Molecular dynamics simulations of CXCL-8 and its interactions with a receptor peptide, heparin fragments, and sulfated linked cyclitols

CXCL-8 (Interleukin 8) is a CXC chemokine with a central role in the human immune response. We have undertaken extensive in silico analyses to elucidate the interactions of CXCL-8 with its various binding partners, which are crucial for its biological function. Sequence and structure analyses showed that residues in the thirdq β-sheet and basic residues in the heparin binding site are highly variable, while residues in the second β-sheet are highly conserved. Molecular dynamics simulations in aqueous solution of dimeric CXCL-8 have been performed with starting geometries from both X-ray and NMR structures showed shearing movements between the two antiparallel C-terminal helices. Dynamic conservation analyses of these simulations agreed with experimental data indicating that structural differences between the two structures at quaternary level arise from changes in the secondary structure of the N-terminal loop, the 310-helix, the 30s, 40s, and 50s loops and the third β-sheet, resulting in a different interhelical separation. Nevertheless, the observation of these different states indicates that CXCL-8 has the potential to undergo conformational changes, and it seems likely that this feature is relevant to the mode of binding of glycosaminoglycan (GAG) mimetics such as cyclitols. Simulations of the receptor peptide fragment−CXCL-8 complex identified several specific interactions of the receptor peptide with CXCL-8 that could be exploited in the structure-based design of competitive peptides and nonpeptidic molecules targeting CXCL-8 for combating inflammatory diseases. Simulations of the CXCL-8 dimer complexed with a 24-mer heparin fragment and of the CXCL-8−receptor peptide complex revealed that Arg60, Lys64, and Arg68 in the dimer bind to cyclitols in a horseshoe pattern, defining a region which is spatially distinct from the receptor binding site. There appears to be an optimum number of sulfates and an optimum length of alkyl spacers required for the interaction of cyclitol inhibitors with the dimeric form of CXCL-8. Calculation of the binding affinities of cyclitol inhibitors reflected satisfactorily the ranking of experimentally determined inhibitory potencies. The findings of these molecular modeling studies will help in the search for inhibitors which can modulate various CXCL-8 biological activities and serve as an excellent model system to study CXC-inhibitor interactions.

Molecular dynamics simulation of the phosphorylation-induced conformational changes of a tau peptide fragment

Aggregation of the microtubule associated protein tau (MAPT) within neurons of the brain is the leading cause of tauopathies such as Alzheimer's disease. MAPT is a phospho-protein that is selectively phosphorylated by a number of kinases in vivo to perform its biological function. However, it may become pathogenically hyperphosphorylated, causing aggregation into paired helical filaments and neurofibrillary tangles. The phosphorylation induced conformational change on a peptide of MAPT (htau225−250) was investigated by performing molecular dynamics simulations with different phosphorylation patterns of the peptide (pThr231 and/or pSer235) in different simulation conditions to determine the effect of ionic strength and phosphate charge. All phosphorylation patterns were found to disrupt a nascent terminal β-sheet pattern (226VAVVR230 and 244QTAPVP249), replacing it with a range of structures. The double pThr231/pSer235 phosphorylation pattern at experimental ionic strength resulted in the best agreement with NMR structural characterization, with the observation of a transient α-helix (239AKSRLQT245). PPII helical conformations were only found sporadically throughout the simulations. Proteins 2014; 82:1907–1923. © 2014 Wiley Periodicals, Inc.

Annual nitrogen dynamics and urea fertilizer recoveries from a dairy pasture using 15N; effect of nitrification inhibitor DMPP and reduced application rates

Direct nitrogen (N) losses from pastures contribute to the poor nitrogen use efficiency of the dairy industry, though the exact fate of applied N and the processes involved are largely unknown. Nitrification inhibitors such as DMPP can potentially increase fertilizer N use efficiency (NUE), though few studies globally have examined the effectiveness of DMPP coated urea in pastures. This study quantified the NUE of DMPP combined with reduced application rates, and the effect on N dynamics and plant–soil interactions over an annual ryegrass/kikuyu rotation in Queensland, Australia. Labeled 15N urea and DMPP was applied over 7 winter applications at standard farmer (45 kg N ha−1) and half (23 kg N ha−1) rates. Fertilizer recoveries and NUE were calculated over 13 harvests, and the contribution of fertilizer and soil N estimated. Up to 85% of the annual N harvested was from soil organic matter. DMPP at the lower rate increased annual yields by 31% compared to the equivalent urea treatment with no difference to the high N rates. Almost 40% of the N added at the conventional fertilizer application rate as urea was lost to the environment; 80 kg N ha−1 higher than the low DMPP. Combining the nitrification inhibitor DMPP with reduced fertilizer application rates shows substantial potential to reduce N losses to the environment while sustaining productivity in subtropical dairy pastures.

Towards an understanding of the information dynamics of the handover process in aged care settings: A prerequisite for the safe and effective use of ICT

Background Poor clinical handover has been associated with inaccurate clinical assessment and diagnosis, delays in diagnosis and test ordering, medication errors and decreased patient satisfaction in the acute care setting. Research on the handover process in the residential aged care sector is very limited. Purpose The aims of this study were to: (i) Develop an in-depth understanding of the handover process in aged care by mapping all the key activities and their information dynamics, (ii) Identify gaps in information exchange in the handover process and analyze implications for resident safety, (iii) Develop practical recommendations on how information communication technology (ICT) can improve the process and resident safety. Methods The study was undertaken at a large metropolitan facility in NSW with more than 300 residents and a staff including 55 registered nurses (RNs) and 146 assistants in nursing (AINs). A total of 3 focus groups, 12 interviews and 3 observation sessions were conducted over a period from July to October 2010. Process mapping was undertaken by translating the qualitative data via a five-category code book that was developed prior to the analysis. Results Three major sub-processes were identified and mapped. The three major stages are Handover process (HOP) I “Information gathering by RN”, HOP II “Preparation of preliminary handover sheet” and HOP III “Execution of handover meeting”. Inefficient processes were identified in relation to the handover including duplication of information, utilization of multiple communication modes and information sources, and lack of standardization. Conclusion By providing a robust process model of handover this study has made two critical contributions to research in aged care: (i) a means to identify important, possibly suboptimal practices; and (ii) valuable evidence to plan and improve ICT implementation in residential aged care. The mapping of this process enabled analysis of gaps in information flow and potential impacts on resident safety. In addition it offers the basis for further studies into a process that, despite its importance for securing resident safety and continuity of care, lacks research.

Highly efficient spin-conversion effect leading to energy up-converted electroluminescence in singlet fission photovoltaics

Free charge generation in donor-acceptor (D-A) based organic photovoltaic diodes (OPV) progresses through formation of charge-transfer (CT) and charge-separated (CS) states and excitation decay to the triplet level is considered as a terminal loss. On the other hand a direct excitation decay to the triplet state is beneficial for multiexciton harvesting in singlet fission photovoltaics (SF-PV) and the formation of CT-state is considered as a limiting factor for multiple triplet harvesting. These two extremes when present in a D-A system are expected to provide important insights into the mechanism of free charge generation and spin-character of bimolecular recombination in OPVs. Herein, we present the complete cycle of events linked to spin conversion in the model OPV system of rubrene/C60. By tracking the spectral evolution of photocurrent generation at short-circuit and close to open-circuit conditions we are able to capture spectral changes to photocurrent that reveal the triplet character of CT-state. Furthermore, we unveil an energy up-conversion effect that sets in as a consequence of triplet population build-up where triplet-triplet annihilation (TTA) process effectively regenerates the singlet excitation. This detailed balance is shown to enable a rare event of photon emission just above the open-circuit voltage (VOC) in OPVs.

Uncoupled surface spin induced exchange bias in α-MnO 2 nanowires

We have studied the microstructure, surface states, valence fluctuations, magnetic properties, and exchange bias effect in MnO2 nanowires. High purity α-MnO 2 rectangular nanowires were synthesized by a facile hydrothermal method with microwave-assisted procedures. The microstructure analysis indicates that the nanowires grow in the [0 0 1] direction with the (2 1 0) plane as the surface. Mn3+ and Mn2+ ions are not found in the system by X-ray photoelectron spectroscopy. The effective magnetic moment of the manganese ions fits in with the theoretical and experimental values of Mn4+ very well. The uncoupled spins in 3d3 orbitals of the Mn 4+ ions in MnO 6 octahedra on the rough surface are responsible for the net magnetic moment. Spin glass behavior is observed through magnetic measurements. Furthermore, the exchange bias effect is observed for the first time in pure α-MnO2 phase due to the coupling of the surface spin glass with the antiferromagnetic α-MnO2 matrix. These α-MnO2 nanowires, with a spin-glass-like behavior and with an exchange bias effect excited by the uncoupled surface spins, should therefore inspire further study concerning the origin, theory, and applicability of surface structure induced magnetism in nanostructures.