Discovery of novel inhibitors of Streptococcus pneumoniae based on the virtual screening with the homology-modeled structure of histidine kinase (VicK)

<p>Abstract</p> <p>Background</p> <p>Due to the widespread abusage of antibiotics, antibiotic-resistance in <it>Streptococcus pneumoniae </it>(<it>S. pneumoniae</it>) has been increasing quickly in recent years, and it is obviously urgent to develop new types of antibiotics. Two-component systems (TCSs) are the major signal transduction pathways in bacteria and have emerged as potential targets for antibacterial drugs. Among the 13 pairs of TCSs proteins presenting in <it>S. pneumoniae</it>, VicR/K is the unique one essential for bacterium growth, and block agents to which, if can be found, may be developed as effective antibiotics against <it>S. pneumoniae </it>infection.</p> <p>Results</p> <p>Using a structure-based virtual screening (SBVS) method, 105 compounds were computationally identified as potential inhibitors of the histidine kinase (HK) VicK protein from the compound library SPECS. Six of them were then validated <it>in vitro </it>to be active in inhibiting the growth of <it>S. pneumoniae </it>without obvious cytotoxicity to Vero cell. In mouse sepsis models, these compounds are still able to decrease the mortality of the mice infected by <it>S. pneumoniae </it>and one compound even has significant therapeutic effect.</p> <p>Conclusion</p> <p>To our knowledge, these compounds are the first reported inhibitors of HK with antibacterial activity <it>in vitro </it>and <it>in vivo</it>, and are novel lead structures for developing new drugs to combat pneumococcal infection.</p

Direct transformation of-alkane into all-conjugated polyene via cascade dehydrogenation

Selective C(sp$^{3}$) −H activation is of fundamental importance in processing alkane feedstocks to produce high-value-added chemical products. By virtue of an on-surface synthesis strategy, we report selective cascade dehydrogenation of n-alkane molecules under surface constraints, which yields monodispersed all-trans conjugated polyenes with unprecedented length controllability. We are also able to demonstrate the generality of this concept for alkyl-substituted molecules with programmable lengths and diverse functionalities, and more importantly its promising potential in molecular wiring

Human helicase RECQL4 drives cisplatin resistance in gastric cancer by activating an AKT-YB1-MDR1 signaling pathway

Elevation of the DNA-unwinding helicase RECQL4, which participates in various DNA repair pathways, has been suggested to contribute to the pathogenicity of various human cancers, including gastric cancer. In this study, we addressed the prognostic and chemotherapeutic significance of RECQL4 in human gastric cancer, which has yet to be determined. We observed significant increases in RECQL4 mRNA or protein in >70% of three independent sets of human gastric cancer specimens examined, relative to normal gastric tissues. Strikingly, high RECQL4 expression in primary tumors correlated well with poor survival and gastric cancer lines with high RECQL4 expression displayed increased resistance to cisplatin treatment. Mechanistic investigations revealed a novel role for RECQL4 in transcriptional regulation of the multidrug resistance gene MDR1, through a physical interaction with the transcription factor YB1. Notably, ectopic expression of RECQL4 in cisplatin-sensitive gastric cancer cells with low endogenous RECQL4 was sufficient to render them resistant to cisplatin, in a manner associated with YB1 elevation and MDR1 activation. Conversely, RECQL4 silencing in cisplatin-resistant gastric cancer cells with high endogenous RECQL4 suppressed YB1 phosphorylation, reduced MDR1 expression, and resensitized cells to cisplatin. In establishing RECQL4 as a critical mediator of cisplatin resistance in gastric cancer cells, our findings provide a therapeutic rationale to target RECQL4 or the downstream AKT-YB1-MDR1 axis to improve gastric cancer treatment

The Tianlai Cylinder Pathfinder array: System functions and basic performance analysis

The Tianlai Cylinder Pathfinder is a radio interferometer array designed to test techniques for 21 cm intensity mapping in the post-reionization Universe, with the ultimate aim of mapping the large scale structure and measuring cosmological parameters such as the dark energy equation of state. Each of its three parallel cylinder reflectors is oriented in the north-south direction, and the array has a large field of view. As the Earth rotates, the northern sky is observed by drift scanning. The array is located in Hongliuxia, a radio-quiet site in Xinjiang, and saw its first light in September 2016. In this first data analysis paper for the Tianlai cylinder array, we discuss the sub-system qualification tests, and present basic system performance obtained from preliminary analysis of the commissioning observations during 2016-2018. We show typical interferometric visibility data, from which we derive the actual beam profile in the east-west direction and the frequency band-pass response. We describe also the calibration process to determine the complex gains for the array elements, either using bright astronomical point sources, or an artificial on site calibrator source, and discuss the instrument response stability, crucial for transit interferometry. Based on this analysis, we find a system temperature of about 90 K, and we also estimate the sensitivity of the array

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals &lt;1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Mechanistic investigations of chemical reactions on 2D MXenes and metal surfaces from first-principles

Chemical reactions on surfaces play a central role both for our daily life and industrial purposes, including the storage and release of energy, as well as the formation of new materials. To achieve high efficiency, catalysis lies in the heart of chemical reactions as it plays a critical role in accelerating the chemical transformation to target products. However, environmental issues arise as the applications of catalytic technologies and current synthetic approaches such as pollution from undesirable byproducts and massive emission of carbon dioxides due to the usage of fossil fuels. This calls for developing improved strategies for fabricating new materials with highly efficient catalytic properties. In recent years, on-surface chemical reactions have also been used to synthesize new low-dimensional materials with atomic precision, by coupling molecules into nanostructures. It is crucial to not only obtain high activity for chemical reactions, but also achieve distinct selectivity towards desired products. For this purpose, understanding mechanisms of target chemical reactions and origins of catalysts’ activity are of great significance to facilitate chemical processes. In this thesis, three types of chemical reactions are investigated within the framework of density functional theory (DFT), in which chemical reactions relevant for both heterogeneous catalysis and electrochemical synthesis are considered on two-dimensional transition metal carbides (2D MXenes), and chemical reactions for synthesizing organic nanostructures are studied on metal surfaces. Focusing on one of the most fundamental chemical reaction, C(sp3)-H activation, we demonstrate that MXenes can serve as highly efficient heterogeneous catalysts and exhibit high activity. The thermally triggered C-H activations are shown to follow the “radical-like” mechanism on MXenes, in which O terminations serve as active sites. By adopting the hydrogen affinity (EH) as a descriptor, both the geometry configuration and the catalytic activity of MXenes can be quantitatively characterized. In the context of on-surface synthesis, we theoretically propose reaction mechanisms of two types of chemical reactions on surface. A new strategy for constructing C-C bonds via the desulfonylation reaction was achieved experimentally for the first time by collaborators. With DFT calculations, an observed discrepancy between Ag(111) and Au(111) is ascribed to interactions between surfaces and molecules. Secondly, the formation mechanism of the 2D biphenylene network (BPN), a recently realized carbon allotrope formed by intermolecular HF zipping on Au(111), has been computationally investigated. With the tool of DFT calculations, a single Ni atom catalyst supported by Ti3C2T2 MXenes for electrochemical nitrogen reduction has been theoretically proposed. Such single atom catalyst (SAC) is computationally screened from three aspects including stability, activity, and selectivity. Our theoretical results show that not only the catalytic performance of the Ni SAC predicted by screening criteria can be verified, but also a H rich environment can be beneficial for the electrochemical nitrogen reduction on such SACs. In summary, first-principles calculations have been performed to evaluate the catalytic performance of 2D MXenes towards C-H activation, unravel formation mechanisms of organic materials synthesized via on-surface reactions, and design effective catalysts towards the synthesis of ammonia. It is anticipated that this thesis can pave the way for the rational design of high-efficient catalysts for various reactions and shed lights on developing synthetic strategies of unprecedented organic materials

C-H activation of light alkanes on MXenes predicted by hydrogen affinity

C-H activation of light alkanes is one of the most important reactions for a plethora of applications but requires catalysts to operate at feasible conditions. MXenes, a new group of two-dimensional materials, have shown great promise as heterogeneous catalysts for several applications. However, the catalytic activity of MXenes depends on the type and distribution of termination groups. Theoretically, it is desired to search for a relation between the catalytic activity and the termination configuration by employing a simple descriptor in order to avoid tedious activation energy calculations. Here, we show that MXenes are promising for splitting C-H bonds of light alkanes. Furthermore, we present how a quantitative descriptor - the hydrogen affinity - can be used to characterize the termination configuration of Ti2CTz(T = O, OH) MXenes, as well as the catalytic activity towards dehydrogenation reactions, using propane as model system. First-principles calculations reveal that the hydrogen affinity can be considered as an intrinsic property of O and OH terminated Ti2C MXenes, in which the mean hydrogen affinity for the terminated Ti2C MXenes is linearly correlated to the statistical average of their OH fraction. In addition, the C-H activation energies exhibit a strong scaling relationship to the hydrogen affinity. This quantity can therefore yield quick predictions of catalytic activity of terminated Ti2C MXenes towards C-H activations, and even predict their chemical selectivity toward scissoring different C-H bonds. We believe that the hydrogen affinity will accelerate the discovery of further applications of the broad family of MXenes in heterogeneous catalysis.Funding Agencies|Swedish Research CouncilSwedish Research Council; Swedish Government Strategic Research Area in Materials Science on Functional Materials at Linkoping University [2009 00971]; National Natural Science Foundation of China (NSFC)National Natural Science Foundation of China (NSFC) [21790053, 51821002]; Major State Basic Research Development Program of ChinaNational Basic Research Program of China [2017YFA0205000]; Knut and Alice Wallenberg (KAW) FoundationKnut &amp; Alice Wallenberg Foundation; Swedish Foundation for Strategic Research (SSF)Swedish Foundation for Strategic Research [EM16-0004]</p

Effects of Fermented Manure Bedding Thickness on Bulls’ Growth, Behavior, and Welfare as Well as Barn Gases Concentration in the Barn

Providing clean, comfortable bedding is essential for the growth and welfare of bulls. This study was aimed to investigate the effects of bedding thickness on growth performance, behavior, and welfare of bulls as well as gases concentration in the barn. Thirty-six healthy Simmental bulls (7–9 months old) were randomly divided into three groups and raised on 0 cm (concrete floor, CF), 15 cm (shallow fermented bedding, SFB), and 30 cm (deep fermented bedding, DFB) fermented manure bedding. The results showed that the DFB group exhibited the optimal ADG (average daily gain), F/G (ratio of feed to gain), hoof health, body hygiene, and lying time, followed by the SFB group and the CF group (p 0.05). As for the barn gas environment, the contents of ammonia and carbon dioxide were the lowest in the DFB group, followed by the SFB group, and they were the highest in the CF group at the same time points (p 0.01). In summary, fermented manure bedding significantly improves the growth performances, behavior, and welfare of bulls as well as gases concentration, and the improvement effect achieved by deep fermented bedding is more obvious than by shallow fermented bedding

Structure-activity correlation of Ti2CT2 MXenes for C-H activation

As a bourgeoning class of 2D materials, MXenes have recently attracted significant attention within heterogeneous catalysis for promoting reactions such as hydrogen evolution and C-H activation. However, the catalytic activity of MXenes is highly dependent on the structural configuration including termination groups and their distribution. Therefore, understanding the relation between the structure and the activity is desired for the rational design of MXenes as high-efficient catalysts. Here, we present that the correlation between the structure and activity of Ti2CT2 (T is a combination of O, OH and/or F) MXenes for C-H activation can be linked by a quantitative descriptor: the hydrogen affinity (E (H)). A linear correlation is observed between the mean hydrogen affinity and the overall ratio of O terminations (x (O)) in Ti2CT2 MXenes, in which hydrogen affinity increases as the x (O) decreases, regardless to the species of termination groups. In addition, the hydrogen affinity is more sensitive to the presence of OH termination than F terminations. Moreover, the linear correlation between the hydrogen affinity and the activity of Ti2CT2 MXenes for C-H activation of both -CH3 and -CH2- groups can be extended to be valid for all three possible termination groups. Such a correlation provides fast prediction of the activity of general Ti2CT2 MXenes, avoiding tedious activation energy calculations. We anticipate that the findings have the potential to accelerate the development of MXenes for heterogeneous catalysis applications.Funding Agencies|Swedish Research CouncilSwedish Research CouncilEuropean Commission; Swedish Government Strategic Research Area in Materials Science on Functional Materials at Linkoping University (Faculty Grant SFO-Mat-LiU) [2009 00971]; National Natural Science Foundation of China (NSFC)National Natural Science Foundation of China (NSFC) [21790053, 51821002]; Ministry of Science and Technology [2017YFA0205002]; Swedish Foundation for Strategic Research (SSF)Swedish Foundation for Strategic Research [EM16-0004]; Knut and Alice Wallenberg (KAW) FoundationKnut &amp; Alice Wallenberg Foundation</p

Static and Dynamic Load Transfer Behaviors of the Composite Foundation Reinforced by the Geosynthetic-Encased Stone Column

An accurate description of the load transfer behaviors of the geosynthetic-encased stone column (GESC) is of great importance for revealing the bearing capacity of GESC. Static load tests and shake table model tests were performed to characterize the static and dynamic load transfer behaviors of the composite foundation reinforced by the GESC. Under static loading, static load tests were conducted on a fully geosynthetic-encased stone column (FGESC), partially geosynthetic-encased stone column (PGESC) and traditional stone column (TSC). The influence of length and stiffness of the encasement on the stone columns were investigated. Under seismic loading, the shake table model tests were performed to analyze the differences of the dynamic pile-soil stress responses between the composite foundations with the GESC and the TSC. The results show that the static pile-soil stress ratios of the composite foundation with the FGESC are about three to six times of those of the composite foundation with the TSC, and the difference increases with the increase in the stiffness or length of the encasement. The static vertical stress of 60% acting on the pile top can be transferred to the pile bottom for the FGESC, while only 27~45% for the TSC. The dynamic pile-soil stress ratios of the GESC and the TSC first decrease and then increase slightly with the increase of the input peak acceleration. The dynamic pile-soil stress ratio of the GESC is about three times that of the TSC under seismic excitation with the same type and peak acceleration. The attenuation rate of dynamic stress along the pile body under dynamic loading is much faster than that under the static loading. Under the static and dynamic conditions, the load transfer capacity and pile efficacy of the GESC are always better than those of the TSC