Computing exponentially faster: Implementing a nondeterministic universal Turing machine using DNA

The theory of computer science is based around Universal Turing Machines (UTMs): abstract machines able to execute all possible algorithms. Modern digital computers are physical embodiments of UTMs. The nondeterministic polynomial (NP) time complexity class of problems is the most significant in computer science, and an efficient (i.e. polynomial P) way to solve such problems would be of profound economic and social importance. By definition nondeterministic UTMs (NUTMs) solve NP complete problems in P time. However, NUTMs have previously been believed to be physically impossible to construct. Thue string rewriting systems are computationally equivalent to UTMs, and are naturally nondeterministic. Here we describe the physical design for a NUTM that implements a universal Thue system. The design exploits the ability of DNA to replicate to execute an exponential number of computational paths in P time. Each Thue rewriting step is embodied in a DNA edit implemented using a novel combination of polymerase chain reactions and site-directed mutagenesis. We demonstrate that this design works using both computational modelling and in vitro molecular biology experimentation. The current design has limitations, such as restricted error-correction. However, it opens up the prospect of engineering NUTM based computers able to outperform all standard computers on important practical problems

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Quantifying the benefits of wetland restoration under projected sea level rise

The capacity of vegetated coastal habitats to mitigate erosion and build elevation in response to sea-level rise (SLR) has led to growing interest in their application as Nature Based Solutions (NBS) for shoreline protection. However, a significant uncertainty in the performance of NBS is how these features will respond to future rates of SLR. In this study, we applied the Sea Level Affecting Marshes Model (SLAMM) to a fringing shoreline wetland complex that is directly adjacent to the primary runway of a regional airport in coastal North Carolina, US. The SLAMM model was run at high spatial resolution (1 m cell size) to investigate the effects of projected SLR by 2100 on the wetland communities and to estimate the potential benefits of a proposed NBS project involving the use of dredged sediment to increase wetland surface elevation. Modeling future habitat extent under three SLR scenarios (i.e., intermediate, intermediate-high, and high) with no land modification reveals a consistent pattern of salt marsh expanding into fresh marsh, salt marsh transitioning to higher elevations, and substantially larger overall extents of intertidal and subtidal habitats within the project footprint at relatively high rates of SLR. Simulations that include the NBS indicate changes in the composition of wetland types over time compared with the no-action scenario. Model results help to better understand the long-term behavior of fringing coastal wetlands and the efficacy of their use as part of coastal resilience strategies

Tracker Dyes to Probe Mitochondrial Autophagy (Mitophagy) in Rat Hepatocytes

Mitochondria become targets for autophagic degradation after nutrient deprivation, a process also termed mitophagy. In this study, we used LysoTracker Red (LTR) and MitoTracker Green to characterize the kinetics of autophagosomal proliferation and mitophagy in cultured rat hepatocytes. Autophagy induced by nutrient deprivation plus glucagon increased LTR uptake assessed with a fluorescence plate reader and the number of LTR-labeled acidic organelles assessed with confocal microscopy in individual hepatocytes both by 4- to 6-fold. Serial imaging of hepatocytes coloaded with MitoTracker Green (MTG) revealed an average mitochondrial digestion time of 7.5 min after autophagic induction. In the presence of protease inhibitors, digestion time more than doubled, and the total number of LTR-labeled organelles increased about 40%, but the proportion of the LTR-labeled acidic organelles containing MTG fluorescence remained constant at about 75%. Autophagy inhibitors, 3-methyladenine, wortmannin and LY204002, suppressed the increase of LTR uptake after nutrient deprivation by up to 85%, confirming that increased LTR uptake reflected autophagy induction. Cyclosporin A and NIM811, specific inhibitors of the mitochondrial permeability transition (MPT), also decreased LTR uptake, whereas tacrolimus, an immunosuppressive reagent that does not inhibit the MPT, was without effect. In addition, the c-Jun N-terminal kinase (JNK) inhibitors, SCP25041 and SP600125, blocked LTR uptake by 47% and 61%, respectively, but ERK1, p38 and caspase inhibitors had no effect. The results show that mitochondria once selected for mitophagy are rapidly digested and support the concept that mitochondrial autophagy involves the MPT and signaling through PI3 kinase and possibly JNK

Understanding breast cancer survivors’ information-seeking behaviours and overall experiences:a comparison of themes derived from social media posts and focus groups

Objective: Using two different analysis techniques, this study explored differences and similarities in information-seeking discourse and overall breast cancer experiences between posters to a Reddit board and breast cancer survivor focus groups. Design: This study incorporates two qualitative methods for determining themes in breast cancer survivors’ information-seeking behaviours and overall cancer experiences. First, posts from a breast cancer-specific Reddit community were extracted and analysed using the meaning extraction method (MEM) to determine core themes. Then, investigators performed a thematic analysis of two focus groups of breast cancer survivors (N = 18). Finally, themes derived from each analysis method were compared. Main Outcome Measures: Outcome measures include themes extracted from Reddit posts and themes generated from breast cancer survivor focus groups. Results: Findings between qualitative methodologies represent similar yet nuanced themes in survivors’ discourse. The MEM resulted in seven themes: diagnosis, treatment process, social support, existentialism, risk, information-seeking and surgery. Focus groups revealed the same initial four MEM themes plus the following: disclosure, coping and fears. Conclusions: The MEM is a cost-effective research mechanism for informing common themes of experiences of cancer patients and survivors and may offer initial data to guide psychosocial oncology research design and recruitment

Sea Level Rise Explains Changing Carbon Accumulation Rates in a Salt Marsh Over the Past Two Millennia

High rates of carbon burial observed in wetland sediments have garnered attention as a potential “natural fix” to reduce the concentration of carbon dioxide (CO2) in Earth's atmosphere. A carbon accumulation rate (CAR) can be determined through various methods that integrate a carbon stock over different time periods, ranging from decades to millennia. Our goal was to assess how CAR changed over the lifespan of a salt marsh. We applied a geochronology to a series of salt marsh cores using both 14C and 210Pb markers to calculate CARs that were integrated between 35 and 2,460 years before present. CAR was 39 g C·m−2·year−1 when integrated over millennia but was upward of 148 g C·m−2·year−1 for the past century. We present additional evidence to account for this variability by linking it to changes in relative sea level rise (RSLR), where higher rates of RSLR were associated with higher CARs. Thus, the CAR calculated for a wetland should integrate timescales that capture the influence of contemporary RSLR. Therefore, caution should be exercised not to utilize a CAR calculated over inappropriately short or long timescales as a current assessment or forecasting tool for the climate change mitigation potential of a wetland

Roles of mitophagy and the mitochondrial permeability transition in remodeling of cultured rat hepatocytes

In primary culture, hepatocytes dedifferentiate, and their cytoplasm undergoes remodeling. Here, our aim was to characterize changes of mitochondria during remodeling. Hepatocytes were cultured one to five days in complete serum-containing Waymouth’s medium. In rat hepatocytes loaded with MitoTracker Green (MTG), tetramethylrhodamine methylester (TMRM), and/or LysoTracker Red (LTR), confocal microscopy revealed that mitochondria number and mass decreased by approximately 50% between Day 1 and Day 3 of culture. As mitochondria disappeared, lysosomes/autophagosomes proliferated five-fold. Decreased mitochondrial content correlated with (a) decreased cytochrome c oxidase activity and mitochondrial number observed by electron microscopy and (b) a profound decrease of PGC-1α mRNA expression. By contrast, mtDNA content per cell remained constant from the first to the third day of culture, although ethidium bromide (de novo mtDNA synthesis inhibitor) caused mtDNA to decrease by half from the first to the third culture day. As mitochondria disappeared, their MTG label moved into LTR-labeled lysosomes, which was indicative of autophagic degradation. A multiwell fluorescence assay revealed a 2.5-fold increase of autophagy on Day 3 of culture, which was decreased by 3-methyladenine, an inhibitor of autophagy, and also by cyclosporin A and NIM811, both selective inhibitors of the mitochondrial permeability transition (MPT). These findings indicate that mitochondrial autophagy (mitophagy) and the MPT underlie mitochondrial remodeling in cultured hepatocytes

Sequential design of computer experiments for the estimation of a probability of failure

This paper deals with the problem of estimating the volume of the excursion set of a function $f:\mathbb{R}^d \to \mathbb{R}$ above a given threshold, under a probability measure on $\mathbb{R}^d$ that is assumed to be known. In the industrial world, this corresponds to the problem of estimating a probability of failure of a system. When only an expensive-to-simulate model of the system is available, the budget for simulations is usually severely limited and therefore classical Monte Carlo methods ought to be avoided. One of the main contributions of this article is to derive SUR (stepwise uncertainty reduction) strategies from a Bayesian-theoretic formulation of the problem of estimating a probability of failure. These sequential strategies use a Gaussian process model of $f$ and aim at performing evaluations of $f$ as efficiently as possible to infer the value of the probability of failure. We compare these strategies to other strategies also based on a Gaussian process model for estimating a probability of failure.Comment: This is an author-generated postprint version. The published version is available at http://www.springerlink.co

NIM811 (N-Methyl-4-isoleucine Cyclosporine), a Mitochondrial Permeability Transition Inhibitor, Attenuates Cholestatic Liver Injury but Not Fibrosis in Mice

Cholestasis causes hepatocyte death, possibly due to mitochondrial injury. This study investigated whether NIM811, an inhibitor of the mitochondrial permeability transition (MPT), attenuates cholestatic liver injury in vivo. Cholestasis was induced in mice by bile duct ligation (BDL). NIM811 was gavaged (20 mg/kg) before BDL and daily (10 mg/kg) afterwards. Mitochondrial depolarization, cell death and MPT onset were assessed by intravital confocal/multiphoton microscopy of rhodamine 123 (Rh123), propidium iodide (PI) and calcein. After BDL, serum alanine aminotransferase (ALT), hepatic necrosis and apoptosis all increased. NIM811 decreased ALT, necrosis and apoptosis by 60 to 86%. In vehicle-treated mice at 6 h after BDL, viable hepatocytes with depolarized mitochondria were 18/high power field (hpf), and non-viable cells were ∼1/hpf, showing that depolarization preceded necrosis. Calcein entered mitochondria after BDL, indicating MPT onset in vivo. NIM811 decreased depolarization by 72%, prevented calcein entry into mitochondria and blocked release of cytochrome c. Hepatic TNFα, TGF-β1 and procollagen α1(I) mRNA, α-smooth muscle actin, and Sirius red staining for collagen increased after BDL but were not different in vehicle- and NIM811-treated mice. Taken together, NIM811 decreased cholestatic necrosis and apoptosis but did not block fibrosis, indicating that the MPT plays an important role in cholestatic cell death in vivo