Degeneracy: a link between evolvability, robustness and complexity in biological systems

A full accounting of biological robustness remains elusive; both in terms of the mechanisms by which robustness is achieved and the forces that have caused robustness to grow over evolutionary time. Although its importance to topics such as ecosystem services and resilience is well recognized, the broader relationship between robustness and evolution is only starting to be fully appreciated. A renewed interest in this relationship has been prompted by evidence that mutational robustness can play a positive role in the discovery of adaptive innovations (evolvability) and evidence of an intimate relationship between robustness and complexity in biology. This paper offers a new perspective on the mechanics of evolution and the origins of complexity, robustness, and evolvability. Here we explore the hypothesis that degeneracy, a partial overlap in the functioning of multi-functional components, plays a central role in the evolution and robustness of complex forms. In support of this hypothesis, we present evidence that degeneracy is a fundamental source of robustness, it is intimately tied to multi-scaled complexity, and it establishes conditions that are necessary for system evolvability

Cavity QED with a Bose-Einstein condensate

Cavity quantum electrodynamics (cavity QED) describes the coherent interaction between matter and an electromagnetic field confined within a resonator structure, and is providing a useful platform for developing concepts in quantum information processing. By using high-quality resonators, a strong coupling regime can be reached experimentally in which atoms coherently exchange a photon with a single light-field mode many times before dissipation sets in. This has led to fundamental studies with both microwave and optical resonators. To meet the challenges posed by quantum state engineering and quantum information processing, recent experiments have focused on laser cooling and trapping of atoms inside an optical cavity. However, the tremendous degree of control over atomic gases achieved with Bose-Einstein condensation has so far not been used for cavity QED. Here we achieve the strong coupling of a Bose-Einstein condensate to the quantized field of an ultrahigh-finesse optical cavity and present a measurement of its eigenenergy spectrum. This is a conceptually new regime of cavity QED, in which all atoms occupy a single mode of a matter-wave field and couple identically to the light field, sharing a single excitation. This opens possibilities ranging from quantum communication to a wealth of new phenomena that can be expected in the many-body physics of quantum gases with cavity-mediated interactions.Comment: 6 pages, 4 figures; version accepted for publication in Nature; updated Fig. 4; changed atom numbers due to new calibratio

ULTRAVIOLET SPECTROSCOPY OF TYPE IIB SUPERNOVAE: DIVERSITY AND THE IMPACT OF CIRCUMSTELLAR MATERIAL

We present new Hubble Space Telescope (HST) multi-epoch ultraviolet (UV) spectra of the bright Type IIb SN 2013df, and undertake a comprehensive analysis of the set of four SNe IIb for which HST UV spectra are available (SN 1993J, SN 2001ig, SN 2011dh, and SN 2013df). We find strong diversity in both continuum levels and line features among these objects. We use radiative-transfer models that fit the optical part of the spectrum well, and find that in three of these four events we see a UV continuum flux excess, apparently unaffected by line absorption. We hypothesize that this emission originates above the photosphere, and is related to interaction with circumstellar material (CSM) located in close proximity to the SN progenitor. In contrast, the spectra of SN 2001ig are well fit by single-temperature models, display weak continuum and strong reverse-fluorescence features, and are similar to spectra of radioactive 56Ni-dominated SNe Ia. A comparison of the early shock-cooling components in the observed light curves with the UV continuum levels which we assume trace the strength of CSM interaction suggests that events with slower cooling have stronger CSM emission. The radio emission from events having a prominent UV excess is perhaps consistent with slower blast-wave velocities, as expected if the explosion shock was slowed down by the CSM that is also responsible for the strong UV, but this connection is currently speculative as it is based on only a few events

Spectra of supernovae in the nebular phase

When supernovae enter the nebular phase after a few months, they reveal spectral fingerprints of their deep interiors, glowing by radioactivity produced in the explosion. We are given a unique opportunity to see what an exploded star looks like inside. The line profiles and luminosities encode information about physical conditions, explosive and hydrostatic nucleosynthesis, and ejecta morphology, which link to the progenitor properties and the explosion mechanism. Here, the fundamental properties of spectral formation of supernovae in the nebular phase are reviewed. The formalism between ejecta morphology and line profile shapes is derived, including effects of scattering and absorption. Line luminosity expressions are derived in various physical limits, with examples of applications from the literature. The physical processes at work in the supernova ejecta, including gamma-ray deposition, non-thermal electron degradation, ionization and excitation, and radiative transfer are described and linked to the computation and application of advanced spectral models. Some of the results derived so far from nebular-phase supernova analysis are discussed.Comment: Book chapter for 'Handbook of Supernovae,' edited by Alsabti and Murdin, Springer. 51 pages, 14 figure

CP violation Beyond the MSSM: Baryogenesis and Electric Dipole Moments

We study electroweak baryogenesis and electric dipole moments in the presence of the two leading-order, non-renormalizable operators in the Higgs sector of the MSSM. Significant qualitative and quantitative differences from MSSM baryogenesis arise due to the presence of new CP-violating phases and to the relaxation of constraints on the supersymmetric spectrum (in particular, both stops can be light). We find: (1) spontaneous baryogenesis, driven by a change in the phase of the Higgs vevs across the bubble wall, becomes possible; (2) the top and stop CP-violating sources can become effective; (3) baryogenesis is viable in larger parts of parameter space, alleviating the well-known fine-tuning associated with MSSM baryogenesis. Nevertheless, electric dipole moments should be measured if experimental sensitivities are improved by about one order of magnitude.Comment: 33 pages, 6 figure

Mechanochemical basis of protein degradation by a double-ring AAA+ machine

Molecular machines containing double or single AAA+ rings power energy-dependent protein degradation and other critical cellular processes, including disaggregation and remodeling of macromolecular complexes. How the mechanical activities of double-ring and single-ring AAA+ enzymes differ is unknown. Using single-molecule optical trapping, we determine how the double-ring ​ClpA enzyme from Escherichia coli, in complex with the ​ClpP peptidase, mechanically degrades proteins. We demonstrate that ​ClpA unfolds some protein substrates substantially faster than does the single-ring ​ClpX enzyme, which also degrades substrates in collaboration with ​ClpP. We find that ​ClpA is a slower polypeptide translocase and that it moves in physical steps that are smaller and more regular than steps taken by ​ClpX. These direct measurements of protein unfolding and translocation define the core mechanochemical behavior of a double-ring AAA+ machine and provide insight into the degradation of proteins that unfold via metastable intermediates.Howard Hughes Medical InstituteNational Institutes of Health (U.S.) (Grant AI-16892

The predictive and prognostic potential of plasma telomerase reverse transcriptase (TERT) RNA in rectal cancer patients

Background: Preoperative chemoradiotherapy (CRT) followed by surgery is the standard care for locally advanced rectal cancer, but tumour response to CRT and disease outcome are variable. The current study aimed to investigate the effectiveness of plasma telomerase reverse transcriptase (TERT) levels in predicting tumour response and clinical outcome. Methods: 176 rectal cancer patients were included. Plasma samples were collected at baseline (before CRT\ubcT0), 2 weeks after CRT was initiated (T1), post-CRT and before surgery (T2), and 4\u20138 months after surgery (T3) time points. Plasma TERT mRNA levels and total cell-free RNA were determined using real-time PCR. Results: Plasma levels of TERT were significantly lower at T2 (Po0.0001) in responders than in non-responders. Post-CRT TERT levels and the differences between pre- and post-CRT TERT levels independently predicted tumour response, and the prediction model had an area under curve of 0.80 (95% confidence interval (CI) 0.73\u20130.87). Multiple analysis demonstrated that patients with detectable TERT levels at T2 and T3 time points had a risk of disease progression 2.13 (95% CI 1.10\u20134.11)-fold and 4.55 (95% CI 1.48\u201313.95)-fold higher, respectively, than those with undetectable plasma TERT levels. Conclusions: Plasma TERT levels are independent markers of tumour response and are prognostic of disease progression in rectal cancer patients who undergo neoadjuvant therapy

Feasibility of Image-Guided Radiotherapy for Elderly Patients with Locally Advanced Rectal Cancer

PURPOSE: The study aims to assess the tolerance of elderly patients (70 years or older) with locally advanced rectal cancers to image-guided radiotherapy (IGRT). A retrospective review of 13 elderly patients with locally advanced rectal cancer who underwent preoperative chemoradiation using IGRT was performed. Grade 3-4 acute toxicities, survival, and long-term complications were compared to 17 younger patients (<70 years) with the same disease stage. RESULTS: Grade 3-4 hematologic toxicities occurred in 7.6% and 0% (p = 0.4) and gastrointestinal toxicities, and, in 15.2% and 5% (p = 0.5), of elderly and younger patients, respectively. Surgery was aborted in three patients, two in the elderly group and one in the younger group. One patient in the elderly group died after surgery from cardiac arrhythmia. After a median follow-up of 34 months, five patients had died, two in the elderly and three in the younger group. The 3-year survival was 90.9% and 87.5% (p = 0.7) for the elderly and younger group respectively. Two patients in the younger group developed ischemic colitis and fecal incontinence. There was no statistically significant difference in acute and late toxicities as well as survival between the two groups. CONCLUSIONS AND CLINICAL RELEVANCE: Elderly patients with locally advanced rectal cancers may tolerate preoperative chemoradiation with IGRT as well as younger patients. Further prospective studies should be performed to investigate the potential of IGRT for possible cure in elderly patients with locally advanced rectal cancer

The deep-subsurface sulfate reducer Desulfotomaculum kuznetsovii employs two methanol-degrading pathways

Methanol is generally metabolized through a pathway initiated by a cobalamine-containing methanol methyltransferase by anaerobic methylotrophs (such as methanogens and acetogens), or through oxidation to formaldehyde using a methanol dehydrogenase by aerobes. Methanol is an important substrate in deep-subsurface environments, where thermophilic sulfate-reducing bacteria of the genus Desulfotomaculum have key roles. Here, we study the methanol metabolism of Desulfotomaculum kuznetsovii strain 17T, isolated from a 3000-m deep geothermal water reservoir. We use proteomics to analyze cells grown with methanol and sulfate in the presence and absence of cobalt and vitamin B12. The results indicate the presence of two methanol-degrading pathways in D. kuznetsovii, a cobalt-dependent methanol methyltransferase and a cobalt-independent methanol dehydrogenase, which is further confirmed by stable isotope fractionation. This is the first report of a microorganism utilizing two distinct methanol conversion pathways. We hypothesize that this gives D. kuznetsovii a competitive advantage in its natural environment.Research was funded by grants of the Division of Chemical Sciences (CW-TOP 700.55.343) and Earth and Life Sciences (ALW 819.02.014) of The Netherlands Organisation for Scientific Research (NWO), the European Research Council (ERC grant 323009), and the Gravitation grant (024.002.002) of the Netherlands Ministry of Education, Culture and Scienceinfo:eu-repo/semantics/publishedVersio

Industrial Systems Biology of Saccharomyces cerevisiae Enables Novel Succinic Acid Cell Factory.

Saccharomyces cerevisiae is the most well characterized eukaryote, the preferred microbial cell factory for the largest industrial biotechnology product (bioethanol), and a robust commerically compatible scaffold to be exploitted for diverse chemical production. Succinic acid is a highly sought after added-value chemical for which there is no native pre-disposition for production and accmulation in S. cerevisiae. The genome-scale metabolic network reconstruction of S. cerevisiae enabled in silico gene deletion predictions using an evolutionary programming method to couple biomass and succinate production. Glycine and serine, both essential amino acids required for biomass formation, are formed from both glycolytic and TCA cycle intermediates. Succinate formation results from the isocitrate lyase catalyzed conversion of isocitrate, and from the alpha-keto-glutarate dehydrogenase catalyzed conversion of alpha-keto-glutarate. Succinate is subsequently depleted by the succinate dehydrogenase complex. The metabolic engineering strategy identified included deletion of the primary succinate consuming reaction, Sdh3p, and interruption of glycolysis derived serine by deletion of 3-phosphoglycerate dehydrogenase, Ser3p/Ser33p. Pursuing these targets, a multi-gene deletion strain was constructed, and directed evolution with selection used to identify a succinate producing mutant. Physiological characterization coupled with integrated data analysis of transcriptome data in the metabolically engineered strain were used to identify 2nd-round metabolic engineering targets. The resulting strain represents a 30-fold improvement in succinate titer, and a 43-fold improvement in succinate yield on biomass, with only a 2.8-fold decrease in the specific growth rate compared to the reference strain. Intuitive genetic targets for either over-expression or interruption of succinate producing or consuming pathways, respectively, do not lead to increased succinate. Rather, we demonstrate how systems biology tools coupled with directed evolution and selection allows non-intuitive, rapid and substantial re-direction of carbon fluxes in S. cerevisiae, and hence show proof of concept that this is a potentially attractive cell factory for over-producing different platform chemicals