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991.
Kristine Faye R. Pobre David L. Powers Kingshuk Ghosh Lila M. Gierasch Evan T. Powers 《Protein science : a publication of the Protein Society》2019,28(7):1324-1339
The effect of mutations in individual proteins on protein homeostasis, or “proteostasis,” can in principle depend on the mutations' effects on the thermodynamics or kinetics of folding, or both. Here, we explore this issue using a computational model of in vivo protein folding that we call FoldEcoSlim. Our model predicts that kinetic versus thermodynamic control of mutational effects on proteostasis hinges on the relationship between how fast a protein's folding reaction reaches equilibrium and a critical time scale that characterizes the lifetime of a protein in its environment: for rapidly dividing bacteria, this time scale is that of cell division; for proteins that are produced in heterologous expression systems, this time scale is the amount of time before the protein is harvested; for proteins that are synthesized in and then exported from the eukaryotic endoplasmic reticulum, this time scale is that of protein secretion, and so forth. This prediction was validated experimentally by examining the expression yields of the wild type and several destabilized mutants of a model protein, the mouse ortholog of cellular retinoic acid‐binding protein 1. 相似文献
992.
Agnieszka Wujeska‐Klause Kristine Y. Crous Oula Ghannoum David S. Ellsworth 《Global Change Biology》2019,25(4):1282-1295
Rising atmospheric CO2 concentrations is expected to stimulate photosynthesis and carbohydrate production, while inhibiting photorespiration. By contrast, nitrogen (N) concentrations in leaves generally tend to decline under elevated CO2 (eCO2), which may reduce the magnitude of photosynthetic enhancement. We tested two hypotheses as to why leaf N is reduced under eCO2: (a) A “dilution effect” caused by increased concentration of leaf carbohydrates; and (b) inhibited nitrate assimilation caused by reduced supply of reductant from photorespiration under eCO2. This second hypothesis is fully tested in the field for the first time here, using tall trees of a mature Eucalyptus forest exposed to Free‐Air CO2 Enrichment (EucFACE) for five years. Fully expanded young and mature leaves were both measured for net photosynthesis, photorespiration, total leaf N, nitrate () concentrations, carbohydrates and reductase activity to test these hypotheses. Foliar N concentrations declined by 8% under eCO2 in new leaves, while the fraction and total carbohydrate concentrations remained unchanged by CO2 treatment for either new or mature leaves. Photorespiration decreased 31% under eCO2 supplying less reductant, and in situ reductase activity was concurrently reduced (?34%) in eCO2, especially in new leaves during summer periods. Hence, assimilation was inhibited in leaves of E. tereticornis and the evidence did not support a significant dilution effect as a contributor to the observed reductions in leaf N concentration. This finding suggests that the reduction of reductase activity due to lower photorespiration in eCO2 can contribute to understanding how eCO2‐induced photosynthetic enhancement may be lower than previously expected. We suggest that large‐scale vegetation models simulating effects of eCO2 on N biogeochemistry include both mechanisms, especially where is major N source to the dominant vegetation and where leaf flushing and emergence occur in temperatures that promote high photorespiration rates. 相似文献
993.
Nicholas G. Smith Trevor F. Keenan I. Colin Prentice Han Wang Ian J. Wright Ülo Niinemets Kristine Y. Crous Tomas F. Domingues Rossella Guerrieri F. Yoko Ishida Jens Kattge Eric L. Kruger Vincent Maire Alistair Rogers Shawn P. Serbin Lasse Tarvainen Henrique F. Togashi Philip A. Townsend Meng Wang Lasantha K. Weerasinghe Shuang‐Xi Zhou 《Ecology letters》2019,22(3):506-517
Earth system models (ESMs) use photosynthetic capacity, indexed by the maximum Rubisco carboxylation rate (Vcmax), to simulate carbon assimilation and typically rely on empirical estimates, including an assumed dependence on leaf nitrogen determined from soil fertility. In contrast, new theory, based on biochemical coordination and co‐optimization of carboxylation and water costs for photosynthesis, suggests that optimal Vcmax can be predicted from climate alone, irrespective of soil fertility. Here, we develop this theory and find it captures 64% of observed variability in a global, field‐measured Vcmax dataset for C3 plants. Soil fertility indices explained substantially less variation (32%). These results indicate that environmentally regulated biophysical constraints and light availability are the first‐order drivers of global photosynthetic capacity. Through acclimation and adaptation, plants efficiently utilize resources at the leaf level, thus maximizing potential resource use for growth and reproduction. Our theory offers a robust strategy for dynamically predicting photosynthetic capacity in ESMs. 相似文献
994.
Audrey N. Chang Pavan K. Battiprolu Patrick M. Cowley Guohua Chen Robert D. Gerard Jose R. Pinto Joseph A. Hill Anthony J. Baker Kristine E. Kamm James T. Stull 《The Journal of biological chemistry》2015,290(17):10703-10716
In beating hearts, phosphorylation of myosin regulatory light chain (RLC) at a single site to 0.45 mol of phosphate/mol by cardiac myosin light chain kinase (cMLCK) increases Ca2+ sensitivity of myofilament contraction necessary for normal cardiac performance. Reduction of RLC phosphorylation in conditional cMLCK knock-out mice caused cardiac dilation and loss of cardiac performance by 1 week, as shown by increased left ventricular internal diameter at end-diastole and decreased fractional shortening. Decreased RLC phosphorylation by conventional or conditional cMLCK gene ablation did not affect troponin-I or myosin-binding protein-C phosphorylation in vivo. The extent of RLC phosphorylation was not changed by prolonged infusion of dobutamine or treatment with a β-adrenergic antagonist, suggesting that RLC is constitutively phosphorylated to maintain cardiac performance. Biochemical studies with myofilaments showed that RLC phosphorylation up to 90% was a random process. RLC is slowly dephosphorylated in both noncontracting hearts and isolated cardiac myocytes from adult mice. Electrically paced ventricular trabeculae restored RLC phosphorylation, which was increased to 0.91 mol of phosphate/mol of RLC with inhibition of myosin light chain phosphatase (MLCP). The two RLCs in each myosin appear to be readily available for phosphorylation by a soluble cMLCK, but MLCP activity limits the amount of constitutive RLC phosphorylation. MLCP with its regulatory subunit MYPT2 bound tightly to myofilaments was constitutively phosphorylated in beating hearts at a site that inhibits MLCP activity. Thus, the constitutive RLC phosphorylation is limited physiologically by low cMLCK activity in balance with low MLCP activity. 相似文献
995.
996.
Marie Kim Huynh M. Le Xiulan Xie Xueyang Feng Yinjie J. Tang Housna Mouttaki Michael J. McInerney Wolfgang Buckel 《Applied and environmental microbiology》2015,81(24):8434-8444
The anaerobic metabolism of crotonate, benzoate, and cyclohexane carboxylate by Syntrophus aciditrophicus grown syntrophically with Methanospirillum hungatei provides a model to study syntrophic cooperation. Recent studies revealed that S. aciditrophicus contains Re-citrate synthase but lacks the common Si-citrate synthase. To establish whether the Re-citrate synthase is involved in glutamate synthesis via the oxidative branch of the Krebs cycle, we have used [1-13C]acetate and [1-14C]acetate as well as [13C]bicarbonate as additional carbon sources during axenic growth of S. aciditrophicus on crotonate. Our analyses showed that labeled carbons were detected in at least 14 amino acids, indicating the global utilization of acetate and bicarbonate. The labeling patterns of alanine and aspartate verified that pyruvate and oxaloacetate were synthesized by consecutive carboxylations of acetyl coenzyme A (acetyl-CoA). The isotopomer profile and 13C nuclear magnetic resonance (NMR) spectroscopy of the obtained [13C]glutamate, as well as decarboxylation of [14C]glutamate, revealed that this amino acid was synthesized by two pathways. Unexpectedly, only the minor route used Re-citrate synthase (30 to 40%), whereas the majority of glutamate was synthesized via the reductive carboxylation of succinate. This symmetrical intermediate could have been formed from two acetates via hydration of crotonyl-CoA to 4-hydroxybutyryl-CoA. 4-Hydroxybutyrate was detected in the medium of S. aciditrophicus when grown on crotonate, but an active hydratase could not be measured in cell extracts, and the annotated 4-hydroxybutyryl-CoA dehydratase (SYN_02445) lacks key amino acids needed to catalyze the hydration of crotonyl-CoA. Besides Clostridium kluyveri, this study reveals the second example of a microbial species to employ two pathways for glutamate synthesis. 相似文献
997.
Cristina?T. Vicente Stacey?L. Edwards Kristine?M. Hillman Susanne Kaufmann Hayley Mitchell Lisa Bain Dylan?M. Glubb Jason?S. Lee Juliet?D. French Manuel?A.R. Ferreira 《American journal of human genetics》2015,96(2):329-339
In recent years, a number of large-scale genome-wide association studies have been published for human traits adjusted for other correlated traits with a genetic basis. In most studies, the motivation for such an adjustment is to discover genetic variants associated with the primary outcome independently of the correlated trait. In this report, we contend that this objective is fulfilled when the tested variants have no effect on the covariate or when the correlation between the covariate and the outcome is fully explained by a direct effect of the covariate on the outcome. For all other scenarios, an unintended bias is introduced with respect to the primary outcome as a result of the adjustment, and this bias might lead to false positives. Here, we illustrate this point by providing examples from published genome-wide association studies, including large meta-analysis of waist-to-hip ratio and waist circumference adjusted for body mass index (BMI), where genetic effects might be biased as a result of adjustment for body mass index. Using both theory and simulations, we explore this phenomenon in detail and discuss the ramifications for future genome-wide association studies of correlated traits and diseases. 相似文献
998.
Jonathan E. Kolby Kristine M. Smith Sara D. Ramirez Falitiana Rabemananjara Allan P. Pessier Jesse L. Brunner Caren S. Goldberg Lee Berger Lee F. Skerratt 《PloS one》2015,10(6)
We performed a rapid response investigation to evaluate the presence and distribution of amphibian pathogens in Madagascar following our identification of amphibian chytrid fungus (Batrachochytrium dendrobatidis, Bd) and ranavirus in commercially exported amphibians. This targeted risk-based field surveillance program was conducted from February to April 2014 encompassing 12 regions and 47 survey sites. We simultaneously collected amphibian and environmental samples to increase survey sensitivity and performed sampling both in wilderness areas and commercial amphibian trade facilities. Bd was not detected in any of 508 amphibian skin swabs or 68 water filter samples, suggesting pathogen prevalence was below 0.8%, with 95% confidence during our visit. Ranavirus was detected in 5 of 97 amphibians, including one adult Mantidactylus cowanii and three unidentified larvae from Ranomafana National Park, and one adult Mantidactylus mocquardi from Ankaratra. Ranavirus was also detected in water samples collected from two commercial amphibian export facilities. We also provide the first report of an amphibian mass-mortality event observed in wild amphibians in Madagascar. Although neither Bd nor ranavirus appeared widespread in Madagascar during this investigation, additional health surveys are required to disentangle potential seasonal variations in pathogen abundance and detectability from actual changes in pathogen distribution and rates of spread. Accordingly, our results should be conservatively interpreted until a comparable survey effort during winter months has been performed. It is imperative that biosecurity practices be immediately adopted to limit the unintentional increased spread of disease through the movement of contaminated equipment or direct disposal of contaminated material from wildlife trade facilities. The presence of potentially introduced strains of ranaviruses suggests that Madagascar''s reptile species might also be threatened by disease. Standardized population monitoring of key amphibian and reptile species should be established with urgency to enable early detection of potential impacts of disease emergence in this global biodiversity hotspot. 相似文献
999.
Kristine von Bargen Aurélie Gagnaire Vilma Arce-Gorvel Béatrice de Bovis Fannie Baudimont Lionel Chasson Mile Bosilkovski Alexia Papadopoulos Anna Martirosyan Sandrine Henri Jean-Louis Mège Bernard Malissen Jean-Pierre Gorvel 《PloS one》2015,10(4)
Cervical lymph nodes (CLN) are the first lymph nodes encountered by material taking the oral route. To study their role in orally acquired infections, we analyzed 307 patients of up to 14 years treated in the university clinic of Skopje, Macedonia, for brucellosis, a zoonotic bacterial disease frequently acquired by ingestion of contaminated dairy products. From these children, 36% had lymphadenopathy. Among orally infected children, lymphadenopathy with CLN being the only lymph nodes affected was significantly more frequent as compared to those infected by contact with animals (83% vs. 63%), suggesting a possible involvement of CLN during orally acquired human brucellosis. Using a murine model where bacteria are delivered into the oral cavity, we show that Brucella quickly and selectively colonize the CLN where they proliferate and persist over long periods of time for up to 50 days post-infection. A similar efficient though less specific drainage to CLN was found for Brucella, Salmonella typhimurium and fluorescent microspheres delivered by gavage, a pathway likely representing a mixed infection mode of intragastric and oral infection, suggesting a central pathway of drained material. Microspheres as well as bacteria drained to CLN predominately reside in cells expressing CD68 and no or low levels of CD11c. Even though no systemic response could be detected, Brucella induced a locally restricted inflammatory reaction with increased expression levels of interferon γ, interleukin (IL)-6, IL-12, granzyme B and a delayed induction of Nos2. Inflammation led to pronounced lymphadenopathy, infiltration of macrophages/monocytes expressing high levels of major histocompatibility complex II and to formation of epitheloid granulomas. Together, these results highlight the role of CLN in oral infections as both, an initial and efficient trap for bacterial invaders and as possible reservoir for chronic pathogens. They likewise cast a new light on the significance of oral routes for means of vaccination. 相似文献
1000.
Eser Kirkizlar Bernhard Zimmermann Tudor Constantin Ryan Swenerton Bin Hoang Nicholas Wayham Joshua E. Babiarz Zachary Demko Robert J. Pelham Stephanie Kareht Alexander L. Simon Kristine N. Jinnett Matthew Rabinowitz Styrmir Sigurjonsson Matthew Hill 《Translational oncology》2015,8(5):407-416
We demonstrate proof-of-concept for the use of massively multiplexed PCR and next-generation sequencing (mmPCR-NGS) to identify both clonal and subclonal copy-number variants (CNVs) in circulating tumor DNA. This is the first report of a targeted methodology for detection of CNVs in plasma.Using an in vitro model of cell-free DNA, we show that mmPCR-NGS can accurately detect CNVs with average allelic imbalances as low as 0.5%, an improvement over previously reported whole-genome sequencing approaches. Our method revealed differences in the spectrum of CNVs detected in tumor tissue subsections and matching plasma samples from 11 patients with stage II breast cancer. Moreover, we showed that liquid biopsies are able to detect subclonal mutations that may be missed in tumor tissue biopsies. We anticipate that this mmPCR-NGS methodology will have broad applicability for the characterization, diagnosis, and therapeutic monitoring of CNV-enriched cancers, such as breast, ovarian, and lung cancer. 相似文献