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The retrosplenial cortex (RSC) is a key component of the brain's memory systems, with anatomical connections to the hippocampus, anterior thalamus, and entorhinal cortex. This circuit has been implicated in episodic memory and many of these structures have been shown to encode temporal information, which is critical for episodic memory. For example, hippocampal time cells reliably fire during specific segments of time during a delay period. Although RSC lesions are known to disrupt temporal memory, time cells have not been observed there. In this study, we reanalyzed archival RSC neuronal firing data during the intertrial delay period from two previous experiments involving different behavioral tasks, a blocked alternation task and a cued T‐maze task. For the blocked alternation task, rats were required to approach the east or west arm of a plus maze for reward during different blocks of trials. Because the reward locations were not cued, the rat had to remember the goal location for each trial. In the cued T‐maze task, the reward location was explicitly cued with a light and the rats simply had to approach the light for reward, so there was no requirement to hold a memory during the intertrial delay. Time cells were prevalent in the blocked alternation task, and most time cells clearly differentiated the east and west trials. We also found that RSC neurons could exhibit off‐response time fields, periods of reliably inhibited firing. Time cells were also observed in the cued T‐maze, but they were less prevalent and they did not differentiate left and right trials as well as in the blocked alternation task, suggesting that RSC time cells are sensitive to the memory demands of the task. These results suggest that temporal coding is a prominent feature of RSC firing patterns, consistent with an RSC role in episodic memory. [ABSTRACT FROM AUTHOR]

The hippocampus (HPC) and retrosplenial cortex (RSC) are key components of the brain's memory and navigation systems. Lesions of either region produce profound deficits in spatial cognition and HPC neurons exhibit well‐known spatial firing patterns (place fields). Recent studies have also identified an array of navigation‐related firing patterns in the RSC. However, there has been little work comparing the response properties and information coding mechanisms of these two brain regions. In the present study, we examined the firing patterns of HPC and RSC neurons in two tasks which are commonly used to study spatial cognition in rodents, open field foraging with an environmental context manipulation and continuous T‐maze alternation. We found striking similarities in the kinds of spatial and contextual information encoded by these two brain regions. Neurons in both regions carried information about the rat's current spatial location, trajectories and goal locations, and both regions reliably differentiated the contexts. However, we also found several key differences. For example, information about head direction was a prominent component of RSC representations but was only weakly encoded in the HPC. The two regions also used different coding schemes, even when they encoded the same kind of information. As expected, the HPC employed a sparse coding scheme characterized by compact, high contrast place fields, and information about spatial location was the dominant component of HPC representations. RSC firing patterns were more consistent with a distributed coding scheme. Instead of compact place fields, RSC neurons exhibited broad, but reliable, spatial and directional tuning, and they typically carried information about multiple navigational variables. The observed similarities highlight the closely related functions of the HPC and RSC, whereas the differences in information types and coding schemes suggest that these two regions likely make somewhat different contributions to spatial cognition. [ABSTRACT FROM AUTHOR]

During the 2022 New Mexico monsoon season, we deployed two X‐ray scintillation detectors, coupled with a 180 MHz data acquisition system to detect X‐rays from natural lightning at the Langmuir Lab mountain‐top facility, located at 3.3 km above mean sea level. Data acquisition was triggered by an electric field antenna calibrated to pick up lightning within a few km of the X‐ray detectors. We report the energies of over 240 individual photons, ranging between 13 keV and 3.8 MeV, as registered by the LaBr3(Ce) scintillation detector. These detections were associated with four lightning flashes. Particularly, four‐stepped leaders and seven dart leaders produced energetic radiation. The reported photon energies allowed us to confirm that the X‐ray energy distribution of natural stepped and dart leaders follows a power‐law distribution with an exponent ranging between 1.09 and 1.96, with stepped leaders having a harder spectrum. Characterization of the associated leaders and return strokes was done with four different electric field sensing antennas, which can measure a wide range of time scales, from the static storm field to the fast change associated with dart leaders. Plain Language Summary: During the 2022 monsoon season in New Mexico, Langmuir Lab scientists used special X‐ray detectors to study natural lightning over a mountain‐top facility. The team detected X‐ray emissions from 4 natural lightning flashes. The X‐rays are produced by the lightning precursor stage, called leader. Leaders travel long distances in the atmosphere and carve the way for lightning to transfer charge from the cloud to ground. After careful inspection of the energy content of the X‐ray photons, the team concluded that leaders traveling in virgin air, known as stepped leaders, emit more energetic X‐rays than leaders retracing previously established lightning channels, called dart leaders. Key Points: 5‐ns resolution allowed for the measurement of individual X‐ray photon energies from natural lightning and to confirm its power‐law spectrumStepped leader X‐rays come in a train of bursts lasting milliseconds, while dart leader X‐rays come effectively in a single burstStepped leaders have a harder energy spectrum than dart leaders, with a larger population of >1 MeV photons [ABSTRACT FROM AUTHOR]

Established model theories, developed to capture the mechanical behavior of soft, complex materials composed of semiflexible polymers, assume that entropic interactions between filaments are primarily responsible for determining the mechanical response. In recent studies, the generally accepted tube model has been challenged in terms of this basic assumption about filament–filament interactions, but also because of its predictions regarding the frequency dependence of the elastic modulus in the intermediate frequency regime. A central question is how molecular interactions and friction between network constituents influence the rheological response of isotropic entangled networks of semiflexible polymers. It has been previously shown that friction forces between aligned pairs of actin filaments are not negligible. Here, the influence of friction forces and attractive interactions on network rheology is systematically investigated by means of targeted surface modification. It is shown that these forces have a qualitative and quantitative influence on the viscoelastic properties of semiflexible polymer networks and contribute to their response to nonlinear deformations. By comparing two polymer model systems with respect to their surface compositions, a possible explanation is given about the origin of acting forces on a molecular level. [ABSTRACT FROM AUTHOR]

We report on the mountain top observation of three terrestrial gamma‐ray flashes (TGFs) that occurred during the summer storm season of 2021. To our knowledge, these are the first TGFs observed in a mountaintop environment and the first published European TGFs observed from the ground. A gamma‐ray sensitive detector was located at the base of the Säntis Tower in Switzerland and observed three unique TGF events with coincident radio sferic data characteristic of TGFs seen from space. We will show an example of a "slow pulse" radio signature (Cummer et al., 2011, https://doi.org/10.1029/2011GL048099; Lu et al., 2011, https://doi.org/10.1029/2010JA016141; Pu et al., 2019, https://doi.org/10.1029/2019GL082743; Pu et al., 2020, https://doi.org/10.1029/2020GL089427), a −EIP (Lyu et al., 2016, https://doi.org/10.1002/2016GL070154; Lyu et al., 2021, https://doi.org/10.1029/2021GL093627; Wada et al., 2020, https://doi.org/10.1029/2019JD031730), and a double peak TGF associated with an extraordinarily powerful and complicated positive‐polarity sferic, where each TGF peak is possibly preceded by a short burst of stepped leader emission. Plain Language Summary: We present the first report of mountain top observations of terrestrial gamma‐ray flashes (TGFs) that occurred during the summer storm season of 2021. A gamma‐ray sensitive detector was placed at the base of the Säntis Tower in Switzerland and detected three distinct TGF events. Each event is associated with a coincident lightning flash. We analyze the radio emission of the associated lightning flash and make comparisons with previously published associations between TGFs and certain radio sferics. Additionally, one of the observed TGFs is likely a two‐pulse event where each gamma‐ray peak may be preceded in time by a brief burst of X‐ray stepped leader emission. Key Points: First terrestrial gamma ray flashe (TGF) observations from a mountaintopFirst ground observation of a TGF associated with a "slow pulse" radio sfericPossible stepped leader X‐rays preceding a double pulsed TGF [ABSTRACT FROM AUTHOR]

We observed two Terrestrial Gamma‐ray Flashes (TGFs) in Uchinada, Japan associated with negative cloud‐to‐ground lightning strokes exactly 1 year apart on 18 December 2020 and 2021. The events were remarkable for their lateral distance from the associated strokes—each about 5 km away from the detector site. Not only was that lateral distance remarkable on its own for a ground based detection, but the low‐altitude profile of winter thunderstorms in Japan would suggest the detections occurred at unprecedented nadir angles—73.3° off axis for the 2020 event with the standard assumption of a vertically oriented TGF. Unsurprisingly, Monte Carlo simulations of the straightforward interpretation of these events yield fluences 2 orders of magnitude lower than observed data. We investigate a variety of ways to attempt to resolve the contradiction between expected and observed behavior. Plain Language Summary: We observed two terrestrial gamma‐ray flashes at a distance and angle from which we should have seen nothing given our current understanding of how bright and wide these events can be. We investigate what must have been different about these events to make them visible to our detectors. Key Points: We detected two downward TGFs in Uchinada, Japan, approximately 5 km away laterally from the associated lightning flash's ground strike pointEstimates of the altitude of the tops of the associated leader channels from radio, optical, and climate data suggest we were, remarkably, up to 73.3° off of the vertical axes of the TGFsMonte Carlo simulations show our observations were 1–2 orders of magnitude brighter than what would be expected from a standard TGF at that geometry [ABSTRACT FROM AUTHOR]

We provide an updated analysis of the gamma ray signature of a terrestrial gamma ray flash (TGF) detected by the Fermi Gamma ray Burst Monitor first reported by Pu et al. (2020, https://doi.org/10.1029/2020GL089427). A TGF produced 3 ms prior to a negative cloud‐to‐ground return stroke was close to simultaneous with an isolated low‐frequency radio pulse during the leader's propagation, with a polarity indicating downward moving negative charge. In previous observations, this "slow" low‐frequency signal has been strongly correlated with upward‐directed (opposite polarity) TGF events (Pu et al., 2019, https://doi.org/10.1029/2019GL082743; Cummer et al., 2011, https://doi.org/10.1029/2011GL048099), leading the authors to conclude that the Fermi gamma ray observation is actually the result of a reverse positron beam generating upward‐directed gamma rays. We investigate the feasibility of this scenario and determine a lower limit on the luminosity of the downward TGF from the perspective of gamma ray timing uncertainties, TGF Monte Carlo simulations, and meteorological analysis of a model storm cell and its possible charge structure altitudes. We determined that the most likely source altitude of the TGF reverse beam was 7.5 km ± 2.6 km, just below an estimated negative charge center at 8 km. At that altitude, the Monte Carlo simulations indicate a lower luminosity limit of 2 × 1018 photons above 1 MeV for the main downward beam of the TGF, making the reverse beam detectable by the Fermi Gamma ray Burst Monitor. Plain Language Summary: Pu et al. (2020, https://doi.org/10.1029/2020GL089427) published an article on a terrestrial gamma ray flash (TGF) observation made by the Fermi satellite with a simultaneous radio wave observation of a lightning event almost directly below Fermi's position. The radio data unequivocally showed that the lightning event was negative cloud to ground (−CG). This implied that the electric field orientation of the lightning would have produced a downward TGF with a source altitude near 6 km. Fermi must have seen the reverse beam, which is the consequence of antimatter production within the strong electric fields that produce the TGF. Predictions of the reverse beam indicate that it is far less bright than the main forward beam. The scenario seems at first glance very unlikely, as it would require the TGF to be far brighter than any previous observation. It turns out that characteristics of the antimatter‐induced reverse beam, such as its higher average energy and narrower beaming, make the reverse beam more penetrating and thus more likely to be observed from lower altitudes at TGF intensities that are within the upper range of previous observations. Key Points: Multiwavelength observations and estimates of thunderstorm charging altitudes estimate the likely altitude of the terrestrial gamma ray flash (TGF) at 7.5 kmMinimum luminosity estimate for a downward TGF at 7.5 km detectable by Fermi via the reverse beam is 2 × 1018 photons above 1 MeVThe e‐folding attenuation length in grammage for the reverse beam component of a TGF was found to be 58 g/cm2 [ABSTRACT FROM AUTHOR]

The hippocampus is critical for contextual memory and has recently been implicated in various kinds of social memory. Traditionally, studies of hippocampal context coding have manipulated elements of the background environment, such as the shape and color of the apparatus. These manipulations produce large shifts in the spatial firing patterns, a phenomenon known as remapping. These findings suggest that the hippocampus encodes and differentiates contexts by generating unique spatial firing patterns for each environment a subject encounters. However, we do not know whether the hippocampus encodes social contexts defined by the presence of particular conspecifics. We examined this by exposing rats to a series of manipulations of the social context, including the presence of familiar male, unfamiliar male and female conspecifics, in order to determine whether remapping is a plausible mechanism for encoding socially‐defined contexts. Because the dorsal and ventral regions of the hippocampus are thought to play different roles in spatial and social cognition, we recorded neurons in both regions. Surprisingly, we found little evidence of remapping in response to manipulation of the social context in either the dorsal or ventral hippocampus, although we saw typical remapping in response to changing the background color. This result suggests that remapping is not the primary mechanism for encoding different social contexts. However, we found that a subset of hippocampal neurons fired selectively near the cages that contained the conspecifics, and these responses were most prevalent in the ventral hippocampus. We also found a striking increase in the spatial information content of ventral hippocampal firing patterns. These results indicate that the ventral hippocampus is sensitive to changes in the social context and neurons that respond selectively near the conspecific cages could play an important, if not fully understood role in encoding the conjunction of conspecifics, their location and the environment. [ABSTRACT FROM AUTHOR]

Electrically controllable deoxyribonuclic acid (DNA) nanolevers are used to investigate the binding interaction between Influenza A/Aichi/2/1968 and the peptide called "PeB", which specifically binds the viral surface protein hemagglutinin. PeB is immobilized on gold electrodes of a "switchSENSE" biochip by conjugation to DNA‐strands that are hybridized to complementary anchors. The surface‐tethered DNA strand carries a fluorophore while the complementary strand is a multivalent arrangement carrying up to three PeB peptides. The nanolevers are kept upright (static) by applying a negative potential. Signal read‐out for this static measurement mode is the change in fluorescence intensity due to changes in the local environment of the dye upon binding. Measurements of virus‐peptide interaction show that the virus material specifically binds to the immobilized peptides and remains bound throughout the measurement time. Immobilized viruses are subsequently used as ligands to characterize oligovalent peptide binding to hemagglutinin, revealing rate constants of the interaction. Moreover, three Influenza A subtypes are compared in their binding behavior. Overall, this paper shows the ability to immobilize virus material on a sensor surface, which allows to target virus‐proteins in their native environment. The "switchSENSE" method is therefore applicable to characterize virus‐receptor interactions. [ABSTRACT FROM AUTHOR]

Many of the details of how terrestrial gamma-ray flashes (TGFs) are produced, including their association with upward-propagating in-cloud lightning leader channels, remain poorly understood. Measurements of the low-frequency radio emissions associated with TGF production continue to provide unique views and key insights into the electrodynamics of this process. Here we report further details on the connection between energetic in-cloud pulses (EIPs) and TGFs. With coordinated measurements from both ground-based radio sensors and space-based gamma-ray detectors on the Fermi and Reuven Ramaty High Energy Solar Spectroscopic Imager spacecraft, we find that all ten +EIPs that occurred within the searched space-and-time window are associated with simultaneous TGFs, including two new TGFs that were not previously identified by the gamma-ray measurements alone. The results in this study not only solidify the tight connection between +EIPs and TGFs, but also demonstrate the practicability of detecting a subpopulation of TGFs with ground-based radio sensors alone. Plain Language Summary Terrestrial gamma-ray flashes (TGFs) are kinds of high-energy emissions produced during thunderstorms and are almost exclusively detected with spacecraft-based gamma-ray detectors. Because of the strong atmospheric gamma-ray attenuation from the low-altitude atmosphere and the geometry-driven short horizontal detection range, the ground detection of TGFs with gamma-ray detectors is challenging. Recently a class of distinct radio emissions during thunderstorms, called energetic in-cloud pulses (EIPs), was found to be closely linked to the production of some TGFs. In this study, we present several additional lines of strong evidence that strengthen the connection between a subpopulation of TGFs and EIPs. Importantly, by identifying EIPs from radio signals, we found two new TGFs that were previously unreported from space-based detection. This demonstrates that some TGFs can be detected from the radio measurements alone when the spacecraft-based detectors are unavailable. [ABSTRACT FROM AUTHOR]

We report on anomalously long duration (2 ms) count rate bursts following the impact of cosmic ray showers near a 7.62 cm x⊘7.62 cm LaBr3 scintillation detector at the High Altitude Water Cherenkov array in Mexico, previously described by Stenkin et al. (2001), and termed "neutron bursts." The largest burst produced 198 counts within 2 ms in our LaBr3 detector. We simulate the neutron burst albedo flux (that is, secondary emissions from an extensive air shower core impacting the ground), and show that (1) the characteristic spectra and count rates are well explained by neutron absorption in the ground and (2) any cosmic ray secondary that produces neutrons, either through hadron inelastic collisions, or photoneutron production by gamma‐rays, produces the same characteristic spectra. This implies that other natural phenomena that produce downward beams of gamma‐rays, like Terrestrial gamma ray flashes, should produce a similar "neutron burst" signature from the photoneutron reactions occurring in the soil. Plain Language Summary: When very large cosmic ray showers (CRS) impact the ground, neutrons are produced in the soil that will rattle around until they become captured by soil particles and release energetic gamma‐rays. This produces a slow explosion of particles emanating from the ground following a CRS impact, and is termed a 'neutron burst'. We present recent observations of neutron bursts from a hand held sized gamma‐ray detector at the High Altitude Water Cherenkov (HAWC) array in Mexico, that exhibit interesting spectral features (the presence of positron annihilation), and an interesting time structure (hundreds of counts within a few ms). Our simulations indicate that Terrestrial gamma‐ray flashes (TGFs, bursts of gamma‐rays associated with lightning) should also produce these neutron bursts. An implication of this work is that existing deployments of ground based TGF instruments, comprised of small gamma‐ray detectors, can additionally be used to observe signatures of large cosmic ray showers on clear days. Key Points: We report on fairweather count rate bursts with 2 ms duration following the impact of a large cosmic ray shower near a small scintillation detector at HAWCSimulations show that the spectra and decay time can be produced by either hadronic interactions, or photoneutron reactions from gamma‐raysThese results imply that downward TGFs could produce a similar delayed neutron signature in the soil near ground based detectors [ABSTRACT FROM AUTHOR]

Aim: To test the hypothesis that glucokinase activators (GKAs) induce hepatic adaptations that alter intra-hepatocyte metabolite homeostasis. Methods: C57BL/6 mice on a standard rodent diet were treated with a GKA (AZD1656) acutely or chronically. Hepatocytes were isolated from the mice after 4 or 8 weeks of treatment for analysis of cellular metabolites and gene expression in response to substrate challenge. Results: Acute exposure of mice to AZD1656 or a liver-selective GKA (PF- 04991532), before a glucose tolerance test, or challenge of mouse hepatocytes with GKAs ex vivo induced various Carbohydrate response element binding protein (ChREBP) target genes, including Carbohydrate response element binding protein beta isoform (ChREBP-β), Gckr and G6pc. Both glucokinase activation and ChREBP target gene induction by PF-04991532 were dependent on the chirality of the molecule, confirming a mechanism linked to glucokinase activation. Hepatocytes from mice treated with AZD1656 for 4 or 8 weeks had lower basal glucose 6-phosphate levels and improved ATP homeostasis during high substrate challenge. They also had raised basal ChREBP-β mRNA and AMPK-α mRNA (Prkaa1, Prkaa2) and progressively attenuated substrate induction of some ChREBP target genes and Prkaa1 and Prkaa2. Conclusions: Chronic GKA treatment of C57BL/6 mice for 8 weeks activates liver ChREBP and improves the resilience of hepatocytes to compromised ATP homeostasis during high-substrate challenge. These changes are associated with raised mRNA levels of ChREBP-β and both catalytic subunits of AMP-activated protein kinase. [ABSTRACT FROM AUTHOR]

The hippocampus encodes distinct contexts with unique patterns of activity. Representational shifts with changes in context, referred to as remapping, have been extensively studied. However, less is known about transitions between representations. In this study, we leverage a large dataset of neuronal recordings taken while rats performed an olfactory memory task with a predictable temporal structure involving trials and intertrial intervals (ITIs), separated by salient boundaries at the trial start and trial end. We found that trial epochs were associated with stable hippocampal representations despite moment‐to‐moment variability in stimuli and behavior. Representations of trial and ITI epochs were far more distinct than spatial factors would predict and the transitions between the two were abrupt. The boundary was associated with a large spike in multiunit activity, with many individual cells specifically active at the start or end of each trial. Both epochs and boundaries were encoded by hippocampal populations, and these representations carried information on orthogonal axes readily identified using principal component analysis. We suggest that the hippocampus orthogonalizes representations of the trial and ITI epochs and the activity spike at trial boundaries might serve to drive hippocampal activity from one stable state to the other. [ABSTRACT FROM AUTHOR]

In 2015, Bowers et al. (2018, https://doi.org/10.1029/2017JD027771) detected a terrestrial gamma ray flash (TGF) in Hurricane Patricia from an aircraft flying at 2.6 km through what they argued to be a beam of downward gamma radiation produced by the positron component of the TGF. This paper uses the energy spectrum for gamma rays produced by the positrons of a relativistic runaway electron avalanche as simulated by the REAM code, propagated through a model of the Earth's atmosphere in Geant4, to examine the feasibility of detecting a typical upward TGF through its reverse positron beam at various altitudes on the ground. We find that, with patience, modest‐sized scintillators on mountains as low as 1 km should be able to observe the same TGFs seen from spacecraft. Key Points: An upward‐directed terrestrial gamma ray flash produces a reverse beam with 1% of the brightness of the main beamGEANT4 simulations show that the downward beam could be easily detectable at an altitude 1 km or greaterCoastal mountainous regions in the tropics would be good candidates for this reverse beam detection [ABSTRACT FROM AUTHOR]

Rationale: Mass spectra processing in protein hydrogen/deuterium (H/D) exchange has been remarkably improved by the introduction of fitting of the amide exchange probabilities to peptide isotopic envelope intensities (Kan et al., 2013), in contrast to methods in which only the peptide deuterium uptakes (centroid shifts of isotopic envelopes) are used. However, the known implementations are based on the general fitting routines that use only the objective function values. Besides, applicability of more than one fitting method makes necessary their comparative evaluation. Methods: Two fitting methods were considered: the common least squares and the fitting of the multinomial distribution representing the number of deuterium atoms exchanged in the individual peptides. Both methods were applied either directly to the isotopic envelope data or to the deuterium distributions obtained by envelope deconvolution (i.e. de‐isotoping). Results: An autonomous Matlab script was prepared, based on the exact expressions for the gradient and Hessian of the objective function, with the trust‐region algorithm implemented in the compact analytical form recently made available. The least‐squares fitting to the envelope data produced the best results, with the greatest precision and good coverage of exact values by the confidence intervals. The deuterium distributions were sensitive to the (simulated) experimental error whose progression by envelope deconvolution caused degradation in accuracy. The multinomial distribution fitting exhibited poor performance due to inadequate representation of the experimental error and missing of the appropriate weight parameters. Some specific peptide arrangement details were discussed as potential sources of ambiguity in the fitting results. Conclusions: The method of fitting to peptide isotopic envelopes has been improved by using the exact gradient and Hessian of the objective function. The fitting should be repeated with different initial guesses in order to find not only the global minimum, but also the local minima with similar depths which may exist due to eventual ambiguity of the fitting results. [ABSTRACT FROM AUTHOR]

Pyruvate formate‐lyase (PFL) catalyzes the reversible conversion of pyruvate and coenzyme A (CoA) into formate and acetyl‐CoA in two half‐reactions. For the second half‐reaction to take place, the S−H group of CoA must enter the active site of the enzyme to retrieve a protein‐bound acetyl group. However, CoA is bound at the protein surface, whereas the active site is buried in the protein interior, some 20–30 Å away. The PFL system was therefore subjected to a series of extensive molecular dynamics simulations (in the μs range) and a host of advanced analysis procedures. Models representing PFL before and after the first half‐reaction were used to examine the possible effect of enzyme acetylation. All simulated structures were found to be relatively stable compared to the initial crystal structure. Although the adenine portion of CoA remained predominantly bound at the protein surface, the binding of the S−H group was significantly more labile. A potential entry channel for CoA, which would allow the S−H group to reach the active site, was identified and characterized. The channel was found to be associated with accentuated fluctuations and a higher probability of being in an open state in acetylated systems. This result suggests that the acetylation of the enzyme assumes a prominent functional role, whereby the formation of the acyl intermediate serves to initiate a subtle signaling cascade that influences the protein dynamics and facilitates the entry of the second substrate. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?Urotensin II is upregulated in patients in the later stages of chronic kidney disease (CKD), particularly in individuals requiring dialysis. Could treatment with a urotensin II receptor antagonist slow progression of renal disease?What is the main finding and its importance?In the rat, expression of urotensin II and its receptor increased, extending into cortical structures as CKD progressed towards end‐stage renal failure. Subchronic treatment with a urotensin receptor antagonist slowed but did not prevent progression of CKD. This suggests that urotensin II contributes to the decline in renal function in CKD. Elevated serum and urine urotensin II (UII) concentrations have been reported in patients with end‐stage chronic kidney disease (CKD). Similar increases in UII and its receptor, UT, have been reported in animal models of CKD, but only at much earlier stages of renal dysfunction. The aim of this study was to characterize urotensin system expression as renal disease progresses to end‐stage failure in a ⅚ subtotal nephrectomy (SNx) rat model. Male Sprague–Dawley rats underwent SNx or sham surgery and were killed at 8 weeks postsurgery [early (E)] or immediately before end‐stage renal failure [30 ± 3 weeks postsurgery; late (L)]. Systolic blood pressure, urinary albumin:creatinine ratio and glomerulosclerosis index were all increased in SNx‐E rats compared with sham‐E by 8 weeks postsurgery. These changes were associated with an increase in renal immunoreactive UII staining but little change in UT expression. As CKD progressed to end‐stage disease in the SNx‐L group, markers of renal function deteriorated further, in association with a marked increase in immunoreactive UII and UT staining. Subchronic administration of a UT antagonist, SB‐611812, at 30 mg kg−1 day−1 for 13 weeks, in a separate group of SNx rats resulted in a 2 week delay in the increase in both systolic blood pressure and urinary albumin:creatinine ratio observed in vehicle‐treated SNx but did not prevent the progression of renal dysfunction. The urotensin system is upregulated as renal function deteriorates in the rat; UT antagonism can slow but not prevent disease progression, suggesting that UII plays a role in CKD. [ABSTRACT FROM AUTHOR]

Supported ionic liquid phase (SILP) catalysis enables a highly efficient, Ru‐based, homogeneously catalyzed water‐gas shift reaction (WGSR) between 100 °C and 150 °C. The active Ru‐complexes have been found to exist in imidazolium chloride melts under operating conditions in a dynamic equilibrium, which is dominated by the [Ru(CO)3Cl3]− complex. Herein we present state‐of‐the‐art theoretical calculations to elucidate the reaction mechanism in more detail. We show that the mechanism includes the intermediate formation and degradation of hydrogen chloride, which effectively reduces the high barrier for the formation of the requisite dihydrogen complex. The hypothesis that the rate‐limiting step involves water is supported by using D2O in continuous catalytic WGSR experiments. The resulting mechanism constitutes a highly competitive alternative to earlier reported generic routes involving nucleophilic addition of hydroxide in the gas phase and in solution. Shift work: Using high‐level quantum chemical techniques, leads to a new mechanism for the low temperature water–gas shift reaction (WGSR) using ruthenium‐based supported ionic liquid phase (SILP) catalysts. A mechanism involving anionic, chloride‐rich ruthenium carbonyl complexes is supported by the kinetic isotope effect of the reaction. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study? Tumour necrosis factor‐α (TNFα) has been shown to impair vascular function, but the impact of thoracic aorta perivascular adipose tissue (tPVAT)‐derived TNFα on tPVAT and aortic function in metabolic syndrome is unknown. What is the main finding and its importance? Release of TNFα by tPVAT causes production of reactive oxygen species in tPVAT through activation of an NADPH‐oxidase 2 (NOX2)‐dependent pathway, activates production of aortic reactive oxygen species and mediates aortic stiffness, potentially through matrix metalloproteinase 9 activity. Neutralization of TNFα and/or inhibition of NOX2 blocks the tPVAT‐induced impairment of aortic function. These data partly implicate tPVAT NOX2 and TNFα in mediating the vascular pathology of metabolic syndrome. Abstract: Perivascular adipose tissue (PVAT) is recognized for its vasoactive effects, but it is unclear how metabolic syndrome impacts thoracic aorta (t)PVAT and the subsequent effect on functional and structural aortic stiffness. Thoracic aorta and tPVAT were removed from 16‐ to 17‐week‐old lean (LZR, n = 16) and obese Zucker rats (OZR, n = 16). The OZR presented with aortic endothelial dysfunction, assessed by wire myography, and increased aortic stiffness, assessed by elastic modulus. The OZR tPVAT exudate further exacerbated the endothelial dysfunction, reducing nitric oxide and endothelium‐dependent relaxation (P < 0.05). Additionally, OZR tPVAT exudate had increased MMP9 activity (P < 0.05) and further increased the elastic modulus of the aorta after 72 h of co‐culture (P < 0.05). We found that the observed aortic dysfunction caused by OZR tPVAT was mediated through increased production and release of tumour necrosis factor‐α (TNFα; P < 0.01), which was dependent on tPVAT NADPH‐oxidase 2 (NOX2) activity. The OZR tPVAT release of reactive oxygen species and subsequent aortic dysfunction were inhibited by TNFα neutralization and/or inhibition of NOX2. Additionally, we found that OZR tPVAT had reduced activity of the active sites of the 20S proteasome (P < 0.05) and reduced superoxide dismutase activity (P < 0.01). In conclusion, metabolic syndrome causes tPVAT dysfunction through an interplay between TNFα and NOX2 that leads to tPVAT‐mediated aortic stiffness by activation of aortic reactive oxygen species and increased MMP9 activity. [ABSTRACT FROM AUTHOR]

Background and Purpose: Free fatty acid receptors FFA1 and FFA4 are located on enteroendocrine L cells with the highest gastrointestinal (GI) expression in descending colon. Their activation causes the release of glucagon-like peptide 1 and peptide YY (PYY) from L cells. Additionally, FFA1 agonism releases insulin from pancreatic β cells. As these receptors are modulators of nutrient-stimulated glucose regulation, the aim of this study was to compare the pharmacology of commercially available agonists (TUG424, TUG891, GW9508) with proven selective agonists (JTT, TAK-875, AZ423, Metabolex-36) in mice.Experimental Approach: Mouse mucosa was mounted in Ussing chambers, voltage-clamped and the resultant short-circuit current (Isc ) was recorded continuously. Pretreatments included antagonists of FFA1, Y1  or Y2 receptors. Glucose sensitivity was investigated by mannitol replacement apically, and colonic and upper GI transit was assessed in vitro and in vivo.Key Results: FFA1 and FFA4 agonism required glucose and reduced Isc in a PYY-Y1 receptor-dependent manner. The novel compounds were more potent than GW9508. The FFA1 antagonists (GW1100 and ANT825) blocked FFA1 activity only and revealed FFA1 tonic activity. The FFA4 agonist, Metabolex-36, slowed colonic transit in vitro but increased small intestinal transit in vivo.Conclusions and Implications: The selective FFA1 and FFA4 agonists were more potent at reducing Isc than GW9508, a dual FFA1 and FFA4 agonist. A paracrine epithelial mechanism involving PYY-stimulated Y1 receptors mediated their responses, which were glucose sensitive, potentially limiting hypoglycaemia. ANT825 revealed tonic activity and the possibility of endogenous FFA1 ligands causing PYY release. Finally, FFA4 agonism induced regional differences in transit. [ABSTRACT FROM AUTHOR]

Monte Carlo simulations are used to determine source properties of terrestrial gamma ray flashes (TGFs) as a function of atmospheric column depth and beaming geometry. The total mass per unit area traversed by all the runaway electrons (i.e., the total grammage) during a TGF, Ξ, is introduced, defined to be the total distance traveled by all the runaway electrons along the electric field lines multiplied by the local air mass density along their paths. It is shown that key properties of TGFs may be directly calculated from Ξ and its time derivative, including the gamma ray emission rate, the current moment, and the optical power of the TGF. For the calculations presented in this paper, a standard TGF gamma ray fluence, F0 = 0.1 cm−2 above 100 keV for a spacecraft altitude of 500 km, and a standard total grammage, Ξ0 = 1018 g/cm2, are introduced, and results are presented in terms of these values. In particular, the current moments caused by the runaway electrons and their accompanying ionization are found for a standard TGF fluence, as a function of source altitude and beaming geometry, allowing a direct comparison between the gamma rays measured in low-Earth orbit and the VLF-LF radio frequency emissions recorded on the ground. Such comparisons should help test and constrain TGF models and help identify the roles of lightning leaders and streamers in the production of TGFs. [ABSTRACT FROM AUTHOR]

Background and Purpose: Hyperglycaemia increases glucose concentrations in airway surface liquid and increases the risk of pulmonary Pseudomonas aeruginosa infection. We determined whether reduction of blood and airway glucose concentrations by the anti-diabetic drug dapagliflozin could reduce P. aeruginosa growth/survival in the lungs of diabetic mice.Experimental Approach: The effect of dapagliflozin on blood and airway glucose concentration, the inflammatory response and infection were investigated in C57BL/6J (wild type, WT) or leptin receptor-deficient (db/db) mice, treated orally with dapagliflozin prior to intranasal dosing with LPS or inoculation with P. aeruginosa. Pulmonary glucose transport and fluid absorption were investigated in Wistar rats using the perfused fluid-filled lung technique.Key Results: Fasting blood, airway glucose and lactate concentrations were elevated in the db/db mouse lung. LPS challenge increased inflammatory cells in bronchoalveolar lavage fluid from WT and db/db mice with and without dapagliflozin treatment. P. aeruginosa colony-forming units (CFU) were increased in db/db lungs. Pretreatment with dapagliflozin reduced blood and bronchoalveolar lavage glucose concentrations and P. aeruginosa CFU in db/db mice towards those seen in WT. Dapagliflozin had no adverse effects on the inflammatory response in the mouse or pulmonary glucose transport or fluid absorption in the rat lung.Conclusion and Implications: Pharmacological lowering of blood glucose with dapagliflozin effectively reduced P. aeruginosa infection in the lungs of diabetic mice and had no adverse pulmonary effects in the rat. Dapagliflozin has potential to reduce the use, or augment the effect, of antimicrobials in the prevention or treatment of pulmonary infection. [ABSTRACT FROM AUTHOR]

We present a procedure for localization of deuterium uptake from overlapping proteolytic peptides to contiguous protein parts called segments. A system of linear equations expressing experimental peptide uptakes in segments cannot be solved by ordinary methods because of insufficient rank and/or linearly dependent peptides. Solvable segments are identified, and their uptakes and associated variances are evaluated by using the Moore-Penrose pseudoinverse. The method also allows consistency check of experimental data and detection of outliers. The conditions for segment solvability are formulated in a peptide graph. From the peptide graph, it is easy to find more useful information hidden in the experimental data, like sums or differences of unsolvable segment uptakes. Expected localization gain was estimated from simulations with random peptide arrangements. The recently proposed averaging method (Keppel TR, Weis DD. J. Am. Soc. Mass Spectrom. 2015; 26: 547) for resolution of exchange halftimes was extended to resolution of uptakes and combined with the present approach to achieve maximum uptake localization, which is also consistent with experimental data. [ABSTRACT FROM AUTHOR]

ABSTRACT Hippocampal neurons exhibit spatially localized firing patterns that, at the population level, represent a particular environment or context. Many studies have examined how hippocampal neurons switch from an existing representation to a new one when the environment is changed, a process referred to as remapping. New representations were commonly thought to emerge rapidly, within a few minutes and then remain remarkably stable thereafter. However, a number of recent studies suggest that hippocampal representations may be more fluid than previously thought and most of the previous studies only required that subjects switch from a familiar environment to a novel one. In the present study, we examined the concurrent development of two distinct hippocampal representations by exposing rats to two distinct environmental contexts in an ABAB pattern and we recorded neuronal activity for eight daily training sessions. Hippocampal neurons exhibited normal place fields with typical firing properties during the initial exposure to each context on the first day. However, when the rats were returned to the original context after having spent 15 min in the second context, many of the neurons fired in new locations (i.e., they remapped) as if the rat had encountered a new environment. By the third day, the representations had stabilized and were highly consistent across visits to the same context. These results suggest that when subjects concurrently encode multiple contexts, hippocampal representations may require repeated experiences to fully stabilize. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

ABSTRACT Returning to a familiar context triggers retrieval of relevant memories, making memories from other contexts less likely to intrude and cause interference. We investigated the physiology that underlies the use of context to prevent interference by recording hippocampal neurons while rats learned two conflicting sets of discrimination problems, either in the same context or in two distinct contexts. Rats that learned the conflicting problem sets in the same context maintained similar neural representations, and performed poorly because conflicting memories interfered with new learning. In contrast, rats that learned in different contexts formed distinct ensemble representations and performed significantly better. We also measured trial-to-trial variation in representations and found that hippocampal activity was directly linked with performance: on trials where an old representation was active, rats were far more likely to make errors. These results show that the formation of distinct hippocampal representations is critical for contextually appropriate memory retrieval. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Model studies of prebiotic chemistry have revealed compelling routes for the formation of the building blocks of proteins and RNA, but not DNA. Today, deoxynucleotides required for the construction of DNA are produced by reduction of nucleotides catalysed by ribonucleotide reductases, which are radical enzymes. This study considers potential non-enzymatic routes via intermediate radicals for the ancient formation of deoxynucleotides. In this context, several mechanisms for ribonucleotide reduction, in a putative H2S/HS. environment, are characterized using computational chemistry. A bio-inspired mechanistic cycle involving a keto intermediate and HSSH production is found to be potentially viable. An alternative pathway, proceeding through an enol intermediate is found to exhibit similar energetic requirements. Non-cyclical pathways, in which HSS. is generated in the final step instead of HS., show a markedly increased thermodynamic driving force (ca. 70 kJ mol−1) and thus warrant serious consideration in the context of the prebiotic ribonucleotide reduction. [ABSTRACT FROM AUTHOR]