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Complex History and Differentiation Patterns of the t-Haplotype, a Mouse Meiotic Driver
Full text linkThe t-haplotype, a mouse meiotic driver found on chromosome 17, has been a model for autosomal segregation distortion for close to a century, but several questions remain regarding its biology and evolutionary history. A recently published set of population genomics resources for wild mice includes several individuals heterozygous for the t-haplotype, which we use to characterize this selfish element at the genomic and transcriptomic level. Our results show that large sections of the t-haplotype have been replaced by standard homologous sequences, possibly due to occasional events of recombination, and that this complicates the inference of its history. As expected for a long genomic segment of very low recombination, the t-haplotype carries an excess of fixed nonsynonymous mutations compared to the standard chromosome. This excess is stronger for regions that have not undergone recent recombination, suggesting that occasional gene flow between the t and the standard chromosome may provide a mechanism to regenerate coding sequences that have accumulated deleterious mutations. Finally, we find that t-complex genes with altered expression largely overlap with deleted or amplified regions, and that carrying a t-haplotype alters the testis expression of genes outside of the t-complex, providing new leads into the pathways involved in the biology of this segregation distorter
Differential association of GABAB receptors with their effector ion channels in Purkinje cells
Full text linkMetabotropic GABAB receptors mediate slow inhibitory effects presynaptically and postsynaptically through the modulation of different effector signalling pathways. Here, we analysed the distribution of GABAB receptors using highly sensitive SDS-digested freeze-fracture replica labelling in mouse cerebellar Purkinje cells. Immunoreactivity for GABAB1 was observed on presynaptic and, more abundantly, on postsynaptic compartments, showing both scattered and clustered distribution patterns. Quantitative analysis of immunoparticles revealed a somato-dendritic gradient, with the density of immunoparticles increasing 26-fold from somata to dendritic spines. To understand the spatial relationship of GABAB receptors with two key effector ion channels, the G protein-gated inwardly rectifying K+ (GIRK/Kir3) channel and the voltage-dependent Ca2+ channel, biochemical and immunohistochemical approaches were performed. Co-immunoprecipitation analysis demonstrated that GABAB receptors co-assembled with GIRK and CaV2.1 channels in the cerebellum. Using double-labelling immunoelectron microscopic techniques, co-clustering between GABAB1 and GIRK2 was detected in dendritic spines, whereas they were mainly segregated in the dendritic shafts. In contrast, co-clustering of GABAB1 and CaV2.1 was detected in dendritic shafts but not spines. Presynaptically, although no significant co-clustering of GABAB1 and GIRK2 or CaV2.1 channels was detected, inter-cluster distance for GABAB1 and GIRK2 was significantly smaller in the active zone than in the dendritic shafts, and that for GABAB1 and CaV2.1 was significantly smaller in the active zone than in the dendritic shafts and spines. Thus, GABAB receptors are associated with GIRK and CaV2.1 channels in different subcellular compartments. These data provide a better framework for understanding the different roles played by GABAB receptors and their effector ion channels in the cerebellar network
Palladium gates for reproducible quantum dots in silicon
Full text linkWe replace the established aluminium gates for the formation of quantum dots in silicon with gates made from palladium. We study the morphology of both aluminium and palladium gates with transmission electron microscopy. The native aluminium oxide is found to be formed all around the aluminium gates, which could lead to the formation of unintentional dots. Therefore, we report on a novel fabrication route that replaces aluminium and its native oxide by palladium with atomic-layer-deposition-grown aluminium oxide. Using this approach, we show the formation of low-disorder gate-defined quantum dots, which are reproducibly fabricated. Furthermore, palladium enables us to further shrink the gate design, allowing us to perform electron transport measurements in the few-electron regime in devices comprising only two gate layers, a major technological advancement. It remains to be seen, whether the introduction of palladium gates can improve the excellent results on electron and nuclear spin qubits defined with an aluminium gate stack
Efficient Parameterized Algorithms for Data Packing
Full text linkThere is a huge gap between the speeds of modern caches and main memories, and therefore cache misses account for a considerable loss of efficiency in programs. The predominant technique to address this issue has been Data Packing: data elements that are frequently accessed within time proximity are packed into the same cache block, thereby minimizing accesses to the main memory.
We consider the algorithmic problem of Data Packing on a two-level memory system. Given a reference sequence R of accesses to data elements, the task is to partition the elements into cache blocks such that the number of cache misses on R is minimized. The problem is notoriously difficult: it is NP-hard even when the cache has size 1, and is hard to approximate for any cache size larger than 4. Therefore, all existing techniques for Data Packing are based on heuristics and lack theoretical guarantees.
In this work, we present the first positive theoretical results for Data Packing, along with new and stronger negative results. We consider the problem under the lens of the underlying access hypergraphs, which are hypergraphs of affinities between the data elements, where the order of an access hypergraph corresponds to the size of the affinity group. We study the problem parameterized by the treewidth of access hypergraphs, which is a standard notion in graph theory to measure the closeness of a graph to a tree. Our main results are as follows:
We show there is a number q* depending on the cache parameters such that
(a) if the access hypergraph of order q* has constant treewidth, then there is a linear-time algorithm for Data Packing;
(b)the Data Packing problem remains NP-hard even if the access hypergraph of order q*-1 has constant treewidth.
Thus, we establish a fine-grained dichotomy depending on a single parameter, namely, the highest order among access hypegraphs that have constant treewidth; and establish the optimal value q* of this parameter.
Finally, we present an experimental evaluation of a prototype implementation of our algorithm.
Our results demonstrate that, in practice, access hypergraphs of many commonly-used algorithms have small treewidth. We compare our approach with several state-of-the-art heuristic-based algorithms and show that our algorithm leads to significantly fewer cache-misses
Cost Analysis of Nondeterministic Probabilistic Programs
Full text linkWe consider the problem of expected cost analysis over nondeterministic probabilistic programs, which aims at automated methods for analyzing the resource-usage of such programs. Previous approaches for this problem could only handle nonnegative bounded costs. However, in many scenarios, such as queuing networks or analysis of cryptocurrency protocols, both positive and negative costs are necessary and the costs are unbounded as well.
In this work, we present a sound and efficient approach to obtain polynomial bounds on the expected accumulated cost of nondeterministic probabilistic programs. Our approach can handle (a) general positive and negative costs with bounded updates in variables; and (b) nonnegative costs with general updates to variables. We show that several natural examples which could not be handled by previous approaches are captured in our framework.
Moreover, our approach leads to an efficient polynomial-time algorithm, while no previous approach for cost analysis of probabilistic programs could guarantee polynomial runtime. Finally, we show the effectiveness of our approach by presenting experimental results on a variety of programs, motivated by real-world applications, for which we efficiently synthesize tight resource-usage bounds
Fast and efficient genetic engineering of hematopoietic precursor cells for the study of dendritic cell migration
Full text linkGenetic determinants of antibiotic resistance evolution
No full textAntibiotic resistance can emerge spontaneously through genomic mutation and render treatment ineffective. To counteract this process, in addition to the discovery and description of resistance mechanisms, a deeper understanding of resistance evolvability and its determinants is needed. To address this challenge, this thesis uncovers new genetic determinants of resistance evolvability using a customized robotic setup, explores systematic ways in which resistance evolution is perturbed due to dose response characteristics of drugs and mutation rate differences, and mathematically investigates the evolutionary fate of one specific type of evolvability modifier - a stress induced mutagenesis allele.
We find several genes which strongly inhibit or potentiate resistance evolution. In order to identify them, we first developed an automated high-throughput feedback-controlled protocol which keeps the population size and selection pressure approximately constant for hundreds of cultures by dynamically re-diluting the cultures and adjusting the antibiotic concentration. We implemented this protocol on a customized liquid handling robot and propagated 100 different gene deletion strains of Escherichia coli in triplicate for over 100 generations in tetracycline and in chloramphenicol, and compared their adaptation rates. We find a diminishing returns pattern, where initially sensitive strains adapted more compared to less sensitive ones. Our data uncover that deletions of certain genes which do not affect mutation rate, including efflux pump components, a chaperone and several structural and regulatory genes can strongly and reproducibly alter resistance evolution. Sequencing analysis of evolved populations indicates that epistasis with resistance mutations is the most likely explanation. This work could inspire treatment strategies in which targeted inhibitors of evolvability mechanisms will be given alongside antibiotics to slow down resistance evolution and extend the efficacy of antibiotics.
We implemented a stochastic population genetics model, to verify ways in which general properties, namely, dose-response characteristics of drugs and mutation rates, influence evolutionary dynamics. In particular, under the exposure to antibiotics with shallow dose-response curves, bacteria have narrower distributions of fitness effects of new mutations. We show that in silico this also leads to slower resistance evolution. We see and confirm with experiments that increased mutation rates, apart from speeding up evolution, also lead to high reproducibility of phenotypic adaptation in a context of continually strong selection pressure. Knowledge of these patterns can aid in predicting the dynamics of antibiotic resistance evolution and adapting treatment schemes accordingly.
Focusing on a previously described type of evolvability modifier – a stress-induced mutagenesis allele – we find conditions under which it can persist in a population under periodic selection akin to clinical treatment. We set up a deterministic infinite population continuous time model tracking the frequencies of a mutator and resistance allele and evaluate various treatment schemes in how well they maintain a stress-induced mutator allele. In particular, a high diversity of stresses is crucial for the persistence of the mutator allele. This leads to a general trade-off where exactly those diversifying treatment schemes which are likely to decrease levels of resistance could lead to stronger selection of highly evolvable genotypes.
In the long run, this work will lead to a deeper understanding of the genetic and cellular mechanisms involved in antibiotic resistance evolution and could inspire new strategies for slowing down its rate
Persistence of translational symmetry in the BCS model with radial pair interaction
Full text linkWe consider the two-dimensional BCS functional with a radial pair interaction. We show that the translational symmetry is not broken in a certain temperature interval below the critical temperature. In the case of vanishing angular momentum, our results carry over to the three-dimensional case
Computational Design of Nanostructural Color for Additive Manufacturing
Full text linkAdditive manufacturing has recently seen drastic improvements in resolution, making it now possible to fabricate features at scales of hundreds or even dozens of nanometers, which previously required very expensive lithographic methods.
As a result, additive manufacturing now seems poised for optical applications, including those relevant to computer graphics, such as material design, as well as display and imaging applications.
In this work, we explore the use of additive manufacturing for generating structural colors, where the structures are designed using a fabrication-aware optimization process.
This requires a combination of full-wave simulation, a feasible parameterization of the design space, and a tailored optimization procedure.
Many of these components should be re-usable for the design of other optical structures at this scale.
We show initial results of material samples fabricated based on our designs.
While these suffer from the prototype character of state-of-the-art fabrication hardware, we believe they clearly demonstrate the potential of additive nanofabrication for structural colors and other graphics applications
From the left to the right: A tale of asymmetries, environments, and hippocampal development
No full textAsymmetries have long been known about in the central nervous system. From gross anatomical differences, such as the presence of the parapineal organ in only one hemisphere of the developing zebrafish, to more subtle differences in activity between both hemispheres, as seen in freely roaming animals or human participants under PET and fMRI imaging analysis. The presence of asymmetries has been demonstrated to have huge behavioural implications, with their disruption often leading to the generation of neurological disorders, memory problems, changes in personality, and in an organism's health and well-being.
For my Ph.D. work I aimed to tackle two important avenues of research. The first being the process of input-side dependency in the hippocampus, with the goal of finding a key gene responsible for its development (Gene X). The second project was to do with experience-induced laterality formation in the hippocampus. Specifically, how laterality in the synapse density of the CA1 stratum radiatum (s.r.) could be induced purely through environmental enrichment.
Through unilateral tracer injections into the CA3, I was able to selectively measure the properties of synapses within the CA1 and investigate how they differed based upon which hemisphere the presynaptic neurone originated. Having found the existence of a previously unreported reversed (left-isomerism) i.v. mutant, through morpholocal examination of labelled terminals in the CA1 s.r., I aimed to elucidate a key gene responsible for the process of left or right determination of inputs to the CA1 s.r.. This work relates to the previous finding of input-side dependent asymmetry in the wild-type rodent, where the origin of the projecting neurone to the CA1 will determine the morphology of a synapse, to a greater degree than the hemisphere in which the projection terminates. Using left- and right-isomerism i.v. mice, in combination with whole genome sequence analysis, I highlight Ena/VASP-like (Evl) as a potential target for Gene X. In relation to this topic, I also highlight my work in the recently published paper of how knockout of PirB can lead to a lack of input-side dependency in the murine hippocampus.
For the second question, I show that the environmental enrichment paradigm will lead to an asymmetry in the synapse densities in the hippocampus of mice. I also highlight that the nature of the enrichment is of less consequence than the process of enrichment itself. I demonstrate that the CA3 region will dramatically alter its projection targets, in relation to environmental stimulation, with the asymmetry in synaptic density, caused by enrichment, relying heavily on commissural fibres. I also highlight the vital importance of input-side dependent asymmetry, as a necessary component of experience-dependent laterality formation in the CA1 s.r.. However, my results suggest that it isn't the only cause, as there appears to be a CA1 dependent mechanism also at play. Upon further investigation, I highlight the significant, and highly important, finding that the changes seen in the CA1 s.r. were predominantly caused through projections from the left-CA3, with the right-CA3 having less involvement in this mechanism