Discovery of a Non-Nucleoside SETD2 Methyltransferase Inhibitor against Acute Myeloid Leukemia

Histone methyltransferases (HMTs) have attracted considerable attention as potential targets for pharmaceutical intervention in various malignant diseases. These enzymes are known for introducing methyl marks at specific locations of histone proteins, creating a complex system that regulates epigenetic control of gene expression and cell differentiation. Here, we describe the identification of first-generation cell-permeable non-nucleoside type inhibitors of SETD2, the only mammalian HMT that is able to tri-methylate the K36 residue of histone H3. By generating the epigenetic mark H3K36me3, SETD2 is involved in the progression of acute myeloid leukemia. We developed a structure-based virtual screening protocol that was first validated in retrospective studies. Next, prospective screening was performed on a large library of commercially available compounds. Experimental validation of 22 virtual hits led to the discovery of three compounds that showed dose-dependent inhibition of the enzymatic activity of SETD2. Compound C13 effectively blocked the proliferation of two acute myeloid leukemia (AML) cell lines with MLL rearrangements and led to decreased H3K36me3 levels, prioritizing this chemotype as a viable chemical starting point for drug discovery projects.     

Algorithms for Dynamic Routing in All-Optical Networks

In this paper, we have studied a number of algorithms for routing in all-optical wavelength routed networks. We have considered situations where a lightpath is dynamically created in response to a request for communication and the WDM channels constituting the lightpath are reclaimed when the communication is over. We have looked at two schemes for dynamic wavelength allocation. In the first scheme we have assumed the existence of a central agent to maintain a database of existing lightpaths where the central agent attempts to generate a new lightpath in response to a request for communication. In the second scheme, we attempt to generate a new lightpath using a distributed algorithm. In the first scheme we have exploited the existence of multiple paths between any pair of nodes in a network in order to reduce the blocking probability. For the second scheme, we have proposed three distributed strategies to determine, if possible, a lightpath when there is a request for communication. Each of these strategies have their advantages and disadvantages in terms of the expected blocking probability and the set-up time. We have studied the performances of both the schemes using Monte Carlo simulation.     

The Phagocytosis of Lacticaseibacillus casei and Its Immunomodulatory Properties on Human Monocyte-Derived Dendritic Cells Depend on the Expression of Lc-p75, a Bacterial Peptidoglycan Hydrolase

The human gut symbiont Lacticaseibacillus (L.) casei (previously Lactobacillus casei) is under intense research due to its wide range of immunomodulatory effects on the human host. Dendritic cells (DCs) are crucial players in the direct and indirect communication with lactobacilli in the gastrointestinal tract. Here, we demonstrate that human monocyte-derived DCs (moDCs) are able to engulf L. casei BL23, in which the intact bacterial cell wall and morphology have a key role. The absence of the bacterial cell-wall-degrading enzyme, Lc-p75, in L. casei cells causes remarkable morphological changes, which have important consequences in the phagocytosis of L. casei by moDCs. Our results showed that the Lc-p75 mutation induced defective internalization and impaired proinflammatory and T-cell-polarizing cytokine secretion by bacteria-exposed moDCs. The T helper (Th) 1 and Th17 cell activating capacity of moDCs induced by the mutant L. casei was consequently reduced. Moreover, inhibition of the phagocytosis of wild-type bacteria showed similar results. Taken together, these data suggested that formation of short bacterial chains helps to exert the potent immunomodulatory properties of L. casei BL23.     

Detection of Antimicrobial Peptides in Stratum Corneum by Mass Spectrometry

Antimicrobial and immunomodulatory peptides (AMPs) are considered as the key players in the maintenance of skin barrier functions. Here, we developed a novel approach for the examination of AMPs in the outermost layer of the epidermis, namely stratum corneum (SC). The SC sample collection by tape stripping was coupled with detection by highly specific and sensitive parallel reaction monitoring (PRM)-based mass spectrometry. We found that hexane-free processing of SC samples produced higher protein yield compared to hexane-based extraction. Of the 18 investigated peptides, 9 could be detected either in healthy or in inflamed skin specimens. Regarding the amount of S100A8, LCN2, LACRT and LYZ significant topographical differences were described among gland poor (GP), sebaceous gland rich (SGR) and apocrine gland rich (AGR) healthy skin regions. We applied a minimally invasive, reproducible approach for sampling, which can be assessed for research and diagnostic purposes and for monitoring the effectiveness of therapies in skin diseases.     

Male and Female Animals Respond Differently to High-Fat Diet and Regular Exercise Training in a Mouse Model of Hyperlipidemia

Inappropriate nutrition and a sedentary lifestyle can lead to obesity, one of the most common risk factors for several chronic diseases. Although regular physical exercise is an efficient approach to improve cardiometabolic health, the exact cellular processes are still not fully understood. We aimed to analyze the morphological, gene expression, and lipidomic patterns in the liver and adipose tissues in response to regular exercise. Healthy (wild type on a normal diet) and hyperlipidemic, high-fat diet-fed (HFD-fed) apolipoprotein B-100 (APOB-100)-overexpressing mice were trained by treadmill running for 7 months. The serum concentrations of triglyceride and tumor necrosis factor α (TNFα), as well as the level of lipid accumulation in the liver, were significantly higher in HFD-fed APOB-100 males compared to females. However, regular exercise almost completely abolished lipid accumulation in the liver of hyperlipidemic animals. The expression level of the thermogenesis marker, uncoupling protein-1 (Ucp1), was significantly higher in the subcutaneous white adipose tissue of healthy females, as well as in the brown adipose tissue of HFD-fed APOB-100 females, compared to males. Lipidomic analyses revealed that hyperlipidemia essentially remodeled the lipidome of brown adipose tissue, affecting both the membrane and storage lipid fractions, which was partially restored by exercise in both sexes. Our results revealed more severe metabolic disturbances in HFD-fed APOB-100 males compared to females. However, exercise efficiently reduced the body weight, serum triglyceride levels, expression of pro-inflammatory factors, and hepatic lipid accumulation in our model.     

Risk principle of case classification and the prevention of residential placements: An outcome evaluation of the Share the Parenting program.

Conducted a quasi-experimental outcome evaluation of intensive, nonresidential support services in a child protection agency. 146 families with 11–15 yr old children were assigned to low- and high-risk categories according to prereferral assessments of their chances of remaining intact. These assessments addressed factors such as children's personality/skills, educational problems, and delinquent behaviors; family relationships and finances; and parental problems. The placement rates and mean days in care of high-risk program participants were half those of high-risk nonparticipants. Participation in the program was unrelated to the placements of lower-risk youths. It is concluded that pretreatment assessments of risk have important roles to play in case classification as well as in the design of program evaluations. However, applications of the risk principle are imperfect substitutes for random assignment in program evaluations. (18 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Simultaneous modelling of rock freezing and water seepage and its practical applications

All existing models of the rock freezing process are able to simulate the conductive heat transfer, but, however the convective terms are dominant in many cases, when water seepage also occurs. The origin of the majority of failures were caused by the effect of water seepage. A new integrated finite difference simulation technique has been developed to model rock freezing and water seepage simultaneously. The mathematical model, the base of numerical algorithm, the input and output data, the verification of the model using analytical solutions and a rather sophisticated practical case history are discussed in the paper. Finally, the first practical application of the model to support decisions on the proper system of freezing and on the proper combination with depressurization of water bearing layers is presented as well.     

The Personal Interaction Panel – a Two-Handed Interface for Augmented Reality

This paper describes the introduction of a new interaction paradigm to augmented reality applications. The everyday tool handling experience of working with pen and notebooks is extended to create a three dimensional two-handed interface, that supports easy-to-understand manipulation tasks in augmented and virtual environments. In the design step we take advantage from the freedom, given by our very low demands on hardware and augment form and functionality to this device. On the basis of examples from object manipulation, augmented research environments and scientific visualization we show the generality of applicability. Although being in the first stages implementation, we consider the wide spectrum of suitability for different purposes.