True Reversal Research Articles

Kinetic Profiling of RAS Mutations With Circulating Tumor DNA in the Canadian Cancer Trials Group CO.26 Trial Suggests the Loss of RAS Mutations in Neo-RAS-Wildtype Metastatic Colorectal Cancer Is Transient.

In metastatic colorectal cancer (mCRC), RAS mutations drive resistance to anti-epidermal growth factor receptor antibodies. It is unclear whether RAS mutations ever become clonally undetectable. CO.26 was a phase II clinical trial that assessed durvalumab + tremelimumab in heavily pretreated mCRC. RAS mutation status was tracked over time using circulating tumor DNA (ctDNA) sequencing at baseline, week 8, and on progression. Among the 95 patients with KRAS/NRAS mutations in their archival tumor tissue, 6.3% (6/95) had undetectable RAS mutations in ctDNA collected at baseline or week 8 of the CO.26 study. Of these, 67% (4/6) of disappearances were transient, with the same mutation reappearing with progressive disease. In three cases, the simultaneous persistence of other preexisting CRC-associated truncal mutations could not be demonstrated, suggestive of low tumor shedding of ctDNA, leaving the incidence of true clonal reversion to RAS-wildtype (WT) possibly as low as 3.2% (3/95). Fewer patients in the neo-RAS-WT group (33%) had greater than four lesions at trial baseline compared with patients with persistent RAS mutations (75%), P = .046. The likelihood of synchronous metastases at cancer diagnosis (33% v 63%; P = .15) or liver metastases at trial baseline (50% v 68.5%; P = .17) was not significantly different between patients with disappearing versus persistent RAS mutations. Overall survival from stage IV diagnosis (hazard ratio, 0.77 [95% CI, 0.35 to 1.72]; P = .52) was not significantly different between those with disappearing versus persistent RAS mutations. The disappearance of RAS mutations was not associated with primary tumor sidedness (P = .41), archival BRAF/MEK/ERK-mutant status (P = .16/1.00/.09), nor baseline ctDNA HER2 amplifications (P = 1.00). We identified a 3.2%-6.3% prevalence of the neo-RAS-WT phenomenon in the CO.26 trial. However, 67% of apparent cases were transient with subsequent re-emergence.

Utilizing the capacity below 0 V to maximize lithium storage of hard carbon anodes

Compared with conventional graphite anode, hard carbons have the potential to make reversible lithium storage below 0 V accessible due to the formation of dendrites is slow. However, under certain conditions of high currents and lithiation depths, the irreversible plated lithium occurs and then results in the capacity losses. Herein, we systematically explore the true reversibility of hard carbon anodes below 0 V. We identify the lithiation boundary parameters that control the reversible capacity of hard carbon anodes. When the boundary capacity is controlled below 400 mAh g−1 with current density below 50 mA g−1, no lithium dendrites are observed during the lithiation process. Compared with the discharge cut-off voltage to 0 V, this boundary provides a nearly twice reversible capacity with the capacity retention of 80% after 172 cycles. The results of characterization and finite element model reveal that the large reversible capacity below 0 V of hard carbon anodes is mainly benefited from the dual effect of lithium intercalation and reversible lithium film. After the lithium intercalation, the over-lithiation induces the quick growth of lithium dendrites, worsening the electrochemical irreversibility. This work enables insights of the potentially low-voltage performance of hard carbons in lithium-ion batteries.

A Logically Reversible Double Feynman Gate with Molecular Engineered Bacteria Arranged in an Artificial Neural Network-Type Architecture.

Reversible logic gates are the key components of reversible computing that map inputs and outputs in a certain one-to-one pattern so that the output signals can reveal the pattern of the input signals. One of the main research foci of reversible computing is the implementation of basic reversible gates by various modalities. Though true thermodynamic reversibility cannot be attained within living cells, the high energy efficiency of biological reactions inspires the implementation of reversible computation in living cells. The implementation of synthetic genetic circuits is mostly based on conventional irreversible computing, and the implementation of logical reversibility in living cells is rare. Here, we constructed a 3-input-3-output synthetic genetic reversible double Feynman logic gate with a population of genetically engineered E. coli cells. Instead of following hierarchical electronic design principles, we adapted the concept of artificial neural networks (ANN) and built a single-layer artificial network-type architecture with five different engineered bacteria, named bactoneurons. We used three extracellular chemicals as input signals and the expression of three fluorescence proteins as the output signals. The cellular devices, which combine the input chemical signals linearly and pass them through a nonlinear activation function and represent specific bactoneurons, were built by designing and creating small synthetic genetic networks inside E. coli. The weights of each of the inputs and biases of individual bactoneurons in the bacterial ANN were adjusted by optimizing the synthetic genetic networks. When arranging the five bactoneurons through an ANN-type architecture, the system generated a double Feynman gate function at the population level. To our knowledge, this is the first reversible double Feynman gate realization with living cells. This work may have significance in development of biocomputer technology, reversible computation, ANN wetware, and synthetic biology.

Synthesis and structure of high-purity BaCe0.25Mn0.75O3: an improved material for thermochemical water splitting

Solar thermochemical hydrogen production (STCH) via redox-active metal oxides is an approach for direct solar-driven hydrogen generation typically using a high-temperature redox cycle involving refractory oxides and steam. Typical cycles involve high-temperature reduction of oxides to form oxygen vacancies, followed by lower temperature reaction between oxygen vacancies and steam where the oxide is re-oxidized and the steam is reduced to hydrogen. Only a few materials have demonstrated reversible cycling under the typically harsh STCH conditions (e.g. 1500°C reduction, 900°C re-oxidation) and critical questions remain on the true reversibility of non-stoichiometric multi-cation oxide systems, significantly hampered by the lack of single-phase samples for these material systems. To date, most STCH processes have relied on CeO2 as a benchmark active material, but more recently, the 12R phase of BaCe0.25Mn0.75O3 (BCM) has demonstrated greater hydrogen-generation potential at lower peak temperatures. However, previous reports of 12R-BCM have included large fractions, > 10 wt%, of secondary phases, which complicate analysis of the stability and performance. A comprehensive understanding of the redox mechanism and reversibility of the process in BCM can only be achieved with nearly single-phase samples which, to date, have been difficult to produce. Here two approaches to BCM synthesis are reported: solid state and sol–gel-based routes. It is demonstrated that both routes can be tuned to produce the 12R structure with > 97 wt% yield when annealed ≥1450°C. Herein synchrotron-based diffraction measurements of rhombohedral 12R-BCM enabled characterization of the anisotropy between thermal expansion along the c-axis and within the ab plane. The impact of high-temperature redox cycling on the stability and phase fraction of the 12R-BCM polytype was also investigated. These results offer two viable routes for synthesis of high-purity 12R-BCM critically needed for evaluating the efficacy of BCM as a STCH material and validate its ability to split water at lower temperatures over extended numbers of redox cycles.

Are palm reversals the pronoun reversals of sign language? Evidence from a fingerspelling task.

Acquisition of pronominal forms by children with autism spectrum disorder (ASD) continues to garner significant attention due to the unusual ways that such children produce and comprehend them. In particular, pronoun reversal errors (e.g., using the 2nd-person pronoun “you” to refer to oneself) have been noted in the speech of children with ASD since the very first report of the disorder. In more recent years, investigations of the signing of deaf children with ASD have documented a different phenomenon: palm orientation reversals, such that signs typically produced with an outward-facing palm are produced with the palm towards the signer, or vice versa. At the same time, true pronoun reversals have yet to be documented in the signing of deaf children on the autism spectrum. These two curious facts have led us to ask if there is evidence that palm orientation reversals in signed languages and pronoun reversals in spoken languages could be surface manifestations of the same underlying differences present in ASD. In this paper we seek to establish whether there is evidence for such an analogy, by comparing the ages at which the two phenomena appear in both typically-developing (TD) children and those with ASD, the frequency and consistency with which they appear, and their relationships with other linguistic and cognitive skills. Data are presented from a fingerspelling task given to a sample of 17 native-signing children with ASD and 24 native-signing TD children. We conclude that there are provocative parallels between pronoun reversals in spoken languages and palm reversals in signed languages, though more research is needed to definitively answer these questions.

Quantification of reversible and irreversible lithium in practical lithium-metal batteries

Accurate assessment of the reversibility of electrodes is crucial for battery performance evaluations. However, it is challenging to acquire the true reversibility of the Li anode in lithium-metal batteries, mainly because an excessive amount of Li is commonly used. Here we propose an analytic approach to quantitatively evaluate the reversibility of practical lithium-metal batteries. We identify key parameters that govern the anode reversibility and subsequently establish their relationship with the cycle number by considering the mass of active and inactive Li of the cycled Li anode. Using this method, we show that the mass of active Li can be quantitatively distinguished from the mass of inactive Li of the cycled anodes in Amp hour-level pouch cells. This work opens an avenue for accurately assessing degradation and failure in lithium-metal batteries.

A Review Article of Polyherbal Tablet for the Management of Osteoporosis

Osteoporosis is an aging problem. The declining bone mineral density (BMD) enhances the chances of fractures during minor falls. Effective pharmaceuticals are available for a rapid improvement of BMD Osteoporosis is an enormous and growing public health problem. Once considered an inevitable consequence of ageing, it is now eminently preventable and treatable. Ironically, despite tremendous therapeutic advances, there is an increasing treatment gap for patients at high fracture risk. In this Series paper, we trace the evolution of drug therapy for osteoporosis, which began in the 1940s with the demonstration by Fuller Albright that treatment with oestrogen could reverse the negative calcium balance that developed in women after menopause or oophorectomy. We note a watershed in osteoporosis drug discovery around the year 2000, when the approach to developing novel therapeutics shifted from one driven by discoveries in animal studies and clinical observations (eg, oestrogen, calcitonin, and teriparatide) or opportunistic repurposing of existing compounds (eg, bisphosphonates) to one driven by advances in fundamental bone biology (eg, denosumab) coupled with clues from patients with rare bone diseases (eg, romosozumab, odanacatib). Despite these remarkable advances, concerns about rare side-effects of anti-resorptive drugs, particularly bisphosphonates, and the absence of clear evidence in support of their long-term efficacy is leading many patients who could benefit from drug therapy to not take these drugs. As such, there remains an important clinical need to develop ways to enhance patient acceptance and compliance with these effective drugs, and to continue to develop new drugs that do not cause these side-effects and have prolonged anabolic effects on bone. Such changes could lead to a true reversal of this potentially devastating disease of ageing.

Rotavirus vaccine-derived cases in Belgium: Evidence for reversion of attenuating mutations and alternative causes of gastroenteritis

Since the introduction of live-attenuated rotavirus vaccines in Belgium in 2006, surveillance has routinely detected rotavirus vaccine-derived strains. However, their genomic landscape and potential role in gastroenteritis have not been thoroughly investigated. We compared VP7 and VP4 nucleotide sequences obtained from rotavirus surveillance with the Rotarix vaccine sequence. As a result, we identified 80 vaccine-derived strains in 5125 rotavirus-positive infants with gastroenteritis from 2007 to 2018. Using both viral metagenomics and reverse transcription qPCR, we evaluated the vaccine strains and screened for co-infecting enteropathogens. Among the 45 patients with known vaccination status, 39 were vaccinated and 87% received the vaccine less than a month before the gastroenteritis episode. Reconstruction of 30 near complete vaccine-derived genomes revealed 0–11 mutations per genome, with 88% of them being non-synonymous. This, in combination with several shared amino acid changes among strains, pointed at selection of minor variant(s) present in the vaccine. We also found that some of these substitutions were true revertants (e.g., F167L on VP4, and I45T on NSP4). Finally, co-infections with known (e.g., Clostridioides difficile and norovirus) and divergent or emerging (e.g., human parechovirus A1, salivirus A2) pathogens were detected, and we estimated that 35% of the infants likely had gastroenteritis due to a ‘non-rotavirus’ cause. Conversely, we could not rule out the vaccine-derived gastroenteritis in over half of the cases. Continued studies inspecting reversion to pathogenicity should monitor the long-time safety of live-attenuated rotavirus vaccines. All in all, the complementary approach with NGS and qPCR provided a better understanding of rotavirus vaccine strain evolution in the Belgian population and epidemiology of co-infecting enteropathogens in suspected rotavirus vaccine-derived gastroenteritis cases.

Female Bioengineering: Primordial Germ Cell Differentiation of Mesenchymal Stem Cells onto Placental Scaffolds

Introduction: Female infertility is a condition that is currently treated through the maximization of existing reserves; a necessity due to the fact that a true reversal of the processes leading to infertility is not yet technologically possible. This experiment examined the ability of mesenchymal stem cells to differentiate into primordial germ cells (PGC) when cultured onto the placental scaffold. Methods: To produce the scaffolds, the cotelydons were collected and decellularized by umbilical vessel SDS perfusion. Adipose derived cells were isolated based on rapid adherence to the plastic. Results: The isolated cells displayed the markers CD90 and 105, while lacked CD34 and CD45. When seeded onto the scaffold, the cells successfully differentiated into PGC like cells, displaying typical PGCs markers, including STELLA, OCT4, DAZL and VASA. Discussion: These materials were chosen for their low cost and wide availability. The data in this study show the promising potential of cell-scaffold complex to support the development of female tissue engineering-based regenerative medicine therapies.

On the relationship between excursions and paleomagnetic secular variation – Records from MIS 5, North Atlantic Ocean

We have recovered four new records of the paleomagnetic field variability within Marine Isotope Stage 5 (MIS 5: 71–130 ka) from deep-sea sediment cores of the Bahama Outer Ridge, western North Atlantic Ocean. These cores contain reproducible evidence of the Blake Event and are located within 300 km of cores used by Smith and Foster (1969) to define the Blake Event. Our new paleomagnetic records have both reproducible directions and relative paleointensities, but they should be considered only medium-resolution records because they were recovered from sediments with bulk accumulation rates of only ~6 cm/kyr. Paleomagnetic interpretations of the records are complicated by the fact that the Blake Event occurs partially within two narrow zones of bacterial magnetite. Our rock magnetic and paleomagnetic studies suggest that the bacterial magnetite has not contributed significantly to the directional or relative paleointensity results. Our records indicate that the Blake event occurred ~119–126,000 years BP, within MIS5e (114–130,000 years BP). The Blake Event is a local magnetic field reversal (Class II excursion) with directions flipping quickly to reversed-polarity directions, hovering statically for at least 6000 years, and then flipping quickly back to normal polarity directions. The core dynamo source for the Blake Event must have a strong axisymmetric and global-scale character to produce such a true local polarity reversal. We have carried out detailed short-interval (3 ka and 9 ka) statistical analysis of the PSV (after removal of true excursional directions) from three of our records to assess the pattern of PSV through MIS 5 and associated with the Blake Event. Reproducible statistical results among the three records suggest significant deviations away from long-term average on time scales greater than 3 ka and 9 ka. The overall angular dispersions are generally low (~10°) except for two narrow intervals (~25°). The high dispersion intervals are associated with the lowest paleointensity intervals and excursions.

Indications of seismic station phase reversals detected from parametric data in the ISC bulletin

The goodness of fit of first motion manually picked polarities from the reviewed Bulletin of the International Seismological Centre (ISC) is examined versus available earthquake mechanism solutions in order to study the behavior of seismic stations, and/or reporting agencies, over time. The probability of the reporting polarity data fitting (and not fitting) source mechanisms is quantified by calculating the probability distribution of several Bernoulli trials over a randomly perturbed set of hypocenters and velocity models for each earthquake mechanism–station polarity combination. The overall agreement of first motion polarities against source mechanisms is found to be good with a few cases of seismic stations showing indications of systematic phase reversals over certain time periods. Specifically, results were obtained for 50% of the registered stations at the ISC, and from these stations 70% show reliable operation during the operational time period under investigation, with only 3% showing the opposite, and 7% showing evidence of systematic changes in the quality of the reported first motion polarities. The rest showed great variability over short periods of time, which does not allow one to draw any conclusions. Comparing waveform data with the associated reported polarities revealed a mixture of cases of either questionable picking or true station phase reversals. The ISC is planning to make available on its website the detailed results for each station in order to make data users and seismic network operators aware of cases that need attention.

Realizing high zinc reversibility in rechargeable batteries

Rechargeable zinc metal batteries (RZMBs) offer a compelling complement to existing lithium ion and emerging lithium metal batteries for meeting the increasing energy storage demands of the future. Multiple recent reports have suggested that optimized electrolytes resolve a century-old challenge for RZMBs by achieving extremely reversible zinc plating/stripping with Coulombic efficiencies (CEs) approaching 100%. However, the disparity among published testing methods and conditions severely convolutes electrolyte performance comparisons. The lack of rigorous and standardized protocols is rapidly becoming an impediment to ongoing research and commercialization thrusts. This Perspective examines recent efforts to improve the reversibility of the zinc metal anode in terms of key parameters, including CE protocols, plating morphology, dendrite formation and long-term stability. Then we suggest the most appropriate standard protocols for future CE determination. Finally, we envision future strategies to improve zinc/electrolyte stability so that research efforts can be better aligned towards realistic performance targets for RZMB commercialization. Zinc metal batteries (ZMBs) provide a promising alternative to lithium metal batteries but share the formidable challenges in reversibility. The authors discuss the key performance metrics of ZMBs and propose a protocol to assess the true reversibility of zinc metal anodes.

Out‐of‐sample performance of bias‐corrected estimators for diffusion processes

AbstractWe investigated the out‐of‐sample forecasting performance of six bias‐corrected estimators that have recently emerged in the literature for the Ornstein–Uhlenbeck process: the naïve estimator, the Tang and Chen estimator, the Bao et al. estimator, the bootstrap estimator, the Wang et al. estimator, and the bootstrap estimator based on the Euler method, along with the benchmark least squares (LS) estimator. Our Monte Carlo simulations illustrated that the bias‐corrected estimators, except for the Bao et al. estimator, produced much worse out‐of‐sample forecasting performance than the LS estimator because these other estimators have a tendency to generate negative estimations of the mean reversion parameter when the true value is close to zero. However, if we set a zero lower bound to all of these estimators, including the LS estimator, all the bias‐corrected estimators improved the out‐of‐sample forecasting performance of the LS estimator as long as the true mean reversion parameter was not very large. These main results also hold for the Cox–Ingersoll–Ross process. Our real data applications confirmed these overall findings.

Reversal Learning in Obsessive Compulsive Disorder: Uncertainty, Punishment, Serotonin and Perseveration

Reversal-learning paradigms are key to the translational study of cognitive flexibility in OCD and other psychiatric disorders. Here we address the question of whether true reversal deficits involving perseverative behavior can be demonstrated in OCD under certain conditions by comparing a novel deterministic learning procedure with probabilistic reversal in a large sample of both medicated and unmedicated patients. We additionally investigated the role of serotonin-reuptake-inhibitors (SSRIs), uncertainty and punishment through behavioral and computational analyses.

Vision of Research on Human Linear Growth.

The human body grows in length from conception to the maximal adult height over two decades. The shortest male population averages ∼150 cm and the tallest ∼183 cm. Nonetheless the dimensions of head and trunk are highly comparable, with the vast difference in the leg length. Stunting is a personal condition in which an individual has a standing height-for-age (HAZ) of less than two standard deviations of the standard curve median. It is associated with increased mortality, morbidity, and functional deficits. The process of losing relative stature is known as linear growth retardation, first attributed to chronic protein deficiency, then to an assortment of micronutrient deficiencies, and most recently to inflammation from unhygienic environmental conditions. Public health intervention trials responding to each of these possibilities have failed to produce true reversal responses measured in the 10s of centimeters. As to biological insights, there is no convenient way to separate weight from length growth with sonographic monitoring, but a third of infants can be born stunted. Normative growth (standard curves) competes with epigenetic adaptation (programming) as the beacon for in utero growth. Major investments into field trials allow us to discard multiple micronutrients and water/sanitation/hygiene interventions as measures to reverse established stunting. The preponderance of evidence is against catch-up growth during puberty. Future publications will be in the conceptual domain, resolving metrics, while the full range of stimuli and exposures impeding growth will be elucidated. Advances in measurement techniques in anthropometry and immunology and endocrinology will be mobilized to the literature.

Surgery and paediatric inflammatory bowel disease.

The incidence of paediatric Crohn's disease (CD) and ulcerative colitis (UC) is increasing. Surgical intervention is required during childhood in approximately 25% of children diagnosed with CD, and for 10% of those diagnosed with UC. Although there is evidence that the rate of surgical intervention undertaken in children is decreasing since the introduction of biologic therapy, this may only represent a delay rather than true reversal of the risk of surgery. Surgery for CD is not curative and limited resection is the key principle thus preserving bowel length. For UC, subtotal colectomy is relatively curative; ileo-anal pouch anastomosis can be performed to restore bowel continuity.

A review of the etiologies, clinical characteristics, and treatment of canities.

Hair pigmentation is regulated by follicular melanogenesis, in which the process consists of melanin formation and transfer to keratinocytes in the hair shaft. Human hair follicles contain two types of melanin: the brown-black eumelanin and yellow-red pheomelanin. Eumelanin is commonly present in black and brown hair while pheomelanin is found in auburn and blonde hair. Hair follicle melanogenesis is under cyclical control and is concurrently coupled to hair growth. Many factors including intrinsic and extrinsic factors affect the follicular melanogenesis. Though many studies have been conducted to identify the pathogenesis and regulation of hair pigmentation, the etiology of canities and hair pigmentation is still unclear. The pathogenesis of canities or gray hair is believed to occur either from insufficient melanin formation due to melanocyte degeneration or a defect in melanosomal transfer. Canities is an aging sign which often interferes with one's socio-cultural adjustment. On the other hand, premature canities correlate with diseases such as osteopenia and cardiovascular disease. Risk factors associated with canities are not only genetic but also external causes. For example, smoking, alcohol consumption, and stress are among the most common factors. Camouflage techniques are still used as the primary treatment of canities. Further treatments for canities are being developed to achieve the true reversal of hair pigmentation.

Synoptically classified lake-effect snowfall trends to the lee of Lakes Erie and Ontario

CR Climate Research Contact the journal Facebook Twitter RSS Mailing List Subscribe to our mailing list via Mailchimp HomeLatest VolumeAbout the JournalEditorsSpecials CR 74:1-13 (2017) - DOI: https://doi.org/10.3354/cr01480 Synoptically classified lake-effect snowfall trends to the lee of Lakes Erie and Ontario Zachary J. Suriano*, Daniel J. Leathers Department of Geography, University of Delaware, Newark, DE 19716, USA *Corresponding author: zsuriano@udel.edu ABSTRACT: Recent research has indicated that snowfall in portions of the North American Great Lakes region subject to lake-effect snow has undergone a trend reversal, with snowfall declining in recent decades. This study examines the seasonal variability and trends specifically in synoptically classified lake-effect snow across the eastern Great Lakes region, and investigates the mechanisms responsible for observed changes. Using a synoptic climatological approach, days are identified where the synoptic-scale conditions are conducive to lake-effect snowfall and the associated snowfall is analyzed. Seven synoptic types over the November to March snowfall season are identified with characteristics of lake-effect conditions. Snowfall from these 7 lake-effect synoptic types represents between 45 and 53% of the seasonal snowfall total along the eastern shores of Lakes Erie and Ontario, with snowfall totals being highest during January. Lake-effect snowfall exhibits a 60 yr increasing trend downwind of Lakes Erie and Ontario; however, through examination over shorter 30 yr periods, a change in the trend of snowfall is observed around 1980. While a true trend reversal is not detected, lake-effect snowfall significantly increases from 1950-1979 before exhibiting no significant trend from 1980-2009. The inter-annual variability of seasonal lake-effect snowfall is highly related to the frequency of lake-effect synoptic types where an increase (decrease) in synoptic type occurrence leads to enhanced (diminished) lake-effect snowfall totals. Depending on the period examined, long-term changes in the frequency of lake-effect synoptic types and snowfall rates represent between 89 and 95% of the observed changes in lake-effect snow. KEY WORDS: Great Lakes · Synoptic classification · Snowfall variability · Climate change · Lake effect Full text in pdf format NextCite this article as: Suriano ZJ, Leathers DJ (2017) Synoptically classified lake-effect snowfall trends to the lee of Lakes Erie and Ontario. Clim Res 74:1-13. https://doi.org/10.3354/cr01480 Export citation RSS - Facebook - Tweet - linkedIn Cited by Published in CR Vol. 74, No. 1. Online publication date: October 16, 2017 Print ISSN: 0936-577X; Online ISSN: 1616-1572 Copyright © 2017 Inter-Research.

LC-MS/MS proteomic analysis of starved Bacillus subtilis cells overexpressing ribonucleotide reductase (nrdEF): implications in stress-associated mutagenesis.

The non-appropriate conditions faced by nutritionally stressed bacteria propitiate error-prone repair events underlying stationary-phase- or stress-associated mutagenesis (SPM). The genetic and molecular mechanisms involved in SPM have been deeply studied but the biochemical aspects of this process have so far been less explored. Previous evidence showed that under conditions of nutritional stress, non-dividing cells of strain B. subtilis YB955 overexpressing ribonucleotide reductase (RNR) exhibited a strong propensity to generate true reversions in the hisC952 (amber), metB5 (ochre) and leuC425 (missense) mutant alleles. To further advance our knowledge on the metabolic conditions underlying this hypermutagenic phenotype, a high-throughput LC-MS/MS proteomic analysis was performed in non-dividing cells of an amino acid-starved strain, deficient for NrdR, the RNR repressor. Compared with the parental strain, the level of 57 proteins was found to increase and of 80 decreases in the NrdR-deficient strain. The proteomic analysis revealed an altered content in proteins associated with the stringent response, nucleotide metabolism, DNA repair, and cell signaling in amino acid-starved cells of the ∆nrdR strain. Overall, our results revealed that amino acid-starved cells of strain B. subtilis ∆nrdR that escape from growth-limiting conditions exhibit a complex proteomic pattern reminiscent of a disturbed metabolism. Future experiments aimed to understand the consequences of disrupting the cell signaling pathways unveiled in this study, will advance our knowledge on the genetic adaptations deployed by bacteria to escape from growth-limiting environments.

New Insights into Parasitic Reactions in Non-Aqueous Alkaline-O2 Batteries

Non-aqueous lithium-oxygen batteries depend critically on the reversible formation and on the decomposition of lithium oxides on cycling [1-3]. The discharge reaction in the cathode of nonaqueous Li-O2 batteries involves the reduction of O2 and the formation of solid Li2O2. The process is reverse on charge. True reversibility of the cathode reaction in the Li-O2 battery requires a set of qualities to obey the stoichiometry and to match each other during discharge and subsequent charge. These are 1) e-/O2 = 2 both on discharge and charge, 2) to produce/consume exactly one mole of Li2O2 and one mole of O2 per 2e- and on discharge/charge, 3) absence of any other gas evolution, e.g. CO2, or generation of solid products other than Li2O2 during discharge and charge, 4) O2 consumed during discharge matches the amount released on subsequent charge. Typically these measures deviate more or less significantly from the ideal due to parasitic reactions, whose source has not been entirely identified. Irreversible parasitic reactions have predominantly been ascribed to the reactivity of reduced oxygen species, e.g., superoxide with cell components [4-6]. These species, however, cannot fully explain these observed side reactions. Only better knowledge of parasitic reactions will allow inhibiting them and reaching towards fully reversible cell reactions. We will discuss recent insights into irreversible parasitic reactions during cycling of a Li-O2 battery, that have so far been overlooked, their detection via newly developed methods and strategies to suppress them effectively [7]. Awareness of these reactions in non-aqueous Li-O2batteries gives a rationale for future research towards achieving highly reversible cell operation.