Strategies To Design Selective Histone Deacetylase Inhibitors

This review classifies drug-design strategies successfully implemented in the development of histone deacetylase (HDAC) inhibitors, which have many applications including cancer treatment. Our focus is on especially demanded selective HDAC inhibitors and their structure-activity relationships in relation to corresponding protein structures. The main part of the paper is divided into six subsections each narrating how optimization of one of six structural features can influence inhibitor selectivity. It starts with the impact of the zinc binding group on selectivity, continues with the optimization of the linker placed in the substrate binding tunnel as well as the adjustment of the cap group interacting with the surface of the protein, and ends with the addition of groups targeting class-specific sub-pockets: the side-pocket-, lower-pocket- and foot-pocket-targeting groups. The review is rounded off with a conclusion and an outlook on the future of HDAC inhibitor design.     

The Adaptive Immune Landscape of the Colorectal Adenoma–Carcinoma Sequence

Background. The tumor immune microenvironment exerts a pivotal influence in tumor initiation and progression. The aim of this study was to analyze the immune context of sporadic and familial adenomatous polyposis (FAP) lesions along the colorectal adenoma–carcinoma sequence (ACS). Methods. We analyzed immune cell counts (CD3+, CD4+, CD8+, Foxp3+, and CD57+), tumor mutation burden (TMB), MHC-I expression and PD-L1 expression of 59 FAP and 74 sporadic colorectal lesions, encompassing adenomas with low-grade dysplasia (LGD) (30 FAP; 30 sporadic), adenomas with high-grade dysplasia (22 FAP; 30 sporadic), and invasive adenocarcinomas (7 FAP; 14 sporadic). Results. The sporadic colorectal ACS was characterized by (1) a stepwise decrease in immune cell counts, (2) an increase in TMB and MHC-I expression, and (3) a lower PD-L1 expression. In FAP lesions, we observed the same patterns, except for an increase in TMB along the ACS. FAP LGD lesions harbored lower Foxp3+ T cell counts than sporadic LGD lesions. A decrease in PD-L1 expression occurred earlier in FAP lesions compared to sporadic ones. Conclusions. The colorectal ACS is characterized by a progressive loss of adaptive immune infiltrate and by the establishment of a progressively immune cold microenvironment. These changes do not appear to be related with the loss of immunogenicity of tumor cells, or to the onset of an immunosuppressive tumor microenvironment.     

Dual Activity BLEG-1 from Bacillus lehensis G1 Revealed Structural Resemblance to B3 Metallo-β-Lactamase and Glyoxalase II: An Insight into Its Enzyme Promiscuity and Evolutionary Divergence

Metallo-β-lactamases (MBLs) are class B β-lactamases from the metallo-hydrolase-like MBL-fold superfamily which act on a broad range of β-lactam antibiotics. A previous study on BLEG-1 (formerly called Bleg1_2437), a hypothetical protein from Bacillus lehensis G1, revealed sequence similarity and activity to B3 subclass MBLs, despite its evolutionary divergence from these enzymes. Its relatedness to glyoxalase II (GLXII) raises the possibility of its enzymatic promiscuity and unique structural features compared to other MBLs and GLXIIs. This present study highlights that BLEG-1 possessed both MBL and GLXII activities with similar catalytic efficiencies. Its crystal structure revealed highly similar active site configuration to YcbL and GloB GLXIIs from Salmonella enterica, and L1 B3 MBL from Stenotrophomonas maltophilia. However, different from GLXIIs, BLEG-1 has an insertion of an active-site loop, forming a binding cavity similar to B3 MBL at the N-terminal region. We propose that BLEG-1 could possibly have evolved from GLXII and adopted MBL activity through this insertion.     

Electrorheological behavior of low filled suspensions of highly anisometric montmorillonite particles

The electrorheological (ER) behavior of modified montmorillonite (MMT) suspensions in polydimethylsiloxane is studied. As established by rotational viscometry, the samples with a dispersed phase concentration from 1 to 8 wt % reveal viscous Newtonian behavior and dramatically change their properties to elastic when electric field is applied. The rheological characteristics of the suspensions over 0–7 kV mm⁻¹ range of electric field strengths are also studied. Novel X-ray diffraction method is developed to evaluate the suspension of the filler in a siloxane medium and to calculate the degree of its exfoliation. The dependence of exfoliation degree, dielectric, and ER characteristics on the type of modifier in the MMT structure is considered. Based on the obtained data, a new model of system behavior with the various types of fillers is proposed and the prospects of utilizing MMT as a filler for ER fluids are demonstrated. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47678.     

A log mining approach for process monitoring in SCADA

SCADA (supervisory control and data acquisition) systems are used for controlling and monitoring industrial processes. We propose a methodology to systematically identify potential process-related threats in SCADA. Process-related threats take place when an attacker gains user access rights and performs actions, which look legitimate, but which are intended to disrupt the SCADA process. To detect such threats, we propose a semi-automated approach of log processing. We conduct experiments on a real-life water treatment facility. A preliminary case study suggests that our approach is effective in detecting anomalous events that might alter the regular process workflow.     

Construction of discrete-time models for port-controlled Hamiltonian systems with applications

The issues of constructing a discrete-time model for Hamiltonian systems are in general different from those for dissipative systems. We propose an algorithm for constructing an approximate discrete-time model, which guarantees Hamiltonian conservation. We show that the algorithm also preserves, in a weaker sense, the losslessness property of a class of port-controlled Hamiltonian systems. An application of the algorithm to port-controlled Hamiltonian systems with quadratic Hamiltonian is presented, and we use this to solve the stabilization problem for this class of systems based on the approximate discrete-time model constructed using the proposed algorithm. We illustrate the usefulness of the algorithm in designing a discrete-time controller to stabilize the angular velocity of the dynamics of a rigid body.     

Comparative study of three training methods for enhancing process control performance: Emphasis shift training,situation awareness training,and drill and practice

Three training methods to improve attention management skills in process control were compared. Forty students from technical disciplines participated in a five-hour module of emphasis shift training (EST), EST combined with situation awareness training (EST/SA), and drill and practice (D&P) on a simulated process control task. Participants were then tested three times for 45 min each (immediately after training, two weeks after training, and six weeks after training) for system control performance and diagnostic performance on familiar and nonfamiliar fault states. D&P led to superior diagnostic performance on familiar system faults. EST/SA training supported the diagnosis of novel system faults. EST was less effective than expected for system control performance. Implications for training design in process control are discussed.     

Formalizing process-based risk with Value-Focused Process Engineering

Following calls to advance the integration of risk and business process modeling paradigms, this paper formalizes the process of incorporating risk into business process models through the principles of Value-Focused Process Engineering (VFPE). In doing so, the paper aims to extend the existing VFPE modeling notation to reflect a set of necessary constructs required to adequately represent risk in goal-oriented business-process models. The extended set of constructs is proposed to support a formal systems view of process-based risk. Process-based risk is formalized on the one hand, as a product of complex interactions between activity-based elements, and on the other hand, as a natural component of the value creation mechanism of an elementary function or a complex process. The proposed risk-aware VFPE formalism also formulates rules for decomposing risk in process models according to the organizational values, thereby enabling better risk visibility, reducing process complexity, and ensuring continuity of business processes.     

Using a neural network for predicting the average grain size in friction stir welding processes

In the paper the microstructural phenomena in terms of average grain size occurring in friction stir welding (FSW) processes are focused. A neural network was linked to a finite element model (FEM) of the process to predict the average grain size values. The utilized net was trained starting from experimental data and numerical results of butt joints and then tested on further butt, lap and T-joints. The obtained results show the capability of the AI technique in conjunction with the FE tool to predict the final microstructure in the FSW joints.