Rapid Redistribution Research Articles

Extensive co-binding and rapid redistribution of NANOG and GATA6 during emergence of divergent lineages

Fate-determining transcription factors (TFs) can promote lineage-restricted transcriptional programs from common progenitor states. The inner cell mass (ICM) of mouse blastocysts co-expresses the TFs NANOG and GATA6, which drive the bifurcation of the ICM into either the epiblast (Epi) or the primitive endoderm (PrE), respectively. Here, we induce GATA6 in embryonic stem cells–that also express NANOG–to characterize how a state of co-expression of opposing TFs resolves into divergent lineages. Surprisingly, we find that GATA6 and NANOG co-bind at the vast majority of Epi and PrE enhancers, a phenomenon we also observe in blastocysts. The co-bound state is followed by eviction and repression of Epi TFs, and quick remodeling of chromatin and enhancer-promoter contacts thus establishing the PrE lineage while repressing the Epi fate. We propose that co-binding of GATA6 and NANOG at shared enhancers maintains ICM plasticity and promotes the rapid establishment of Epi- and PrE-specific transcriptional programs.

Effects of natural surfactants on the spatial variability of surface water temperature under intermittent light winds on Lake Geneva

The spatial variability of lake surface water temperature (LSWT) between smooth and rough surface areas and its potential association with the natural surfactant distribution in the surface microlayer were investigated for the first time in a lake. In spring 2019, two different field campaigns were carried out in Lake Geneva to measure: i) the enrichment factor of fluorescent dissolved organic matter (FDOM) as a proxy for biogenic surfactants, and ii) LSWT and near-surface water temperature profiles while simultaneously monitoring water surface roughness in both cases. Results indicate that, under intense incoming short-wave radiation and intermittent light wind conditions, the atmospheric boundary layer (ABL) was stable and the accumulation of heat due to short-wave radiation in near-surface waters was greater than heat losses by surface cooling, thus creating a diurnal warm layer with strong thermal stratification in the water near-surface layer. A threshold wind speed of 1.5 m s-1 was determined as a transition between different dynamic regimes. For winds just above 1.5 m s-1, the lake surface became patchy, and smooth surface areas (slicks) were more enriched with FDOM than rough areas (non-slick) covered with gravity-capillary waves (GCW). Sharp thermal boundaries appeared between smooth and rough areas. LSWT in smooth slicks was found to be more than 1.5°C warmer than in rough non-slick areas, which differs from previous observations in oceans that reported a slight temperature reduction inside slicks. Upon the formation of GCW in non-slick areas, the near-surface stratification was destroyed and the surface temperature was reduced. Furthermore, winds above 1.5 m s-1 continuously fragmented slicks causing a rapid spatial redistribution of LSWT patterns mainly aligned with the wind. For wind speeds below 1.5 m s‑1 the surface was smooth, no well-developed GCW were observed, LSWT differences were small, and strong near-surface stratification was established. These results contribute to the understanding and the quantification of air-water exchange processes, which are presently lacking for stable Atmospheric Boundary Layer conditions in lakes.

B800-to-B850 relaxation of excitation energy in bacterial light harvesting: All-state, all-mode path integral simulations.

We report fully quantum mechanical simulations of excitation energy transfer within the peripheral light harvesting complex (LH2) of Rhodopseudomonas molischianum at room temperature. The exciton-vibration Hamiltonian comprises the 16 singly excited bacteriochlorophyll states of the B850 (inner) ring and the 8 states of the B800 (outer) ring with all available electronic couplings. The electronic states of each chromophore couple to 50 intramolecular vibrational modes with spectroscopically determined Huang-Rhys factors and to a weakly dissipative bath that models the biomolecular environment. Simulations of the excitation energy transfer following photoexcitation of various electronic eigenstates are performed using the numerically exact small matrix decomposition of the quasiadiabatic propagator path integral. We find that the energy relaxation process in the 24-state system is highly nontrivial. When the photoexcited state comprises primarily B800 pigments, a rapid intra-band redistribution of the energy sharply transitions to a significantly slower relaxation component that transfers 90% of the excitation energy to the B850 ring. The mixed character B850* state lacks the slow component and equilibrates very rapidly, providing an alternative energy transfer channel. This (and also another partially mixed) state has an anomalously large equilibrium population, suggesting a shift to lower energy by virtue of exciton-vibration coupling. The spread of the vibrationally dressed states is smaller than that of the eigenstates of the bare electronic Hamiltonian. The total population of the B800 band is found to decay exponentially with a 1/e time of 0.5ps, which is in good agreement with experimental results.

Rapid regulations of metabolic reactions in Escherichia coli via light-responsive enzyme redistribution.

Protein-based condensates have been proposed to accelerate biochemical reactions by enriching reactants and enzymes simultaneously. Here, we engineered those condensates into a photo-activated switch in Escherichia coli (PhASE) to regulate enzymatic reactions via tuning the spatial correlation of enzymes and substrates. In this system, scaffold proteins undergo liquid-liquid phase separation (LLPS) to form light-responsive compartments. Tethered with a light-responsive protein, enzymes of interest (EOIs) can be recruited by those compartments from cytosol within only a few seconds after a pulse of light induction and fully released in 15min. Furthermore, we managed to enrich small molecular substrates simultaneously with enzymes in the compartments and achieved the acceleration of luciferin and catechol oxidation by 2.3- and 1.6-folds, respectively. We also developed a quantitative model to guide the further optimization of this demixed regulatory system. Our tool can thus be used to study the rapid redistribution of proteins, and reversibly regulate enzymatic reactions in E. coli.

HGG-12. Rapid PTEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy

BACKGROUND: Dynamic regulation of gene expression is fundamental for cellular adaptation to exogenous stressors. PTEFb-mediated promoter proximal pause-release of Pol II is a conserved regulatory mechanism for synchronous transcriptional induction best described in response to heat shock, but this pro-survival role has not been examined in the applied context of cancer therapy. DESIGN/METHOD: In order to examine the dynamics of chromatin reorganization following radiotherapy, we performed a combination of ChIP-, ATAC-, and RNA-seq in model systems of diffuse intrinsic pontine glioma (DIPG) and other pediatric high-grade gliomas (pHGG) following IR exposure. We interrogated IR-induced gene expression in the presence or absence of PTEFb blockade, including both mechanistic and functional consequences of concurrent inhibition or genetic depletion. We utilized culture models with live cell imaging to assess the therapeutic synergy of PTEFb inhibition with IR, as well as the therapeutic index of this intervention relative to normal controls. Finally, we employed orthotopic models of pHGG treated with conformal radiotherapy and CNS-penetrant PTEFb inhibitors in order to assess tolerability and anti-tumor effect in vivo. RESULTS: Rapid genome-wide redistribution of active chromatin features and PTEFb facilitates Pol II pause-release to drive nascent transcriptional induction within hours of exposure to therapeutic ionizing radiation. Concurrent inhibition of PTEFb imparts a transcription elongation defect, abrogating canonical adaptive programs such as DNA damage repair and cell cycle regulation. This combination demonstrates a potent, synergistic therapeutic potential agnostic of glioma subtype, leading to a marked induction of tumor cell apoptosis and prolongation of xenograft survival. CONCLUSION: These studies reveal a central role for PTEFb underpinning the early adaptive response to radiotherapy, opening new avenues for combinatorial treatment in these lethal malignancies.

Randomised prospective comparative study of hemodynamic variables using propofol versus sevoflurane for induction and maintanence of anaesthesia in adult nasal surgeries

Introduction: Intravenous agents are commonly used for induction of anaesthesia in adults followed by inhalational agents for maintenance. A problem with this technique is transition phase from induction to maintenance. Rapid redistribution of Intravenous agent could lead to lightening of anaesthesia before adequate depth is attained with inhalational agent. As nasal surgeries like FESS requires a blood less field with minimal hemodynamic variability, present study is undertaken to compare hemodynamic variability and induction time using Propofol versus Sevoflurane for both induction and maintenance of anaesthesia in adult nasal surgeries. Materials and Methods: This Quasi Experimental study was conducted in Department of Anaesthesia, Yenepoya Medical College Hospital, Mangalore during the period between October 2015 and October 2017. 60 patients were randomly divided into one of the two groups by envelope method in which Group P patients (n = 30) was induced with Propofol 2 mg/kg and maintained with Propofol infusion at 100 mcg/kg/min and Group S patients (n = 30) was induced with Sevoflurane 8% and maintained with Sevoflurane 2%. Induction time was noted.

Optimization of the Employment Structure Using the Multi-sector Bounded-Neighbourhood Model

This article presents an approach to optimizing the employment structure using an extended multi-sector bounded-neighbourhood model. The main problem associated with the optimization of the employment structure is the impossibility of implementing a strategy for the rapid redistribution of labour resources from less efficient low-tech sectors of the economy to high-tech ones. The reasons for the difficulties are due to the complex system of decision-making by agent-individuals on the choice of the most preferable jobs, based on a comprehensive assessment of a number of factors, such as the amount of wages, distance to the workplace, the influence of the parents’ opinions and their immediate environment, the presence or absence of previous work experience in the relevant industry, etc. The problem of dynamic optimization of the employment structure is formulated and solved using the genetic algorithm that has need proposed previously, within one generation (30 years), the transformation of the employment structure to the target (suboptimal) state is ensured to maximize the average GDP rates and minimize the share of non-assimilated migrants.

Molecular mechanisms for environmentally induced and evolutionarily rapid redistribution (plasticity) of meiotic recombination.

It has long been known (circa 1917) that environmental conditions, as well as speciation, can affect dramatically the frequency distribution of Spo11/Rec12-dependent meiotic recombination. Here, by analyzing DNA sequence-dependent meiotic recombination hotspots in the fission yeast Schizosaccharomyces pombe, we reveal a molecular basis for these phenomena. The impacts of changing environmental conditions (temperature, nutrients, and osmolarity) on local rates of recombination are mediated directly by DNA site-dependent hotspots (M26, CCAAT, and Oligo-C). This control is exerted through environmental condition-responsive signal transduction networks (involving Atf1, Pcr1, Php2, Php3, Php5, and Rst2). Strikingly, individual hotspots modulate rates of recombination over a very broad dynamic range in response to changing conditions. They can range from being quiescent to being highly proficient at promoting activity of the basal recombination machinery (Spo11/Rec12 complex). Moreover, each different class of hotspot functions as an independently controlled rheostat; a condition that increases the activity of one class can decrease the activity of another class. Together, the independent modulation of recombination rates by each different class of DNA site-dependent hotspots (of which there are many) provides a molecular mechanism for highly dynamic, large-scale changes in the global frequency distribution of meiotic recombination. Because hotspot-activating DNA sites discovered in fission yeast are conserved functionally in other species, this process can also explain the previously enigmatic, Prdm9-independent, evolutionarily rapid changes in hotspot usage between closely related species, subspecies, and isolated populations of the same species.

Characteristics of blood proteome changes in hemorrhagic syndrome after head-up tilt test during 21-day Dry Immersion

The effect of the rapid redistribution of blood during head-up tilt tests in 21-day Dry Immersion suddenly became relevant in connection with the occurrence of mild hemorrhagic syndrome in the study participants. It became necessary to analyze the processes of occurrence of hemorrhagic syndrome as orthostatic and congestive purpura. The aim of this work was to study the features of the proteomic response of the human body to the rapid redistribution of blood during head-up tilt tests during 21-day immersion, which led to stagnant and orthostatic purpura. According to the results of examination of 10 healthy male volunteers aged 23–34 years after head-up tilt tests, pitting edema and local petechial hemorrhages in the soft tissues of the legs and feet were observed. Proteomic analysis of the samples was carried out by high performance liquid chromatography with tandem mass spectrometry. For bioinformatic analysis, the software packages Perseus, ANDSystem were used. From reliably different (p-value <0.05) proteins, proteins directly related to injury and changes in vascular permeability were determined. Сhanges in the levels of plasminogen, fibronectin, other factors of coagulation and fibrinolysis, activation of the complement system, changes in the coagulation cascade and concentrations of plasminogen and its activators (kallikrein, etc.), increased content of fibrinolysis products were revealed. A panel of proteins indicating changes in plasmin-antiplasmin, fibrinogen-soluble fibrin-monomeric complexes and other systems is identified. The obtained data are of scientific and practical interest in the direction of stratification of the risk of secondary hemosiderosis and evaluation of new treatment methods aimed at reducing reperfusion damage to soft tissues and parenchymal organs.

Rapid redistribution and long-term aggregation of mulch residues by earthworms (Lumbricus terrestris)

There has been minimal study of how ecosystem engineering anecic earthworms such as Lumbricus terrestris L. may influence the distribution of mulch amendments across the soil surface by collecting residues into middens. The two primary research objectives of this study were: (1) to determine how rapidly earthworms change the surface distribution of mulch following amendment, and (2) to produce a more spatially explicit map of earthworm aggregation of mulch. This study used a microcosm experiment to assess the immediate, short-term impacts of earthworms on recently added mulch at a small scale, and an opportunistic field study of the longer-term impacts of earthworms on the distribution of corn ‘stubble’ mulch in a former agricultural field. In the microcosm experiment, earthworms rapidly redistributed mulch within the first week post amendment, decreasing initial ground cover (15-29% decrease). Over the subsequent five weeks, initial cover continued to decrease (20-45% decrease) as mulch was spread thinly onto adjacent, initially bare soil (49-69% increase). Higher mulch amendment mitigated losses in initial cover. In the field study, earthworms aggregated mulch across the soil surface, collecting 40% of the woody corn residues into 17% of the total area in regularly distributed middens. These results demonstrate the potential for L. terrestris to alter the distribution of mulch rapidly in the first several days and weeks following application and in the longer term over several years, increasing the spatial heterogeneity of soil resources. This physical redistribution has only been minimally investigated and may help inform models of earthworm impacts on various ecological processes and improve soil amendment and residue management in earthworm-occupied soils.

Controlling Interfacial Reduction Kinetics and Suppressing Electrochemical Oscillations in Li4Ti5O12 Thin‐Film Anodes

AbstractUnderstanding the fundamentals of surface decoration effects in phase‐separation materials, such as lithium titanate (LTO), is important for optimizing the lithium‐ion battery (LIB) performance. LTO polycrystalline thin‐film electrodes with and without doped Al–ZnO (AZO) surface coating decoration are used as ideal models to gain insights into the mechanisms involved. Operando shear force modulation spectroscopy is used to observe for the first time the nanoscale dynamics of solid‐electrolyte‐interphase (SEI) formation on the electrode surfaces, confirming that the AZO coating is electrochemically converted into a stiff, homogenous SEI layer that protects the surface from the electrolyte‐induced decomposition. This AZO layer and its resultant artificial SEI‐layer have higher Li‐ion transport rates than the unmodified surface. These layers can reduce barriers to surface nucleation and facilitate rapid redistribution of lithium‐ions during the Li4Ti5O12 ⇄ Li7Ti5O12 phase separation, significantly inhabiting the orderly collective phase‐separation behavior (electrochemical oscillation) in the LTO electrode. The suppressed voltage oscillations indicate more homogeneous local exchange current density and de/intercalation states with the decorated electrodes, thereby extending their battery efficiency and long‐term cycling stability. This work highlights the ultimate importance of surface treatment for LIB materials for determining their interfacial chemistry and phase transition during the intercalation/deintercalation.

Ultrafast vibrational dynamics of the tyrosine ring mode and its application to enkephalin insertion into phospholipid membranes as probed by two-dimensional infrared spectroscopy.

Enkephalins are small opioid peptides whose binding conformations are catalyzed by phospholipid membranes. Binding to opioid receptors is determined by the orientation of tyrosine and phenylalanine side chains. In this work, we investigate the effects of different charged phospholipid headgroups on the insertion of the tyrosine side chain into a lipid bilayer using a combination of 2D IR spectroscopy, anharmonic DFT calculations, and third order response function modeling. The insertion is probed by using the ∼1515cm-1 tyrosine ring breathing mode, which we found exhibits rich vibrational dynamics on the picosecond timescale. These dynamics include rapid intramolecular vibrational energy redistribution (IVR), where some of the energy ends up in a dark state that shows up as an anharmonically shifted combination band. The waiting-time dependent 2D IR spectra also show an unusual line shape distortion that affects the extraction of the frequency-frequency correlation function (FFCF), which is the dynamic observable of interest that reflects the tyrosine side chain's insertion into the lipid bilayer. We proposed three models to account for this distortion: a hot-state exchange model, a local environment dependent IVR model, and a coherence transfer model. A qualitative analysis of these models suggests that the local environment dependent IVR rate best explains the line shape distortion, while the coherence transfer model best reproduced the effects on the FFCF. Even with these complex dynamics, we found that the tyrosine ring mode's FFCF is qualitatively correlated with the degree of insertion expected from the different phospholipid headgroups.

Early onset effects of single substrate accumulation recapitulate major features of LSD in patient-derived lysosomes

SummaryLysosome functions mainly rely on their ability to either degrade substrates or release them into the extracellular space. Lysosomal storage disorders (LSDs) are commonly characterized by a chronic lysosomal accumulation of different substrates, thereby causing lysosomal dysfunctions and secretion defects. However, the early effects of substrate accumulation on lysosomal homeostasis have not been analyzed so far. Here, we describe how the acute accumulation of a single substrate determines a rapid centripetal redistribution of the lysosomes, triggering their expansion and reducing their secretion, by limiting the motility of these organelles toward the plasma membrane. Moreover, we provide evidence that such defects could be explained by a trapping mechanism exerted by the extensive contacts between the enlarged lysosomes and the highly intertwined membrane structures of the endoplasmic reticulum which might represent a crucial biological cue ultimately leading to the clinically relevant secondary defects observed in the LSD experimental models and patients.

A biosensor for the direct visualization of auxin

One of the most important regulatory small molecules in plants is indole-3-acetic acid, also known as auxin. Its dynamic redistribution has an essential role in almost every aspect of plant life, ranging from cell shape and division to organogenesis and responses to light and gravity1,2. So far, it has not been possible to directly determine the spatial and temporal distribution of auxin at a cellular resolution. Instead it is inferred from the visualization of irreversible processes that involve the endogenous auxin-response machinery3–7; however, such a system cannot detect transient changes. Here we report a genetically encoded biosensor for the quantitative in vivo visualization of auxin distribution. The sensor is based on the Escherichia coli tryptophan repressor8, the binding pocket of which is engineered to be specific to auxin. Coupling of the auxin-binding moiety with selected fluorescent proteins enables the use of a fluorescence resonance energy transfer signal as a readout. Unlike previous systems, this sensor enables direct monitoring of the rapid uptake and clearance of auxin by individual cells and within cell compartments in planta. By responding to the graded spatial distribution along the root axis and its perturbation by transport inhibitors—as well as the rapid and reversible redistribution of endogenous auxin in response to changes in gravity vectors—our sensor enables real-time monitoring of auxin concentrations at a (sub)cellular resolution and their spatial and temporal changes during the lifespan of a plant.

Crm1-Dependent Nuclear Export of Bach1 is Involved in the Protective Effect of Hyperoside on Oxidative Damage in Hepatocytes and CCl4-induced Acute Liver Injury.

BackgroundNrf2-Bach1 antioxidant signaling pathway is considered as one of the most important mechanisms of cellular resistance to oxidative injury. The effect of hyperoside (Hyp) on the expression and distribution of Bach1, the relationship of Hyp’s antioxidative effect and the influence of Bach1 remains unclear.PurposeThe aim of this study was to investigate the role and mechanisms of Bach1 in the protective effect of Hyp on oxidative liver injury.MethodsThe protective effect of Hyp on oxidative stress injury was observed in vivo and in vitro. Next, the influence of Hyp on Bach1 expression and distribution, and competitive combination of Nrf2-Bach1 with ARE in H2O2-induced L02 cell was studied by Western blot, RT-PCR, immunofluorescence and CHIP assay. Finally, the expressions of Crm1, ERK and p38 and their roles on Hyp mediated nuclear export of Bach1 were investigated by Western blot.ResultsHyp ameliorated the pathological damage, reduced the liver index, AST, ALT and MDA activities, and increased SOD and GSH levels in the CCl4-induced acute liver injury mouse model. Hyp attenuated H2O2-induced oxidative stress injury in L02 cells. Hyp promoted the early rapid redistribution of Bach1 from nucleus to cytoplasm. CHIP analyses demonstrated that Hyp enhanced the levels of Nrf2-ARE complex, and weakened the levels of Bach1-ARE complex within three hours. In addition, Hyp enhanced transport protein Crm1 expression and ERK1/2 activity. And LMB, a Crm1 inhibitor, attenuated the effect of Hyp on Bach1 nuclear export and anti-oxidation. U0126, an ERK1/2 inhibitor, reduced the effect of Hyp on Crm1 expression and the Bach1 redistribution.ConclusionThe hepatoprotective mechanism of Hyp was related to improve Bach1 nuclear export depending on ERK1/2-Crm1 to upregulate the level of Nrf2 binding to ARE.

The homeoviscous adaptation to dietary lipids (HADL) model explains controversies over saturated fat, cholesterol, and cardiovascular disease risk

SFAs play the leading role in 1 of the greatest controversies in nutrition science. Relative to PUFAs, SFAs generally increase circulating concentrations of LDL cholesterol, a risk factor for atherosclerotic cardiovascular disease (ASCVD). However, the purpose of regulatory mechanisms that control the diet-induced lipoprotein cholesterol dynamics is rarely discussed in the context of human adaptive biology. We argue that better mechanistic explanations can help resolve lingering controversies, with the potential to redefine aspects of research, clinical practice, dietary advice, public health management, and food policy. In this paper we propose a novel model, the homeoviscous adaptation to dietary lipids (HADL) model, which explains changes in lipoprotein cholesterol as adaptive homeostatic adjustments that serve to maintain cell membrane fluidity and hence optimal cell function. Due to the highly variable intake of fatty acids in humans and other omnivore species, we propose that circulating lipoproteins serve as a buffer to enable the rapid redistribution of cholesterol molecules between specific cells and tissues that is necessary with changes in dietary fatty acid supply. Hence, circulating levels of LDL cholesterol may change for nonpathological reasons. Accordingly, an SFA-induced raise in LDL cholesterol in healthy individuals could represent a normal rather than a pathologic response. These regulatory mechanisms may become disrupted secondarily to pathogenic processes in association with insulin resistance and the presence of other ASCVD risk factors, as supported by evidence showing diverging lipoprotein responses in healthy individuals as opposed to those with metabolic disorders such as insulin resistance and obesity. Corresponding with the model, we suggest alternative contributing factors to the association between elevated LDL cholesterol concentrations and ASCVD, involving dietary factors beyond SFAs, such as an increased endotoxin load from diet-gut microbiome interactions and subsequent chronic low-grade inflammation that interferes with fine-tuned signaling pathways.

Spatiotemporal analysis of the runaway distribution function from synchrotron images in an ASDEX Upgrade disruption

Synchrotron radiation images from runaway electrons (REs) in an ASDEX Upgrade discharge disrupted by argon injection are analysed using the synchrotron diagnostic tool Soft and coupled fluid-kinetic simulations. We show that the evolution of the runaway distribution is well described by an initial hot-tail seed population, which is accelerated to energies between 25–50 MeV during the current quench, together with an avalanche runaway tail which has an exponentially decreasing energy spectrum. We find that, although the avalanche component carries the vast majority of the current, it is the high-energy seed remnant that dominates synchrotron emission. With insights from the fluid-kinetic simulations, an analytic model for the evolution of the runaway seed component is developed and used to reconstruct the radial density profile of the RE beam. The analysis shows that the observed change of the synchrotron pattern from circular to crescent shape is caused by a rapid redistribution of the radial profile of the runaway density.

LPS-induced epithelial barrier disruption via hyperactivation of CACC and ENaC.

Gram-negative bacterial lipopolysaccharide (LPS) increases the susceptibility of cells to pathogenic diseases, including inflammatory diseases and septic syndrome. In our experiments, we examined whether LPS induces epithelial barrier disruption in secretory epithelia and further investigated its underlying mechanism. The activities of Ca2+-activated Cl- channels (CACC) and epithelial Na+ channels (ENaC) were monitored with a short-circuit current using an Ussing chamber. Epithelial membrane integrity was estimated via transepithelial electrical resistance and paracellular permeability assays. We found that the apical application of LPS evoked short-circuit current (Isc) through the activation of CACC and ENaC. Although LPS disrupted epithelial barrier integrity, this was restored with the inhibition of CACC and ENaC, indicating the role of CACC and ENaC in the regulation of paracellular pathways. We confirmed that LPS, CACC, or ENaC activation evoked apical membrane depolarization. The exposure to a high-K+ buffer increased paracellular permeability. LPS induced the rapid redistribution of zonula occludens-1 (ZO-1) and reduced the expression levels of ZO-1 in tight junctions through apical membrane depolarization and tyrosine phosphorylation. However, the LPS-induced epithelial barrier disruption and degradation of ZO-1 were largely recovered by blocking CACC and ENaC. Furthermore, although LPS-impaired epithelial barrier became vulnerable to secondary bacterial infections, this vulnerability was prevented by inhibiting CACC and ENaC. We concluded that LPS induces the disruption of epithelial barrier integrity through the activation of CACC and ENaC, resulting in apical membrane depolarization and the subsequent tyrosine phosphorylation of ZO-1.

Rapid charge redistribution leading to core hollowing in a high-intensity ion beam

Recently, the first direct measurement of a full 6D accelerator beam distribution was reported [1]. That work observed a correlation between energy and transverse coordinates, for which the energy distribution becomes hollowed and double-peaked near the transverse core. In this article, a similar structure is shown to emerge in expansion of an initially uncorrelated, high density bunched beam as the result of velocity perturbation from nonlinear space charge forces. This hollowing is obscured when the 6D phase space is projected onto one- and two-dimensional axes. This phenomenon has not been widely recognized in accelerator systems, but parallels can be drawn to observations of laser-ionized nanoclusters and electron sources for diffraction. While this effect provides insight into the origin of the measured core correlation, it does not provide a complete description. A better reproduction of the measured structure can be obtained via self-consistent simulation through the radio-frequency quadrupole. [1] B. Cathey, S. Cousineau, A. Aleksandrov, and A. Zhukov, PRL 121, 064804 (2018).

Gadolinium retention within multiple rat organs after intra-articular administration of gadolinium-based contrast agents

ObjectiveTo characterize the extent of retention and biodistribution of gadolinium (Gd) following intra-articular (IA) injection of linear and macrocyclic gadolinium-based contrast agents (GBCAs) into the knee joint of a rat model.Materials and methodsFifteen Wistar rats were divided into five groups and underwent fluoroscopically-guided injections of both knee joints of (1) clinical 1:200 dilution (low dose, LD) gadodiamide (linear GBCA), (2) LD gadobutrol (macrocyclic GBCA), (3) undiluted (high dose, HD) gadodiamide, (4) HD gadobutrol, and (5) saline. Gd concentrations were quantified by inductively coupled plasma mass spectrometry in (1) blood and urine samples obtained over a 72 h period and (2) knee joint tissues, brain, kidney, and bone marrow at 3 days post-injection.ResultsBoth HD and LD gadodiamide and gadobutrol were rapidly absorbed from the joint with peak serum and urine concentration at 1 h post-injection, with relatively faster clearance of gadobutrol. All GBCA-exposed groups had detectable levels of Gd in the joint tissues, bone marrow, and/or kidneys (median tissue gadolinium range: 0.1–71 μg Gd/g tissue), with higher amounts observed with gadodiamide versus gadobutrol. Retention within brain tissues was only detected following HD gadodiamide administration but not LD gadodiamide nor HD or LD gadobutrol.ConclusionThere was rapid systemic absorption, redistribution, and widespread multi-organ retention of Gd following IA injection of both linear and macrocyclic GBCAs, despite substantial amounts of urinary excretion. Higher concentrations of Gd were observed with administration of gadodiamide compared to gadobutrol in most tissues and biofluids.