A TBK1 variant causes autophagolysosomal and motoneuron pathology without neuroinflammation in mice.

Heterozygous mutations in the TBK1 gene can cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The majority of TBK1-ALS/FTD patients carry deleterious loss-of-expression mutations, and it is still unclear which TBK1 function leads to neurodegeneration. We investigated the impact of the pathogenic TBK1 missense variant p.E696K, which does not abolish protein expression, but leads to a selective loss of TBK1 binding to the autophagy adaptor protein and TBK1 substrate optineurin. Using organelle-specific proteomics, we found that in a knock-in mouse model and human iPSC-derived motor neurons, the p.E696K mutation causes presymptomatic onset of autophagolysosomal dysfunction in neurons precipitating the accumulation of damaged lysosomes. This is followed by a progressive, age-dependent motor neuron disease. Contrary to the phenotype of mice with full Tbk1 knock-out, RIPK/TNF-α-dependent hepatic, neuronal necroptosis, and overt autoinflammation were not detected. Our in vivo results indicate autophagolysosomal dysfunction as a trigger for neurodegeneration and a promising therapeutic target in TBK1-ALS/FTD.

Experimental evidence that shear bands in metallic glasses nucleate like cracks.

Highly time-resolved mechanical measurements, modeling, and simulations show that large shear bands in bulk metallic glasses nucleate in a manner similar to cracks. When small slips reach a nucleation size, the dynamics changes and the shear band rapidly grows to span the entire sample. Smaller nucleation sizes imply lower ductility. Ductility can be increased by increasing the nucleation size relative to the maximum ("cutoff") shear band size at the upper edge of the power law scaling range of their size distribution. This can be achieved in three ways: (1) by increasing the nucleation size beyond this cutoff size of the shear bands, (2) by keeping all shear bands smaller than the nucleation size, or (3) by choosing a sample size smaller than the nucleation size. The discussed methods can also be used to rapidly order metallic glasses according to ductility.

Applied-force oscillations in avalanche dynamics.

Until now most studies of discrete plasticity have focused on systems that are assumed to be driven by a monotonically increasing force; in many real systems, however, the driving force includes damped oscillations or oscillations induced by the propagation of discrete events or "slip avalanches." In both cases, these oscillations may obscure the true dynamics. Here we effectively consider both cases by investigating the effects of damped oscillations in the external driving force on avalanche dynamics. We compare model simulations of slip avalanches under mean-field dynamics with observations in slip-avalanche experiments on slowly compressed micrometer-sized Au specimens using open-loop force control. The studies show very good agreement between simulations and experiments. We find that an oscillatory external driving force changes the average avalanche shapes only for avalanches with durations close to the period of oscillation of the external force. This effect on the avalanche shapes can be addressed in experiments by choosing suitable specimen dimensions so that the mechanical resonance does not interact with the avalanche dynamics. These results are important for the interpretation of avalanche experiments with built-in oscillators, and for the prediction and analysis of avalanche dynamics in systems with resonant vibrations.

Aftershocks in slowly compressed bulk metallic glasses: Experiments and theory.

We observe two distinct interevent time patterns in the slip avalanches of compressed bulk metallic glasses (BMGs). Small slip avalanches cluster together in time, but large slip avalanches recur roughly periodically. We compare the timing patterns of BMG slip avalanches with timing patterns of earthquakes and with the predictions of a mean-field model. The time clustering of small avalanches is similar to the known time clustering of earthquake foreshocks and aftershocks.

Universal slip dynamics in metallic glasses and granular matter - linking frictional weakening with inertial effects.

Slowly strained solids deform via intermittent slips that exhibit a material-independent critical size distribution. Here, by comparing two disparate systems - granular materials and bulk metallic glasses - we show evidence that not only the statistics of slips but also their dynamics are remarkably similar, i.e. independent of the microscopic details of the material. By resolving and comparing the full time evolution of avalanches in bulk metallic glasses and granular materials, we uncover a regime of universal deformation dynamics. We experimentally verify the predicted universal scaling functions for the dynamics of individual avalanches in both systems, and show that both the slip statistics and dynamics are independent of the scale and details of the material structure and interactions, thus settling a long-standing debate as to whether or not the claim of universality includes only the slip statistics or also the slip dynamics. The results imply that the frictional weakening in granular materials and the interplay of damping, weakening and inertial effects in bulk metallic glasses have strikingly similar effects on the slip dynamics. These results are important for transferring experimental results across scales and material structures in a single theory of deformation dynamics.

Probabilistic model of waiting times between large failures in sheared media.

Using a probabilistic approximation of a mean-field mechanistic model of sheared systems, we analytically calculate the statistical properties of large failures under slow shear loading. For general shear F(t), the distribution of waiting times between large system-spanning failures is a generalized exponential distribution, ρ_{T}(t)=λ(F(t))P(F(t))exp[-∫_{0}^{t}dτλ(F(τ))P(F(τ))], where λ(F(t)) is the rate of small event occurrences at stress F(t) and P(F(t)) is the probability that a small event triggers a large failure. We study the behavior of this distribution as a function of fault properties, such as heterogeneity or shear rate. Because the probabilistic model accommodates any stress loading F(t), it is particularly useful for modeling experiments designed to understand how different forms of shear loading or stress perturbations impact the waiting-time statistics of large failures. As examples, we study how periodic perturbations or fluctuations on top of a linear shear stress increase impact the waiting-time distribution.

Universal Quake Statistics: From Compressed Nanocrystals to Earthquakes.

Slowly-compressed single crystals, bulk metallic glasses (BMGs), rocks, granular materials, and the earth all deform via intermittent slips or "quakes". We find that although these systems span 12 decades in length scale, they all show the same scaling behavior for their slip size distributions and other statistical properties. Remarkably, the size distributions follow the same power law multiplied with the same exponential cutoff. The cutoff grows with applied force for materials spanning length scales from nanometers to kilometers. The tuneability of the cutoff with stress reflects "tuned critical" behavior, rather than self-organized criticality (SOC), which would imply stress-independence. A simple mean field model for avalanches of slipping weak spots explains the agreement across scales. It predicts the observed slip-size distributions and the observed stress-dependent cutoff function. The results enable extrapolations from one scale to another, and from one force to another, across different materials and structures, from nanocrystals to earthquakes.

Probing failure susceptibilities of earthquake faults using small-quake tidal correlations.

Mitigating the devastating economic and humanitarian impact of large earthquakes requires signals for forecasting seismic events. Daily tide stresses were previously thought to be insufficient for use as such a signal. Recently, however, they have been found to correlate significantly with small earthquakes, just before large earthquakes occur. Here we present a simple earthquake model to investigate whether correlations between daily tidal stresses and small earthquakes provide information about the likelihood of impending large earthquakes. The model predicts that intervals of significant correlations between small earthquakes and ongoing low-amplitude periodic stresses indicate increased fault susceptibility to large earthquake generation. The results agree with the recent observations of large earthquakes preceded by time periods of significant correlations between smaller events and daily tide stresses. We anticipate that incorporating experimentally determined parameters and fault-specific details into the model may provide new tools for extracting improved probabilities of impending large earthquakes.

Bulk metallic glasses deform via slip avalanches.

For the first time in metallic glasses, we extract both the exponents and scaling functions that describe the nature, statistics, and dynamics of slip events during slow deformation, according to a simple mean field model. We model the slips as avalanches of rearrangements of atoms in coupled shear transformation zones (STZs). Using high temporal resolution measurements, we find the predicted, different statistics and dynamics for small and large slips thereby excluding self-organized criticality. The agreement between model and data across numerous independent measures provides evidence for slip avalanches of STZs as the elementary mechanism of inhomogeneous deformation in metallic glasses.

Tuned critical avalanche scaling in bulk metallic glasses.

Ingots of the bulk metallic glass (BMG), Zr64.13Cu15.75Ni10.12Al10 in atomic percent (at. %), are compressed at slow strain rates. The deformation behavior is characterized by discrete, jerky stress-drop bursts (serrations). Here we present a quantitative theory for the serration behavior of BMGs, which is a critical issue for the understanding of the deformation characteristics of BMGs. The mean-field interaction model predicts the scaling behavior of the distribution, D(S), of avalanche sizes, S, in the experiments. D(S) follows a power law multiplied by an exponentially-decaying scaling function. The size of the largest observed avalanche depends on experimental tuning-parameters, such as either imposed strain rate or stress. Similar to crystalline materials, the plasticity of BMGs reflects tuned criticality showing remarkable quantitative agreement with the slip statistics of slowly-compressed nanocrystals. The results imply that material-evaluation methods based on slip statistics apply to both crystalline and BMG materials.

Statistics of dislocation slip avalanches in nanosized single crystals show tuned critical behavior predicted by a simple mean field model.

We show that slowly sheared metallic nanocrystals deform via discrete strain bursts (slips), whose size distributions follow power laws with stress-dependent cutoffs. We show for the first time that plasticity reflects tuned criticality, by collapsing the stress-dependent slip-size distributions onto a predicted scaling function. Both power-law exponents and scaling function agree with mean-field theory predictions. Our study of 7 materials and 2 crystal structures, at various deformation rates, stresses, and crystal sizes down to 75 nm, attests to the universal characteristics of plasticity.

Micromechanical model for deformation in solids with universal predictions for stress-strain curves and slip avalanches.

A basic micromechanical model for deformation of solids with only one tuning parameter (weakening epsilon) is introduced. The model can reproduce observed stress-strain curves, acoustic emissions and related power spectra, event statistics, and geometrical properties of slip, with a continuous phase transition from brittle to ductile behavior. Exact universal predictions are extracted using mean field theory and renormalization group tools. The results agree with recent experimental observations and simulations of related models for dislocation dynamics, material damage, and earthquake statistics.

Information Rx: Evaluation of a new informatics tool for physicians, patients, and libraries.

This paper reports selected results from two comprehensive evaluation studies of the Information Prescription (or "Information Rx") Program implementation conducted from 2002-05 by the American College of Physicians Foundation (ACPF) and the U.S. National Library of Medicine (NLM). In this Program physicians are provided with Information Prescription pads, analogous to pads used to prescribe medications, that are used to direct patients to the MedlinePlus web site and its contents that are applicable to a patient's health condition. The results describe the Program's potential to enhance patient education and interpersonal communication from physician and patient perspectives. The findings suggest once physicians adopt the use of an information prescription, they perceive they are providing an additional clinical service that enhances patient education and interpersonal communication. For physicians, participation in information prescription may improve patient communication, encourage information seeking, and lessen the number of poor quality Internet searches that patients frequently self-perform and bring to a doctor's office. Similarly, once patients receive a recommendation from a physician to seek health information on the web, patients may be more comfortable with health seeking on the Internet and discussing their findings with their doctor. The conclusions of the two evaluation studies imply an Information Prescription fosters a dialogue between providers and patients, helps patients use the Internet more effectively and seems to favorably impact patient education. As the medical community and patient advocacy groups continue to emphasize the importance of evidence-based information as the gold standard for accepted care, it can be expected that informatics tools such as Information Rx will come to play an increasingly important role as a vehicle to help identify and access high quality health information on the Internet.