@article{9647, abstract = {Gene expression is regulated by the set of transcription factors (TFs) that bind to the promoter. The ensuing regulating function is often represented as a combinational logic circuit, where output (gene expression) is determined by current input values (promoter bound TFs) only. However, the simultaneous arrival of TFs is a strong assumption, since transcription and translation of genes introduce intrinsic time delays and there is no global synchronisation among the arrival times of different molecular species at their targets. We present an experimentally implementable genetic circuit with two inputs and one output, which in the presence of small delays in input arrival, exhibits qualitatively distinct population-level phenotypes, over timescales that are longer than typical cell doubling times. From a dynamical systems point of view, these phenotypes represent long-lived transients: although they converge to the same value eventually, they do so after a very long time span. The key feature of this toy model genetic circuit is that, despite having only two inputs and one output, it is regulated by twenty-three distinct DNA-TF configurations, two of which are more stable than others (DNA looped states), one promoting and another blocking the expression of the output gene. Small delays in input arrival time result in a majority of cells in the population quickly reaching the stable state associated with the first input, while exiting of this stable state occurs at a slow timescale. In order to mechanistically model the behaviour of this genetic circuit, we used a rule-based modelling language, and implemented a grid-search to find parameter combinations giving rise to long-lived transients. Our analysis shows that in the absence of feedback, there exist path-dependent gene regulatory mechanisms based on the long timescale of transients. The behaviour of this toy model circuit suggests that gene regulatory networks can exploit event timing to create phenotypes, and it opens the possibility that they could use event timing to memorise events, without regulatory feedback. The model reveals the importance of (i) mechanistically modelling the transitions between the different DNA-TF states, and (ii) employing transient analysis thereof.}, author = {Petrov, Tatjana and Igler, Claudia and Sezgin, Ali and Henzinger, Thomas A and Guet, Calin C}, issn = {0304-3975}, journal = {Theoretical Computer Science}, pages = {1--16}, publisher = {Elsevier}, title = {{Long lived transients in gene regulation}}, doi = {10.1016/j.tcs.2021.05.023}, volume = {893}, year = {2021}, } @article{9761, abstract = {The important roles of mitochondrial function and dysfunction in the process of neurodegeneration are widely acknowledged. Retinal ganglion cells (RGCs) appear to be a highly vulnerable neuronal cell type in the central nervous system with respect to mitochondrial dysfunction but the actual reasons for this are still incompletely understood. These cells have a unique circumstance where unmyelinated axons must bend nearly 90° to exit the eye and then cross a translaminar pressure gradient before becoming myelinated in the optic nerve. This region, the optic nerve head, contains some of the highest density of mitochondria present in these cells. Glaucoma represents a perfect storm of events occurring at this location, with a combination of changes in the translaminar pressure gradient and reassignment of the metabolic support functions of supporting glia, which appears to apply increased metabolic stress to the RGC axons leading to a failure of axonal transport mechanisms. However, RGCs themselves are also extremely sensitive to genetic mutations, particularly in genes affecting mitochondrial dynamics and mitochondrial clearance. These mutations, which systemically affect the mitochondria in every cell, often lead to an optic neuropathy as the sole pathologic defect in affected patients. This review summarizes knowledge of mitochondrial structure and function, the known energy demands of neurons in general, and places these in the context of normal and pathological characteristics of mitochondria attributed to RGCs. }, author = {Muench, Nicole A. and Patel, Sonia and Maes, Margaret E and Donahue, Ryan J. and Ikeda, Akihiro and Nickells, Robert W.}, issn = {20734409}, journal = {Cells}, number = {7}, publisher = {MDPI}, title = {{The influence of mitochondrial dynamics and function on retinal ganglion cell susceptibility in optic nerve disease}}, doi = {10.3390/cells10071593}, volume = {10}, year = {2021}, } @article{9641, abstract = {At the encounter with a novel environment, contextual memory formation is greatly enhanced, accompanied with increased arousal and active exploration. Although this phenomenon has been widely observed in animal and human daily life, how the novelty in the environment is detected and contributes to contextual memory formation has lately started to be unveiled. The hippocampus has been studied for many decades for its largely known roles in encoding spatial memory, and a growing body of evidence indicates a differential involvement of dorsal and ventral hippocampal divisions in novelty detection. In this brief review article, we discuss the recent findings of the role of mossy cells in the ventral hippocampal moiety in novelty detection and put them in perspective with other novelty-related pathways in the hippocampus. We propose a mechanism for novelty-driven memory acquisition in the dentate gyrus by the direct projection of ventral mossy cells to dorsal dentate granule cells. By this projection, the ventral hippocampus sends novelty signals to the dorsal hippocampus, opening a gate for memory encoding in dentate granule cells based on information coming from the entorhinal cortex. We conclude that, contrary to the presently accepted functional independence, the dorsal and ventral hippocampi cooperate to link the novelty and contextual information, and this dorso-ventral interaction is crucial for the novelty-dependent memory formation.}, author = {Fredes, Felipe and Shigemoto, Ryuichi}, issn = {10959564}, journal = {Neurobiology of Learning and Memory}, publisher = {Elsevier}, title = {{The role of hippocampal mossy cells in novelty detection}}, doi = {10.1016/j.nlm.2021.107486}, volume = {183}, year = {2021}, } @inproceedings{9646, abstract = {We consider the fundamental problem of deriving quantitative bounds on the probability that a given assertion is violated in a probabilistic program. We provide automated algorithms that obtain both lower and upper bounds on the assertion violation probability. The main novelty of our approach is that we prove new and dedicated fixed-point theorems which serve as the theoretical basis of our algorithms and enable us to reason about assertion violation bounds in terms of pre and post fixed-point functions. To synthesize such fixed-points, we devise algorithms that utilize a wide range of mathematical tools, including repulsing ranking supermartingales, Hoeffding's lemma, Minkowski decompositions, Jensen's inequality, and convex optimization. On the theoretical side, we provide (i) the first automated algorithm for lower-bounds on assertion violation probabilities, (ii) the first complete algorithm for upper-bounds of exponential form in affine programs, and (iii) provably and significantly tighter upper-bounds than the previous approaches. On the practical side, we show our algorithms can handle a wide variety of programs from the literature and synthesize bounds that are remarkably tighter than previous results, in some cases by thousands of orders of magnitude.}, author = {Wang, Jinyi and Sun, Yican and Fu, Hongfei and Chatterjee, Krishnendu and Goharshady, Amir Kafshdar}, booktitle = {Proceedings of the 42nd ACM SIGPLAN International Conference on Programming Language Design and Implementation}, isbn = {9781450383912}, location = {Online}, pages = {1171--1186}, publisher = {Association for Computing Machinery}, title = {{Quantitative analysis of assertion violations in probabilistic programs}}, doi = {10.1145/3453483.3454102}, year = {2021}, } @inproceedings{9645, abstract = {We consider the fundamental problem of reachability analysis over imperative programs with real variables. Previous works that tackle reachability are either unable to handle programs consisting of general loops (e.g. symbolic execution), or lack completeness guarantees (e.g. abstract interpretation), or are not automated (e.g. incorrectness logic). In contrast, we propose a novel approach for reachability analysis that can handle general and complex loops, is complete, and can be entirely automated for a wide family of programs. Through the notion of Inductive Reachability Witnesses (IRWs), our approach extends ideas from both invariant generation and termination to reachability analysis. We first show that our IRW-based approach is sound and complete for reachability analysis of imperative programs. Then, we focus on linear and polynomial programs and develop automated methods for synthesizing linear and polynomial IRWs. In the linear case, we follow the well-known approaches using Farkas' Lemma. Our main contribution is in the polynomial case, where we present a push-button semi-complete algorithm. We achieve this using a novel combination of classical theorems in real algebraic geometry, such as Putinar's Positivstellensatz and Hilbert's Strong Nullstellensatz. Finally, our experimental results show we can prove complex reachability objectives over various benchmarks that were beyond the reach of previous methods.}, author = {Asadi, Ali and Chatterjee, Krishnendu and Fu, Hongfei and Goharshady, Amir Kafshdar and Mahdavi, Mohammad}, booktitle = {Proceedings of the 42nd ACM SIGPLAN International Conference on Programming Language Design and Implementation}, isbn = {9781450383912}, location = {Online}, pages = {772--787}, publisher = {Association for Computing Machinery}, title = {{Polynomial reachability witnesses via Stellensätze}}, doi = {10.1145/3453483.3454076}, year = {2021}, } @article{9759, author = {Bartlett, Michael John and Arslan, Feyza N and Bankston, Adriana and Sarabipour, Sarvenaz}, issn = {15537358}, journal = {PLoS Computational Biology}, number = {7}, publisher = {Public Library of Science}, title = {{Ten simple rules to improve academic work- life balance}}, doi = {10.1371/journal.pcbi.1009124}, volume = {17}, year = {2021}, } @article{9822, abstract = {Attachment of adhesive molecules on cell culture surfaces to restrict cell adhesion to defined areas and shapes has been vital for the progress of in vitro research. In currently existing patterning methods, a combination of pattern properties such as stability, precision, specificity, high-throughput outcome, and spatiotemporal control is highly desirable but challenging to achieve. Here, we introduce a versatile and high-throughput covalent photoimmobilization technique, comprising a light-dose-dependent patterning step and a subsequent functionalization of the pattern via click chemistry. This two-step process is feasible on arbitrary surfaces and allows for generation of sustainable patterns and gradients. The method is validated in different biological systems by patterning adhesive ligands on cell-repellent surfaces, thereby constraining the growth and migration of cells to the designated areas. We then implement a sequential photopatterning approach by adding a second switchable patterning step, allowing for spatiotemporal control over two distinct surface patterns. As a proof of concept, we reconstruct the dynamics of the tip/stalk cell switch during angiogenesis. Our results show that the spatiotemporal control provided by our “sequential photopatterning” system is essential for mimicking dynamic biological processes and that our innovative approach has great potential for further applications in cell science.}, author = {Zisis, Themistoklis and Schwarz, Jan and Balles, Miriam and Kretschmer, Maibritt and Nemethova, Maria and Chait, Remy P and Hauschild, Robert and Lange, Janina and Guet, Calin C and Sixt, Michael K and Zahler, Stefan}, issn = {19448252}, journal = {ACS Applied Materials and Interfaces}, number = {30}, pages = {35545–35560}, publisher = {American Chemical Society}, title = {{Sequential and switchable patterning for studying cellular processes under spatiotemporal control}}, doi = {10.1021/acsami.1c09850}, volume = {13}, year = {2021}, } @article{9819, abstract = {Photorealistic editing of head portraits is a challenging task as humans are very sensitive to inconsistencies in faces. We present an approach for high-quality intuitive editing of the camera viewpoint and scene illumination (parameterised with an environment map) in a portrait image. This requires our method to capture and control the full reflectance field of the person in the image. Most editing approaches rely on supervised learning using training data captured with setups such as light and camera stages. Such datasets are expensive to acquire, not readily available and do not capture all the rich variations of in-the-wild portrait images. In addition, most supervised approaches only focus on relighting, and do not allow camera viewpoint editing. Thus, they only capture and control a subset of the reflectance field. Recently, portrait editing has been demonstrated by operating in the generative model space of StyleGAN. While such approaches do not require direct supervision, there is a significant loss of quality when compared to the supervised approaches. In this paper, we present a method which learns from limited supervised training data. The training images only include people in a fixed neutral expression with eyes closed, without much hair or background variations. Each person is captured under 150 one-light-at-a-time conditions and under 8 camera poses. Instead of training directly in the image space, we design a supervised problem which learns transformations in the latent space of StyleGAN. This combines the best of supervised learning and generative adversarial modeling. We show that the StyleGAN prior allows for generalisation to different expressions, hairstyles and backgrounds. This produces high-quality photorealistic results for in-the-wild images and significantly outperforms existing methods. Our approach can edit the illumination and pose simultaneously, and runs at interactive rates.}, author = {Mallikarjun, B. R. and Tewari, Ayush and Dib, Abdallah and Weyrich, Tim and Bickel, Bernd and Seidel, Hans Peter and Pfister, Hanspeter and Matusik, Wojciech and Chevallier, Louis and Elgharib, Mohamed A. and Theobalt, Christian}, issn = {15577368}, journal = {ACM Transactions on Graphics}, number = {4}, publisher = {Association for Computing Machinery}, title = {{PhotoApp: Photorealistic appearance editing of head portraits}}, doi = {10.1145/3450626.3459765}, volume = {40}, year = {2021}, } @article{9816, abstract = {Aims: Mass antigen testing programs have been challenged because of an alleged insufficient specificity, leading to a large number of false positives. The objective of this study is to derive a lower bound of the specificity of the SD Biosensor Standard Q Ag-Test in large scale practical use. Methods: Based on county data from the nationwide tests for SARS-CoV-2 in Slovakia between 31.10.–1.11. 2020 we calculate a lower confidence bound for the specificity. As positive test results were not systematically verified by PCR tests, we base the lower bound on a worst case assumption, assuming all positives to be false positives. Results: 3,625,332 persons from 79 counties were tested. The lowest positivity rate was observed in the county of Rožňava where 100 out of 34307 (0.29%) tests were positive. This implies a test specificity of at least 99.6% (97.5% one-sided lower confidence bound, adjusted for multiplicity). Conclusion: The obtained lower bound suggests a higher specificity compared to earlier studies in spite of the underlying worst case assumption and the application in a mass testing setting. The actual specificity is expected to exceed 99.6% if the prevalence in the respective regions was non-negligible at the time of testing. To our knowledge, this estimate constitutes the first bound obtained from large scale practical use of an antigen test.}, author = {Hledik, Michal and Polechova, Jitka and Beiglböck, Mathias and Herdina, Anna Nele and Strassl, Robert and Posch, Martin}, issn = {1932-6203}, journal = {PLoS ONE}, number = {7}, publisher = {Public Library of Science}, title = {{Analysis of the specificity of a COVID-19 antigen test in the Slovak mass testing program}}, doi = {10.1371/journal.pone.0255267}, volume = {16}, year = {2021}, } @article{9821, abstract = {Heart rate variability (hrv) is a physiological phenomenon of the variation in the length of the time interval between consecutive heartbeats. In many cases it could be an indicator of the development of pathological states. The classical approach to the analysis of hrv includes time domain methods and frequency domain methods. However, attempts are still being made to define new and more effective hrv assessment tools. Persistent homology is a novel data analysis tool developed in the recent decades that is rooted at algebraic topology. The Topological Data Analysis (TDA) approach focuses on examining the shape of the data in terms of connectedness and holes, and has recently proved to be very effective in various fields of research. In this paper we propose the use of persistent homology to the hrv analysis. We recall selected topological descriptors used in the literature and we introduce some new topological descriptors that reflect the specificity of hrv, and we discuss their relation to the standard hrv measures. In particular, we show that this novel approach provides a collection of indices that might be at least as useful as the classical parameters in differentiating between series of beat-to-beat intervals (RR-intervals) in healthy subjects and patients suffering from a stroke episode.}, author = {Graff, Grzegorz and Graff, Beata and Pilarczyk, Pawel and Jablonski, Grzegorz and Gąsecki, Dariusz and Narkiewicz, Krzysztof}, issn = {19326203}, journal = {PLoS ONE}, number = {7}, publisher = {Public Library of Science}, title = {{Persistent homology as a new method of the assessment of heart rate variability}}, doi = {10.1371/journal.pone.0253851}, volume = {16}, year = {2021}, }