Página 19 dos resultados de 60878 itens digitais encontrados em 1.446 segundos

‣ Estrogen receptor-α expression in the mammary epithelium is required for ductal and alveolar morphogenesis in mice

Feng, Yuxin; Manka, David; Wagner, Kay-Uwe; Khan, Sohaib A.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.609604%
The estrogen receptor-α (ERα) is a critical transcription factor that regulates epithelial cell proliferation and ductal morphogenesis during postnatal mammary gland development. Tissue recombination and transplantation studies using the first generation of ERα knockout (ERKO) mice suggested that this steroid hormone receptor is required in the mammary stroma that subsequently exerts its effect on the epithelium through additional paracrine signaling events. A more detailed analysis revealed that ERKO mice produce a truncated ERα protein with detectable transactivation activity, and it is likely that this functional ERα variant has masked the biological significance of this steroid receptor in the mammary epithelium. In this article, we describe the generation a Cre-lox-based conditional knockout of the ERα gene to study the biological function of this steroid receptor in the epithelial compartment at defined stages of mammary gland development. The mouse mammary tumor virus (MMTV)-Cre-mediated, epithelial-specific ablation of exon 3 of the ERα gene in virgin mice severely impaired ductal elongation and side branching. The conditional knockout resulted in ablation of the ERα protein, and the progesterone receptor (PR), whose expression is under the control of ERα...

‣ In vitro synthesis of the iron–molybdenum cofactor of nitrogenase from iron, sulfur, molybdenum, and homocitrate using purified proteins

Curatti, Leonardo; Hernandez, Jose A.; Igarashi, Robert Y.; Soboh, Basem; Zhao, Dehua; Rubio, Luis M.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.609604%
Biological nitrogen fixation, the conversion of atmospheric N2 to NH3, is an essential process in the global biogeochemical cycle of nitrogen that supports life on Earth. Most of the biological nitrogen fixation is catalyzed by the molybdenum nitrogenase, which contains at its active site one of the most complex metal cofactors known to date, the iron–molybdenum cofactor (FeMo-co). FeMo-co is composed of 7Fe, 9S, Mo, R-homocitrate, and one unidentified light atom. Here we demonstrate the complete in vitro synthesis of FeMo-co from Fe2+, S2−, MoO42−, and R-homocitrate using only purified Nif proteins. This synthesis provides direct biochemical support to the current model of FeMo-co biosynthesis. A minimal in vitro system, containing NifB, NifEN, and NifH proteins, together with Fe2+, S2−, MoO42−, R-homocitrate, S-adenosyl methionine, and Mg-ATP, is sufficient for the synthesis of FeMo-co and the activation of apo-dinitrogenase under anaerobic-reducing conditions. This in vitro system also provides a biochemical approach to further study the function of accessory proteins involved in nitrogenase maturation (as shown here for NifX and NafY). The significance of these findings in the understanding of the complete FeMo-co biosynthetic pathway and in the study of other complex Fe-S cluster biosyntheses is discussed.

‣ A cold phase of the East Pacific triggers new phytoplankton blooms in San Francisco Bay

Cloern, James E.; Jassby, Alan D.; Thompson, Janet K.; Hieb, Kathryn A.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.609604%
Ecological observations sustained over decades often reveal abrupt changes in biological communities that signal altered ecosystem states. We report a large shift in the biological communities of San Francisco Bay, first detected as increasing phytoplankton biomass and occurrences of new seasonal blooms that began in 1999. This phytoplankton increase is paradoxical because it occurred in an era of decreasing wastewater nutrient inputs and reduced nitrogen and phosphorus concentrations, contrary to the guiding paradigm that algal biomass in estuaries increases in proportion to nutrient inputs from their watersheds. Coincidental changes included sharp declines in the abundance of bivalve mollusks, the key phytoplankton consumers in this estuary, and record high abundances of several bivalve predators: Bay shrimp, English sole, and Dungeness crab. The phytoplankton increase is consistent with a trophic cascade resulting from heightened predation on bivalves and suppression of their filtration control on phytoplankton growth. These community changes in San Francisco Bay across three trophic levels followed a state change in the California Current System characterized by increased upwelling intensity, amplified primary production, and strengthened southerly flows. These diagnostic features of the East Pacific “cold phase” lead to strong recruitment and immigration of juvenile flatfish and crustaceans into estuaries where they feed and develop. This study...

‣ Methane oxidation at 55°C and pH 2 by a thermoacidophilic bacterium belonging to the Verrucomicrobia phylum

Islam, Tajul; Jensen, Sigmund; Reigstad, Laila Johanne; Larsen, Øivind; Birkeland, Nils-Kåre
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.609604%
Methanotrophic bacteria constitute a ubiquitous group of microorganisms playing an important role in the biogeochemical carbon cycle and in control of global warming through natural reduction of methane emission. These bacteria share the unique ability of using methane as a sole carbon and energy source and have been found in a great variety of habitats. Phylogenetically, known methanotrophs constitute a rather limited group and have so far only been affiliated with the Proteobacteria. Here, we report the isolation and initial characterization of a nonproteobacterial obligately methanotrophic bacterium. The isolate, designated Kam1, was recovered from an acidic hot spring in Kamchatka, Russia, and is more thermoacidophilic than any other known methanotroph, with optimal growth at ≈55°C and pH 3.5. Kam1 is only distantly related to all previously known methanotrophs and belongs to the Verrucomicrobia lineage of evolution. Genes for methane monooxygenases, essential for initiation of methane oxidation, could not be detected by using standard primers in PCR amplification and Southern blot analysis, suggesting the presence of a different methane oxidation enzyme. Kam1 also lacks the well developed intracellular membrane systems typical for other methanotrophs. The isolate represents a previously unrecognized biological methane sink...

‣ Plant cyclotides disrupt epithelial cells in the midgut of lepidopteran larvae

Barbeta, Barbara L.; Marshall, Alan T.; Gillon, Amanda D.; Craik, David J.; Anderson, Marilyn A.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.609604%
Several members of the Rubiaceae and Violaceae plant families produce a series of cyclotides or macrocyclic peptides of 28–37 aa with an embedded cystine knot. The cyclic peptide backbone together with the knotted and strongly braced structure confers exceptional chemical and biological stability that has attracted attention for potential pharmaceutical applications. Cyclotides display a diverse range of biological activities, such as uterotonic action, anti-HIV activity, and neurotensin antagonism. In plants, their primary role is probably protection from insect attack. Ingestion of the cyclotide kalata B1 severely retards the growth of larvae from the Lepidopteran species Helicoverpa armigera. We examined the gut of these larvae after consumption of kalata B1 by light, scanning, and transmission electron microscopy. We established that kalata B1 induces disruption of the microvilli, blebbing, swelling, and ultimately rupture of the cells of the gut epithelium. The histology of this response is similar to the response of H. armigera larvae to the Bacillus thuringiensis delta-endotoxin, which is widely used to control these insect pests of crops such as cotton.

‣ Discovery of a lysophospholipid acyltransferase family essential for membrane asymmetry and diversity

Hishikawa, Daisuke; Shindou, Hideo; Kobayashi, Saori; Nakanishi, Hiroki; Taguchi, Ryo; Shimizu, Takao
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.609604%
All organisms consist of cells that are enclosed by a cell membrane containing bipolar lipids and proteins. Glycerophospholipids are important not only as structural and functional components of cellular membrane but also as precursors of various lipid mediators. Polyunsaturated fatty acids comprising arachidonic acid or eicosapentaenoic acid are located at sn-2 position, but not at sn-1 position of glycerophospholipids in an asymmetrical manner. In addition to the asymmetry, the membrane diversity is important for membrane fluidity and curvature. To explain the asymmetrical distribution of fatty acids, the rapid turnover of sn-2 position was proposed in 1958 by Lands [Lands WE (1958) Metabolism of glycerolipides: A comparison of lecithin and triglyceride synthesis. J Biol Chem 231:883–888]. However, the molecular mechanisms and biological significance of the asymmetry remained unknown. Here, we describe a putative enzyme superfamily consisting mainly of three gene families, which catalyzes the transfer of acyl-CoAs to lysophospholipids to produce different classes of phospholipids. Among them, we characterized three important enzymes with different substrate specificities and tissue distributions; one, termed lysophosphatidylcholine acyltransferase-3 (a mammalian homologue of Drosophila nessy critical for embryogenesis)...

‣ Role of the Akt pathway in mRNA translation of interferon-stimulated genes

Kaur, Surinder; Sassano, Antonella; Dolniak, Blazej; Joshi, Sonali; Majchrzak-Kita, Beata; Baker, Darren P.; Hay, Nissim; Fish, Eleanor N.; Platanias, Leonidas C.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.609604%
Multiple signaling pathways are engaged by the type I and II IFN receptors, but their specific roles and possible coordination in the generation of IFN-mediated biological responses remain unknown. We provide evidence that activation of Akt kinases is required for IFN-inducible engagement of the mTOR/p70 S6 kinase pathway. Our data establish that Akt activity is essential for up-regulation of key IFN-α- and IFN-γ-inducible proteins, which have important functional consequences in the induction of IFN responses. Such effects of the Akt pathway are unrelated to regulatory activities on IFN-dependent STAT phosphorylation/activation or transcriptional regulation. By contrast, they reflect regulatory activities on mRNA translation via direct control of the mTOR pathway. In studies using Akt1 and Akt2 double knockout cells, we found that the absence of Akt kinases results in dramatic reduction in IFN-induced antiviral responses, establishing a critical role of the Akt pathway in IFN signaling. Thus, activation of the Akt pathway by the IFN receptors complements the function of IFN-activated JAK–STAT pathways, by allowing mRNA translation of IFN-stimulated genes and, ultimately, the induction of the biological effects of IFNs.

‣ Impacts of climate warming on terrestrial ectotherms across latitude

Deutsch, Curtis A.; Tewksbury, Joshua J.; Huey, Raymond B.; Sheldon, Kimberly S.; Ghalambor, Cameron K.; Haak, David C.; Martin, Paul R.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.609604%
The impact of anthropogenic climate change on terrestrial organisms is often predicted to increase with latitude, in parallel with the rate of warming. Yet the biological impact of rising temperatures also depends on the physiological sensitivity of organisms to temperature change. We integrate empirical fitness curves describing the thermal tolerance of terrestrial insects from around the world with the projected geographic distribution of climate change for the next century to estimate the direct impact of warming on insect fitness across latitude. The results show that warming in the tropics, although relatively small in magnitude, is likely to have the most deleterious consequences because tropical insects are relatively sensitive to temperature change and are currently living very close to their optimal temperature. In contrast, species at higher latitudes have broader thermal tolerance and are living in climates that are currently cooler than their physiological optima, so that warming may even enhance their fitness. Available thermal tolerance data for several vertebrate taxa exhibit similar patterns, suggesting that these results are general for terrestrial ectotherms. Our analyses imply that, in the absence of ameliorating factors such as migration and adaptation...

‣ Functional specialization among insect chitinase family genes revealed by RNA interference

Zhu, Qingsong; Arakane, Yasuyuki; Beeman, Richard W.; Kramer, Karl J.; Muthukrishnan, Subbaratnam
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.609604%
The biological functions of individual members of the large family of chitinase-like proteins from the red flour beetle, Tribolium castaneum (Tc), were examined by using gene-specific RNAi. One chitinase, TcCHT5, was found to be required for pupal–adult molting only. A lethal phenotype was observed when the transcript level of TcCHT5 was down-regulated by injection of TcCHT5-specific dsRNA into larvae. The larvae had metamorphosed into pupae and then to pharate adults but did not complete adult eclosion. Specific knockdown of transcripts for another chitinase, TcCHT10, which has multiple catalytic domains, prevented embryo hatch, larval molting, pupation, and adult metamorphosis, indicating a vital role for TcCHT10 during each of these processes. A third chitinase-like protein, TcCHT7, was required for abdominal contraction and wing/elytra extension immediately after pupation but was dispensable for larval–larval molting, pupation, and adult eclosion. The wing/elytra abnormalities found in TcCHT7-silenced pupae were also manifest in the ensuing adults. A fourth chitinase-like protein, TcIDGF4, exhibited no chitinolytic activity but contributed to adult eclosion. No phenotypic effects were observed after knockdown of transcripts for several other chitinase-like proteins...

‣ Iodide accumulation provides kelp with an inorganic antioxidant impacting atmospheric chemistry

Küpper, Frithjof C.; Carpenter, Lucy J.; McFiggans, Gordon B.; Palmer, Carl J.; Waite, Tim J.; Boneberg, Eva-Maria; Woitsch, Sonja; Weiller, Markus; Abela, Rafael; Grolimund, Daniel; Potin, Philippe; Butler, Alison; Luther, George W.; Kroneck, Peter M. H
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.609604%
Brown algae of the Laminariales (kelps) are the strongest accumulators of iodine among living organisms. They represent a major pump in the global biogeochemical cycle of iodine and, in particular, the major source of iodocarbons in the coastal atmosphere. Nevertheless, the chemical state and biological significance of accumulated iodine have remained unknown to this date. Using x-ray absorption spectroscopy, we show that the accumulated form is iodide, which readily scavenges a variety of reactive oxygen species (ROS). We propose here that its biological role is that of an inorganic antioxidant, the first to be described in a living system. Upon oxidative stress, iodide is effluxed. On the thallus surface and in the apoplast, iodide detoxifies both aqueous oxidants and ozone, the latter resulting in the release of high levels of molecular iodine and the consequent formation of hygroscopic iodine oxides leading to particles, which are precursors to cloud condensation nuclei. In a complementary set of experiments using a heterologous system, iodide was found to effectively scavenge ROS in human blood cells.

‣ Universal scaling law of electrical turbulence in the mammalian heart

Noujaim, Sami F.; Berenfeld, Omer; Kalifa, Jérôme; Cerrone, Marina; Nanthakumar, Kumaraswamy; Atienza, Felipe; Moreno, Javier; Mironov, Sergey; Jalife, José
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.609604%
Many biological processes, such as metabolic rate and life span, scale with body mass (BM) according to the universal law of allometric scaling: Y = aBMb (Y, biological process; b, scaling exponent). We investigated whether the temporal properties of ventricular fibrillation (VF), the major cause of sudden and unexpected cardiac death, scale with BM. By using high-resolution optical mapping, numerical simulations and metaanalysis of VF data in 11 mammalian species, we demonstrate that the interbeat interval of VF scales as VFcycle length = 53 × BM1/4, spanning more than four orders of magnitude in BM from mouse to horse.

‣ Stage-specific gene expression is a fundamental characteristic of rat spermatogenic cells and Sertoli cells

Johnston, Daniel S.; Wright, William W.; DiCandeloro, Paul; Wilson, Ewa; Kopf, Gregory S.; Jelinsky, Scott A.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.609604%
Mammalian spermatogenesis is a complex biological process that occurs within a highly organized tissue, the seminiferous epithelium. The coordinated maturation of spermatogonia, spermatocytes, and spermatids suggests the existence of precise programs of gene expression in these cells and in their neighboring somatic Sertoli cells. The objective of this study was to identify the genes that execute these programs. Rat seminiferous tubules at stages I, II–III, IV–V, VI, VIIa,b, VIIc,d, VIII, IX–XI, XII, and XIII–XIV of the cycle were isolated by microdissection, whereas Sertoli cells, spermatogonia plus early spermatocytes, pachytene spermatocytes, and round spermatids were purified from enzymatically dispersed testes. Microarray analysis by using Rat Genome 230 2.0 arrays identified 16,971 probe sets that recognized testicular transcripts, and 398 of these were identified as testis-specific. Expression of 1,286 probe sets were found to differ at least 4-fold between two cell types and also across the stages of the cycle. Pathway and annotated cluster analyses of those probe sets predicted that entire biological pathways and processes are regulated cyclically in specific cells. Important among these are the cell cycle, DNA repair...

‣ Induction of angiogenesis in tissue-engineered scaffolds designed for bone repair: A combined gene therapy–cell transplantation approach

Jabbarzadeh, Ehsan; Starnes, Trevor; Khan, Yusuf M.; Jiang, Tao; Wirtel, Anthony J.; Deng, Meng; Lv, Qing; Nair, Lakshmi S.; Doty, Steven B.; Laurencin, Cato T.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.609604%
One of the fundamental principles underlying tissue engineering approaches is that newly formed tissue must maintain sufficient vascularization to support its growth. Efforts to induce vascular growth into tissue-engineered scaffolds have recently been dedicated to developing novel strategies to deliver specific biological factors that direct the recruitment of endothelial cell (EC) progenitors and their differentiation. The challenge, however, lies in orchestration of the cells, appropriate biological factors, and optimal factor doses. This study reports an approach as a step forward to resolving this dilemma by combining an ex vivo gene transfer strategy and EC transplantation. The utility of this approach was evaluated by using 3D poly(lactide-co-glycolide) (PLAGA) sintered microsphere scaffolds for bone tissue engineering applications. Our goal was achieved by isolation and transfection of adipose-derived stromal cells (ADSCs) with adenovirus encoding the cDNA of VEGF. We demonstrated that the combination of VEGF releasing ADSCs and ECs results in marked vascular growth within PLAGA scaffolds. We thereby delineate the potential of ADSCs to promote vascular growth into biomaterials.

‣ Oncogenic bystander radiation effects in Patched heterozygous mouse cerebellum

Mancuso, Mariateresa; Pasquali, Emanuela; Leonardi, Simona; Tanori, Mirella; Rebessi, Simonetta; Di Majo, Vincenzo; Pazzaglia, Simonetta; Toni, Maria Pia; Pimpinella, Maria; Covelli, Vincenzo; Saran, Anna
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.609604%
The central dogma of radiation biology, that biological effects of ionizing radiation are a direct consequence of DNA damage occurring in irradiated cells, has been challenged by observations that genetic/epigenetic changes occur in unexposed “bystander cells” neighboring directly-hit cells, due to cell-to-cell communication or soluble factors released by irradiated cells. To date, the vast majority of these effects are described in cell-culture systems, while in vivo validation and assessment of biological consequences within an organism remain uncertain. Here, we describe the neonatal mouse cerebellum as an accurate in vivo model to detect, quantify, and mechanistically dissect radiation-bystander responses. DNA double-strand breaks and apoptotic cell death were induced in bystander cerebellum in vivo. Accompanying these genetic events, we report bystander-related tumor induction in cerebellum of radiosensitive Patched-1 (Ptch1) heterozygous mice after x-ray exposure of the remainder of the body. We further show that genetic damage is a critical component of in vivo oncogenic bystander responses, and provide evidence supporting the role of gap-junctional intercellular communication (GJIC) in transmission of bystander signals in the central nervous system (CNS). These results represent the first proof-of-principle that bystander effects are factual in vivo events with carcinogenic potential...

‣ An engineered selenocysteine defines a unique class of antibody derivatives

Hofer, Thomas; Thomas, Joshua D.; Burke, Terrence R.; Rader, Christoph
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.609604%
Selenocysteine is cotranslationally inserted into proteins by recoding the stop codon UGA from termination to selenocysteine insertion. The nucleophilic selenol group of selenocysteine endows this rare amino acid with unique chemical reactivity that allows regiospecific covalent conjugation in the presence of the other natural amino acids. Using a mammalian expression system, we generated an IgG1-derived Fc fragment with a C-terminal selenocysteine in yields comparable to conventional monoclonal antibodies and conjugated it to an electrophilic derivative of a peptidomimetic that binds with high affinity and specificity to integrin α4β1. Through this conjugation, both the biological and chemical components are endowed with pharmacological advantages. We demonstrate that whereas the Fc protein increases the circulatory half-life from minutes to days and mediates transcytosis through binding to the neonatal Fc receptor, the peptidomimetic introduces cross-species binding to cell surface integrin α4β1 and blocks its interaction with vascular cell adhesion molecule-1. Compared with conventional monoclonal antibodies, our technology benefits economically from combining a generic biological component with a variable chemical component.

‣ Water-stable organic transistors and their application in chemical and biological sensors

Roberts, Mark E.; Mannsfeld, Stefan C. B.; Queraltó, Núria; Reese, Colin; Locklin, Jason; Knoll, Wolfgang; Bao, Zhenan
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.609604%
The development of low-cost, reliable sensors will rely on devices capable of converting an analyte binding event to an easily read electrical signal. Organic thin-film transistors (OTFTs) are ideal for inexpensive, single-use chemical or biological sensors because of their compatibility with flexible, large-area substrates, simple processing, and highly tunable active layer materials. We have fabricated low-operating voltage OTFTs with a cross-linked polymer gate dielectric, which display stable operation under aqueous conditions over >104 electrical cycles using the p-channel semiconductor 5,5′-bis-(7-dodecyl-9H-fluoren-2-yl)-2,2′-bithiophene (DDFTTF). OTFT sensors were demonstrated in aqueous solutions with concentrations as low as parts per billion for trinitrobenzene, methylphosphonic acid, cysteine, and glucose. This work demonstrates of reliable OTFT operation in aqueous media, hence opening new possibilities of chemical and biological sensing with OTFTs.

‣ Mechanoenzymatics of titin kinase

Puchner, Elias M.; Alexandrovich, Alexander; Kho, Ay Lin; Hensen, Ulf; Schäfer, Lars V.; Brandmeier, Birgit; Gräter, Frauke; Grubmüller, Helmut; Gaub, Hermann E.; Gautel, Mathias
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.609604%
Biological responses to mechanical stress require strain-sensing molecules, whose mechanically induced conformational changes are relayed to signaling cascades mediating changes in cell and tissue properties. In vertebrate muscle, the giant elastic protein titin is involved in strain sensing via its C-terminal kinase domain (TK) at the sarcomeric M-band and contributes to the adaptation of muscle in response to changes in mechanical strain. TK is regulated in a unique dual autoinhibition mechanism by a C-terminal regulatory tail, blocking the ATP binding site, and tyrosine autoinhibition of the catalytic base. For access to the ATP binding site and phosphorylation of the autoinhibitory tyrosine, the C-terminal autoinhibitory tail needs to be removed. Here, we use AFM-based single-molecule force spectroscopy, molecular dynamics simulations, and enzymatics to study the conformational changes during strain-induced activation of human TK. We show that mechanical strain activates ATP binding before unfolding of the structural titin domains, and that TK can thus act as a biological force sensor. Furthermore, we identify the steps in which the autoinhibition of TK is mechanically relieved at low forces, leading to binding of the cosubstrate ATP and priming the enzyme for subsequent autophosphorylation and substrate turnover.

‣ The kernel energy method of quantum mechanical approximation carried to fourth-order terms

Huang, Lulu; Massa, Lou; Karle, Jerome
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.609604%
It is now possible to calculate the ab initio quantum mechanics of very large biological molecules. Two things lead to this perspective, namely, (i) the advances of parallel supercomputers, and (ii) the discovery of a quantum formalism called quantum crystallography and the use of quantum kernels, a method that is well suited for parallel computation. The kernel energy method (KEM) carried to second order has been used to calculate the quantum mechanical ab initio molecular energy of peptides, protein (insulin and collagen), DNA, and RNA and the interaction of drugs with their biochemical molecular targets. The results were found to have good accuracy. In this article, the accuracy of the KEM is investigated up to an approximation including fourth-order interactions among kernels. Remarkable accuracy is achieved in the calculation of the energy of the ground state of the important biological molecule Leu1-zervamicin, whose crystal structure is known and used in the calculations.

‣ Gene expression dynamics in the macrophage exhibit criticality

Nykter, Matti; Price, Nathan D.; Aldana, Maximino; Ramsey, Stephen A.; Kauffman, Stuart A.; Hood, Leroy E.; Yli-Harja, Olli; Shmulevich, Ilya
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.609604%
Cells are dynamical systems of biomolecular interactions that process information from their environment to mount diverse yet specific responses. A key property of many self-organized systems is that of criticality: a state of a system in which, on average, perturbations are neither dampened nor amplified, but are propagated over long temporal or spatial scales. Criticality enables the coordination of complex macroscopic behaviors that strike an optimal balance between stability and adaptability. It has long been hypothesized that biological systems are critical. Here, we address this hypothesis experimentally for system-wide gene expression dynamics in the macrophage. To this end, we have developed a method, based on algorithmic information theory, to assess macrophage criticality, and we have validated the method on networks with known properties. Using global gene expression data from macrophages stimulated with a variety of Toll-like receptor agonists, we found that macrophage dynamics are indeed critical, providing the most compelling evidence to date for this general principle of dynamics in biological systems.

‣ FOXO3A genotype is strongly associated with human longevity

Willcox, Bradley J.; Donlon, Timothy A.; He, Qimei; Chen, Randi; Grove, John S.; Yano, Katsuhiko; Masaki, Kamal H.; Willcox, D. Craig; Rodriguez, Beatriz; Curb, J. David
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.609604%
Human longevity is a complex phenotype with a significant familial component, yet little is known about its genetic antecedents. Increasing evidence from animal models suggests that the insulin/IGF-1 signaling (IIS) pathway is an important, evolutionarily conserved biological pathway that influences aging and longevity. However, to date human data have been scarce. Studies have been hampered by small sample sizes, lack of precise phenotyping, and population stratification, among other challenges. Therefore, to more precisely assess potential genetic contributions to human longevity from genes linked to IIS signaling, we chose a large, homogeneous, long-lived population of men well-characterized for aging phenotypes, and we performed a nested-case control study of 5 candidate longevity genes. Genetic variation within the FOXO3A gene was strongly associated with human longevity. The OR for homozygous minor vs. homozygous major alleles between the cases and controls was 2.75 (P = 0.00009; adjusted P = 0.00135). Long-lived men also presented several additional phenotypes linked to healthy aging, including lower prevalence of cancer and cardiovascular disease, better self-reported health, and high physical and cognitive function, despite significantly older ages than controls. Several of these aging phenotypes were associated with FOXO3A genotype. Long-lived men also exhibited several biological markers indicative of greater insulin sensitivity and this was associated with homozygosity for the FOXO3A GG genotype. Further exploration of the FOXO3A gene...