Phosphorylation of the HCN channel auxiliary subunit TRIP8b is altered in an animal model of temporal lobe epilepsy and modulates channel function

Temporal lobe epilepsy (TLE) is a prevalent neurological disorder with many patients experiencing poor seizure control with existing anti-epileptic drugs. Thus, novel insights into the mechanisms of epileptogenesis and identification of new drug targets can be transformative. Changes in ion channel function have been shown to play a role in generating the aberrant neuronal activity observed in TLE. Previous work demonstrates that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate neuronal excitability and are mislocalized within CA1 pyramidal cells in a rodent model of TLE. The subcellular distribution of HCN channels is regulated by an auxiliary subunit, tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b), and disruption of this interaction correlates with channel mislocalization. However, the molecular mechanisms responsible for HCN channel dysregulation in TLE are unclear. Here we investigated whether changes in TRIP8b phosphorylation are sufficient to alter HCN channel function. We identified a phosphorylation site at residue Ser237 of TRIP8b that enhances binding to HCN channels and influences channel gating by altering the affinity of TRIP8b for the HCN cytoplasmic domain. Using a phosphospecific antibody, we demonstrate that TRIP8b phosphorylated at Ser237 is enriched in CA1 distal dendrites and that phosphorylation is reduced in the kainic acid model of TLE. Overall, our findings indicate that the TRIP8b-HCN interaction can be modulated by changes in phosphorylation and suggest that loss of TRIP8b phosphorylation may affect HCN channel properties during epileptogenesis. These results highlight the potential of drugs targeting posttranslational modifications to restore TRIP8b phosphorylation to reduce excitability in TLE

Controlling quantum many-body dynamics in driven Rydberg atom arrays

The control of nonequilibrium quantum dynamics in many-body systems is challenging because interactions typically lead to thermalization and a chaotic spreading throughout Hilbert space. We investigate nonequilibrium dynamics after rapid quenches in a many-body system composed of 3 to 200 strongly interacting qubits in one and two spatial dimensions. Using a programmable quantum simulator based on Rydberg atom arrays, we show that coherent revivals associated with so-called quantum many-body scars can be stabilized by periodic driving, which generates a robust subharmonic response akin to discrete time-crystalline order. We map Hilbert space dynamics, geometry dependence, phase diagrams, and system-size dependence of this emergent phenomenon, demonstrating new ways to steer complex dynamics in many-body systems and enabling potential applications in quantum information science

The Effect of Body Mass on the Shoe-Athlete Interaction

Long-distance running is known to induce joint overloading and elevate cytokine levels, which are the hallmarks for a variety of running-related injuries. To address this, footwear systems incorporate cushioning midsoles to mitigate injurious mechanical loading. The aim of this study was to evaluate the effect of athlete body mass on the cushioning capacity of technical footwear. An artificial heel was prototyped to fit the impact pattern of a heel-strike runner and used to measure shock attenuation by an automated drop test. Impact mass and velocity were modulated to simulate runners of various body mass and speeds. The investigation provided refined insight on running-induced impact transmission to the human body. The examined midsole system was optimized around anthropometric data corresponding to an average (normal) body mass. The results suggest that although modern footwear is capable of attenuating the shock waves occurring during foot strike, improper shoe selection could expose an athlete to high levels of peak stress that could provoke an abnormal cartilage response. The selection of a weight-specific cushioning system could provide optimum protection and could thus prolong the duration of physical exercise beneficial to maintaining a simulated immune system

British HIV Association guidelines for the management of tuberculosis in adults living with HIV 2019

The overall purpose of these guidelines is to help physicians manage adults with tuberculosis (TB)/human immunodeficiency virus (HIV) co‐infection. Recommendations for the treatment of TB in HIV‐positive adults are similar to those in HIV‐negative adults. Of note, the term “HIV” refers to HIV‐1 throughout these guidelines

Emergent SU(2) dynamics and perfect quantum many-body scars

Motivated by recent experimental observations of coherent many-body revivals in a constrained Rydberg atom chain, we construct a weak quasi-local deformation of the Rydberg blockade Hamiltonian, which makes the revivals virtually perfect. Our analysis suggests the existence of an underlying non-integrable Hamiltonian which supports an emergent SU(2)-spin dynamics within a small subspace of the many-body Hilbert space. We show that such perfect dynamics necessitates the existence of atypical, nonergodic energy eigenstates - quantum many-body scars. Furthermore, using these insights, we construct a toy model that hosts exact quantum many-body scars, providing an intuitive explanation of their origin. Our results offer specific routes to enhancing coherent many-body revivals, and provide a step towards establishing the stability of quantum many-body scars in the thermodynamic limit

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Identifiability of flow distributions from link measurements with applications to computer networks

We study the problem of identifiability of distributions of flows on a graph from aggregate measurements collected on its edges. This is a canonical example of a statistical inverse problem motivated by recent developments in computer networks. In this paper (i) we introduce a number of models for multi-modal data that capture their spatio-temporal correlation, (ii) provide sufficient conditions for the identifiability of nth order cumulants and also for a special class of heavy tailed distributions. Further, we investigate conditions on network routing for the flows that prove sufficient for identifiability of their distributions (up to mean). Finally, we extend our results to directed acyclic graphs and discuss some open problems.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58107/2/ip7_5_004.pd

EXMOTIF: efficient structured motif extraction

BACKGROUND: Extracting motifs from sequences is a mainstay of bioinformatics. We look at the problem of mining structured motifs, which allow variable length gaps between simple motif components. We propose an efficient algorithm, called EXMOTIF, that given some sequence(s), and a structured motif template, extracts all frequent structured motifs that have quorum q. Potential applications of our method include the extraction of single/composite regulatory binding sites in DNA sequences. RESULTS: EXMOTIF is efficient in terms of both time and space and is shown empirically to outperform RISO, a state-of-the-art algorithm. It is also successful in finding potential single/composite transcription factor binding sites. CONCLUSION: EXMOTIF is a useful and efficient tool in discovering structured motifs, especially in DNA sequences. The algorithm is available as open-source at:

THINK Back: KNowledge-based Interpretation of High Throughput data

Results of high throughput experiments can be challenging to interpret. Current approaches have relied on bulk processing the set of expression levels, in conjunction with easily obtained external evidence, such as co-occurrence. While such techniques can be used to reason probabilistically, they are not designed to shed light on what any individual gene, or a network of genes acting together, may be doing. Our belief is that today we have the information extraction ability and the computational power to perform more sophisticated analyses that consider the individual situation of each gene. The use of such techniques should lead to qualitatively superior results