerio de Economía y Competitividad (CTQ2016-77270-R)Junta de Andalucía (FQM-345

Visibility Estimation of Traffic Signals under Rainy Weather Conditions for Smart Driving Support

Abstract-The aim of this work is to support a driver by notifying the information of traffic signals in accordance with their visibility. To avoid traffic accidents, the driver should detect and recognize surrounding objects, especially traffic signals. However, when driving a vehicle under rainy weather conditions, it is difficult for drivers to detect or to recognize objects existing in the road environment in comparison with fine weather conditions. Therefore, this paper proposes a method for estimating the visibility of traffic signals for drivers under rainy weather conditions by image processing. The proposed method is based on the concept of visual noise known in the field of cognitive science, and extracts two types of visual noise features which ware considered that they affect the visibility of traffic signals. We expect to improve the accuracy of visibility estimation by combining the visual noise features with the texture feature introduced in a previous work. Experimental results showed that the proposed method could estimate the visibility of traffic signals more accurately under rainy weather conditions

Attribute-Aware Loss Function for Accurate Semantic Segmentation Considering the Pedestrian Orientations

Numerous applications such as autonomous driving, satellite imagery sensing, and biomedical imaging use computer vision as an important tool for perception tasks. For Intelligent Transportation Systems (ITS), it is required to precisely recognize and locate scenes in sensor data. Semantic segmentation is one of computer vision methods intended to perform such tasks. However, the existing semantic segmentation tasks label each pixel with a single object's class. Recognizing object attributes, e.g., pedestrian orientation, will be more informative and help for a better scene understanding. Thus, we propose a method to perform semantic segmentation with pedestrian attribute recognition simultaneously. We introduce an attribute-aware loss function that can be applied to an arbitrary base model. Furthermore, a re-annotation to the existing Cityscapes dataset enriches the ground-truth labels by annotating the attributes of pedestrian orientation. We implement the proposed method and compare the experimental results with others. The attribute-aware semantic segmentation shows the ability to outperform baseline methods both in the traditional object segmentation task and the expanded attribute detection task

Acute Pancreatitis due to pH-Dependent Mesalazine That Occurred in the Course of Ulcerative Colitis

We report the case of a 26-year-old male who presented with acute pancreatitis during the course of treatment for pancolitic ulcerative colitis (UC) with a time-dependent mesalazine formulation, prednisolone and azathioprine (AZA). Despite a review of his clinical history and various tests, the cause of pancreatitis could not be determined. Since drug-induced pancreatitis was considered possible, administration of the time-dependent mesalazine preparation and AZA was discontinued, and conservative treatment for acute pancreatitis was performed. The pancreatitis promptly improved with these treatments, but drug lymphocyte stimulation test (DLST) for both the time-dependent mesalazine formulation and AZA was negative. A pH-dependent mesalazine formulation was given for maintenance therapy of UC. Subsequently, as the pancreatitis relapsed, drug-induced pancreatitis was strongly suspected. Administration of mesalazine was discontinued, and pancreatitis was smoothly in remission by conservative treatment. According to the positive DLST result for the pH-dependent mesalazine formulation and the clinical course, a diagnosis of pH-dependent mesalazine-induced pancreatitis due to this formulation was made. During the clinical course of UC, occurrence of drug-induced pancreatitis must always be considered

NUDT16 and ITPA play a dual protective role in maintaining chromosome stability and cell growth by eliminating dIDP/IDP and dITP/ITP from nucleotide pools in mammals

Mammalian inosine triphosphatase encoded by ITPA gene hydrolyzes ITP and dITP to monophosphates, avoiding their deleterious effects. Itpa− mice exhibited perinatal lethality, and significantly higher levels of inosine in cellular RNA and deoxyinosine in nuclear DNA were detected in Itpa− embryos than in wild-type embryos. Therefore, we examined the effects of ITPA deficiency on mouse embryonic fibroblasts (MEFs). Itpa− primary MEFs lacking ITP-hydrolyzing activity exhibited a prolonged doubling time, increased chromosome abnormalities and accumulation of single-strand breaks in nuclear DNA, compared with primary MEFs prepared from wild-type embryos. However, immortalized Itpa− MEFs had neither of these phenotypes and had a significantly higher ITP/IDP-hydrolyzing activity than Itpa− embryos or primary MEFs. Mammalian NUDT16 proteins exhibit strong dIDP/IDP-hydrolyzing activity and similarly low levels of Nudt16 mRNA and protein were detected in primary MEFs derived from both wild-type and Itpa− embryos. However, immortalized Itpa− MEFs expressed significantly higher levels of Nudt16 than the wild type. Moreover, introduction of silencing RNAs against Nudt16 into immortalized Itpa− MEFs reproduced ITPA-deficient phenotypes. We thus conclude that NUDT16 and ITPA play a dual protective role for eliminating dIDP/IDP and dITP/ITP from nucleotide pools in mammals

NUDT16 is a (deoxy)inosine diphosphatase, and its deficiency induces accumulation of single-strand breaks in nuclear DNA and growth arrest

Nucleotides function in a variety of biological reactions; however, they can undergo various chemical modifications. Such modified nucleotides may be toxic to cells if not eliminated from the nucleotide pools. We performed a screen for modified-nucleotide binding proteins and identified human nucleoside diphosphate linked moiety X-type motif 16 (NUDT16) protein as an inosine triphosphate (ITP)/xanthosine triphosphate (XTP)/GTP-binding protein. Recombinant NUDT16 hydrolyzes purine nucleoside diphosphates to the corresponding nucleoside monophosphates. Among 29 nucleotides examined, the highest kcat/Km values were for inosine diphosphate (IDP) and deoxyinosine diphosphate (dIDP). Moreover, NUDT16 moderately hydrolyzes (deoxy)inosine triphosphate ([d]ITP). NUDT16 is mostly localized in the nucleus, and especially in the nucleolus. Knockdown of NUDT16 in HeLa MR cells caused cell cycle arrest in S-phase, reduced cell proliferation, increased accumulation of single-strand breaks in nuclear DNA as well as increased levels of inosine in RNA. We thus concluded that NUDT16 is a (deoxy)inosine diphosphatase that may function mainly in the nucleus to protect cells from deleterious effects of (d)ITP

Selective Trihydroxylated Azepane Inhibitors of NagZ, a Glycosidase Involved in Pseudomonas Aeruginosa Resistance to β-lactam Antibiotics

The synthesis of a series of D-gluco-like configured 4,5,6-trihydroxyazepanes bearing a triazole, a sulfonamide or a fluorinated acetamide moiety at C-3 is described. These synthetic derivatives have been tested for their ability to selectively inhibit the muropeptide recycling glucosaminidase NagZ and to thereby increase sensitivity of Pseudomonas aeruginosa to β-lactams, a pathway with substantial therapeutic potential. While introduction of triazole and sulfamide groups failed to lead to glucosaminidase inhibitors, the NHCOCF3 analog proved to be a selective inhibitor of NagZ over other glucosaminidases including human OGA and lysosomal hexosaminidases HexA and B. The synthesis of a series of D-gluco-like configured 4,5,6-trihydroxyazepanes bearing a triazole, a sulfonamide or a fluorinated acetamide moiety at C-3 is described. These synthetic derivatives have been tested for their ability to selectively inhibit the muropeptide recycling glucosaminidase NagZ and to thereby increase sensitivity of Pseudomonas aeruginosa to β-lactams, a pathway with substantial therapeutic potential. While introduction of triazole and sulfamide groups failed to lead to glucosaminidase inhibitors, the NHCOCF3 analog proved to be a selective inhibitor of NagZ over other glucosaminidases including human OGA and lysosomal hexosaminidases HexA and B &nbsp