Quantitative Comparison against Experiments Reveals Imperfections in Force Fields’ Descriptions of POPC-Cholesterol Interactions

Cholesterol is a central building block in biomembranes, where it induces orientational order, slows diffusion, renders the membrane stiffer, and drives domain formation. Molecular dynamics (MD) simulations have played a crucial role in resolving these effects at the molecular level; yet, it has recently become evident that different MD force fields predict quantitatively different behavior. Although easily neglected, identifying such limitations is increasingly important as the field rapidly progresses toward simulations of complex membranes mimicking the in vivo conditions: pertinent multicomponent simulations must capture accurately the interactions between their fundamental building blocks, such as phospholipids and cholesterol. Here, we define quantitative quality measures for simulations of binary lipid mixtures in membranes against the C–H bond order parameters and lateral diffusion coefficients from NMR spectroscopy as well as the form factors from X-ray scattering. Based on these measures, we perform a systematic evaluation of the ability of commonly used force fields to describe the structure and dynamics of binary mixtures of palmitoyloleoylphosphatidylcholine (POPC) and cholesterol. None of the tested force fields clearly outperforms the others across the tested properties and conditions. Still, the Slipids parameters provide the best overall performance in our tests, especially when dynamic properties are included in the evaluation. The quality evaluation metrics introduced in this work will, particularly, foster future force field development and refinement for multicomponent membranes using automated approaches.publishedVersio

Quantitative Comparison against Experiments Reveals Imperfections in Force Fields’ Descriptions of POPC–Cholesterol Interactions

Cholesterol is a central building block in biomembranes, where it induces orientational order, slows diffusion, renders the membrane stiffer, and drives domain formation. Molecular dynamics (MD) simulations have played a crucial role in resolving these effects at the molecular level; yet, it has recently become evident that different MD force fields predict quantitatively different behavior. Although easily neglected, identifying such limitations is increasingly important as the field rapidly progresses toward simulations of complex membranes mimicking the in vivo conditions: pertinent multicomponent simulations must capture accurately the interactions between their fundamental building blocks, such as phospholipids and cholesterol. Here, we define quantitative quality measures for simulations of binary lipid mixtures in membranes against the C–H bond order parameters and lateral diffusion coefficients from NMR spectroscopy as well as the form factors from X-ray scattering. Based on these measures, we perform a systematic evaluation of the ability of commonly used force fields to describe the structure and dynamics of binary mixtures of palmitoyloleoylphosphatidylcholine (POPC) and cholesterol. None of the tested force fields clearly outperforms the others across the tested properties and conditions. Still, the Slipids parameters provide the best overall performance in our tests, especially when dynamic properties are included in the evaluation. The quality evaluation metrics introduced in this work will, particularly, foster future force field development and refinement for multicomponent membranes using automated approaches

Expanding bubbles in Orion A: [CII] observations of M42, M43, and NGC 1977

The Orion Molecular Cloud is the nearest massive-star forming region. Massive stars have profound effects on their environment due to their strong radiation fields and stellar winds. Velocity-resolved observations of the [CII] $158\,\mu\mathrm{m}$ fine-structure line allow us to study the kinematics of UV-illuminated gas. Here, we present a square-degree-sized map of [CII] emission from the Orion Nebula complex obtained by the upGREAT instrument onboard SOFIA, covering the entire Orion Nebula (M42) plus M43 and the nebulae NGC 1973, 1975, and 1977. We compare the stellar characteristics of these three regions with the kinematics of the expanding bubbles surrounding them. The bubble blown by the O7V star $\theta^1$ Ori C in the Orion Nebula expands rapidly, at $13\,\mathrm{km\,s^{-1}}$. Simple analytical models reproduce the characteristics of the hot interior gas and the neutral shell of this wind-blown bubble and give us an estimate of the expansion time of $0.2\,\mathrm{Myr}$. M43 with the B0.5V star NU Ori also exhibits an expanding bubble structure, with an expansion velocity of $6\,\mathrm{km\,s^{-1}}$. Comparison with analytical models for the pressure-driven expansion of H\,{\sc ii} regions gives an age estimate of $0.02\,\mathrm{Myr}$. The bubble surrounding NGC 1973, 1975, and 1977 with the central B1V star 42 Orionis expands at $1.5\,\mathrm{km\,s^{-1}}$, likely due to the over-pressurized ionized gas as in the case of M43. We derive an age of $0.4\,\mathrm{Myr}$ for this structure. We conclude that the bubble of the Orion Nebula is driven by the mechanical energy input by the strong stellar wind from $\theta^1$ Ori C, while the bubbles associated with M43 and NGC 1977 are caused by the thermal expansion of the gas ionized by their central later-type massive stars

Subduction zone forearc serpentinites as incubators for deep microbial life

Serpentinization-fueled systems in the cool, hydrated forearc mantle of subduction zones may provide an environment that supports deep chemolithoautotrophic life. Here, we examine serpentinite clasts expelled from mud volcanoes above the Izu–Bonin–Mariana subduction zone forearc (Pacific Ocean) that contain complex organic matter and nanosized Ni–Fe alloys. Using time-of-flight secondary ion mass spectrometry and Raman spectroscopy, we determined that the organic matter consists of a mixture of aliphatic and aromatic compounds and functional groups such as amides. Although an abiotic or subduction slab-derived fluid origin cannot be excluded, the similarities between the molecular signatures identified in the clasts and those of bacteria-derived biopolymers from other serpentinizing systems hint at the possibility of deep microbial life within the forearc. To test this hypothesis, we coupled the currently known temperature limit for life, 122 °C, with a heat conduction model that predicts a potential depth limit for life within the forearc at ∼10,000 m below the seafloor. This is deeper than the 122 °C isotherm in known oceanic serpentinizing regions and an order of magnitude deeper than the downhole temperature at the serpentinized Atlantis Massif oceanic core complex, Mid-Atlantic Ridge. We suggest that the organic-rich serpentinites may be indicators for microbial life deep within or below the mud volcano. Thus, the hydrated forearc mantle may represent one of Earth’s largest hidden microbial ecosystems. These types of protected ecosystems may have allowed the deep biosphere to thrive, despite violent phases during Earth’s history such as the late heavy bombardment and global mass extinctions

Naphthoquinones and Anthraquinones from Scent Glands of a Dyspnoid Harvestman, Paranemastoma quadripunctatum

Extracts of Paranemastoma quadripunctatum (Opiliones, Dyspnoi, Nemastomatidae) contained seven components, all of which likely originated from the secretion of well-developed prosomal scent glands. The two main components (together accounting for more than 90% of the secretion) were identified as 1,4-naphthoquinone and 6-methyl-1,4-naphthoquinone. The minor components were 1,4-naphthalenediol, two methoxy-naphthoquinones (2-methoxy-1,4-naphthoquinone, and 2-methoxy-6-methyl-1,4-naphthoquinone) and two anthraquinones (2-methyl-9,10-anthraquinone and a dimethyl-9,10-anthraquinone). While some chemical data on scent gland secretions of the other suborders of Opiliones (Cyphophthalmi, palpatorean Eupnoi, and Laniatores) already exist, this is the first report on the scent gland chemistry in the Dyspnoi. Naphthoquinones are known scent gland exudates of Cyphophthalmi and certain Eupnoi, methoxy-naphthoquinones and anthraquinones are new for opilionid scent gland secretions

Observation and calibration strategies for large-scale multi-beam velocity-resolved mapping of the [CII] emission in the Orion molecular cloud

24 pags., 32 figs., 3 tabs.Context. The [CII] 158 μm far-infrared fine-structure line is one of the dominant cooling lines of the star-forming interstellar medium. Hence [CII] emission originates in and thus can be used to trace a range of ISM processes. Velocity-resolved large-scale mapping of [CII] in star-forming regions provides a unique perspective of the kinematics of these regions and their interactions with the exciting source of radiation. Aims. We explore the scientific applications of large-scale mapping of velocity-resolved [CII] observations. With the [CII] observations, we investigate the effect of stellar feedback on the ISM. We present the details of observation, calibration, and data reduction using a heterodyne array receiver mounted on an airborne observatory. Methods. A 1.15 square degree velocity-resolved map of the Orion molecular cloud centred on the bar region was observed using the German REceiver for Astronomy at Terahertz Frequencies (upGREAT) heterodyne receiver flying on board the Stratospheric Observatory for Infrared Astronomy. The data were acquired using the 14 pixels of the German REceiver for Astronomy at Terahertz Frequencies that were observed in an on-the-fly mapping mode. 2.4 million spectra were taken in total. These spectra were gridded into a three-dimensional cube with a spatial resolution of 14.1 arcseconds and a spectral resolution of 0.3 km s-1. Results. A square-degree [CII] map with a spectral resolution of 0.3 km s-1 is presented. The scientific potential of this data is summarized with discussion of mechanical and radiative stellar feedback, filament tracing using [CII], [CII] opacity effects, [CII] and carbon recombination lines, and [CII] interaction with the large molecular cloud. The data quality and calibration is discussed in detail, and new techniques are presented to mitigate the effects of unavoidable instrument deficiencies (e.g. baseline stability) and thus to improve the data quality. A comparison with a smaller [CII] map taken with the Herschel/Heterodyne Instrument for the Far-Infrared spectrometer is presented. Conclusions. Large-scale [CII] mapping provides new insight into the kinematics of the ISM. The interaction between massive stars and the ISM is probed through [CII] observations. Spectrally resolving the [CII] emission is necessary to probe the microphysics induced by the feedback of massive stars. We show that certain heterodyne instrument data quality issues can be resolved using a spline-based technique, and better data correction routines allow for more efficient observing strategies.This work is based on observations made with the NASA/DLR Stratospheric Observatory for Infrared Astronomy (SOFIA). SOFIA is jointly operated by the Universities Space Research Association, Inc.(USRA), under NASA contract NAS2-97001, and the Deutsches SOFIA Institut (DSI) under DLR contract 50 OK 0901 to the University of Stuttgart. This work is carried out within the Collaborative Research Centre 956, subproject [A4], funded by the Deutsche Forschungsgemeinschaft (DFG) – project ID 184018867. We thank the Spanish MICIU for funding support under grant AYA2017-85111-P

NKX2-3 Transcriptional Regulation of Endothelin-1 and VEGF Signaling in Human Intestinal Microvascular Endothelial Cells

BACKGROUND: NKX2-3 is associated with inflammatory bowel disease (IBD). NKX2-3 is expressed in microvascular endothelial cells and the muscularis mucosa of the gastrointestinal tract. Human intestinal microvascular endothelial cells (HIMECs) are actively involved in the pathogenesis of IBD and IBD-associated microvascular dysfunction. To understand the cellular function of NKX2-3 and its potential role underlying IBD pathogenesis, we investigated the genes regulated by NKX2-3 in HIMEC using cDNA microarray. METHODOLOGY/PRINCIPAL FINDINGS: NKX2-3 expression was suppressed by shRNA in two HIMEC lines and gene expression was profiled by cDNA microarray. Pathway Analysis was used to identify gene networks according to biological functions and associated pathways. Validation of microarray and genes expression in intestinal tissues was assessed by RT-PCR. NKX2-3 regulated genes are involved in immune and inflammatory response, cell proliferation and growth, metabolic process, and angiogenesis. Several inflammation and angiogenesis related signaling pathways that play important roles in IBD were regulated by NKX2-3, including endothelin-1 and VEGF-PI3K/AKT-eNOS. Expression levels of NKX2-3, VEGFA, PI3K, AKT, and eNOS are increased in intestinal tissues from IBD patients and expression levels of EDN1 are decreased in intestinal tissues from IBD patients. These results demonstrated the important roles of NKX2-3, VEGF, PI3K, AKT, eNOS, and EDN1 in IBD pathogenesis. Correlation analysis showed a positive correlation between mRNA expression of NKX2-3 and VEGFA and a negative correlation between mRNA expression of NKX2-3 and EDN1 in intestinal tissues from IBD patients. CONCLUSION/RELEVANCE: NKX2-3 may play an important role in IBD pathogenesis by regulating endothelin-1 and VEGF signaling in HIMECs