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Genetic studies are rapidly identifying non-protein-coding human disease-associated loci. Understanding the regulatory mechanisms underlying these loci remains a challenge because the causal variants and the tissues in which they act are often unclear. Massively parallel reporter assays (MPRAs) have the potential to link differences in genome sequence, including genetic variants, to tissue-specific regulatory function. Although MPRA and similar technologies have been widely adopted in cell culture, there have been several barriers to widespread use in animals. We overcome these challenges with a new whole-animal MPRA (WhAMPRA), where systemic intravenous AAV effectively transduces the plasmid MPRA library to mouse tissues. Our WhAMPRA approach revealed models of tissue-specific regulation that generally match machine learning model predictions. In addition, we measured the regulatory effects of disrupting MEF2C transcription factor binding sites and impacts of late onset Alzheimer’s disease-associated genetic variations. Overall, our WhAMPRA technology simultaneously determines the transcriptional functions of hundreds of enhancersin vivoacross multiple tissues.

Recent discoveries of extreme cellular diversity in the brain warrant rapid development of technologies to access specific cell populations within heterogeneous tissue. Available approaches for engineering-targeted technologies for new neuron subtypes are low yield, involving intensive transgenic strain or virus screening. Here, we present Specific Nuclear-Anchored Independent Labeling (SNAIL), an improved virus-based strategy for cell labeling and nuclear isolation from heterogeneous tissue. SNAIL works by leveraging machine learning and other computational approaches to identify DNA sequence features that confer cell type-specific gene activation and then make a probe that drives an affinity purification-compatible reporter gene. As a proof of concept, we designed and validated two novel SNAIL probes that target parvalbumin-expressing (PV+) neurons. Nuclear isolation using SNAIL in wild-type mice is sufficient to capture characteristic open chromatin features of PV+ neurons in the cortex, striatum, and external globus pallidus. The SNAIL framework also has high utility for multispecies cell probe engineering; expression from a mouse PV+ SNAIL enhancer sequence was enriched in PV+ neurons of the macaque cortex. Expansion of this technology has broad applications in cell type-specific observation, manipulation, and therapeutics across species and disease models.

Introducing students to the challenges and rewards of legitimate experimentation has become an essential part of many undergraduate lab courses. However, this objective can be difficult to achieve if the students find the topic uninteresting and therefore do not take ownership of the project. Additionally, the budgets of most undergraduate courses do not allow for the purchase of new equipment for student-generated projects. Here we describe a lab project where students engaged in the process of designing and building their own inexpensive apparatus. Driven by their interest in anxiety research, students in a Neuroscience Methods course developed the following protocol to build an elevated plus maze (EPM) and optional data acquisition module, for less than $100 each. The project engaged students in work that required applied critical thinking and real-world problem solving, and produced a functional EPM that was used in multiple projects beyond this course.

Inconel alloys have been used as engineering materials in high temperature and high stress applications due to their excellent mechanical properties. Tribological performances of these alloys, however, have not been conducted extensively. This is because in tribological applications, these materials have not often been utilized in friction and wear-related applications, resulting in a deficiency in the characterization of their tribomechanical properties. In the present research, we investigate the mechanisms of tribological performance of two different Inconel alloys in terms of contact pressures and sliding speeds. We studied their frictional behavior. The wear data were plotted against the pressure×velocity (PV parameter) in order to investigate the changes of surface properties and wear behaviors of the same under the influence of mechanical energy input. It was interesting to find that the wear mechanisms were influenced by the process of tribotesting. There are three competing wear mechanisms found, abrasion, adhesion, and oxidation. Each of those dominates the tribological performance under different conditions.

Mechanical failure of integrated circuits and micro-electro-mechanical systems (MEMS) demands new understanding of friction in small devices. In present research, we demonstrated an in situ approach to measure sliding friction of a patterned surface composing multi-materials and structures. The effects of materials and surface morphology on friction and electrical contact resistance were investigated. The material transfer at the interface of dissimilar materials was found to play dominating roles in friction. The current work provides important insights from the fundamentals of friction that benefit the design of new micro-devices.

International audience; We study alternating register automata on data words and data trees in relation to logics. A data word (resp. data tree) is a word (resp. tree) whose every position carries a label from a finite alphabet and a data value from an infinite domain. We investigate one-way automata with alternating control over data words or trees, with one register for storing data and comparing them for equality. This is a continuation of the study started by Demri, Lazi´cLazi´c and Jurdzi´nskiJurdzi´nski. From the standpoint of register automata models, this work aims at two objectives: (1) simplifying the existent decidability proofs for the emptiness problem for alternating register automata; and (2) exhibiting decidable extensions for these models. From the logical perspective, we show that (a) in the case of data words, satisfiability of LTL with one register and quantification over data values is decidable; and (b) the satisfiability problem for the so-called forward fragment of XPath on xml documents is decidable, even in the presence of DTDs and even of key constraints. The decidability is obtained through a reduction to the automata model introduced. This fragment contains the child, descendant, next-sibling and following-sibling axes, as well as data equality and inequality tests.

International audience; We consider the enumeration problem of first-order queries over structures of bounded degree. In [3] it was shown that this problem is in Constant-Delay lin. An enumeration problem belongs to Constant-Delay lin if for an input of size n it can be solved by: • an O(n) precomputation phase building an index structure, • followed by a phase enumerating the answers with no repetition and a constant delay between two consecutive outputs. In this article we give a different proof of this result based on Gaifman's locality theorem for first-order logic. Moreover, the constants we obtain yield a total evaluation time that is triply exponential in the size of the input formula, matching the complexity of the best known evaluation algorithms.