Zentrum für Innovation und Technik in Nordrhein-Westfalen

The first-generation approved PARP inhibitors (PARPi) inhibit both PARP1 and PARP2, which may result in significant hematological toxicity. To overcome this potential issue, we designed and synthesized a series of small molecules that are highly selective PARP1 inhibitors. Among these, (S)-G9 exhibited an IC50 of 0.19 nM against PARP1, with a remarkable 137-fold selectivity over PARP2 and high antiproliferative activity in BRCA mutant MDA-MB-436 cells with an IC50 of 1.5 nM. Furthermore, (S)-G9 is a PARP1 selective trapper, with a thousand-fold less activity toward PARP2. (S)-G9 inhibited tumor growth in the BRCA mutant MDA-MB-436 xenograft model and showed synergistic efficacy in combination with irinotecan in the HCT116 xenograft model, suggesting that it could be a promising candidate drug combined with chemotherapy for the treatment of cancer. These findings indicate that the strategy proposed in this study is highly significant for the development of selective PARP1 inhibitors.

This document introduces a rapid control prototyping (RCP) approach applied to the industrial sector using a non-linear Quadratic Buck Converter (QBC) DC-DC. The goal is to reduce manufacturing costs for materials and electronic devices while enhancing the power quality in the system’s response. An experimental setup is utilized to create a functional model, converting 380 VDC to 48 VDC at a power level of 500 W. dSPACE CP1103 is employed to implement Model in the Loop (MIL), Software in the Loop (SIL), and Hardware in the Loop (HIL) simulations. Modern control techniques, including sliding mode control (SMC) and passivity-based control (PBC), are employed to devise a robust control scheme capable of maintaining stability in real-time (RT) and resisting disturbances. The document concludes with a performance analysis, PI, Cp, CpK, Z-score, and ITAE considering response time, signal accuracy, system stability, and resource utilization efficiency.

We propose a motion generation model for simultaneous control of motion and force using deep learning. Conventional force control methods require expensive torque sensors and complex control theory, and implementing force control for each task requires huge development costs. In this paper, we realize rubbing motions against an uneven object at low cost by using a motion generation method that takes as input the joint angles and current values of an inexpensive servo motor. We evaluated the generalization ability of the model by confirming that the robot can perform rubbing motions against unlearned uneven or tilted objects. In addition, by comparing several motion generation models, we clarified that the following two components are important for simultaneous control of motion and force. (1) The joint angles and the current values are input to different neuron layers to extract the features. A time constant, which is the speed of information transfer, is set for each layer in order to integrate and learn input information with different time characteristics. (2) In the output part of the model, a single neuron layer is used to predict the joint angle and current value simultaneously. This makes it easy to extract features and integrate learning from two inputs with different time characteristics, and the robot can generate appropriate motions based on the contact situation in real time.

The iPRODUCE Content Marketing and Growth Hacking Playbook is a living document that details the strategy for generation of awareness and outreach through communication and marketing of project content, growth of the project and its target groups through development and absorption of knowledge, and the dissemination of results. The deliverable describes the iPRODUCE main target groups; channels, tools and activities for implementing the strategy; role of partners; timeline; and how the consortium will monitor and assess the impact of its efforts. This deliverable will be updated continuously.

Covalent co-assembly holds great promise for the fabrication of hydrogels with controllable nanostructure, versatile chemical composition, and enhanced mechanical properties given its relative simplicity, high efficiency, and bond stability. This report describes our approach to designing functional multicomponent hydrogels based on photo-induced chemical interactions between an acrylamide-functionalized resilin-like polypeptide (RLP) and a peptide amphiphile (PA). Circular dichroism (CD) spectroscopy, electron microscopy, and amplitude sweep rheology were used to demonstrate that the co-assembled hydrogel systems acquired distinct structural conformations, tunable nanostructures, and enhanced elasticity in a PA concentration-dependent manner. We envisage the use of these materials in numerous biomedical applications such as controlled drug release systems, microfluidic devices, and scaffolds for tissue engineering.

With the rapid growth and appearance of novel psychoactive substances (NPS) onto the global drug market, the need for alternative screening methodologies for implementation within clinical environments is substantial. The immunoassay methods currently in use are inadequate for this new drug trend with the potential for misdiagnosis and subsequent administration of incorrect patient treatment increased. This contribution illustrates a strong proof-of-concept for the use of electrochemiluminescence (ECL) as a screening methodology for NPS within biological fluids, using the hallucinogen scopolamine as a model compound. A low cost, easy-to-use and portable sensor has been developed and successfully employed for the detection of scopolamine at clinically relevant concentrations within a variety of biological matrices, including human pooled serum, urine, artificial saliva and sweat, without any prior sample preparation required. Moreover, assessment of the sensor's potential as a point-of-care wearable device was performed with sample collection from the surface of skin, demonstrating its capability for the qualitative identification of scopolamine despite collection of only minimal volumes off the skins surface. The developed sensor described herein exhibits a strong proof-of-concept for the employment of such ECL sensors as point-of-care devices, where the sensors ease of use and removal of time-consuming and complex sample preparation methods will ultimately increase its usability by physicians, widening the avenues where ECL sensors could be employed.

Background: The delay from onset of the first symptoms to a definite ALS diagnosis depends also on the elusiveness of the initial clinical manifestations. The lack of disease-specific biomarkers to detect early pathology when ALS is supposed complicates the situation. This latency reduces the therapeutic time frame, in which neuron-rescuing strategies exert their greatest chance to work. Various biomarkers are currently promised, but none of them are specific enough to allow monitoring of disease progression. This, as well as the heterogeneity of the disease concerning clinical onset pattern and survival rates, makes difficult the correct stratification of patients into clinical trials, masking the potential positive outcome in some patients.Objective: Our main objective is to establish and test an early diagnostic tool based on microscopic immune cell monitoring of ALS patients' blood samples by using the Toponome Imaging System (TIS).Methods: TIS is based on automatically controlled microscopic device involving conjugated dye-tag incubation, protein-tag-dye-imaging, and tag-dye bleaching (1). This leads to the collection of at least 21 cycle images of fixated peripheral blood mononuclear cells (PBMCs) isolated from freshly drawn blood of ALS patients and healthy "control" donors. Resulting data sets contain combinatorial molecular information about the spatial protein network, called toponome. The PBMC toponome architectures are quantitatively analyzed as a threshold-binary code with 1 = protein is present and 0 = protein is absent.Results: Preliminary screening data of PBMCs from 4 ALS patients reveal a subpopulation of lymphocytes expressing a specific surface protein pattern, called "ALS toponome". These aberrant T cells could not be found in blood samples of controls. We observe that the number of these cells correlate with the ALS progression rate of patients, supporting the conclusion that these cells may be causal for the disease.Discussion and conclusion: Although these findings open up a potential strategy to detect early ALS disease and to monitor disease progression, a statistical analysis with many more patients, as well as data based differentiation to other neurodegenerative diseases, is mandatory. A clinical trial initiated by our faceALS foundation with at least 60 patients classified in three subsets (1. control, 2. ALS, and 3. Multiple Sclerosis (MS)) and in close cooperation with leading ALS centres in Germany is still in progress. The detection of specific and/or aberrant immune cells in blood samples of ALS patients may provide a key to understand disease onset and progression, could be used for the "staging" of disease, and contribute to effective therapy options.

Over a third of brain tumour patients visit their general practitioner more than five times prior to diagnosis in the UK, leading to 62% of patients being diagnosed as emergency presentations. Unfortunately, symptoms are non-specific to brain tumours, and the majority of these patients complain of headaches on multiple occasions before being referred to a neurologist. As there are currently no methods in place for the early detection of brain cancer, the affected patients' average life expectancy is reduced by 20 years. These statistics indicate that the current pathway is ineffective, and there is a vast need for a rapid diagnostic test. Attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy is sensitive to the hallmarks of cancer, as it analyses the full range of macromolecular classes. The combination of serum spectroscopy and advanced data analysis has previously been shown to rapidly and objectively distinguish brain tumour severity. Recently, a novel high-throughput ATR accessory has been developed, which could be cost-effective to the National Health Service in the UK, and valuable for clinical translation. In this study, 765 blood serum samples have been collected from healthy controls and patients diagnosed with various types of brain cancer, contributing to one of the largest spectroscopic studies to date. Three robust machine learning techniques - random forest, partial least squares-discriminant analysis and support vector machine - have all provided promising results. The novel high-throughput technology has been validated by separating brain cancer and non-cancer with balanced accuracies of 90% which is comparable to the traditional fixed diamond crystal methodology. Furthermore, the differentiation of brain tumour type could be useful for neurologists, as some are difficult to distinguish through medical imaging alone. For example, the highly aggressive glioblastoma multiforme and primary cerebral lymphoma can appear similar on magnetic resonance imaging (MRI) scans, thus are often misdiagnosed. Here, we report the ability of infrared spectroscopy to distinguish between glioblastoma and lymphoma patients, at a sensitivity and specificity of 90.1% and 86.3%, respectively. A reliable serum diagnostic test could avoid the need for surgery and speed up time to definitive chemotherapy and radiotherapy.

A new approach to examine electrochemiluminescence (ECL), in which the potentials at both the working and counter electrodes are measured and the emitted light is detected by a photomultiplier tube, camera and then a charge-coupled device (CCD) spectrometer, provides unequivocal evidence that the purported cathodic ECL of [Ru(bpy)3]2+ and tri-n-propylamine actually arises from anodic reactions at the counter electrode.