Recent studies have propagated the model that the mitochondrial unfolded protein response (UPR(mt)) is causal for lifespan extension from inhibition of the electron transport chain (ETC) in ...Caenorhabditis elegans. Here we report a genome-wide RNAi screen for negative regulators of the UPR(mt). Lifespan analysis of nineteen RNAi clones that induce the hsp-6p::gfp reporter demonstrate differential effects on longevity. Deletion of atfs-1, which is required for induction of the UPR(mt), fails to prevent lifespan extension from knockdown of two genes identified in our screen or following knockdown of the ETC gene cco-1. RNAi knockdown of atfs-1 also has no effect on lifespan extension caused by mutation of the ETC gene isp-1. Constitutive activation of the UPR(mt) by gain of function mutations in atfs-1 fails to extend lifespan. These observations identify several new factors that promote mitochondrial homoeostasis and demonstrate that the UPR(mt), as currently defined, is neither necessary nor sufficient for lifespan extension.
Digital computing is nearing its physical limits as computing needs and energy consumption rapidly increase. Analogue‐memory‐based neuromorphic computing can be orders of magnitude more energy ...efficient at data‐intensive tasks like deep neural networks, but has been limited by the inaccurate and unpredictable switching of analogue resistive memory. Filamentary resistive random access memory (RRAM) suffers from stochastic switching due to the random kinetic motion of discrete defects in the nanometer‐sized filament. In this work, this stochasticity is overcome by incorporating a solid electrolyte interlayer, in this case, yttria‐stabilized zirconia (YSZ), toward eliminating filaments. Filament‐free, bulk‐RRAM cells instead store analogue states using the bulk point defect concentration, yielding predictable switching because the statistical ensemble behavior of oxygen vacancy defects is deterministic even when individual defects are stochastic. Both experiments and modeling show bulk‐RRAM devices using TiO2‐X switching layers and YSZ electrolytes yield deterministic and linear analogue switching for efficient inference and training. Bulk‐RRAM solves many outstanding issues with memristor unpredictability that have inhibited commercialization, and can, therefore, enable unprecedented new applications for energy‐efficient neuromorphic computing. Beyond RRAM, this work shows how harnessing bulk point defects in ionic materials can be used to engineer deterministic nanoelectronic materials and devices.
A resistive memory cell based on the electrochemical migration of oxygen vacancies for in‐memory neuromorphic computing is presented. By using the average statistical behavior of all oxygen vacancies to store analogue information states, this cell overcomes the stochastic and unpredictable switching plaguing filament‐forming memristors, and instead achieves linear, predictable, and deterministic switching.
Mutations affecting ciliary components cause ciliopathies. As described here, we investigated Tectonic1 (Tctn1), a regulator of mouse Hedgehog signaling, and found that it is essential for ...ciliogenesis in some, but not all, tissues. Cell types that do not require Tctn1 for ciliogenesis require it to localize select membrane-associated proteins to the cilium, including Arl13b, AC3, Smoothened and Pkd2. Tctn1 forms a complex with multiple ciliopathy proteins associated with Meckel and Joubert syndromes, including Mks1, Tmem216, Tmem67, Cep290, B9d1, Tctn2 and Cc2d2a. Components of this complex co-localize at the transition zone, a region between the basal body and ciliary axoneme. Like Tctn1, loss of Tctn2, Tmem67 or Cc2d2a causes tissue-specific defects in ciliogenesis and ciliary membrane composition. Consistent with a shared function for complex components, we identified a mutation in TCTN1 that causes Joubert syndrome. Thus, a transition zone complex of Meckel and Joubert syndrome proteins regulates ciliary assembly and trafficking, suggesting that transition zone dysfunction is the cause of these ciliopathies.
Conspectus Laboratory-based experimental astrochemistry regularly entails simulation of astrophysical environments whereby low-temperature condensed ices are exposed to radiation from ultraviolet ...(UV) photons or energetic charged particles. Here, excited atoms/radicals are generated that are not in thermal equilibrium with their surroundings (i.e., they are nonthermal, or suprathermal). These species can surpass typical reaction barriers and partake in unusual chemical processes leading to novel molecular species. Often, these are uniquely observable under low-temperature conditions where the surrounding ice matrix can stabilize excited intermediates that would otherwise fall apart. Fourier-transform infrared (FTIR) spectroscopy is traditionally utilized to monitor the evolution of chemical species within ices in situ during radiolysis. Yet, the characterization and quantification of novel species and radicals formed within astrophysical ices is often hindered since many of these cannot be synthesized by traditional synthetic chemistry. Computational approaches can provide fundamental vibrational frequencies and isotopic shifts to help aid in assignments alongside infrared intensities and Raman activities to quantify levels of production. In this Account, we begin with a brief history and background regarding the composition and radiation of interstellar ices. We review details of some of the early work on carbon oxides produced during the radiolysis of pure carbon dioxide ices and contention around the carrier of an absorption feature that could potentially be a product of radiation. We then provide an overview of current and emerging experimental methodologies and some of the chemistries that occur via nonthermal processes during radiolysis of low-temperature ices. Next, we detail computational approaches to reliably predict vibrational frequencies, infrared intensities, and Raman activities based on our recent work. Our focus then turns to studies on the formation of complex organics and carbon oxides, highlighting those aided by computational approaches and their role in astrochemistry. Some recent controversies regarding assignments alongside our recent results on the characterization of novel carbon oxide species are discussed. We present an argument for the potential role of carbon oxides within cometary ices as parent molecular species for small volatiles. We provide an overview of some of the complex organic species that can be formed within interstellar and cometary ices that contain either carbon monoxide or carbon dioxide. We examine how Raman spectroscopy could potentially be leveraged to help determine and characterize carbon oxides in future experiments as well as how computational approaches can aid in these assignments. We conclude with brief remarks on future directions our research group is taking to unravel astrochemically relevant carbon oxides using combined computational and experimental approaches.
Formamide, H2NCHO, represents the simplest molecule containing the peptide bond. Consequently, the formamide molecule is of high interest as it is considered an important precursor in the abiotic ...synthesis of amino acids, and thus significant to further prebiotic chemistry, in more suitable environments. Previous experiments have demonstrated that formamide is formed under extreme conditions similar throughout the interstellar medium via photolysis and the energetic processing of ultracold interstellar and solar system ices with high-energy protons; however, no clear reaction mechanism has been identified. Utilizing a laboratory apparatus capable of simulating the effects of galactic cosmic radiation on ultralow temperature ice mixtures, we have examined the formation of formamide starting from a variety of carbon monoxide (CO) to ammonia (NH3) ices of varying composition. Our results suggest that the primary reaction step leading to the production of formamide in low-temperature ices involves the cleavage of the nitrogen-hydrogen bond of ammonia forming the amino radical (NH2) and atomic hydrogen (H), the latter of which containing excess kinetic energy. These suprathermal hydrogen atoms can then add to the carbon-oxygen triple bond of the carbon monoxide (CO) molecule, overcoming the entrance barrier, and ultimately producing the formyl radical (HCO). From here, the formyl radical may combine without an entrance barrier with the neighboring amino radical if the proper geometry for these two species exists within the matrix cage.
The complete assessment of vision-related abilities should consider visual function (the performance of components of the visual system) and functional vision (visual task-related ability). ...Assessment methods are highly dependent upon individual characteristics (eg, the presence and type of visual impairment). Typical visual function tests assess factors such as visual acuity, contrast sensitivity, color, depth, and motion perception. These properties each represent an aspect of visual function and may impact an individual's level of functional vision. The goal of any functional vision assessment should be to measure the visual task-related ability under real-world scenarios. Recent technological advancements such as virtual reality can provide new opportunities to improve traditional vision assessments by providing novel objective and ecologically valid measurements of performance, and allowing for the investigation of their neural basis. In this review, visual function and functional vision evaluation approaches are discussed in the context of traditional and novel acquisition methods.
Many developers wish to capitalize on touch-screen technology for developing aids for the blind, particularly by incorporating vibrotactile stimulation to convey patterns on their surfaces, which ...otherwise are featureless. Our belief is that they will need to take into account basic research on haptic perception in designing these graphics interfaces. We point out constraints and limitations in haptic processing that affect the use of these devices. We also suggest ways to use sound to augment basic information from touch, and we include evaluation data from users of a touch-screen device with vibrotactile and auditory feedback that we have been developing, called a vibro-audio interface.
BACKGROUND:Current standard audible medical alarms are difficult to learn and distinguish from one another. Auditory icons represent a new type of alarm that has been shown to be easier to learn and ...identify in laboratory settings by lay subjects. In this study, we test the hypothesis that icon alarms are easier to learn and identify than standard alarms by anesthesia providers in a simulated clinical setting.
METHODS:Twenty anesthesia providers were assigned to standard or icon groups. Experiments were conducted in a simulated intensive care unit. After a brief group-specific alarm orientation, subjects identified patient-associated alarm sounds during the simulation and logged responses via a tablet computer. Each subject participated in the simulation twice and was exposed to 32 alarm annunciations. Primary outcome measures were response accuracy and response times. Secondary outcomes included assessments of perceived fatigue and task load.
RESULTS:Overall accuracy rate in the standard alarm group was 43% (mean) and in the icon group was 88% (mean). Subjects in the icon group were 26.1 (odds ratio 98.75% CI, 8.4 to 81.5; P < 0.001) times more likely to correctly identify an alarm. Response times in the icon group were shorter than in the standard alarm group (12 vs. 15 s, difference 3 s 98.75% CI ,1 to 5; P < 0.001).
CONCLUSIONS:Under our simulated conditions, anesthesia providers more correctly and quickly identified icon alarms than standard alarms. Subjects were more likely to perceive higher fatigue and task load when using current standard alarms than icon alarms.
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