It has been known for nearly 100 years that pressure unfolds proteins, yet the physical basis of this effect is not understood. Unfolding by pressure implies that the molar volume of the unfolded ...state of a protein is smaller than that of the folded state. This decrease in volume has been proposed to arise from differences between the density of bulk water and water associated with the protein, from pressure-dependent changes in the structure of bulk water, from the loss of internal cavities in the folded states of proteins, or from some combination of these three factors. Here, using 10 cavity-containing variants of staphylococcal nuclease, we demonstrate that pressure unfolds proteins primarily as a result of cavities that are present in the folded state and absent in the unfolded one. High-pressure NMR spectroscopy and simulations constrained by the NMR data were used to describe structural and energetic details of the folding landscape of staphylococcal nuclease that are usually inaccessible with existing experimental approaches using harsher denaturants. Besides solving a 100-year-old conundrum concerning the detailed structural origins of pressure unfolding of proteins, these studies illustrate the promise of pressure perturbation as a unique tool for examining the roles of packing, conformational fluctuations, and water penetration as determinants of solution properties of proteins, and for detecting folding intermediates and other structural details of protein-folding landscapes that are invisible to standard experimental approaches.
O artigo propõe uma análise da ruptura com o regime de tempo historicista em Bodenlos, uma autobiografia filosófica, de Vilém Flusser. A forma não linear e não cronológica da narrativa autobiográfica ...de Flusser reflete um dos argumentos principais do autor: a ruptura com a percepção de tempo historicista. Demonstramos como Vilém Flusser constrói em Bodenlos uma autobiografia filosófica uma estrutura narrativa que definimos como metalinguagem filosófica porque reflete o próprio conteúdo de sua obra que quebra com a linearidade cronológica do tempo historicista.
The MAPK cascade plays a crucial role in tumor cell proliferation and survival. Accumulating evidence suggests that mutations in the BRAF oncogene are not only associated with poor prognosis but also ...linked with less benefit when treated with anti-epidermal growth factor receptor antibodies in metastatic colorectal cancer (mCRC). Targeting this molecular aberration has thus become a matter of particular interest in mCRC drug development. In contrast to other malignances such as BRAF mutant melanoma, efficacy observed with BRAF inhibitors in monotherapy in mCRC is poor. Several mechanisms of resistance have been identified leading to the development of different treatment strategies that have shown promising activity in early clinical trials. Hence, rational combination of targeted therapies is expected to further increase the efficacy of selective BRAF inhibitors. Herein, we discuss the main clinical and molecular characteristics of BRAF mutant colorectal cancer and its translation into the clinic, with a focus on developmental therapeutics and combination strategies. In addition, we contextualize the available data with potential future approaches that include the extended access to next-generation sequencing platforms and gene expression strategies for molecular subtyping. These approaches will facilitate the identification of certain patient profiles providing more therapeutic possibilities.
Water is an essential participant in the stability, structure, dynamics, and function of proteins and other biomolecules. Thermodynamically, changes in the aqueous environment affect the stability of ...biomolecules. Structurally, water participates chemically in the catalytic function of proteins and nucleic acids and physically in the collapse of the protein chain during folding through hydrophobic collapse and mediates binding through the hydrogen bond in complex formation. Water is a partner that slaves the dynamics of proteins, and water interaction with proteins affect their dynamics. Here we provide a review of the experimental and computational advances over the past decade in understanding the role of water in the dynamics, structure, and function of proteins. We focus on the combination of X-ray and neutron crystallography, NMR, terahertz spectroscopy, mass spectroscopy, thermodynamics, and computer simulations to reveal how water assist proteins in their function. The recent advances in computer simulations and the enhanced sensitivity of experimental tools promise major advances in the understanding of protein dynamics, and water surely will be a protagonist.
We provide estimates of the warming of the world ocean for 1955–2008 based on historical data not previously available, additional modern data, correcting for instrumental biases of bathythermograph ...data, and correcting or excluding some Argo float data. The strong interdecadal variability of global ocean heat content reported previously by us is reduced in magnitude but the linear trend in ocean heat content remain similar to our earlier estimate.
The products formed by glycosylation of food proteins with carbohydrates via the Maillard reaction, also known as conjugates, are agents capable of changing and improving techno-functional ...characteristics of proteins. The Maillard reaction uses the covalent bond between a group of a reducing carbohydrates and an amino group of a protein. This reaction does not require additional chemicals as it occurs naturally under controlled conditions of temperature, time, pH, and moisture. Moreover, there is growing interest in modifying proteins for industrial food applications. This review analyses the current state of art of the Maillard reaction on food protein functionalities. It also discusses the influence of the Maillard reaction on the conditions and formulation of reagents that improve desirable techno-functional characteristics of food protein.
We report the de novo folding of three hyperstable RNA tetraloops to 1–3 Å rmsd from their experimentally determined structures using molecular dynamics simulations initialized in the unfolded state. ...RNA tetraloops with loop sequences UUCG, GCAA, or CUUG are hyperstable because of the formation of noncanonical loop-stabilizing interactions, and they are all faithfully reproduced to angstrom-level accuracy in replica exchange molecular dynamics simulations, including explicit solvent and ion molecules. This accuracy is accomplished using unique RNA parameters, in which biases that favor rigid, highly stacked conformations are corrected to accurately capture the inherent flexibility of ssRNA loops, accurate base stacking energetics, and purine syn -anti interconversions. In a departure from traditional quantum chemistrycentric approaches to force field optimization, our parameters are calibrated directly from thermodynamic and kinetic measurements of intra- and internucleotide structural transitions. The ability to recapitulate the signature noncanonical interactions of the three most abundant hyperstable stem loop motifs represents a significant milestone to the accurate prediction of RNA tertiary structure using unbiased all-atom molecular dynamics simulations.
Single-point measurements of fluctuations in the scrape-off layer of magnetized plasmas are generally found to be dominated by large-amplitude bursts which are associated with radial motion of ...bloblike structures. A stochastic model for these fluctuations is presented, with the plasma density given by a random sequence of bursts with a fixed wave form. When the burst events occur in accordance to a Poisson process, this model predicts a parabolic relation between the skewness and kurtosis moments of the plasma fluctuations. In the case of an exponential wave form and exponentially distributed burst amplitudes, the probability density function for the fluctuation amplitudes is shown to be a Gamma distribution with the scale parameter given by the average burst amplitude, and the shape parameter given by the ratio of the burst duration and waiting times.
Nab-paclitaxel and gemcitabine have demonstrated a survival benefit over gemcitabine alone in advanced pancreatic cancer (PDA). This study aimed to investigate the clinical, biological, and imaging ...effects of the regimen in patients with operable PDA.
Patients with operable PDA received two cycles of nab-paclitaxel and gemcitabine before surgical resection. FDG-PET and CA19.9 tumour marker levels were used to measure clinical activity. Effects on tumour stroma were determined by endoscopic ultrasound (EUS) elastography. The collagen content and architecture as well as density of cancer-associated fibroblasts (CAFs) were determined in the resected surgical specimen and compared with a group of untreated and treated with conventional chemoradiation therapy controls. A co-clinical study in a mouse model of PDA was conducted to differentiate between the effects of nab-paclitaxel and gemcitabine.
A total of 16 patients were enrolled. Treatment resulted in significant antitumour effects with 50% of patients achieving a >75% decrease in circulating CA19.9 tumour marker and a response by FDG-PET. There was also a significant decrement in tumour stiffness as measured by EUS elastography. Seven of 12 patients who completed treatment and were operated had major pathological regressions. Analysis of residual tumours showed a marked disorganised collagen with a very low density of CAF, which was not observed in the untreated or conventionally treated control groups. The preclinical co-clinical study showed that these effects were specific of nab-paclitaxel and not gemcitabine.
These data suggest that nab-paclitaxel and gemcitabine decreases CAF content inducing a marked alteration in cancer stroma that results in tumour softening. This regimen should be studied in patients with operable PDA.
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