bluuebunny/crossref_metadata_2025 huggingface dataset:
Actuarial valuations to monitor defined benefit pension funding
Authors: O’Brien Christopher D.
Published: June 2020

This paper is motivated by The Pensions Regulator (TPR)’s review of its Code of Practice on funding for defined benefit schemes and aims to suggest how trustees and regulators should monitor the extent to which scheme assets are adequate to cover liabilities. It concludes that current practice is inadequate and needs to change.

A review is carried out of papers on not only this subject but also (to collect ideas rather than automatically apply them to pensions solvency valuations) pensions and insurance accounting and regulation.

Current practice is “scheme-specific funding” which permits discretion on choice of discount rates and other assumptions; the paper is concerned that this can lead to bias, and that trends in a scheme’s solvency can be obscured by changing assumptions. This also leads to the funding ratio communicated to scheme members having little meaning.

The paper suggests that regulators should require a valuation that is based on sound principles, objective, fair, neutral, transparent and feasible. A prescribed methodology would replace discretion.

It concludes that the benefits to be valued are those arising on discontinuance of the scheme, without allowing for future salary-related benefit increases, which are felt to no longer be a constructive obligation of employers.

The valuation should, it is suggested, use market values of assets, which is largely current practice.

Liabilities should reflect the trustees fulfilling their liabilities, rather than transferring them to an insurer (which may introduce artificialities).

The discount rate should follow the “matching” approach, being a market-consistent risk-free rate: this is consistent with several papers to the profession in recent years. It avoids the problems of the “budgeting” approach, where the discount rate is based on the expected return on assets – this can be used to help set contribution levels but is not suitable for determining the value of liabilities, which depends on salary, service, longevity, etc and (very largely) not on the assets held. In principle, the liability value can be adjusted for illiquidity. Credit risk of the employer should not be allowed for.

Liabilities should reflect the (probability-weighted) expected value of future cash flows and should not be increased by prudent margins or risk margins (which would lead to a non-neutral figure). Risk disclosures are needed to understand and manage risks.

The resulting funding ratio is a consistent measure, to be disclosed to members, which can be used to manage the scheme, and by regulators as the basis for requiring action. Scheme-specific management using data such as the employer covenant means that immediate action to ensure 100% solvency on the proposed basis would not necessarily be appropriate.

The author encourages the profession to advise TPR on the above lines.
The 18 November 2015 Magnetopause Crossing: The GEM Dayside Kinetic Challenge Event Observed by MMS/HPCA
Authors: Trattner K. J. , Burch J. L. , Fuselier S. A. , Petrinec S. M. , Vines S. K.
Published: June 2020

At Earth's dayside magnetopause, the fundamental process known as magnetic reconnection is responsible for connecting geomagnetic field lines to interplanetary magnetic field lines and converting magnetic energy into particle energy and heat. As part of a coordinated analysis effort by the Geospace Environment Modeling (GEM) community to determine the reconnection location and other aspects of reconnection, a magnetopause crossing by the Magnetospheric Multiscale (MMS) mission on 18 November 2015 was selected. The crossing occurred during stable solar wind and dominantly southward interplanetary magnetic field conditions. The MMS satellites were located close to the subsolar region and observed southward accelerated ion jets during encounters with the magnetopause boundary layers, indicating the presence of an active X‐line north of the satellites. Using proton distributions from the Hot Plasma Composition Analyzer (HPCA) instruments, the distance from the spacecraft to the reconnection site was initially determined to be between 5 to 7 RE. A slight rotation of the interplanetary magnetic field caused a change of the magnetic topology at the magnetopause. This topology change produced conditions which are known to change the location of the X‐line. After the change, the location of the component reconnection line was estimated to be less than 4 RE, but most likely was much closer to the observing satellites.
Influences of North Pacific Ocean Domain Extent on the Western U.S. Winter Hydroclimatology in Variable‐Resolution CESM
Authors: Rhoades Alan M. , Jones Andrew D. , O'Brien Travis A. , O'Brien John P. , Ullrich Paul A. , Zarzycki Colin M.
Published: June 2020

Variable‐resolution global climate models (VRGCMs) are a dynamical downscaling method that can reach spatiotemporal scales needed for regional climate assessments. Over the years, several users of VRGCMs have assumed where the location and extent of the refinement domain should be based on knowledge of the prevailing storm tracks and resolution dependence of important regional climate processes (e.g., atmospheric rivers [ARs] and orographic uplift), but the effect of high‐resolution domain size and extent on the simulation of downstream hydroclimatic phenomena has not been systematically evaluated. Here, we use variable resolution in the Community Earth System Model (VR‐CESM) to perform such a test. To do this, three VR‐CESM grids were generated that span the entire, two thirds, and one third of the North Pacific and evaluated for a 30‐year climatology using Atmospheric Model Intercomparison Project protocols. Simulations are compared with reanalysis products offshore (fifth‐generation of the European Centre for Medium‐Range Weather Forecasts atmospheric reanalysis [ERA5]) and onshore (Livneh, 2015, https://doi.org/10.1038/sdata.2015.42, and Parameter‐elevation Regressions on Independent Slopes Model [PRISM]) of the western United States. The westward expansion of refinement domain influenced integrated vapor transport (IVT), which was generally high biased but minimally impacted AR characteristics. Due to slight differences in landfalling AR counts in the western United States, California winter precipitation generally improved with westward expansion of the refinement domain. Western U.S. mountain snowpack and surface temperatures were insensitive to refinement domain size and were more influenced by changes in topographic resolution and/or land surface model version. Given minimal dependence of simulated western U.S. hydroclimate on refinement domain size over the North Pacific, we advise future VR‐CESM studies to focus grid resolution on better resolving land surface heterogeneity.
On the Stability of Deep‐Seated Landslides. The Cases of Vaiont (Italy) and Shuping (Three Gorges Dam, China)
Authors: Seguí Carolina , Rattez Hadrien , Veveakis Manolis
Published: June 2020

Deep‐seated landslides can have catastrophic impacts on human life and infrastructure when they suddenly fail. These events are devastating because of the large volumes of soil and rock masses involved and their often long runout. The present study suggests an energy‐based method to determine when a landslide becomes unstable, giving critical values for measurable variables (velocity and basal temperature) up to which remediation actions can be deployed. This work focuses on large ancient landslides reactivated by dam‐related water table variations that modify landslide stability. The main hypothesis of this work is that most of the deformation of deep‐seated landslides is concentrated on a thin, basal shear band forming the sliding surface. In particular, this assumption allows an approximation of deep‐seated landslides as elastic/rigid blocks sliding over a viscoplastic shear band, featuring weak phases like expansive clays. When the landslide moves, it causes friction in the shear band that raises the temperature of the clays until they become unstable and collapse catastrophically through a thermal runaway instability. The model is applied to the Vaiont landslide in Northern Italy and the Shuping landslide next to the Three Gorges Dam in China. The results of the model reproduce the sliding behavior of both landslides and provide constraints on the critical points of stability.
Intact Ether Lipids in Trench Sediments Related to Archaeal Community and Environmental Conditions in the Deepest Ocean
Authors: Xu Yunping , Wu Weichao , Xiao Wenjie , Ge Huangmin , Wei Yuli , Yin Xiuran , Yao Huimin , Lipp Julius Sebastian , Pan Binbin , Hinrichs Kai‐Uwe
Published: June 2020

Archaea play an important role in marine biogeochemical cycle; however, their phylogenetic distribution and lipid composition in the hadal zone (6–11 km water depth) are poorly known. Here, we analyzed archaeal membrane lipids and 16S rRNA gene sequences in sediments from Mariana Trench (MT), Massau Trench (MS), and New Britain Trench (NBT), varying from 1,560 to 10,840 m depth. Forty‐two intact polar lipids (IPLs) were identified, including glycerol dialkyl glycerol tetraethers (GDGTs), OH‐GDGTs, glycerol dialkyl diethers (GDDs), and archaeol (AR) with polar headgroups of monohexose (1G), dihexose (2G), trihexose (3G), and hexose‐phosphohexose (HPH). Compositional and spatial distribution patterns of archaeal lipids suggest benthic Thaumarchaeota as a major source for IPLs, consistent with the predominance of Thaumarchaeota genes (>80%). The redundancy analysis (RDA) based on lipid and 16S rRNA data separates samples into three groups: extremely deep water (MT), significant terrestrial influence (NBT 1, 4, and 6), and predominant marine influence (MS, NBT 2, 3, 7, and 10). 1G‐GDDs and 1G‐AR positively correlate with water depth, likely reflecting the adaptation of benthic archaea to elevated hydrostatic pressure or variation of archaeal community in trench sediments. Bathyarchaeota are more abundant in sediments receiving terrestrial input; this pattern was attributed to their capability of utilizing terrestrial organic matter as an energy source. Our study highlights important environmental influences (e.g., pressure and organic matter quality and quantity) on benthic archaeal community and archaeal IPL compositions, which should be considered when IPLs and core lipids are applied as chemotaxonomic markers and paleo‐proxies.
Effect of Fluid Viscosity on Earthquake Nucleation
Authors: Cornelio C. , Violay M.
Published: June 2020

Injection of fluids in geo‐reservoirs can reduce the effective stresses at depth, lubricating the nearby faults, promoting slip and, potentially, earthquakes. High‐viscous fluids are often used during hydraulic fracturing and production phases in geo‐reservoirs. Here, we performed dedicated experiments to study the influence of fluid viscosity on earthquake nucleation. We performed frictional sliding experiments at 30 and 50 effective normal stresses and fluids viscosity ranging from 1 to 1,226 mPa s and modeled them with a rate‐and‐state friction law. In the presence of fluid, the state variable is defined as the ability of the fluid to flow. Our results showed that static friction slightly decreases with increasing viscosity, the dynamic friction is governed by the dimensionless Sommerfeld number (S = 6ηVL/(σ'nH2)). Moreover, we observed that the (a − b) parameters of the rate‐and‐state friction law decrease with increasing viscosity down to (a − b) < 0, possibly promoting unstable slip and earthquake nucleation.
Near‐Field Modeling of the 1964 Alaska Tsunami: The Role of Splay Faults and Horizontal Displacements
Authors: Suleimani Elena , Freymueller Jeffrey T.
Published: June 2020

Near‐field observations of tsunami waves generated by the Mw9.2 1964 Alaska earthquake reveal a complex relationship between coseismic slip and the tsunami wavefield in the source area. The documented times and amplitudes of first arrivals, measured run‐up heights and inundation areas along the coasts of the Kenai Peninsula and Kodiak Island show that secondary splay faults played an important role in generating destructive tsunami waves. We find that a splay fault extending to about 150°W is required to fit tsunami first arrivals on the Kenai Peninsula but that the splay fault did not rupture along the entire length of the Kenai Peninsula. This extent supports the connection of splay faulting to a persistent Prince William Sound asperity. Our results also show that the contribution of coseismic horizontal displacements into the initial tsunami wavefield does not change the pattern of tsunami arrivals much but increases the amplitude. The coseismic deformation model of Suito and Freymueller (2009, https://doi.org/10.1029/2008JB005954) explains the pattern of tsunami arrivals in the Kodiak Island region well, indicating that it provides a good estimate of slip on the megathrust in the Kodiak asperity. The sensitivity of the near‐field arrival information to the coseismic slip model shows that such data are important in distinguishing between slip on splay faults and on the megathrust and in discriminating between competing slip models.
Ultrasonic Imaging of the Onset and Growth of Fractures Within Partially Saturated Whitby Mudstone Using Coda Wave Decorrelation Inversion
Authors: Zotz‐Wilson Reuben , Douma Lisanne A. N. R. , Sarout Joel , Dautriat Jeremie , Dewhurst David , Barnhoorn Auke
Published: June 2020

Using active ultrasonic source survey data, coda wave decorrelation (CWD) time‐lapse imaging during the triaxial compression of Whitby Mudstone cores provides a 3‐D description of the evolution and redistribution of inelastic strain concentrations. Acoustic emissions (AEs) monitoring is also performed between any two consecutive surveys. From these data, we investigate the impact of initial water saturation Sw on the onset, growth, and reactivation of inelastic deformation, compared to the postdeformation fracture network extracted from X‐ray tomography scans. Our results indicate for the applied strain rate and degree of initial water saturation, and within the frequency range of our ultrasonic transducers (0.1 to 1 MHz), that inelastic strain localization and propagation in the Whitby Mudstone does not radiate AEs of sufficient magnitude to be detected above the average noise level. This is true for both the initial onset of inelasticity (strain localization) and during macroscopic failure. In contrast, the CWD results indicate the onset of what is interpreted as localized regions of inelastic strain at less than 50% of the peak differential stress the Whitby Mudstone can sustain. The seemingly aseismic nature of these clay‐rich rocks suggests the gradual development of inelastic strain, from the microscopic diffuse damage, up until the macroscopic shear failure.
Globally Consistent Patterns of Asynchrony in Vegetation Phenology Derived From Optical, Microwave, and Fluorescence Satellite Data
Authors: Wang Xian , Dannenberg Matthew P. , Yan Dong , Jones Matthew O. , Kimball John S. , Moore David J. P. , van Leeuwen Willem J. D. , Didan Kamel , Smith William K.
Published: June 2020

Key Points

Asynchrony in phenology metrics derived from optical, microwave, and fluorescence satellite data increases as the growing season progresses

Globally, peak‐/end‐of‐season phenology metrics are temporally organized such that fluorescence < optical < microwave

Integration of these independent satellite‐based indices reveals vegetation senescence as a prolonged, complex, and well‐organized process
Neoproterozoic Windermere Supergroup Near Bayhorse, Idaho: Late‐Stage Rodinian Rifting Was Deflected West Around the Belt Basin
Authors: Brennan Daniel T. , Pearson David M. , Link Paul K. , Chamberlain Kevin R.
Published: June 2020

Conflicting models of Rodinian rifting have been proposed to explain the recognized variation in the Neoproterozoic and early Cambrian tectonostratigraphic architecture of the western Laurentian margin. However, discrimination among rift models is hampered by limited exposure and metamorphism of the rocks. Southeastern Idaho preserves more than 6 km of Neoproterozoic and Cambrian strata. In contrast, along the inferred continuation of the margin in east central Idaho, correlative rocks are missing across the Lemhi arch. Our field mapping and U‐Pb dating studies, located approximately 50 km west of the Lemhi arch unconformity, focused on a succession of regionally extensive rocks that were previously assigned an Ordovician age. We show that ~1.5 km of strata here overlies a ~667 Ma reworked felsic tuff and was intruded by a 601 ± 27 Ma gabbro sill; we thus redesignate these rocks as Cryogenian and Ediacaran in age. These rocks are overlain by a ~1 km thick Ediacaran to middle Cambrian quartzite. Middle Ordovician quartzites overlie these middle Cambrian strata, indicating that though Neoproterozoic and lower Cambrian rocks are present west of the Lemhi arch, upper Cambrian and Lower Ordovician rocks are thin or absent. Comparison of this redesignated section to the closest correlative sections suggests an initial stage of symmetric rifting followed by later asymmetric rifting. We suggest that prerifting ~1,370 Ma magmatism within the Belt basin produced lithospheric rigidity that influenced the final stage of rifting and produced heterogeneity in the geometries of structural domains similar to those documented in other well‐defined, modern rift margins.
Emerging role of extracellular vesicles in the respiratory system
Authors: Holtzman Joshua , Lee Heedoo
Published: June 2020

Extracellular vesicles (EVs) present numerous biomedical ways of studying disease and pathology. They function as protective packaging for the delivery of controlled concentrations of miRNAs and effector molecules, including cytokines, chemokines, genetic material, and small signaling molecules. Previous studies of EVs have yielded valuable insights into pathways of intercellular communication that affect a variety of biological processes and disease responses. The roles of EVs, specifically microRNA-containing EVs (EV-miRNAs), in either mitigating or exacerbating pulmonary disease symptoms are numerous and show promise in helping us understand pulmonary disease pathology. Because of their well-documented involvement in pulmonary diseases, EVs show promise both as possible diagnostic biomarkers and as therapeutic agents. This review surveys the physiological functions of EVs in the respiratory system and outlines the pulmonary disease states in which EVs are involved in intercellular crosstalk. This review also discusses the potential clinical applications of EV-miRNAs in pulmonary diseases.
Iron chelation inhibits mTORC1 signaling involving activation of AMPK and REDD1/Bnip3 pathways
Authors: Shang Chaowei , Zhou Hongyu , Liu Wang , Shen Tao , Luo Yan , Huang Shile
Published: June 2020

The mammalian target of rapamycin (mTOR) functions as two complexes (mTORC1 and mTORC2), regulating cell growth and metabolism. Aberrant mTOR signaling occurs frequently in cancers, so mTOR has become an attractive target for cancer therapy. Iron chelators have emerged as promising anticancer agents. However, the mechanisms underlying the anticancer action of iron chelation are not fully understood. Particularly, reports on the effects of iron chelation on mTOR complexes are inconsistent or controversial. Here, we found that iron chelators consistently inhibited mTORC1 signaling, which was blocked by pretreatment with ferrous sulfate. Mechanistically, iron chelation-induced mTORC1 inhibition was not related to ROS induction, copper chelation, or PP2A activation. Instead, activation of AMPK pathway mainly and activation of both HIF-1/REDD1 and Bnip3 pathways partially contribute to iron chelation-induced mTORC1 inhibition. Our findings indicate that iron chelation inhibits mTORC1 via multiple pathways and iron is essential for mTORC1 activation.
Multimodal network dynamics underpinning working memory
Authors: Murphy Andrew C. , Bertolero Maxwell A. , Papadopoulos Lia , Lydon-Staley David M. , Bassett Danielle S.
Published: June 2020

Complex human cognition arises from the integrated processing of multiple brain systems. However, little is known about how brain systems and their interactions might relate to, or perhaps even explain, human cognitive capacities. Here, we address this gap in knowledge by proposing a mechanistic framework linking frontoparietal system activity, default mode system activity, and the interactions between them, with individual differences in working memory capacity. We show that working memory performance depends on the strength of functional interactions between the frontoparietal and default mode systems. We find that this strength is modulated by the activation of two newly described brain regions, and demonstrate that the functional role of these systems is underpinned by structural white matter. Broadly, our study presents a holistic account of how regional activity, functional connections, and structural linkages together support integrative processing across brain systems in order for the brain to execute a complex cognitive process.
Aβ(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage
Authors: Ciudad Sonia , Puig Eduard , Botzanowski Thomas , Meigooni Moeen , Arango Andres S. , Do Jimmy , Mayzel Maxim , Bayoumi Mariam , Chaignepain Stéphane , Maglia Giovanni , Cianferani Sarah , Orekhov Vladislav , Tajkhorshid Emad , Bardiaux Benjamin , Carulla Natàlia
Published: June 2020

Formation of amyloid-beta (Aβ) oligomer pores in the membrane of neurons has been proposed to explain neurotoxicity in Alzheimerʼs disease (AD). Here, we present the three-dimensional structure of an Aβ oligomer formed in a membrane mimicking environment, namely an Aβ(1-42) tetramer, which comprises a six stranded β-sheet core. The two faces of the β-sheet core are hydrophobic and surrounded by the membrane-mimicking environment while the edges are hydrophilic and solvent-exposed. By increasing the concentration of Aβ(1-42) in the sample, Aβ(1-42) octamers are also formed, made by two Aβ(1-42) tetramers facing each other forming a β-sandwich structure. Notably, Aβ(1-42) tetramers and octamers inserted into lipid bilayers as well-defined pores. To establish oligomer structure-membrane activity relationships, molecular dynamics simulations were carried out. These studies revealed a mechanism of membrane disruption in which water permeation occurred through lipid-stabilized pores mediated by the hydrophilic residues located on the core β-sheets edges of the oligomers.
Early stratification of radiotherapy response by activatable inflammation magnetic resonance imaging
Authors: Zhou Zijian , Deng Hongzhang , Yang Weijing , Wang Zhantong , Lin Lisen , Munasinghe Jeeva , Jacobson Orit , Liu Yijing , Tang Longguang , Ni Qianqian , Kang Fei , Liu Yuan , Niu Gang , Bai Ruiliang , Qian Chunqi , Song Jibin , Chen Xiaoyuan
Published: June 2020

Tumor heterogeneity is one major reason for unpredictable therapeutic outcomes, while stratifying therapeutic responses at an early time may greatly benefit the better control of cancer. Here, we developed a hybrid nanovesicle to stratify radiotherapy response by activatable inflammation magnetic resonance imaging (aiMRI) approach. The high Pearson’s correlation coefficient R values are obtained from the correlations between the T1 relaxation time changes at 24–48 h and the ensuing adaptive immunity (R = 0.9831) at day 5 and the tumor inhibition ratios (R = 0.9308) at day 18 after different treatments, respectively. These results underscore the role of acute inflammatory oxidative response in bridging the innate and adaptive immunity in tumor radiotherapy. Furthermore, the aiMRI approach provides a non-invasive imaging strategy for early prediction of the therapeutic outcomes in cancer radiotherapy, which may contribute to the future of precision medicine in terms of prognostic stratification and therapeutic planning.
Rhythmic light flicker rescues hippocampal low gamma and protects ischemic neurons by enhancing presynaptic plasticity
Authors: Zheng Lifeng , Yu Mei , Lin Rui , Wang Yunxuan , Zhuo Zhan , Cheng Ning , Wang Mengzhen , Tang Yongqiang , Wang Liping , Hou Sheng-Tao
Published: June 2020

The complex relationship between specific hippocampal oscillation frequency deficit and cognitive dysfunction in the ischemic brain is unclear. Here, using a mouse two-vessel occlusion (2VO) cerebral ischemia model, we show that visual stimulation with a 40 Hz light flicker drove hippocampal CA1 slow gamma and restored 2VO-induced reduction in CA1 slow gamma power and theta-low gamma phase-amplitude coupling, but not those of the high gamma. Low gamma frequency lights at 30 Hz, 40 Hz, and 50 Hz, but not 10 Hz, 80 Hz, and arrhythmic frequency light, were protective against degenerating CA1 neurons after 2VO, demonstrating the importance of slow gamma in cognitive functions after cerebral ischemia. Mechanistically, 40 Hz light flicker enhanced RGS12-regulated CA3-CA1 presynaptic N-type calcium channel-dependent short-term synaptic plasticity and associated postsynaptic long term potentiation (LTP) after 2VO. These results support a causal relationship between CA1 slow gamma and cognitive dysfunctions in the ischemic brain.
Hematopoietic stem and progenitor cell-restricted Cdx2 expression induces transformation to myelodysplasia and acute leukemia
Authors: Vu Therese , Straube Jasmin , Porter Amy H. , Bywater Megan , Song Axia , Ling Victoria , Cooper Leanne , Pali Gabor , Bruedigam Claudia , Jacquelin Sebastien , Green Joanne , Magor Graham , Perkins Andrew , Chalk Alistair M. , Walkley Carl R. , Heidel Florian H. , Mukhopadhyay Pamela , Cloonan Nicole , Gröschel Stefan , Mallm Jan-Philipp , Fröhling Stefan , Scholl Claudia , Lane Steven W.
Published: June 2020

The caudal-related homeobox transcription factor CDX2 is expressed in leukemic cells but not during normal blood formation. Retroviral overexpression of Cdx2 induces AML in mice, however the developmental stage at which CDX2 exerts its effect is unknown. We developed a conditionally inducible Cdx2 mouse model to determine the effects of in vivo, inducible Cdx2 expression in hematopoietic stem and progenitor cells (HSPCs). Cdx2-transgenic mice develop myelodysplastic syndrome with progression to acute leukemia associated with acquisition of additional driver mutations. Cdx2-expressing HSPCs demonstrate enrichment of hematopoietic-specific enhancers associated with pro-differentiation transcription factors. Furthermore, treatment of Cdx2 AML with azacitidine decreases leukemic burden. Extended scheduling of low-dose azacitidine shows greater efficacy in comparison to intermittent higher-dose azacitidine, linked to more specific epigenetic modulation. Conditional Cdx2 expression in HSPCs is an inducible model of de novo leukemic transformation and can be used to optimize treatment in high-risk AML.
Spectral cross-cumulants for multicolor super-resolved SOFI imaging
Authors: Grußmayer K. S. , Geissbuehler S. , Descloux A. , Lukes T. , Leutenegger M. , Radenovic A. , Lasser T.
Published: June 2020

Super-resolution optical fluctuation imaging provides a resolution beyond the diffraction limit by analysing stochastic fluorescence fluctuations with higher-order statistics. Using nth order spatio-temporal cross-cumulants the spatial resolution and the sampling can be increased up to n-fold in all spatial dimensions. In this study, we extend the cumulant analysis into the spectral domain and propose a multicolor super-resolution scheme. The simultaneous acquisition of two spectral channels followed by spectral cross-cumulant analysis and unmixing increases the spectral sampling. The number of discriminable fluorophore species is thus not limited to the number of physical detection channels. Using two color channels, we demonstrate spectral unmixing of three fluorophore species in simulations and experiments in fixed and live cells. Based on an eigenvalue/vector analysis, we propose a scheme for an optimized spectral filter choice. Overall, our methodology provides a route for easy-to-implement multicolor sub-diffraction imaging using standard microscopes while conserving the spatial super-resolution property.
A constricted opening in Kir channels does not impede potassium conduction
Authors: Black Katrina A. , He Sitong , Jin Ruitao , Miller David M. , Bolla Jani R. , Clarke Oliver B. , Johnson Paul , Windley Monique , Burns Christopher J. , Hill Adam P. , Laver Derek , Robinson Carol V. , Smith Brian J. , Gulbis Jacqueline M.
Published: June 2020

The canonical mechanistic model explaining potassium channel gating is of a conformational change that alternately dilates and constricts a collar-like intracellular entrance to the pore. It is based on the premise that K+ ions maintain a complete hydration shell while passing between the transmembrane cavity and cytosol, which must be accommodated. To put the canonical model to the test, we locked the conformation of a Kir K+ channel to prevent widening of the narrow collar. Unexpectedly, conduction was unimpaired in the locked channels. In parallel, we employed all-atom molecular dynamics to simulate K+ ions moving along the conduction pathway between the lower cavity and cytosol. During simulations, the constriction did not significantly widen. Instead, transient loss of some water molecules facilitated K+ permeation through the collar. The low free energy barrier to partial dehydration in the absence of conformational change indicates Kir channels are not gated by the canonical mechanism.
Social training reconfigures prediction errors to shape Self-Other boundaries
Authors: Ereira Sam , Hauser Tobias U. , Moran Rani , Story Giles W. , Dolan Raymond J. , Kurth-Nelson Zeb
Published: June 2020

Selectively attributing beliefs to specific agents is core to reasoning about other people and imagining oneself in different states. Evidence suggests humans might achieve this by simulating each other’s computations in agent-specific neural circuits, but it is not known how circuits become agent-specific. Here we investigate whether agent-specificity adapts to social context. We train subjects on social learning tasks, manipulating the frequency with which self and other see the same information. Training alters the agent-specificity of prediction error (PE) circuits for at least 24 h, modulating the extent to which another agent’s PE is experienced as one’s own and influencing perspective-taking in an independent task. Ventromedial prefrontal myelin density, indexed by magnetisation transfer, correlates with the strength of this adaptation. We describe a frontotemporal learning network, which exploits relationships between different agents’ computations. Our findings suggest that Self-Other boundaries are learnable variables, shaped by the statistical structure of social experience.
Vault changes after cyclopentolate instillation in eyes with posterior chamber phakic intraocular lens
Authors: Gargallo-Martinez Beatriz , Garcia-Medina Jose Javier , Rubio-Velazquez Elena , Fernandes Paulo , Villa-Collar César , Gonzalez-Meijome José M. , Gutierrez-Ortega Ramón
Published: June 2020

Posterior chamber phakic intraocular lens (pIOL) implantation is a common option for correcting moderate-to-high ocular refractive defects. Because this pIOL is implanted on ciliary sulcus, the distance between the back surface of the pIOL and the anterior surface of the crystalline lens, that it is known as vault, should be measured in different conditions to ensure the technique’s safety. Cyclopentolate is a drug that dilates the pupil and relaxes accommodation (cycloplegia). It is often used for different ocular examinations and for other medical purposes. However, there is no evidence of the effect of this drug on vault. This study quantified central vault changes associated with cyclopentolate instillation. We measured the vault under normal conditions (pre-cycloplegic instillation) and after instilling cyclopentolate on 39 eyes of 39 patients with implanted pIOL. Our results suggest that cyclopentolate instillation may induce changes to vault in eyes with implanted pIOL. These changes seem safe and are mainly associated with vault under normal conditions, but also with anterior chamber depth, pupillary diameter and pIOL size.
3D Magnetic Resonance Spirometry
Authors: Boucneau Tanguy , Fernandez Brice , Larson Peder , Darrasse Luc , Maître Xavier
Published: June 2020

Spirometry is today the gold standard technique for assessing pulmonary ventilatory function in humans. From the shape of a flow-volume loop measured while the patient is performing forced respiratory cycles, the Forced Vital Capacity (FVC) and the Forced Expiratory Volume in one second (FEV1) can be inferred, and the pulmonologist is able to detect and characterize common respiratory afflictions. This technique is non-invasive, simple, widely available, robust, repeatable and reproducible. Yet, its outcomes rely on the patient’s cooperation and provide only global information over the lung. With 3D Magnetic Resonance (MR) Spirometry, local ventilation can be assessed by MRI anywhere in the lung while the patient is freely breathing. The larger dimensionality of 3D MR Spirometry advantageously allows the extraction of original metrics that characterize the anisotropic and hysteretic regional mechanical behavior of the lung. Here, we demonstrated the potential of this technique on a healthy human volunteer breathing along different respiratory patterns during the MR acquisition. These new results are discussed with lung physiology and recent pulmonary CT data. As respiratory mechanics inherently support lung ventilation, 3D MR Spirometry may open a new way to non-invasively explore lung function while providing improved diagnosis of localized pulmonary diseases.
Diverging Trends in Age at First Myocardial Infarction: Evidence from Two German Population-Based Studies
Authors: Beller Johannes , Bauersachs Johann , Schäfer Andreas , Schwettmann Lars , Heier Margit , Peters Annette , Meisinger Christa , Geyer Siegfried
Published: June 2020

Little is known about trends in the age of onset of first myocardial infarction. Thus, we examined trends in the age of onset distribution of first myocardial infarction using two population-based datasets from Germany. First, we used German claims data based on an annual case number of approximately 2 million women and men covering the period from 2006 to 2016. Second, we used data from the KORA (Cooperative Health Research in the Region of Augsburg) Myocardial Infarction Registry covering the period from 2000–2016. Analyses were performed by means of quantile regression to estimate trends across the whole distribution of age of onset. Overall, NSample 1 = 69627 and NSample 2 = 9954 first myocardial infarctions were observed. In both samples, we found highly heterogeneous trends in age of onset. In men, we consistently found that age of onset increased before 50 and after 70 but decreased within this age bracket. For women, on the other hand, we consistently found that age of onset decreased for first myocardial infarctions before 70 but increased slightly or remained relatively stable thereafter. Therefore, late myocardial infarctions tended to occur later in life, while regular myocardial infarctions tended to occur earlier. These results suggest that in myocardial infarction, both morbidity compression and morbidity expansion might have occurred at the same time but for different parts of the age at onset distribution.
Characterization of starvation-induced autophagy in cerebellar Purkinje cells of pHluorin-mKate2-human LC3B transgenic mice
Authors: Oliva Trejo Juan Alejandro , Tanida Isei , Suzuki Chigure , Kakuta Soichiro , Tada Norihiro , Uchiyama Yasuo
Published: June 2020

We generated a new transgenic mouse model that expresses a pHluorin-mKate2 fluorescent protein fused with human LC3B (PK-LC3 mice) for monitoring autophagy activity in neurons of the central nervous system. Histological analysis revealed fluorescent puncta in neurons of the cerebral cortex, hippocampus, cerebellar Purkinje cells, and anterior spinal regions. Using CLEM analysis, we confirmed that PK-LC3-positive puncta in the perikarya of Purkinje cells correspond to autophagic structures. To validate the usability of PK-LC3 mice, we quantified PK-LC3 puncta in Purkinje cells of mice kept in normal feeding conditions and of mice starved for 24 hours. Our results showed a significant increase in autophagosome number and in individual puncta areal size following starvation. To confirm these results, we used morphometry at the electron microscopic level to analyze the volume densities of autophagosomes and lysosomes/autolysosomes in Purkinje cells of PK-LC3 mice. The results revealed that the volume densities of autophagic structures increase significantly after starvation. Together, our data show that PK-LC3 mice are suitable for monitoring autophagy flux in Purkinje cells of the cerebellum, and potentially other areas in the central nervous system.
Inhaled nitric oxide therapy in acute bronchiolitis: A multicenter randomized clinical trial
Authors: Goldbart Aviv , Golan-Tripto Inbal , Pillar Giora , Livnat-Levanon Galit , Efrati Ori , Spiegel Ronen , Lubetzky Ronit , Lavie Moran , Carmon Lior , Ghaffari Abdi , Nahum Amit
Published: June 2020

Currently, there are no approved treatments for infants with acute bronchiolitis, the leading cause for hospitalization of infants worldwide, and thus the recommended approach is supportive. Inhaled Nitric oxide (iNO), possesses anti-viral properties, improves oxygenation, and was shown to be safe in infants with respiratory conditions. Hospitalized infants with acute bronchiolitis were therefore recruited to a prospective double-blinded, multi-center, randomized controlled pilot study. They received intermittent high dose iNO (160 ppm) plus oxygen/air for 30 min or oxygen/air alone (control), five times/day, up to 5 days. Sixty-nine infants were enrolled. No difference was observed in frequencies of subjects with at least one Adverse Event (AE) in iNO (44.1%) vs. control (55.9%); neither was Methemoglobin >7% safety threshold. No drug-related serious AEs (SAEs) were reported. Analysis of Per-Protocol population revealed that length of stay (LOS), time to SpO2 ≥92%, and time to mTal clinical score ≤5 improved by 26.7 ± 12.7 (Welch’s t-test p = 0.04), 20.8 ± 8.9 (p = 0.023), and 14.6 ± 9.1 (p = 0.118) hours, respectively, in the iNO group compared to the control. Overall, high dose iNO (160ppm) was safe, well-tolerated, reduced LOS and showed rapid improvement of oxygen saturation, compared to the standard therapy. Further investigation in larger cohorts is warranted to validate these encouraging efficacy outcomes. (Trial registration: NCT03053388)
Improvement in Detection Limit for Lateral Flow Assay of Biomacromolecules by Test-Zone Pre-enrichment
Authors: Zhang Yi , Liu Xiao , Wang Lingling , Yang Hanjie , Zhang Xiaoxiao , Zhu Chenglong , Wang Wenlong , Yan Lijing , Li Bowei
Published: June 2020

Lateral flow assay (LFA) is one of the most prevalent commercially available techniques for point-of-care tests due to its simplicity, celerity, low cost and robust operation. However, conventional colorimetric LFAs have inferior limits of detection (LODs) compared to sophisticated laboratory-based assays. Here, we report a simple strategy of test-zone pre-enrichment to improve the LOD of LFA by loading samples before the conjugate pad assembly. The developed method enables visual LODs of miR-210 mimic and human chorionic gonadotropin protein, to be improved by 10–100 fold compared with a conventional LFA setup without introducing any additional instrument and reagent except for phosphate running buffer, while no obvious difference occurred for Aflatoxin B1 (AFB1). It takes about 6–8 min to enrich every 50 μL of sample diluted with phosphate running buffer, therefore we can get visual results within 20 min. We identified a parameter by modeling the entire process, the concentration of probe-analyte conjugate at test zone when signaling unit being loaded, to be important for the improvement of visual limit of detection. In addition, the test-zone pre-enrichment did not impair the selectivity when miR-210 mimic was adopted as target. Integrated with other optimization, amplification and modification of LFAs, the developed test-zone pre-enrichment method can be applied to further improve LOD of LFAs.
Density functional theory studies on cytosine analogues for inducing double-proton transfer with guanine
Authors: Xue Jinjie , Guo Xingping , Wang Xingbao , Xiao Yafeng
Published: June 2020

To induce double-proton transfer (DPT) with guanine in a biological environment, 12 cytosine analogues (Ca) were formed by atomic substitution. The DPT reactions in the Watson–Crick cytosine–guanine model complex (Ca0G) and 12 modified cytosine–guanine complexes (Ca1-12G) were investigated using density functional theory methods at the M06-2X/def2svp level. The intramolecular proton transfers within the analogues are not facile due to high energy barriers. The hydrogen bond lengths of the Ca1-12G complexes are shorter than those in the Ca0G complex, which are conducive to DPT reactions. The DPT energy barriers of Ca1-12G complexes are also lower than that of the Ca0G complex, in particular, the barriers in the Ca7G and Ca11G complexes were reduced to −1.33 and −2.02 kcal/mol, respectively, indicating they are significantly more prone to DPT reactions. The DPT equilibrium constants of Ca1-12G complexes range from 1.60 × 100 to 1.28 × 107, among which the equilibrium constants of Ca7G and Ca11G are over 1.0 × 105, so their DPT reactions may be adequate. The results demonstrate that those cytosine analogues, especially Ca7 and Ca11, are capable of inducing DPT with guanine, and then the guanine tautomer will form mismatches with thymine during DNA replication, which may provide new strategies for gene therapy.
Anchoring of heterologous proteins in multiple Lactobacillus species using anchors derived from Lactobacillus plantarum
Authors: Mathiesen Geir , Øverland Lise , Kuczkowska Katarzyna , Eijsink Vincent G. H.
Published: June 2020

Members of the genus Lactobacillus have a long history in food applications and are considered as promising and safe hosts for delivery of medically interesting proteins. We have assessed multiple surface anchors derived from Lactobacillus plantarum for protein surface display in multiple Lactobacillus species, using a Mycobacterium tuberculosis hybrid antigen as test protein. The anchors tested were a lipoprotein anchor and two cell wall anchors, one non-covalent (LysM domain) and one covalent (sortase-based anchoring using the LPXTG motif). Thus, three different expression vectors for surface-anchoring were tested in eight Lactobacillus species. When using the LPXTG and LysM cell wall anchors, surface display, as assessed by flow cytometry and fluorescence microscopy, was observed in all species except Lactobacillus acidophilus. Use of the cell membrane anchor revealed more variation in the apparent degree of surface-exposure among the various lactobacilli. Overproduction of the secreted and anchored antigen impaired bacterial growth rate to extents that varied among the lactobacilli and were dependent on the type of anchor. Overall, these results show that surface anchors derived from L. plantarum are promising candidates for efficient anchoring of medically interesting proteins in other food grade Lactobacillus species.
Gene-signature-derived IC50s/EC50s reflect the potency of causative upstream targets and downstream phenotypes
Authors: Renner Steffen , Bergsdorf Christian , Bouhelal Rochdi , Koziczak-Holbro Magdalena , Amati Andrea Marco , Techer-Etienne Valerie , Flotte Ludivine , Reymann Nicole , Kapur Karen , Hoersch Sebastian , Oakeley Edward James , Schuffenhauer Ansgar , Gubler Hanspeter , Lounkine Eugen , Farmer Pierre
Published: June 2020

Multiplexed gene-signature-based phenotypic assays are increasingly used for the identification and profiling of small molecule-tool compounds and drugs. Here we introduce a method (provided as R-package) for the quantification of the dose-response potency of a gene-signature as EC50 and IC50 values. Two signaling pathways were used as models to validate our methods: beta-adrenergic agonistic activity on cAMP generation (dedicated dataset generated for this study) and EGFR inhibitory effect on cancer cell viability. In both cases, potencies derived from multi-gene expression data were highly correlated with orthogonal potencies derived from cAMP and cell growth readouts, and superior to potencies derived from single individual genes. Based on our results we propose gene-signature potencies as a novel valid alternative for the quantitative prioritization, optimization and development of novel drugs.
Controlling evolution of protein corona: a prosperous approach to improve chitosan-based nanoparticle biodistribution and half-life
Authors: Tekie Farnaz Sadat Mirzazadeh , Hajiramezanali Maliheh , Geramifar Parham , Raoufi Mohammad , Dinarvand Rassoul , Soleimani Masoud , Atyabi Fatemeh
Published: June 2020

Protein corona significantly affects in vivo fate of nanoparticles including biodistribution and half-life. Without manipulating the physicochemical properties of nanoparticles with considering their biointerference, attaining effective treatment protocols is impossible. For this reason, protein corona evolution and biodistribution of different chitosan (Ch)-based nanoparticles including Ch and carboxymethyl dextran (CMD)/thiolated dextran (TD) polyelectrolyte complexes (PECs) were studied using highly precious and sensitive methods such as liquid chromatography-mass/mass (LC-MS/MS) spectroscopy and positron emission tomography/computed tomography (PET/CT) scan. The importance of serum presence/absence in culture medium with different pH and corona effect on cellular uptake of PECs investigated by in vitro study. Designed PECs have low amounts of proteins in corona mostly enriched by Apolipoproteins, protein C, hemoglobin subunits, and inter-alpha- trypsin inhibitor that beside improving uptake of nanoparticles, they have low liver uptake and notable heart blood pool accumulation that confirmed the long circulation time of the nanoparticles which is favorable for delivery of nanoparticles to the site of action and achieving required therapeutic effect.
On the Molecular Level Cavitation in Soft Gelatin Hydrogel
Authors: Mahmud KAH Al , Hasan Fuad , Khan Md Ishak , Adnan Ashfaq
Published: June 2020

We have studied the molecular level cavitation mechanisms and bubble growth kinetics in soft gelatin hydrogel and water. The apparent difference in cavitation threshold pressure between that generates in pure water and that in gelatin hydrogel is considered. Gelatin, which is derived from collagen, is frequently used as a brain simulant material. In liquid, cavitation bubble is created when surrounding pressure drops below the saturation vapor pressure. In principle, a cavitation bubble should continue to grow as long as tensile pressure continues to increase in the system. In our study, using molecular dynamics simulation, we have investigated the pressure requirement for a nanoscale cavitation to grow in water and gel. First, we have modeled a gel like structure with a preexisting bubble of 5 nm radius. A control model containing a 5 nm bubble in pure water is also created. Then, we have applied hydrostatic tensile pressure at two different expansion rates in the gel and water models. The results show that a gel-like structure requires higher pressure for the cavitation to grow, and both gel and water models exhibit strain rate effect on the cavitation threshold pressure. We have also found that the cavitation collapse time is dominated by the viscosity of the medium.