Van Tilborg Research Articles

NorVIS 1st Young Researchers Conference: Abstracts 2022

The first NorVIS Young researchers conference was held at the University of South-Eastern Norway (USN) in Kongsberg on November 16–18, 2022. The aim of the conference is to be an arena for young researchers (in career, not necessarily in age) to share knowledge, get to know each other and stimulate to more research within vision in stroke or other brain injury. The interdisciplinary meeting was organised as a one-day meeting, with presentations including study protocols, master’s project, PhD and post doc clinical research. The meeting was organised by Torgeir S. Mathisen and Helle K. Falkenberg from USN, who also served in the scientific committee together with Antonio F. Macedo (Linnaeus University) and Mirjam van Tilborg (Hogeschool Utrecht). The abstracts from contributed authors are listed in the order of presentation.

Guessing Random Additive Noise Decoding With Symbol Reliability Information (SRGRAND)

The design and implementation of error correcting codes has long been informed by two fundamental results: Shannon’s 1948 capacity theorem, which established that long codes use noisy channels most efficiently; and Berlekamp, McEliece, and Van Tilborg’s 1978 theorem on the NP-completeness of decoding linear codes. These results shifted focus away from creating code-independent decoders, but recent low-latency communication applications necessitate relatively short codes, providing motivation to reconsider the development of universal decoders. We introduce a scheme for employing binarized symbol soft information within Guessing Random Additive Noise Decoding, a universal hard detection decoder. We incorporate codebook-independent quantization of soft information to indicate demodulated symbols to be reliable or unreliable. We introduce two decoding algorithms: one identifies a conditional Maximum Likelihood (ML) decoding; the other either reports a conditional ML decoding or an error. For random codebooks, we present error exponents and asymptotic complexity, and show benefits over hard detection. As empirical illustrations, we compare performance with majority logic decoding of Reed-Muller codes, with Berlekamp-Massey decoding of Bose-Chaudhuri-Hocquenghem codes, with CA-SCL decoding of CA-Polar codes, and establish the performance of Random Linear Codes, which require a universal decoder and offer a broader palette of code sizes and rates than traditional codes.

Abstract A141: Computational models of synergy contribute to efficient combination screening

Abstract Introduction: Combination drug treatment in cancer therapy aims to improve response rate and decrease the development of drug resistance. The discovery of novel drug combinations is constrained by the cost and effort of carrying out large unbiased screens and is hampered by poor translation towards the clinic. We investigate if computational models combined with screening can more efficiently reveal synergistic combinations and improve translation towards the clinic. The models are based on three different biological views of synergy. First, compounds that exploit similar vulnerabilities in cancer cells frequently show synergy in a particular genetic context (targeted synergy, model 1) [1,2]. Secondly, drugs with non-overlapping resistance mechanisms often yield clinically relevant drug combinations (model 2) [3]. Finally, drugs that mimic synthetic lethal interactions will often act synergistically (model 3) [4]. Experimental procedures Oncolines™ is a panel of 102 genetically characterized cell lines from diverse tumor origins, on which proliferation assays are run in parallel in nine-point dose-response curves. In this cell panel we profiled 162 different cancer therapeutics, including many standard of care, chemotherapeutic agents, epigenetic modulators, and approved and pre-clinical drugs such as CDK4/6, ALK and PI3K-inhibitors [5]. Cancer hotspot mutations and gene expression data were downloaded from the DepMap and CCLE databases. ANOVA and Pearson correlations were used to analyze the single agent response and genetic data in the statistical software R, to determine gene mutation (model 1) and resistance markers (model 2). For model 3, clinically relevant synthetic lethal pairs were combined with gene expression data [4]. The methods were used to predict results from published synergy screens, e.g. DREAM [6] and results from an independent experiment (NTRC SynergyScreen™) in which fixed concentrations of the poly-ADP ribose polymerase (PARP) inhibitor niraparib and the BET bromodomain inhibitor JQ1, were combined with nine-point dose-response curves of 150 anticancer agents. Synergies were quantified using curve-shift and CI-index. Results: Using a cancer cell line IC50 profile of a compound (such as Oncolines™), all three computational models of synergy prediction can be applied. Method 1 is successful in predicting combinations that augment a targeted effect, such as combining BRAF and MEK inhibitors in BRAF-mutant cancer [1]. Method 2 does not distinguish between additive or synergistic combinations but can identify clinically relevant combinations [3]. For method 3, a tool was developed that computationally assesses if drug pairs can pharmacologically mimic clinically validated synthetic lethal interactions [4]. This can predict DREAM data with a high AUC of 0.67 in a ROC curve. The tool successfully predicts synergy between niraparib and the SUMO inhibitor 2-D08, and niraparib and BCL2 inhibitors, which we observed in our screen. Conclusions: Computational tools for synergy have predictive value and can be useful to prioritize libraries for empirical combination screening.

Abstract 2158: Combining cell panel profiling and synthetic lethality data to efficiently screen for synergistic combinations

Abstract In cancer therapy, combination drug treatment aims to improve response rate and decrease the development of drug resistance. The discovery of new effective drug combinations is constrained by the cost and effort of carrying out large unbiased screens and by poor translation of results towards the clinic. Here we describe how focusing on the biological mechanisms underlying the activity of drug candidates may aid a priori selection of promising synergy candidates and help in translate synergistic combinations towards a clinical situation. We have previously shown [1] that curve shift analysis as developed by Straetemans et al. [2] is a better method than combination-matrix screening. Also a dose based score such as the isobologram or the CI-index more robustly assesses synergy than an effect-based score such as the Bliss-additivity [1]. On this basis, we developed a two-step synergy screening approach, called SynergyScreen™. By distinguishing separate synergy screening and synergy confirmation stages, this setup capitalizes on insights from high throughput screening to discover robust and reproducible pharmacologically synergistic pairs. To further improve the efficiency of synergy screening, we focused on pre-selecting compounds in our screening library according to their biological mechanism. We profiled a library of more than 160 anti-cancer agents in a cell panel of 102 cell lines from diverse tumor origins [3]. Agents were clustered according to response and so-called exemplars were collected into a focused library that represents the spectrum of biological mechanisms of current cancer therapy. This synergy screening library includes many standard of care chemotherapeutic agents, approved and pre-clinical kinase inhibitors, epigenetic modulators and compounds acting by other mechanisms. Finally, we harnassed recent insights into the biology of synergy to understand and predict synergistic pairs. A tool was developed that uses the response of a compound in a 102 cell line panel to pick potential synergistic partners from the database of preprofiled compounds. It does this by computationally assessing if pairs can pharmacologically mimick clinically validated synthetic lethal interactions [4]. We optimized prediction accuracy using the results of internal and external synergy screens. The tool was applied to specifically enrich test libraries and to predict synergies at clinically relevant doses, including the results of a SynergyScreen™ with the poly-ADP ribose polymerase (PARP) inhibitor niraparib and the BET bromodomain inhibitor JQ1.

Optimization of low aspect ratio, iron dominated dipole magnets

Author(s): Majernik, N; Barber, SK; Van Tilborg, J; Rosenzweig, JB; Leemans, WP | Abstract: A study of the optimization of iron dominated dipole magnets with pole face widths comparable or less than the gap size, i.e., low aspect ratio (AR), is conducted using both theoretical and computational approaches. This regime of magnet design is particularly relevant in the context of laser plasma accelerators (LPA) due to unique beam parameters and geometric constraints, namely large energy spreads and the requirement for large apertures to accommodate drive laser passage. The breakdown of commonly employed approximations and rules of thumb in typical AR1 magnet design is examined. A library of generalized, optimized pole face geometries is provided to expedite optimization of future magnets. Finally, this methodology is used to design an electromagnetic chicane which has been fabricated, validated, and is currently in use in an x-ray free electron laser driven LPA experiment at LBNL.

First-order Affective Theory of Mind in Persons with Alzheimer's Disease and in Healthy Older Adults.

"Theory of Mind" (ToM) is the capacity to deduce other persons' cognitive and emotional states. Studies investigating affective ToM in healthy older adults and in persons with Alzheimer's disease have reported contradictory results, although evidence indicates that advanced age (Ruffman, Henry, Livingstone, & Phillips, 2008) and Alzheimer's disease (Elferink, van Tilborg, & Kessels, 2015) do not affect the ability to identify or infer different emotions to the same extent. To evaluate affective ToM abilities in these populations, we asked 63 individuals (17 with Alzheimer's disease) to infer the emotional states of characters presented without facial details in emotional situations. We observed similar results in healthy younger and older adults, but poorer performance in persons with Alzheimer's disease for disgust, sadness, and surprise, but not for anger, fear, and joy. Results suggest that persons with Alzheimer's disease have difficulties in inferring several emotional states from contextual information without facial cues.

Sjef van TILBORG, The Sermon on the Mount as an Ideologial Intervention. A Reconstruction of meaning, Van Gorcum, Assen 1986, 374 pp., 16 x 24.

Sjef van TILBORG, The Sermon on the Mount as an Ideologial Intervention. A Reconstruction of meaning, Van Gorcum, Assen 1986, 374 pp., 16 x 24.

Sharper Upper Bounds for Unbalanced Uniquely Decodable Code Pairs

Two sets of 0–1 vectors of fixed length form a uniquely decodeable code pair if their Cartesian product is of the same size as their sumset, where the addition is pointwise over integers. For the size of the sumset of such a pair, van Tilborg has given an upper bound in the general case. Urbanke and Li, and later Ordentlich and Shayevitz, have given better bounds in the unbalanced case, that is, when either of the two sets is sufficiently large. Improvements to the latter bounds are presented.

Control of tunable, monoenergetic laser-plasma-accelerated electron beams using a shock-induced density downramp injector

Author(s): Swanson, KK; Tsai, HE; Barber, SK; Lehe, R; Mao, HS; Steinke, S; Van Tilborg, J; Nakamura, K; Geddes, CGR; Schroeder, CB; Esarey, E; Leemans, WP | Abstract: Control of the properties of laser-plasma-accelerated electron beams that were injected along a shock-induced density downramp through precision tailoring of the density profile was demonstrated using a 1.8 J, 45 fs laser interacting with a mm-scale gas jet. The effects on the beam spatial profile, steering, and absolute energy spread of the density region before the shock and tilt of the shock were investigated experimentally and with particle-in-cell simulations. By adjusting these density parameters, the electron beam quality was controlled and improved while the energy (30-180 MeV) and energy spread (2-11 MeV) were independently tuned. Simple models that are in good agreement with the experimental results are proposed to explain these relationships, advancing the understanding of downramp injection. This technique allows for high-quality electron beams with percent-level energy spread to be tailored based on the application.

Serum AMH levels in healthy women from BRCA1/2 mutated families: are they reduced?

Do BRCA1/2 mutation carriers have a compromised ovarian reserve compared to proven non-carriers, based on serum anti-Müllerian hormone (AMH) levels? BRCA1/2 mutation carriers do not show a lower serum AMH level in comparison to proven non-carriers, after adjustment for potential confounders. It has been suggested that the BRCA genes play a role in the process of ovarian reserve depletion, although previous studies have shown inconsistent results regarding the association between serum AMH levels and BRCA mutation status. Hence, it is yet unclear whether BRCA1/2 mutation carriers may indeed be at risk of a reduced reproductive lifespan. STUDY DESIGN, SIZE,DURATION: A multicenter, cross-sectional study was performed between January 2012 and February 2015 in 255 women. We needed to include 120 BRCA1/2 mutation carriers and 120 proven non-carriers to demonstrate a difference in AMH levels of 0.40 µg/l (SD±0.12 µg/l, two-sided alpha-error 0.05, power 80%). Healthy women aged 18-45 years who were referred to the Clinical Genetics Department and applied for predictive BRCA1/2 testing because of a familial BRCA1/2 mutation were asked to participate. A cross-sectional assessment was performed by measuring serum AMH levels and filling out a questionnaire. Multivariate linear regression analyses adjusted for age, current smoking and current hormonal contraceptive use were performed on log-transformed serum AMH levels. Out of 823 potentially eligible women, 421 (51.2%) were willing to participate, and of those, 166 (39%) did not meet our inclusion criteria. Two hundred and fifty-five women were available for analyses; 124 BRCA1/2 mutation carriers and 131 proven non-carriers. The median [range] AMH level in carriers was 1.90 µg/l [0.11-19.00] compared to 1.80 µg/l [0.11-10.00] in non-carriers (P=0.34). Adjusted linear regression analysis revealed no reduction in AMH level in the carriers (relative change=0.98 (95%CI, 0.77-1.22); P=0.76). Participants were relatively young. Power was insufficient to analyze BRCA1 and BRCA2 mutation carriers separately. AMH levels may have been influenced by the use of hormonal contraceptives, though similar proportions of carriers and non-carriers were current users and adjustments were made to correct for potential confounding in our analysis. Limitations of the current analysis and limitations of the existing literature argue for prospective, well-controlled follow-up studies with recurrent AMH measurements to determine whether carriers might be at risk for low ovarian reserve and to definitively guide care. This study was partially financially supported by a personal grant for Inge A.P. Derks-Smeets, kindly provided by the Dutch Cancer Society (Grant Number UM 2011-5249). Theodora C. van Tilborg, Inge A.P. Derks-Smeets, Anna M.E. Bos, Jan C. Oosterwijk, Christine E. de Die-Smulders, Lizet E. van der Kolk, Wendy A.G. van Zelst-Stams, Maria E. Velthuizen, Marinus J.C. Eijkemans and Margreet G.E.M. Ausems have nothing to disclose. Ron J. van Golde has received unrestricted research grants from Ferring and Merck Serono, outside the submitted work. Annemieke Hoek received an unrestricted educational grant from Ferring pharmaceutical BV, The Netherlands and a speaker's fee for post graduate education from MSD pharmaceutical company, outside the submitted work. Joop S.E. Laven has received unrestricted research grants from Ferring, Merck Serono, Merck Sharpe & Dome, Organon, and Schering Plough, outside the submitted work. Frank J.M. Broekmans is a member of the external advisory board for Merck Serono (The Netherlands), outside the submitted work. NTR no. 4324.

On the improvement of Wiener attack on RSA with small private exponent.

RSA system is based on the hardness of the integer factorization problem (IFP). Given an RSA modulus N = pq, it is difficult to determine the prime factors p and q efficiently. One of the most famous short exponent attacks on RSA is the Wiener attack. In 1997, Verheul and van Tilborg use an exhaustive search to extend the boundary of the Wiener attack. Their result shows that the cost of exhaustive search is 2r + 8 bits when extending the Weiner's boundary r bits. In this paper, we first reduce the cost of exhaustive search from 2r + 8 bits to 2r + 2 bits. Then, we propose a method named EPF. With EPF, the cost of exhaustive search is further reduced to 2r − 6 bits when we extend Weiner's boundary r bits. It means that our result is 214 times faster than Verheul and van Tilborg's result. Besides, the security boundary is extended 7 bits.

Festivals, cultural intertextuality, and the Gospel of John’s rhetoric of distance

Imperial and civic-religious festivals pervaded the late first-century city of Ephesus where John’s Gospel was, if not written, at least read or heard. How did Jesus-believers as likely members of somewhat participationist synagogue communities negotiate such pervasive and public celebration of festivals? Did they participate in, ignore, or oppose such festivals? And how might John’s Gospel have encouraged them to respond?This article engages these questions by focusing on the narrative presentation of festivals in John’s Gospel (some 42 times) as, amongst other things, occasions of conflict and condemnation. Employing Sjef van Tilborg’s notion of ‘interference’, which prioritises the Ephesian civic interface of the Gospel’s audience, the article argues that the cultural intertextuality between the Gospel and an Ephesian context destabilises and problematises Ephesian civic festivals and shows there to be fundamental incompatibilities between Jesus’ work and Ephesian society, thereby seeking Jesus-believers to absent themselves from festivals. The Gospel’s presentation of festivals belongs to the gospel’s rhetoric of distance vis-à-vis societal structures.

Physical Basis behind Achondroplasia, the Most Common Form of Human Dwarfism

Fibroblast growth factor receptor 3 (FGFR3) is a receptor tyrosine kinase that plays an important role in long bone development. The G380R mutation in FGFR3 transmembrane domain is known as the genetic cause for achondroplasia, the most common form of human dwarfism. Despite many studies, there is no consensus about the exact mechanism underlying the pathology. To gain further understanding into the physical basis behind the disorder, here we measure the activation of wild-type and mutant FGFR3 in mammalian cells using Western blots, and we analyze the activation within the frame of a physical-chemical model describing dimerization, ligand binding, and phosphorylation probabilities within the dimers. The data analysis presented here suggests that the mutation does not increase FGFR3 dimerization, as proposed previously. Instead, FGFR3 activity in achondroplasia is increased due to increased probability for phosphorylation of the unliganded mutant dimers. This finding has implications for the design of targeted molecular treatments for achondroplasia.

Some Optimal Binary and Ternary $t$-EC-AUED Codes

Codes that can correct up to t symmetric errors and detect all unidirectional errors are studied. BOumlinck and van Tilborg gave a bound on the length of binary such codes. A generalization of this bound to arbitrary alphabet size is given. This generalized BOumlinck-van Tilborg bound, combined with constructions, is used to determine some optimal binary and ternary codes for correcting t symmetric errors and detecting all unidirectional errors.

The Catalytic Tyr-9 of Glutathione S-Transferase A1-1 Controls the Dynamics of the C terminus

The glutathione S-transferase enzymes (GSTs) have a tyrosine or serine residue at their active site that hydrogen bonds to and stabilizes the thiolate anion of glutathione, GS(-). The importance of this hydrogen bond is obvious, in light of the enhanced nucleophilicity of GS(-) versus the protonated thiol. Several A-class GSTs contain a C-terminal segment that undergoes a ligand-dependent local folding reaction. Here, we demonstrate the effects of the Y9F substitution on binding affinity for glutathione conjugates and on rates of the order-disorder transition of the C terminus in rat GST A1-1. The equilibrium binding affinity of the glutathione conjugate, GS-NBD (NBD-Cl, 7-chloro-4-nitrobenzo-2-oxa-1, 3-diazole), was decreased from 4.09 microm to 0.641 microm upon substitution of Tyr-9 with Phe. This result was supported by isothermal titration calorimetry, with K(d) values of 1.51 microm and 0.391 microm for wild type and Y9F, respectively. The increase in binding affinity for the mutant is associated with dramatic decreases in rates for the C-terminal order-disorder transition, based on a stopped-flow kinetic analysis. The same effects were observed, qualitatively, for a second GSH conjugate, GS-ethacrynic acid. Apparently, the phenolic hydroxyl group of Tyr-9 is critical for orchestrating C-terminal dynamics and efficient product release, in addition to its role in lowering the pK(a) of GSH.

New Colored Visual Secret Sharing Schemes

Visual secret sharing (VSS) schemes are used to protect the visual secret by sending n transparencies to different participants so that k-1 or fewer of them have no information about the original image, but the image can be seen by stacking k or more transparencies. However, the revealed secret image of a conventional VSS scheme is just black and white. The colored k out of n VSS scheme sharing a colored image is first introduced by Verheul and Van Tilborg [1]. In this paper, a new construction for the colored VSS scheme is proposed. This scheme can be easily implemented on basis of a black & white VSS scheme and get much better block length than the Verheul-Van Tilborg scheme.

The Parametrized Complexity of Some Fundamental Problems in Coding Theory

The parametrized complexity of a number of fundamental problems in the theory of linear codes and integer lattices is explored. Concerning codes, the main results are that MAXIMUM-LIKELIHOOD DECODING and WEIGHT DISTRUBUTION are hard for the parametrized complexity class W[1]. The NP-completeness of these two problems was established by Berlekamp, McEliece, and van Tilborg in 1978 using by means of a reduction from THREE-DIMENSIONAL MATCHING. On the other hand, our proof of hardness for W[1] is based on a parametric polynomial-time transformation from PERFECT CODE in graphs. An immediate consequence of our results is that bounded-distance decoding is likely to be hard for binary linear codes. Concerning lattices, we address the THETA SERIES problem of determining for an integer lattice $\L$ %given by a set of generators, and a positive integer k whether there is a vector $x \in \L$ of Euclidean norm k. We prove here for the first time that THETA SERIES is NP-complete and show that it is also hard for W[1]. Furthermore, we prove that the NEAREST VECTOR problem for integer lattices is hard for W[1]. These problems are the counterparts of WEIGHT DISTRUBUTION and MAXIMUM-LIKELIHOOD DECODING for lattices. Relations between all these problems and combinatorial problems in graphs are discussed.

Construction of uniquely decodable codes for the two-user binary adder channel

A construction of uniquely decodable codes for the two-user binary adder channel is presented. The rates of the codes obtained by this construction are greater than the rates guaranteed by the Coebergh van den Braak and van Tilborg construction and these codes can be used with simple encoding and decoding procedures.

Two observations concerning optimum cyclic burst-correcting codes

In (Adbel-Ghaffar et al., 1986) it is shown that for each integer b⩾1 infinitely many optimum cyclic b-burst correcting codes exist. In the first part of this correspondence the parameters of all optimum cyclic four- and five-burst-correcting codes are given explicitly. Tables are included. In (van Tilborg, 1993) a very brief indication of the decoding of optimum cyclic burst-correcting codes is given. In the second part of this correspondence the decoding algorithm is analyzed in further detail. It turns out that the bulk of the decoding steps can be performed completely in parallel.

Upper bound for uniquely decodable codes in a binary input N-user adder channel

The binary input N-user adder channel models a communication media accessed simultaneously by N users. Each user transmits a binary codeword of length n chosen from its codebook and the channel output consists of a componentwise arithmetic sum of the binary digits. Van Tilborg (1978) gave an upper bound on the size of a uniquely decodable code for the two-user case. His work is generalized here to the N-user case. The results give interesting information on the existence and properties of such codes.