Investigation of Indazole Unbinding Pathways in CYP2E1 by Molecular Dynamics Simulations

Human microsomal cytochrome P450 2E1 (CYP2E1) can oxidize not only low molecular weight xenobiotic compounds such as ethanol, but also many endogenous fatty acids. The crystal structure of CYP2E1 in complex with indazole reveals that the active site is deeply buried into the protein center. Thus, the unbinding pathways and associated unbinding mechanisms remain elusive. In this study, random acceleration molecular dynamics simulations combined with steered molecular dynamics and potential of mean force calculations were performed to identify the possible unbinding pathways in CYP2E1. The results show that channel 2c and 2a are most likely the unbinding channels of CYP2E1. The former channel is located between helices G and I and the B-C loop, and the latter resides between the region formed by the F-G loop, the B-C loop and the β1 sheet. Phe298 and Phe478 act as the gate keeper during indazole unbinding along channel 2c and 2a, respectively. Previous site-directed mutagenesis experiments also supported these findings

Sequential versus nonsequential two-photon double ionization of the D2 molecule at 38 eV

ABSTRACT: A simple theoretical model is used to interpret recent experimental results for two-photon double ionization (DI) of D2 at 38 eV. We show that the measured kinetic energy distribution associated with emission of two protons can be interpreted as a sum of two processes: a sequential and an instantaneous absorption of the two incident photons. These processes lead to peaks in di erent regions of the spaectrum

Coupled operation experience at the Holifield Heavy-Ion research Facility

The 25URC Pelletron tandem electrostatic accelerator and the Oak Ridge Isochronous Cyclotron (ORIC) comprise the accelerators of the Holifield Heavy-Ion Research Facility (HHIRF). The two machines may be operated individually or coupled, with ORIC serving as an energy booster for the tandem. In the coupled dode, the ion beam enters the cyclotron through the dee stem and is directed by the inflection magnet so that it is tangent to an orbit suitable for acceleration at a higher charge state. A thin carbon foil, placed at the point of tangency, strips the ions so that a substantial fraction are in the desired higher charge state. This fraction of the beam is then accelerated and extracted in the normal fashion. Full energy performance (25 MeV/A oxygen) was demonstrated during first coupled operation in January 1981. Routine coupled operation for experiments commenced in July 1982

Re-framing the climate change debate in the livestock sector: mitigation and adaptation options

Livestock play a key role in the climate change debate. As with crop-based agriculture, the sector is both a net greenhouse gas emitter and vulnerable to climate change. At the same time, it is an essential food source for millions of people worldwide, with other functions apart from food security such as savings and insurance. By comparison with crop-based agriculture, the interactions of livestock and climate change have been much less studied. The debate around livestock is confusing due to the coexistence of multiple livestock farming systems with differing functions for humans, greenhouse gas (GHG) emission profiles and different characteristics and boundary issues in their measurement, which are often pooled together. Consequently, the diversity of livestock farming systems and their functions to human systems are poorly represented and the role of the livestock sector in the climate change debate has not been adequately addressed. In this article, building upon the Intergovernmental Panel on Climate Change Fifth Assessment Report (IPCC 5AR) findings, we review recent literature on livestock and climate change so as better to include this diversity in the adaptation and mitigation debate around livestock systems. For comparative purposes we use the same categories of managerial, technical, behavioral and policy-related action to organize both mitigation and adaptation options. We conclude that different livestock systems provide different functions to different human systems and require different strategies, so they cannot readily be pooled together. We also observe that, for the different livestock systems, several win-win strategies exist that effectively tackle both mitigation and adaptation options as well as food security

Inclusive V0V^0 Production Cross Sections from 920 GeV Fixed Target Proton-Nucleus Collisions

Inclusive differential cross sections $d\sigma_{pA}/dx_F$ and $d\sigma_{pA}/dp_t^2$ for the production of \kzeros, \lambdazero, and \antilambda particles are measured at HERA in proton-induced reactions on C, Al, Ti, and W targets. The incident beam energy is 920 GeV, corresponding to $\sqrt {s} = 41.6$ GeV in the proton-nucleon system. The ratios of differential cross sections \rklpa and \rllpa are measured to be $6.2\pm 0.5$ and $0.66\pm 0.07$, respectively, for \xf $\approx-0.06$. No significant dependence upon the target material is observed. Within errors, the slopes of the transverse momentum distributions $d\sigma_{pA}/dp_t^2$ also show no significant dependence upon the target material. The dependence of the extrapolated total cross sections $\sigma_{pA}$ on the atomic mass $A$ of the target material is discussed, and the deduced cross sections per nucleon $\sigma_{pN}$ are compared with results obtained at other energies.Comment: 17 pages, 7 figures, 5 table

Water in Cavity−Ligand Recognition

We use explicit solvent molecular dynamics simulations to estimate free energy, enthalpy, and entropy changes along the cavity-ligand association coordinate for a set of seven model systems with varying physicochemical properties. Owing to the simplicity of the considered systems we can directly investigate the role of water thermodynamics in molecular recognition. A broad range of thermodynamic signatures is found in which water (rather than cavity or ligand) enthalpic or entropic contributions appear to drive cavity-ligand binding or rejection. The unprecedented, nanoscale picture of hydration thermodynamics can help the interpretation and design of protein-ligand binding experiments. Our study opens appealing perspectives to tackle the challenge of solvent entropy estimation in complex systems and for improving molecular simulation models

A global FAOSTAT reference database of cropland nutrient budgets and nutrient use efficiency (1961–2020): nitrogen, phosphorus and potassium

Nutrient budgets help to identify the excess or insufficient use of fertilizers and other nutrient sources in agriculture. They allow for the calculation of indicators, such as the nutrient balance (surplus if positive or deficit if negative) and nutrient use efficiency, that help to monitor agricultural productivity and sustainability across the world. We present a global database of country-level budget estimates for nitrogen (N), phosphorus (P) and potassium (K) on cropland. The database, disseminated in FAOSTAT, is meant to provide a global reference, synthesizing and continuously updating the state of the art on this topic. The database covers 205 countries and territories, as well as regional and global aggregates, for the period from 1961 to 2020. Results highlight the wide range in nutrient use and nutrient use efficiencies across geographic regions, nutrients, and time. The average N balance on global cropland has remained fairly steady at about 50–55 kg ha−1 yr−1 during the past 15 years, despite increasing N inputs. Regional trends, however, show recent average N surpluses that range from a low of about 10 kg N ha−1 yr−1 in Africa to more than 90 kg N ha−1 yr−1 in Asia. Encouragingly, average global cropland N use efficiency decreased from about 59 % in 1961 to a low of 43 % in 1988, but it has risen since then to a level of 55 %. Phosphorus deficits are mainly found in Africa, whereas potassium deficits occur in Africa and the Americas. This study introduces improvements over previous work in relation to the key nutrient coefficients affecting nutrient budgets and nutrient use efficiency estimates, especially with respect to nutrient removal in crop products, manure nutrient content, atmospheric deposition and crop biological N fixation rates. We conclude by discussing future research directions and highlighting the need to align statistical definitions across research groups as well as to further refine plant and livestock coefficients and expand estimates to all agricultural land, including nutrient flows in meadows and pastures. Further information is available from https://doi.org/10.5061/dryad.hx3ffbgkh (Ludemann et al., 2023b) as well as the FAOSTAT database (https://www.fao.org/faostat/en/#data/ESB; FAO, 2022a) and is updated annually.</p

Guiding Brain Tumor Resection Using Surface-Enhanced Raman Scattering Nanoparticles and a Hand-Held Raman Scanner

The current difficulty in visualizing the true extent of malignant brain tumors during surgical resection represents one of the major reasons for the poor prognosis of brain tumor patients. Here, we evaluated the ability of a hand-held Raman scanner, guided by surface-enhanced Raman scattering (SERS) nanoparticles, to identify the microscopic tumor extent in a genetically engineered RCAS/tv-a glioblastoma mouse model. In a simulated intraoperative scenario, we tested both a static Raman imaging device and a mobile, hand-held Raman scanner. We show that SERS image-guided resection is more accurate than resection using white light visualization alone. Both methods complemented each other, and correlation with histology showed that SERS nanoparticles accurately outlined the extent of the tumors. Importantly, the hand-held Raman probe not only allowed near real-time scanning, but also detected additional microscopic foci of cancer in the resection bed that were not seen on static SERS images and would otherwise have been missed. This technology has a strong potential for clinical translation because it uses inert gold-silica SERS nanoparticles and a hand-held Raman scanner that can guide brain tumor resection in the operating room