CuATSM effectively ameliorates ALS patient astrocyte-mediated motor neuron toxicity in human in vitro models of amyotrophic lateral sclerosis.

Patient diversity and unknown disease cause are major challenges for drug development and clinical trial design for amyotrophic lateral sclerosis (ALS). Transgenic animal models do not adequately reflect the heterogeneity of ALS. Direct reprogramming of patient fibroblasts to neuronal progenitor cells and subsequent differentiation into patient astrocytes allows rapid generation of disease relevant cell types. Thus, this methodology can facilitate compound testing in a diverse genetic background resulting in a more representative population for therapeutic evaluation. Here, we used established co-culture assays with motor neurons and reprogrammed patient skin-derived astrocytes (iAs) to evaluate the effects of (SP-4-2)-[[2,2'-(1,2-dimethyl-1,2-ethanediylidene)bis[N-methylhydrazinecarbothioamidato-κN2 ,κS]](2-)]-copper (CuATSM), currently in clinical trial for ALS in Australia. Pretreatment of iAs with CuATSM had a differential effect on neuronal survival following co-culture with healthy motor neurons. Using this assay, we identified responding and non-responding cell lines for both sporadic and familial ALS (mutant SOD1 and C9ORF72). Importantly, elevated mitochondrial respiration was the common denominator in all CuATSM-responders, a metabolic phenotype not observed in non-responders. Pre-treatment of iAs with CuATSM restored mitochondrial activity to levels comparable to healthy controls. Hence, this metabolic parameter might allow selection of patient subpopulations best suited for CuATSM treatment. Moreover, CuATSM might have additional therapeutic value for mitochondrial disorders. Enhanced understanding of patient-specific cellular and molecular profiles could help improve clinical trial design in the future.

Should Governments Invest More in Nudging?

Governments are increasingly adopting behavioral science techniques for changing individual behavior in pursuit of policy objectives. The types of "nudge" interventions that governments are now adopting alter people's decisions without coercion or significant changes to economic incentives. We calculated ratios of impact to cost for nudge interventions and for traditional policy tools, such as tax incentives and other financial inducements, and we found that nudge interventions often compare favorably with traditional interventions. We conclude that nudging is a valuable approach that should be used more often in conjunction with traditional policies, but more calculations are needed to determine the relative effectiveness of nudging.

MD-CTS: An integrated terminology reference of clinical and translational medicine.

New vocabularies are rapidly evolving in the literature relative to the practice of clinical medicine and translational research. To provide integrated access to new terms, we developed a mobile and desktop online reference-Marshfield Dictionary of Clinical and Translational Science (MD-CTS). It is the first public resource that comprehensively integrates Wiktionary (word definition), BioPortal (ontology), Wiki (image reference), and Medline abstract (word usage) information. MD-CTS is accessible at http://spellchecker.mfldclin.edu/. The website provides a broadened capacity for the wider clinical and translational science community to keep pace with newly emerging scientific vocabulary. An initial evaluation using 63 randomly selected biomedical words suggests that online references generally provided better coverage (73%-95%) than paper-based dictionaries (57-71%).

Host-to-host variation of ecological interactions in polymicrobial infections.

Host-to-host variability with respect to interactions between microorganisms and multicellular hosts are commonly observed in infection and in homeostasis. However, the majority of mechanistic models used to analyze host-microorganism relationships, as well as most of the ecological theories proposed to explain coevolution of hosts and microbes, are based on averages across a host population. By assuming that observed variations are random and independent, these models overlook the role of differences between hosts. Here, we analyze mechanisms underlying host-to-host variations of bacterial infection kinetics, using the well characterized experimental infection model of polymicrobial otitis media (OM) in chinchillas, in combination with population dynamic models and a maximum entropy (MaxEnt) based inference scheme. We find that the nature of the interactions between bacterial species critically regulates host-to-host variations in these interactions. Surprisingly, seemingly unrelated phenomena, such as the efficiency of individual bacterial species in utilizing nutrients for growth, and the microbe-specific host immune response, can become interdependent in a host population. The latter finding suggests a potential mechanism that could lead to selection of specific strains of bacterial species during the coevolution of the host immune response and the bacterial species.

The ZZ domain of dystrophin in DMD: making sense of missense mutations.

Duchenne muscular dystrophy (DMD) is associated with the loss of dystrophin, which plays an important role in myofiber integrity via interactions with ß-dystroglycan and other members of the transmembrane dystrophin-associated protein complex. The ZZ domain, a cysteine-rich zinc-finger domain near the dystrophin C-terminus, is implicated in forming a stable interaction between dystrophin and ß-dystroglycan, but the mechanism of pathogenesis of ZZ missense mutations has remained unclear because not all such mutations have been shown to alter ß-dystroglycan binding in previous experimental systems. We engineered three ZZ mutations (p.Cys3313Phe, p.Asp3335His, and p.Cys3340Tyr) into a short construct similar to the Dp71 dystrophin isoform for in vitro and in vivo studies and delineated their effect on protein expression, folding properties, and binding partners. Our results demonstrate two distinct pathogenic mechanisms for ZZ missense mutations. The cysteine mutations result in diminished or absent subsarcolemmal expression because of protein instability, likely due to misfolding. In contrast, the aspartic acid mutation disrupts binding with ß-dystroglycan despite an almost normal expression at the membrane, confirming a role for the ZZ domain in ß-dystroglycan binding but surprisingly demonstrating that such binding is not required for subsarcolemmal localization of dystrophin, even in the absence of actin binding domains.

Analysis of dystrophin deletion mutations predicts age of cardiomyopathy onset in becker muscular dystrophy.

BACKGROUND: Becker muscular dystrophy (BMD) and X-linked dilated cardiomyopathy often result from deletion mutations in the dystrophin gene that may lead to expression of an altered dystrophin protein in cardiac muscle. Cardiac involvement is present in approximately 70% of BMD and all X-linked dilated cardiomyopathy cases. To date, the timing of cardiomyopathy development remains unpredictable. We analyzed 78 BMD and X-linked dilated cardiomyopathy patients with common deletion mutations predicted to alter the dystrophin protein and correlated their mutations to cardiomyopathy age of onset. This approach was chosen to connect dystrophin structure with function in the heart. METHODS AND RESULTS: Detailed cardiac information was collected for BMD and X-linked dilated cardiomyopathy patients with defined dystrophin gene deletion mutations. Patients were grouped based on the dystrophin protein domain affected by the deletion. Deletions affecting the amino-terminal domain are associated with early-onset dilated cardiomyopathy (DCM; mid-20s), whereas deletions removing part of the rod domain and hinge 3 have a later-onset DCM (mid-40s). Further, we modeled the effects of the most common mutations occurring in the rod domain on the overall structure of the dystrophin protein. By combining genetic and protein information, this analysis revealed a strong correlation between specific protein structural modifications and DCM age of onset. CONCLUSIONS: We identified specific regions of the dystrophin gene that when mutated predispose BMD patients to early-onset DCM. In addition, we propose that some mutations lead to early-onset DCM by specific alterations in protein folding. These findings have potential implications for early intervention in the cardiac care of BMD patients and for therapeutic approaches that target the heart in dystrophinopathies.

Coherence between two coupled lasers from a dynamics perspective.

We compare a simple dynamical model of fiber laser arrays with independent experiments on two coupled lasers. The degree of agreement with experimental observations is excellent. Collectively the evidence presented supports this dynamical approach as an alternative to the traditional static eigenmode analysis of the coupled laser cavities.

Refined fiber laser model.

With modification, a recently proposed laser array model is found to agree quantitatively with fiber laser experiments. Comparisons of transient behavior, stable dynamical states, and transitions are made using both previously published and new experiments. While the original model agrees well for fibers with relatively low losses, achieving quantitative agreement over a wide range of operating conditions requires more physically appropriate descriptions of gain dynamics. The refined model is derived, and its predictions are found to be in excellent agreement with experiments.

Observation of chaotic itinerancy in the light and carrier dynamics of a semiconductor laser with optical feedback.

We report a direct experimental observation of chaotic itinerancy in simultaneous measurements of the light intensity and voltage fluctuations of a laser diode exhibiting low-frequency fluctuations. The distribution of trajectories leading up to (following) an intensity dropout is computed from the experiment and reveals the presence of itinerant mechanisms before (after) dropout initiation. A phase space reconstruction of the trajectory for the optimal path of motion illustrates sudden shifts between low-dimensional attractor ruins and is shown to correspond to simulations of the laser intensity and carrier number.

Measurement of Hurst exponents for semiconductor laser phase dynamics.

The phase dynamics of a semiconductor laser with optical feedback is studied by construction of the Hilbert phase from its experimentally measured intensity time series. The Hurst exponent is evaluated for the phase fluctuations and grows from 0.5 to approximately 0.7 (indicating fractional Brownian motion) as the feedback strength is increased. A comparison with numerical computations based on a delay-differential equation model shows excellent agreement and reveals the relative roles of spontaneous emission noise and deterministic dynamics for different feedback strengths.

Optimal stimulus coding by neural populations using rate codes.

We create a framework based on Fisher information for determining the most effective population coding scheme for representing a continuous-valued stimulus attribute over its entire range. Using this scheme, we derive optimal single- and multi-neuron rate codes for homogeneous populations using several statistical models frequently used to describe neural data. We show that each neuron's discharge rate should increase quadratically with the stimulus and that statistically independent neural outputs provides optimal coding. Only cooperative populations can achieve this condition in an informationally effective way.