Small molecules as ligands target multifunctional ribonucleic acids (RNA) for therapeutic engagement. This study explores how the anticancer DNA intercalator harmine interacts various motifs of RNAs, including the single-stranded A-form poly (rA), the clover leaf tRNAphe, and the double-stranded A-form poly (rC)-poly (rG). Harmine showed the affinity to the polynucleotides in the order, poly (rA) > tRNAphe > poly (rC)·poly (rG). While no induced circular dichroism change was detected with poly (rC)poly (rG), significant structural alterations of poly (rA) followed by tRNAphe and occurrence of concurrent initiation of optical activity in the attached achiral molecule of alkaloid was reported. At 25 °C, the affinity further showed exothermic and entropy-driven binding. The interaction also highlighted heat capacity (ΔC o p ) and Gibbs energy contribution from the hydrophobic transfer (ΔG hyd) of binding with harmine. Molecular docking calculations indicated that harmine exhibits higher affinity for poly (rA) compared to tRNAphe and poly (rC)·poly (rG). Subsequent molecular dynamics simulations were conducted to investigate the binding mode and stability of harmine with poly(A), tRNAphe, and poly (rC)·poly (rG). The results revealed that harmine adopts a partial intercalative binding with poly (rA) and tRNAphe, characterized by pronounced stacking forces and stronger binding free energy observed with poly (rA), while a comparatively weaker binding free energy was observed with tRNAphe. In contrast, the stacking forces with poly (rC)·poly (rG) were comparatively less pronounced and adopts a groove binding mode. It was also supported by ferrocyanide quenching analysis. All these findings univocally provide detailed insight into the binding specificity of harmine, to single stranded poly (rA) over other RNA motifs, probably suggesting a self-structure formation in poly (rA) with harmine and its potential as a lead compound for RNA based drug targeting.

暂无摘要。

This research investigates the impact of solution concentration and solution-to-binder ratio (S/B) on the volume changes in alkali-activated slags with sodium hydroxide at 20 °C. Autogenous and thermal strains are monitored with a customized testing device in which thermal variations are controlled. Consequently, both the autogenous strain and coefficient of thermal expansion (CTE) are determined. Heat flow and internal relative humidity (IRH) are also monitored in parallel, making this research a multifaceted study. The magnitudes of autogenous strain and CTE are higher than those of ordinary Portland cement paste. Decreasing the solution concentration or S/B generally decreases the autogenous strain (swelling and shrinkage) and the CTE. The shrinkage amounted to 87 to 1981 µm/m, while the swelling reached between 27 and 295 µm/m and was only present in half of the compositions. The amplitude of the CTE, which increases up to 55 µm/m/°C for some compositions while the CTE of OPC remains between 20 and 25 µm/m/°C, can be explained by the high CTE of the solution in comparison with water. The IRH of paste cannot explain the autogenous strain\'s development alone. Increasing S/B eliminates the self-desiccation-related decrease.

Aβ peptides are known to bind neural plasma membranes in a process leading to the deposit of Aβ-enriched plaques. These extracellular structures are characteristic of Alzheimer\'s disease, the major cause of late-age dementia. The mechanisms of Aβ plaque formation and deposition are far from being understood. A vast number of studies in the literature describe the efforts to analyze those mechanisms using a variety of tools. The present review focuses on biophysical studies mostly carried out with model membranes or with computational tools. This review starts by describing basic physical aspects of lipid phases and commonly used model membranes (monolayers and bilayers). This is followed by a discussion of the biophysical techniques applied to these systems, mainly but not exclusively Langmuir monolayers, isothermal calorimetry, density-gradient ultracentrifugation, and molecular dynamics. The Methodological Section is followed by the core of the review, which includes a summary of important results obtained with each technique. The last section is devoted to an overall reflection and an effort to understand Aβ-bilayer binding. Concepts such as Aβ peptide membrane binding, adsorption, and insertion are defined and differentiated. The roles of membrane lipid order, nanodomain formation, and electrostatic forces in Aβ-membrane interaction are separately identified and discussed.

Regulatory cystathionine β-synthase (CBS) domains are widespread in proteins; however, difficulty in structure determination prevents a comprehensive understanding of the underlying regulation mechanism. Tetrameric microbial inorganic pyrophosphatase containing such domains (CBS-PPase) is allosterically inhibited by AMP and ADP and activated by ATP and cell alarmones diadenosine polyphosphates. Each CBS-PPase subunit contains a pair of CBS domains but binds cooperatively to only one molecule of the mono-adenosine derivatives. We used site-directed mutagenesis of Desulfitobacterium hafniense CBS-PPase to identify the key elements determining the direction of the effect (activation or inhibition) and the \"half-of-the-sites\" ligand binding stoichiometry. Seven amino acid residues were selected in the CBS1 domain, based on the available X-ray structure of the regulatory domains, and substituted by alanine and other residues. The interaction of 11 CBS-PPase variants with the regulating ligands was characterized by activity measurements and isothermal titration calorimetry. Lys100 replacement reversed the effect of ADP from inhibition to activation, whereas Lys95 and Gly118 replacements made ADP an activator at low concentrations but an inhibitor at high concentrations. Replacement of these residues for alanine increased the stoichiometry of mono-adenosine phosphate binding by twofold. These findings identified several key protein residues and suggested a \"two non-interacting pairs of interacting regulatory sites\" concept in CBS-PPase regulation.

BACKGROUND: Relapse of Candida albicans urinary tract infection (UTI) is frequent despite appropriate treatment, as commonly used antifungals such fluconazole and flucytosine are only fungistatics. To improve treatment of Candida UTI and decrease relapses, understanding the long-term metabolic activity and survival of C. albicans in urine containing antifungals at minimal inhibitory concentration (MIC) is needed.
METHODS: we monitored the survival, metabolic activity and consumption of glucose and proteins by C. albicans using conventional methods and isothermal microcalorimetry (IMC). We also investigated the influence of dead Candida cells on the growth of their living counterparts.
RESULTS: For 33 days, weak activity was observed in samples containing antifungals in which C. albicans growth rate was reduced by 48%, 60% and 88%, and the lag increased to 172 h, 168 h and 6 h for amphotericin, flucytosine and fluconazole, respectively. The metabolic activity peaks corresponded to the plate counts but were delayed compared to the exhaustion of resources. The presence of dead cells promoted growth in artificial urine, increasing growth rate and reducing lag in similar proportions.
CONCLUSIONS: Even with antifungal treatment, C. albicans relapses are possible. The low metabolic activity of surviving cells leading to regrowth and chlamydospore formation possibly supported by autophagy are likely important factors in relapses.

The amyloidogenic Aβ peptides are widely considered as a pathogenic agent in Alzheimer\'s disease. Aβ(1-42) would form aggregates of amyloid fibrils on the neuron plasma membranes, thus perturbing neuronal functionality. Conflicting data are available on the influence of bilayer order on Aβ(1-42) binding to membranes. In the present study, a biophysical approach was used in which isothermal calorimetry and surface pressure measurements were applied to explore the interaction of Aβ(1-42) in either monomeric, oligomeric, or fibrillar form with model membranes (bilayers or monolayers) in the liquid-ordered state that were either electrically neutral or negatively charged. In the latter case, this contained phosphatidic acid, cardiolipin, or ganglioside. The calorimetric studies showed that Aβ(1-42) fibrils, oligomers, and monomers could bind and/or be inserted into bilayers, irrespective of electric charge, in the liquid-ordered state, except that monomers could not interact with electrically neutral bilayers. The monolayer studies in the Langmuir balance demonstrated that Aβ(1-42) aggregation hindered peptide insertion into the monolayer, hindered insertion in the decreasing order of monomer > oligomer > fibril, and that lipid composition did not cause large differences in insertion, apart from a slight facilitation of monomer and oligomer insertion by gangliosides.

This study examines the impact of particle size on the setting behavior of tricalcium silicate powders. The setting behavior was evaluated using ISO 6876 indentation testing and isothermal induction calorimetry techniques. The objective was to compare the outcomes obtained from these methods and establish a correlation between particle size and setting characteristics. The cement pastes were manually mixed with a water-to-solid ratio of 0.66 for conducting indentation tests according to ISO 6876, while calorimetry measurements were performed using isothermal (conduction) calorimetry at room temperature. The findings demonstrate a significant influence of smaller particle sizes on accelerating the hydration process of cement pastes, resulting in a reduction of setting time by up to 24%. Moreover, the final setting times obtained through the indentation method closely approximate the inflection points of the acceleration curves acquired by calorimetry, with time deviations of less than 12% regardless of particle size.

This study aimed to investigate the heat generated during the hydration process in cementitious composites containing multi-walled carbon nanotubes (MWCNTs). The cumulative heat release and heat flow of these cementitious composites were measured over a period of 168 h using isothermal calorimetry. Three different MWCNT dosages, 0.05 wt%, 0.1 wt%, and 0.2 wt%, along with two different sonication times for the solution, which were 20 min and 60 min, were applied in the experimental program. The results reveal that the incorporation of MWCNTs and the use of a naphthalene-based superplasticizer to disperse the nanotubes generally led to a reduction in heat emission during the early stages of hydration, a lower first peak value in the initial stage of hydration, and a significant delay in the acceleration period compared with the reference sample lacking this superplasticizer. Furthermore, the results demonstrate that both the dosage of multi-walled carbon nanotubes (MWCNTs) and the sonication time have an impact on the heat emission and hydration process since the same amount of superplasticizer was applied to all pastes. An increase in the MWCNT dosage led to a decrease in the rate of hydration heat at the main peak for all pastes. Additionally, longer sonication times resulted in lower values of heat generated, reduced main peak values in the heat rate evolution, and generally extended delays in the occurrence of the main peak.

Cement production contributes significantly to carbon dioxide emissions. Alkali-activated materials offer an environmentally friendly alternative due to their comparable strength, durability and low-carbon emissions while utilizing wastes and industrial by-products. Wood ash is a waste material that shows promising results as a partial replacement for Portland cement and precursors in alkali-activated systems. The aim of this study was to examine the effect of ground wood ash on the mechanical properties of alkali-activated mortars. Wood ash was incorporated as a 0 wt%, 10 wt% and 20 wt% partial replacement for ground granulated blast furnace slag (GGBFS). The wood ashes were ground in a planetary ball mill for 10 and 20 min. Sodium silicate (Na2SiO3), sodium carbonate (Na2CO3), and sodium hydroxide (NaOH) were used as alkali activators. The results demonstrated that ground wood ash improved the mechanical properties of alkali-activated systems compared to untreated wood ash. However, the incorporation of wood ash increased the porosity of the binder matrix.