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Alzheimer's disease (AD) progresses as a continuum, from preclinical stages to late-stage cognitive decline, yet the molecular mechanisms driving this progression remain poorly understood. Here, we provide a systems-level map of protein-protein interaction (PPI) network dysfunction across the AD spectrum and uncover epichaperomes-stable scaffolding platforms formed by chaperones and co-factors-as central drivers of this process. Using over 100 human brain specimens, mouse models, and human neurons, we show that epichaperomes emerge early, even in preclinical AD, and progressively disrupt multiple PPI networks critical for synaptic function and neuroplasticity. Glutamatergic neurons, essential for learning and memory, exhibit heightened vulnerability, with their dysfunction driven by protein sequestration into epichaperome scaffolds, independent of changes in protein expression. Notably, pharmacological disruption of epichaperomes with PU-AD restores PPI network integrity and reverses synaptic and cognitive deficits, directly linking epichaperome-driven network dysfunction to AD pathology. These findings establish epichaperomes as key mediators of molecular collapse in AD and identify network-centric intervention strategies as a promising avenue for disease-modifying therapies.

Introduction: Currently, only little data is available on the impact of the COVID-19 pandemic on inpatient dermatosurgical care in German dermatological clinics., Methods: A retrospective analysis of all dermatosurgical cases that were treated in inpatient setting in nine German dermatological clinics in four federal states in 2019, 2020 and 2021 was performed. The diagnoses were recorded using the ICD-10 codes. In addition, demographic data such as age, gender and the length of inpatient stay were analysed., Results: In 2019, 2020 and 2021, a total of 10,739, 9185 and 9828 dermatosurgical inpatients were treated respectively. Thus, the reduction of inpatient dermatosurgical cases was 14.5% in 2020 and 8.5% in 2021 compared to 2019. Inpatient surgical treatment of melanoma decreased by 10.1% of cases in 2020. This decrease was only 1.4% in 2021 compared to 2019. The number of inpatient surgeries performed for benign lesions such as melanocytic nevi or viral warts reduced sharply in both pandemic years., Conclusion: Our data show for the first time how inpatient care for the entire spectrum of dermatosurgical diseases developed during the COVID-19 pandemic in Germany. After the initial marked decline in inpatient dermatosurgical cases in 2020, there was less difference in 2021 compared to 2019. This trend can be interpreted as an indication that there is still a strong need for inpatient dermatosurgical care that cannot yet be met on an outpatient basis., (© 2024. The Author(s).)

High-level radioactive waste needs to be safely stored for a long time in a deep geological repository by using a multi-barrier system. In this system, suitable barrier materials are selected that ideally show long-term stability to prevent early radionuclide release into the biosphere. In this study, different container matals (copper and cast iron) and pore water compositions (Opalinus Clay pore water and saline cap rock solution) were combined with Bavarian bentonite in static batch experiments to investigate microbial-influenced corrosion. The increasing concentration of iron and copper in the solution as well as detected corrosion products on the metal surface are indicative of anaerobic corrosion of the respective metals during an incubation of 400 days at 37 °C. However, although the intrinsic microbial bentonite community was stimulated with either lactate or H 2 , an acceleration of cast iron- and copper corrosion did not occur. Furthermore, neither corrosive bacteria nor conventional bacterial corrosion products, such as metal sulfides, were detected in any of the analyzed samples. The analyses of geochemical parameters (e.g. ferrous iron-, iron-, copper- and potassium concentrations as well as redox potentials) showed significant changes in some cast iron- and copper-containing setups, but these changes did not correlate with the microbial community structure in the respective microcosms, as confirmed by statistical analyses. Hence, the analyzed Bavarian bentonite (type B25) showed no significant contribution to cast iron and copper corrosion under the applied conditions after 400 days of incubation. From this perspective, bentonite B25 could be a suitable candidate as a geotechnical barrier in future repositories., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Blue corona discharges are often generated in thunderclouds penetrating into the stratosphere and are the optical manifestation of narrow bipolar events (NBEs) observed in radio signals. While their production appears to depend on convection, the cause and nature of such discharges are not well known. Here we show the observations by a lightning detection array of unusual amounts of 982 NBEs during a tropical storm on the coastline of China. NBEs of negative polarity are predominantly observed at the cloud top reaching the stratosphere, and positive NBEs are primarily at lower altitudes. We find that the dominant polarity changes with the typical time of development of thunderstorm cells, suggesting that the polarity depends on the phase of the storm cells. Furthermore, we find that the lightning jump of negative NBEs is associated with above-anvil cirrus plumes of ice crystals and water vapor in the lower stratosphere. We propose that variations in updrafts induce changes in the altitude and charge concentrations of the cloud layers, which lead to the polarity transition. Our results have implications for studies of the chemical perturbations of greenhouse gas concentrations by corona discharges at the tropopause., (© 2024. The Author(s).)

Icosahedral carboranes, C 2 B 10 H 12 , have long been considered to be aromatic but the extent of conjugation between these clusters and their substituents is still being debated. m- and p-Carboranes are compared with m- and p-phenylenes as conjugated bridges in optical functional chromophores with a donor and an acceptor as substituents here. The absorption and fluorescence data for both carboranes from experimental techniques (including femtosecond transient absorption, time-resolved fluorescence and broadband fluorescence upconversion) show that the absorption and emission processes involve strong intramolecular charge transfer between the donor and acceptor substituents via the carborane cluster. From quantum chemical calculations on these carborane systems, the charge transfer process depends on the relative torsional angles of the donor and acceptor groups where an overlap between the two frontier orbitals exists in the bridging carborane cluster., (© 2024. The Author(s).)

The Atmosphere-Space Interactions Monitor (ASIM) on the International Space Station (ISS) includes an instrument designed to geolocate Terrestrial Gamma-ray Flashes (TGF) produced by thunderstorms. It does so with a coded aperture system shadowing the pixelated Low Energy Detector of the Modular X- and Gamma-ray Sensor (MXGS). Additionally, it locates associated lightning flashes with the Modular Multispectral Imaging Array (MMIA). Here we present 3 bright TGFs with very similar duration, fluency and observation distance. The innovative imaging capabilities allow us to determine the TGF position and correlate the TGF-lightning parent event in time and position simultaneously. The accurate position determination and distance to the observer allow us to perform a comparative study of TGF characteristics. These TGFs were produced in association with lightning flashes below the highest cloud tops of developing to mature convective cells. In one event, GLM (Geostationary Lightning Mapper) cloud flash rates were slowing down after the TGF while negative cloud-to-ground flashes suddenly ceased from 10 to 5 min before the TGF. An 8-stroke (strongest: -93 kA) cloud-to-ground flash occurred 31 s before the TGF. Vertical profiles from the ERA5 reanalysis data suggest TGFs may be produced in variety of tropical environments., (© 2024. The Author(s).)

Terrestrial gamma-ray flashes (TGFs) are bursts of energetic X- and gamma-rays emitted from thunderstorms. The Atmosphere-Space Interactions Monitor (ASIM) mounted onto the International Space Station (ISS) is dedicated to measure TGFs and optical signatures of lightning; ISS LIS (Lightning Imaging Sensor) detects lightning flashes allowing for simultaneous measurements with ASIM. Whilst ASIM measures ∼ 300-400 TGFs per year, ISS LIS detects ∼ 10 6 annual lightning flashes giving a disproportion of four orders of magnitude. Based on the temporal evolution of lightning flashes and the spatial pattern of the constituing events, we present an algorithm to reduce the number of space-detected flashes potentially associated with TGFs by ∼ 60% and of associated LIS groups by ∼ 95%. We use ASIM measurements to confirm that the resulting flashes are indeed those associated with TGFs detected at approx. 400 km altitude and thus benchmark our algorithm preserving 70-80% of TGFs from concurrent ASIM-LIS measurements. We compare how the radiance, footprint size and the global distribution of lightning flashes of the reduced set relates to the average of all measured lightning flashes and do not observe any significant difference. Finally, we present a parameter study of our algorithm and discuss which parameters can be tweaked to maximize the reduction efficiency whilst keeping flashes associated to TGFs. In the future, this algorithm will hence be capable of facilitating the search for TGFs in a reduced set of lightning flashes measured from space., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2024.)

Introduction: Based on extracorporeal circulation, targeted reperfusion strategies have been developed to improve survival and neurologic recovery in refractory cardiac arrest: Controlled Automated Reperfusion of the whoLe Body (CARL). Furthermore, animal and human cadaver studies have shown beneficial effects on cerebral pressure due to head elevation during conventional cardiopulmonary resuscitation. Our aim was to evaluate the impact of head elevation on survival, neurologic recovery and histopathologic outcome in addition to CARL in an animal model. Methods: After 20 min of ventricular fibrillation, 46 domestic pigs underwent CARL, including high, pulsatile extracorporeal blood flow, pH-stat acid-base management, priming with a colloid, mannitol and citrate, targeted oxygen, carbon dioxide and blood pressure management, rapid cooling and slow rewarming. N = 25 were head-up (HUP) during CARL, and N = 21 were supine (SUP). After weaning from ECC, the pigs were extubated and followed up in the animal care facility for up to seven days. Neuronal density was evaluated in neurohistopathology. Results: More animals in the HUP group survived and achieved a favorable neurological recovery, 21/25 (84%) versus 6/21 (29%) in the SUP group. Head positioning was an independent factor in neurologically favorable survival ( p < 0.00012). Neurohistopathology showed no significant structural differences between HUP and SUP. Distinct, partly transient clinical neurologic deficits were blindness and ataxia. Conclusions: Head elevation during CARL after 20 min of cardiac arrest independently improved survival and neurologic outcome in pigs. Clinical follow-up revealed transient neurologic deficits potentially attributable to functions localized in the posterior perfusion area, whereas histopathologic findings did not show corresponding differences between the groups. A possible explanation of our findings may be venous congestion and edema as modifiable contributing factors of neurologic injury following prolonged cardiac arrest.

Forests are increasingly exposed to natural disturbances, including drought, wildfires, pest outbreaks, and windthrow events. Due to prolonged droughts in the last years in Europe, European forest stands significantly lost vitality, and their health condition deteriorated, leading to high mortality rates, especially, but not limited to, Norway spruce. This phenomenon is growing, and new regions are being affected; thus, it is necessary to identify stress in the early stages when actions can be taken to protect the forest and living trees. Current detection methods are based on field walks by forest workers or deploying remote sensing methods for coverage of the larger territory. These methods are based on changes in spectral reflectance that can detect attacks only at an advanced stage after the significant changes in the canopy. An innovative approach appears to be a method based on odor mapping, specifically detecting chemical substances which are present in the forest stands and indicate triggering of constitutive defense of stressed trees. The bark beetle attacking a tree, for example, produces a several times higher amount of defense-related volatile organic compounds. At the same time, the bark beetle has an aggregation pheromone to attract conspecifics to overcome the tree defense by mass attack. These substances can be detected using conventional chemical methods (solid-phase microextraction fibers and cartridges), and it is proven that they are detectable by dogs. The disadvantage of classic chemical analysis methods is the long sampling time in the forest, and at the same time, the results must be analyzed in the laboratory using a gas chromatograph. A potential alternative novel device appears to be an electronic nose, which is designed to detect chemical substances online (for example, dangerous gas leaks or measure concentrations above landfills, volcanic activity, etc.). We tested the possibility of early-stage stress detection in the forest stands using an electronic nose Sniffer4D and compared the individual sensors in it for detecting the presence of attacked and dead trees. Our results indicate the promising applicability of the electronic nose for stress mapping in the forest ecosystem, and more data collection could prove this approach.

GPR133 (ADGRD1) is an adhesion G protein-coupled receptor that signals through Gαs and is required for growth of glioblastoma (GBM), an aggressive brain malignancy. The regulation of GPR133 signaling is incompletely understood. Here, we use proximity biotinylation proteomics to identify ESYT1, a Ca 2+ -dependent mediator of endoplasmic reticulum-plasma membrane bridge formation, as an intracellular interactor of GPR133. ESYT1 knockdown or knockout increases GPR133 signaling, while its overexpression has the opposite effect, without altering GPR133 levels in the plasma membrane. The GPR133-ESYT1 interaction requires the Ca 2+ -sensing C2C domain of ESYT1. Thapsigargin-mediated increases in cytosolic Ca 2+ relieve signaling-suppressive effects of ESYT1 by promoting ESYT1-GPR133 dissociation. ESYT1 knockdown or knockout in GBM impairs tumor growth in vitro , suggesting functions of ESYT1 beyond the interaction with GPR133. Our findings suggest a novel mechanism for modulation of GPR133 signaling by increased cytosolic Ca 2+ , which reduces the signaling-suppressive interaction between GPR133 and ESYT1 to raise cAMP levels., Competing Interests: Disclosures and Competing Interests DGP and NYU Grossman School of Medicine own an EU and Hong Kong patent titled “Method for treating high-grade gliomas” on the use of GPR133 as a treatment target in glioma. DGP has received consultant fees from Tocagen, Synaptive Medical, Monteris, Robeaute and Advantis.

The International Space Station (ISS) is in the lowest available orbit at ~400 km altitude, bringing instruments as close to the atmosphere as possible from the vantage point of space. The orbit inclination is 51.6°, which brings the ISS over all the low- and mid-latitude regions of the Earth and at all local times. It is an ideal platform to observe deep convection and electrification of thunderstorms, taken advantage of by the Lightning Imaging Sensor (LIS) and the Atmosphere Space Interaction Monitor (ASIM) experiments. In the coming years, meteorological satellites in geostationary orbit (~36,000 km altitude) will provide sophisticated cloud and lightning observations with almost complete coverage of the Earth's thunderstorm regions. In addition, Earth-observing satellite instruments in geostationary- and low-Earth orbit (LEO) will measure more atmospheric parameters at a higher resolution than we know today. The new infrastructure in space offers an opportunity to advance our understanding of the role of thunderstorms in atmospheric dynamics and climate change. Here, we discuss how observations from the ISS or other LEO platforms with instruments that view the atmosphere at slanted angles can complement the measurements from primarily nadir-oriented instruments of present and planned missions. We suggest that the slanted viewing geometry from LEO may resolve the altitude of electrical activity and the cloud structure where they occur, with implications for modelling thunderstorms' effects on the atmosphere's radiative properties and climate balance., (© 2023. The Author(s).)

We present nighttime worldwide distributions of key features of Blue LUminous Events (BLUEs) detected by the Modular Multispectral Imaging Array of the Atmosphere-Space Interaction Monitor. Around 10% of all detected BLUEs exhibit an impulsive single pulse shape. The rest of BLUEs are unclear (impulsive or not) single, multiple or with ambiguous pulse shapes. BLUEs exhibit two distinct populations with peak power density <25 µWm -2 (common) and ≥25 µWm -2 (rare) with different rise times and durations. The altitude (and depth below cloud tops) zonal distribution of impulsive single pulse BLUEs indicate that they are commonly present between cloud tops and a depth of ≤4 km in the tropics and ≤1 km in mid and higher latitudes. Impulsive single pulse BLUEs in the tropics are the longest (up to ∼4 km height) and have the largest number of streamers (up to ∼3 × 10 9 ). Additionally, the analysis of BLUEs has turned out to be particularly complex due to the abundance of radiation belt particles (at high latitudes and in the South Atlantic Anomaly [SAA]) and cosmic rays all over the planet. True BLUEs can not be fully distinguished from radiation belt particles and cosmic rays unless other ground-based measurements associated with the optically detected BLUEs are available. Thus, the search algorithm of BLUEs presented in Soler et al. (2021), https://doi.org/10.1029/2021gl094657 is now completed with a new additional step that, if used, can considerably smooth the SAA shadow but can also underestimate the number of BLUEs worldwide., (© 2022 The Authors.)

We present 221 Terrestrial Gamma-ray Flashes (TGFs) and associated optical pulses observed by the Atmosphere-Space Interactions Monitor (ASIM) on board the International Space Station. The events were detected between the end of March 2019 and November 2020 and consist of X- and gamma-ray energy detections, as well as photometer data (180-230, 337, and 777 nm) and optical camera data (337 and 777 nm). Using the available ASIM data and applying a consistency check based on TGF characteristics and lightning detections from lightning radio atmospherics close in time, we determine the most likely position of the TGFs in relation to the photometer field of view (FoV), and the association to the observed optical pulses. Out of the 221 events we find 72 events where the TGF and optical data are determined to be associated and inside the photometer FoV. Using the measured TGF durations and the time between the onsets of the TGFs and optical pulses we find: (a) That the TGF onsets are always before or at the same time as the optical pulse onsets (taking into account cloud scattering). (b) A tendency for longer duration TGFs to have longer delays between onsets. (c) Two groups of events: (a) where there is a possible overlap between the TGFs and the optical emissions, as the TGFs last longer than the delay between onsets and (b) where the TGFs and optical emissions do not overlap, as there are long delays between the onsets, which cannot be explained by cloud scattering., (© 2022. The Authors.)

How lightning initiates inside thunderclouds remains a major puzzle of atmospheric electricity. By monitoring optical emissions from thunderstorms, the Atmosphere-Space Interactions Monitor (ASIM) onboard the International Space Station is providing new clues about lightning initiation by detecting Blue LUminous Events (BLUEs), which are manifestations of electrical corona discharges that sometimes precedes lightning. Here we combine optical and radio observations from a thunderstorm near Malaysia to uncover a new type of event containing multiple optical and radio pulses. We find that the first optical pulse coincides with a strong radio signal in the form of a Narrow Bipolar Event (NBE) but subsequent optical pulses, delayed some milliseconds, have weaker radio signals, possibly because they emanate from a horizontally oriented electrical discharges which does not trigger full-fledged lightning. Our results cast light on the differences between isolated and lightning-initiating electrical discharges., (© 2022. The Authors.)

We report on observations of corona discharges at the uppermost region of clouds characterized by emissions in a blue band of nitrogen molecules at 337 nm, with little activity in the red band of lightning leaders at 777.4 nm. Past work suggests that they are generated in cloud tops reaching the tropopause and above. Here we explore their occurrence in two convective environments of the same storm: one is developing with clouds reaching above the tropopause, and one is collapsing with lower cloud tops. We focus on those discharges that form a distinct category with rise times below 20 μs, implying that they are at the very top of the clouds. The discharges are observed in both environments. The observations suggest that a range of storm environments may generate corona discharges and that they may be common in convective surges., (© 2022. The Authors.)

We report rare simultaneous observations of columniform sprites and associated gravity waves (GWs) using the Transient Luminous Events (TLEs) camera and All-sky imager at Prayagraj (25.5° N, 81.9° E, geomag. lat. ~ 16.5° N), India. On 30 May 2014, a Mesoscale Convective System generated a group of sprites over the north horizon that reached the upper mesosphere. Just before this event, GWs (period ~ 14 min) were seen in OH broadband airglow (emission peak ~ 87 km) imaging that propagated in the direction of the sprite occurrence and dissipated in the background atmosphere thereby generating turbulence. About 9-14 min after the sprite event, another set of GWs (period ~ 11 min) was observed in OH imaging that arrived from the direction of the TLEs. At this site, we also record Very Low Frequency navigational transmitter signal JJI (22.2 kHz) from Japan. The amplitude of the JJI signal showed the presence of GWs with ~ 12.2 min periodicities and ~ 18 min period. The GWs of similar features were observed in the ionospheric Total Electron Content variations recorded at a nearby GPS site. The results presented here are important to understand the physical coupling of the troposphere with the lower and upper ionosphere through GWs., (© 2022. The Author(s).)

Magnetars are strongly magnetized, isolated neutron stars 1-3 with magnetic fields up to around 10 15  gauss, luminosities of approximately 10 31 -10 36  ergs per second and rotation periods of about 0.3-12.0 s. Very energetic giant flares from galactic magnetars (peak luminosities of 10 44 -10 47  ergs per second, lasting approximately 0.1 s) have been detected in hard X-rays and soft γ-rays 4 , and only one has been detected from outside our galaxy 5 . During such giant flares, quasi-periodic oscillations (QPOs) with low (less than 150 hertz) and high (greater than 500 hertz) frequencies have been observed 6-9 , but their statistical significance has been questioned 10 . High-frequency QPOs have been seen only during the tail phase of the flare 9 . Here we report the observation of two broad QPOs at approximately 2,132 hertz and 4,250 hertz in the main peak of a giant γ-ray flare 11 in the direction of the NGC 253 galaxy 12-17 , disappearing after 3.5 milliseconds. The flare was detected on 15 April 2020 by the Atmosphere-Space Interactions Monitor instrument 18,19 aboard the International Space Station, which was the only instrument that recorded the main burst phase (0.8-3.2 milliseconds) in the full energy range (50 × 10 3 to 40 × 10 6  electronvolts) without suffering from saturation effects such as deadtime and pile-up. Along with sudden spectral variations, these extremely high-frequency oscillations in the burst peak are a crucial component that will aid our understanding of magnetar giant flares., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Narrow bipolar events (NBEs) are signatures in radio signals from thunderstorms observed by ground-based receivers. NBEs may occur at the onset of lightning, but the discharge process is not well understood. Here, we present spectral measurements by the Atmosphere-Space Interactions Monitor (ASIM) on the International Space Station that are associated with nine negative and three positive NBEs observed by a ground-based array of receivers. We found that both polarities NBEs are associated with emissions at 337 nm with weak or no detectable emissions at 777.4 nm, suggesting that NBEs are associated with streamer breakdown. The rise times of the emissions for negative NBEs are about 10 μs, consistent with source locations at cloud tops where photons undergo little scattering by cloud particles, and for positive NBEs are ~1 ms, consistent with locations deeper in the clouds. For negative NBEs, the emission strength is almost linearly correlated with the peak current of the associated NBEs. Our findings suggest that ground-based observations of radio signals provide a new means to measure the occurrences and strength of cloud-top discharges near the tropopause., (© 2021. The Author(s).)

The Atmosphere-Space Interactions Monitor measures Terrestrial Gamma-Ray Flashes (TGFs) simultaneously with optical emissions from associated lightning activity. We analyzed optical measurements at 180-230, 337, and 777.4 nm related to 69 TGFs observed between June 2018 and October 2019. All TGFs are associated with optical emissions and 90% of them are at the onset of a large optical pulse, suggesting that they are connected with the initiation of current surges. A model of photon delay induced by cloud scattering suggests that the sources of the optical pulses are from 0.7 ms before to 4.4 ms after the TGFs, with a median of -10 ± 80 µs, and 1-5 km below the cloud top. The pulses have rise times comparable to lightning but longer durations. Pulse amplitudes at 337 nm are ∼3 times larger than at 777.4 nm. The results support the leader-streamer mechanism for TGF generation., (© 2020. The Authors.)

Three-dimensional (3D) scaffolds with optimum physicochemical properties are able to elicit specific cellular behaviors and guide tissue formation. However, cell-material interactions are limited in scaffolds fabricated by melt extrusion additive manufacturing (ME-AM) of synthetic polymers, and plasma treatment can be used to render the surface of the scaffolds more cell adhesive. In this study, a hybrid AM technology, which combines a ME-AM technique with an atmospheric pressure plasma jet, was employed to fabricate and plasma treat scaffolds in a single process. The organosilane monomer (3-aminopropyl)trimethoxysilane (APTMS) and a mixture of maleic anhydride and vinyltrimethoxysilane (MA-VTMOS) were used for the first time to plasma treat 3D scaffolds. APTMS treatment deposited plasma-polymerized films containing positively charged amine functional groups, while MA-VTMOS introduced negatively charged carboxyl groups on the 3D scaffolds' surface. Argon plasma activation was used as a control. All plasma treatments increased the surface wettability and protein adsorption to the surface of the scaffolds and improved cell distribution and proliferation. Notably, APTMS-treated scaffolds also allowed cell attachment by electrostatic interactions in the absence of serum. Interestingly, cell attachment and proliferation were not significantly affected by plasma treatment-induced aging. Also, while no significant differences were observed between plasma treatments in terms of gene expression, human mesenchymal stromal cells (hMSCs) could undergo osteogenic differentiation on aged scaffolds. This is probably because osteogenic differentiation is rather dependent on initial cell confluency and surface chemistry might play a secondary role.

Blue jets are lightning-like, atmospheric electric discharges of several hundred millisecond duration that fan into cones as they propagate from the top of thunderclouds into the stratosphere 1 . They are thought to initiate in an electric breakdown between the positively charged upper region of a cloud and a layer of negative charge at the cloud boundary and in the air above. The breakdown forms a leader that transitions into streamers 2 when propagating upwards 3 . However, the properties of the leader, and the altitude to which it extends above the clouds, are not well characterized 4 . Blue millisecond flashes in cloud tops 5,6 have previously been associated with narrow bipolar events 7,8 , which are 10- to 30-microsecond pulses in wideband electric field records, accompanied by bursts of intense radiation at 3 to 300 megahertz from discharges with short (inferred) channel lengths (less than one kilometre) 9-11 . Here we report spectral measurements from the International Space Station, which offers an unimpeded view of thunderclouds, with 10-microsecond temporal resolution. We observe five intense, approximately 10-microsecond blue flashes from a thunderstorm cell. One flash initiates a pulsating blue jet to the stratopause (the interface between the stratosphere and the ionosphere). The observed flashes were accompanied by 'elves' 12 in the ionosphere. Emissions from lightning leaders in the red spectral band are faint and localized, suggesting that the flashes and the jet are streamer ionization waves, and that the leader elements at their origin are short and localized. We propose that the microsecond flashes are the optical equivalent of negative narrow bipolar events observed in radio waves. These are known to initiate lightning within the cloud and to the ground, and blue lightning into the stratosphere, as reported here.

Terrestrial gamma-ray flashes (TGFs) are transient gamma-ray emissions from thunderstorms, generated by electrons accelerated to relativistic energies in electric fields. Elves are ultraviolet and optical emissions excited in the lower ionosphere by electromagnetic waves radiated from lightning current pulses. We observed a TGF and an associated elve using the Atmosphere-Space Interactions Monitor on the International Space Station. The TGF occurred at the onset of a lightning current pulse that generated an elve, in the early stage of a lightning flash. Our measurements suggest that the current onset is fast and has a high amplitude-a prerequisite for elves-and that the TGF is generated in the electric fields associated with the lightning leader., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Superficial wound infections after gastrointestinal surgery markedly impair the affected patients' quality of life. As it is still unknown which method of skin closure is best for the reduction of wound infections in elective gastrointestinal sur- gery, we compared the frequency of wound infections after intracutaneous suturing versus skin stapling., Methods: In a prospective, randomized, single-center study, patients undergoing elective gastrointestinal surgery were intraoperatively randomized to skin closure either with an intracutaneous suture or with staples. The primary endpoint-the occurrence of a grade A1 wound infection within 30 days of surgery-was evaluated according to the intention-to-treat principle., Results: Out of a total of 280 patients, 141 were randomized to intracutaneous suturing and 139 to stapling. The groups did not differ significantly with respect to age, sex, or ASA classification. 19 of the 141 patients in the intracutaneous suturing group (13.5%) had a grade A1 wound infection, compared with 23 of 139 in the stapling group (16.6%) (odds ratio [OR]: 0.79; 95% confidence interval: [0.41; 1.52]; p = 0.47). A multiple regression analysis revealed that the type of surgery (colorectal vs. other), the approach, and the incision length were independent risk factors for a grade A1 wound infection. When wound dehiscences were additionally considered, wound complications were found to have arisen significantly more often in the stapling group than in the intracutaneous suturing group (16.3% [23/141] versus 30.2% [42/139], OR: 0.45 [0.25; 0.80]; p = 0.006)., Conclusion: In elective gastrointestinal surgery, intracutaneous suturing was not found to be associated with a lower rate of superficial wound infections than skin stapling, but fewer wound dehiscences occurred in the intracutaneous suturing group.

Two major aspects need to be focused to accelerate wound healing of mucosal damages especially in the field of otorhinolaryngology. (i) The problem of application due to the small access during surgery, (ii) the fixation of the wound dressing to reveal a stable healing process. In the present work the high request to a mucosal wound dressing which additionally support hemostasis was addressed. We developed an electrospun fabric made of poly(l-lactide-co-d/l-lactide) (PLA) which can be loaded with the hemostatic agents adrenaline and tranexamic acid to cover mucosal lesions analogues to common skin patches. These loaded electrospun fabrics were demonstrated to be biocompatible, thin and flexible, and thus could be adapted individually to the mucosal defect with respect to localization and size of the lesion. The treatment of mucosal defects with these loaded PLA wound dressings induced a faster and time controlled hemostatic reaction, which significantly improved the healing process., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Bursts of X-rays and γ -rays are observed from lightning and laboratory sparks. They are bremsstrahlung from energetic electrons interacting with neutral air molecules, but it is still unclear how the electrons achieve the required energies. It has been proposed that the enhanced electric field of streamers, found in the corona of leader tips, may account for the acceleration; however, their efficiency is questioned because of the relatively low production rate found in simulations. Here we emphasize that streamers usually are simulated with the assumption of homogeneous gas, which may not be the case on the small temporal and spatial scales of discharges. Since the streamer properties strongly depend on the reduced electric field E / n , where n is the neutral number density, fluctuations may potentially have a significant effect. To explore what might be expected if the assumption of homogeneity is relaxed, we conducted simple numerical experiments based on simulations of streamers in a neutral gas with a radial gradient in the neutral density, assumed to be created, for instance, by a previous spark. We also studied the effects of background electron density from previous discharges. We find that X-radiation and γ -radiation are enhanced when the on-axis air density is reduced by more than ∼25%. Pre-ionization tends to reduce the streamer field and thereby the production rate of high-energy electrons; however, the reduction is modest. The simulations suggest that fluctuations in the neutral densities, on the temporal and spacial scales of streamers, may be important for electron acceleration and bremsstrahlung radiation.

Gigantic Jets are electric discharges from thunderstorm cloud tops to the bottom of ionosphere at ~90 km altitude and electrically connect the troposphere and lower ionosphere. Since their first report in 2002, sporadic observations have been reported from ground and space based observations. Here we report first observations of Gigantic Jets in Indian subcontinent over the Indo-Gangetic plains during the monsoon season. Two storms each produced two jets with characteristics not documented so far. Jets propagated ~37 km up remarkably in ~5 ms with velocity of ~7.4 × 10 6 ms -1 and disappeared within ~40-80 ms, which is faster compared to jets reported earlier. The electromagnetic signatures show that they are of negative polarity, transporting net negative charge of ~17-23 C to the lower ionosphere. One jet had an unusual form observed for the first time, which emerged from the leading edge of a slowly drifting complex convective cloud close to the highest regions at ~17 km altitude. A horizontal displacement of ~10 km developed at ~50 km altitude before connecting to the lower ionosphere. Modeling of these Gigantic jets suggests that Gigantic Jets may bend when initiated at the edge of clouds with misaligned vertical charge distribution.

Chronic wounds have a major socioeconomic impact due to their frequency, chronicity, and societal costs. Patients experience substantial quality of life (QoL) impairments. The use of questionnaires for a continuous assessment of QoL and resulting interventions to improve the situation of the individual are an important cornerstone of a guideline-based wound care. The aim of this study was to investigate the validity of the Wound-QoL questionnaire. Patients with chronic wounds from two different centers were included in the prospective study. All patients completed the Wound-QoL and two other QoL questionnaires (European Quality of Life-5 Dimensions, EQ-5D, and Freiburg Life Quality Assessment for wounds, FLQA-wk) at baseline and at two more time points (4 and 8 weeks, respectively). Wound status was defined with an anchor question. Two hundred and twenty-seven patients (48.5% women) participated in the study. Mean age was 66.9 years (range 17-96, median 69.5). Indications were venous leg ulcers (40.1%), pyoderma gangraenosum (14.1%), diabetic or ischemic foot ulcers (5.3%), pressure ulcers (2.6%), and other etiologies (30.0%). The Wound-QoL showed good internal consistency, with high Cronbach's alpha in all the subscales and in the global scale in all time points (>0.8). Convergent validity was satisfactory since there were significantly (p ≤ 0.001) good correlations with the EQ-5D (range = 0.5-0.7) and FLQA-wk global score (r > 0.8) at every time point. Responsiveness was high, too. The Wound-QoL is a simple, valid tool for the longitudinal assessment of QoL in patients with chronic wounds. This questionnaire is suitable for use in clinical trials, quality of care studies and clinical routine., (© 2017 by the Wound Healing Society.)

High-voltage laboratory experiments show that discharges in air, generated over a gap of one meter with maximal voltage of 1 MV, may produce X-rays with photon energies up to 1 MeV. It has been suggested that the photons are bremsstrahlung from electrons accelerated by the impulsive, enhanced field during collisions of negative and a positive streamers. To explore this process, we have conducted the first self-consistent particle simulations of streamer encounters. Our simulation model is a 2-D, cylindrically symmetric, particle-in-cell code tracing the electron dynamics and solving the space charge fields, with a Monte Carlo scheme accounting for collisions and ionization. We present the electron density, the electric field, and the velocity distribution as functions of space and time. Assuming a background electric field 1.5 times the breakdown field, we find that the electron density reaches 2·10 21  m -3 , the size of the encounter region is ∼3·10 -12  m 3 and that the field enhances to ∼9 times the breakdown field during ∼10 -11  s. We further find that the radial component becomes comparable to the parallel component, which together with angular scattering leads to an almost isotropic distribution of electrons. This is consistent with laboratory observations that X-rays are emitted isotropically. However, the maximum energy of electrons reached in the simulation is ∼600 eV, which is well below the energies required to explain observations. The reason is that the encounter region is small in size and duration. For the photon energies observed, the field must be enhanced in a larger region and/or for a longer time.

Pd(II)-catalyzed C(sp(3))-H arylation of saturated heterocycles with a wide range of aryl iodides is enabled by an N-heterocyclic carbene (NHC) ligand. A C(sp(3))-H insertion step by the Pd(II)/NHC complex in the absence of ArI is demonstrated experimentally for the first time. Experimental data suggests that the previously established NHC-mediated Pd(0)/Pd(II) catalytic manifold does not operate in this reaction. This transformation provides a new approach for diversifying pharmaceutically relevant piperidine and tetrahydropyran ring systems., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Au surfaces are functionalized by aminobenzene (AB) and 2-aminotoluene (AT) using the electrochemical reduction of diazotized 1,4-diaminobenzene and 2,5-diaminotoluene. The IR spectroscopic measurements reveal the successful modification of Au surfaces by AB and AT. Both types of layers show similar thicknesses as obtained by microgravimetric measurements via electrochemical quartz crystal microbalance (EQCM). However, the faradaic efficiency for the grafting of AT onto an EQCM-Au sensor was 6% compared to 41% for the grafting of AB. This behavior points to a steric hindrance during the binding of AT to the EQCM surface induced by the additional methyl group present in the toluene derivative. The AB and AT functionalized surfaces have been further modified by the amidation reaction of EDC/NHS activated 4-nitrobenzoic acid. This model system reveals that the amidation reaction is slightly hindered in case of the AT layer due to the presence of the methyl group close to the amino group. This behavior leads to a four times less amount of amide bonds at the AT compared to AB modified Au surfaces as obtained from IR spectroscopic measurements.

Genetically encoded calcium indicators (GECIs) permit imaging intracellular calcium transients. Among GECIs, the GFP-based GCaMPs are the most widely used because of their high sensitivity and rapid response to changes in intracellular calcium concentrations. Here we report that the fluorescence of GCaMPs--including GCaMP3, GCaMP5 and GCaMP6--can be converted from green to red following exposure to blue-green light (450-500 nm). This photoconversion occurs in both insect and mammalian cells and is enhanced in a low oxygen environment. The red fluorescent GCaMPs retained calcium responsiveness, albeit with reduced sensitivity. We identified several amino acid residues in GCaMP important for photoconversion and generated a GCaMP variant with increased photoconversion efficiency in cell culture. This light-induced spectral shift allows the ready labeling of specific, targeted sets of GCaMP-expressing cells for functional imaging in the red channel. Together, these findings indicate the potential for greater utility of existing GCaMP reagents, including transgenic animals.

Two novel series of oxazepine and diazepine based HSP90 inhibitors are reported. This effort relied on structure based design and isothermal calorimetry to identify small drug like macrocycles. Computational modelling was used to build into a solvent exposed pocket near the opening of the ATP binding site, which led to potent inhibitors of HSP90 (25-30)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

A structure-based drug design strategy was used to optimize a novel benzolactam series of HSP90α/β inhibitors to achieve >1000-fold selectivity versus the HSP90 endoplasmic reticulum and mitochondrial isoforms (GRP94 and TRAP1, respectively). Selective HSP90α/β inhibitors were found to be equipotent to pan-HSP90 inhibitors in promoting the clearance of mutant huntingtin protein (mHtt) in vitro, however with less cellular toxicity. Improved tolerability profiles may enable the use of HSP90α/β selective inhibitors in treating chronic neurodegenerative indications such as Huntington's disease (HD). A potent, selective, orally available HSP90α/β inhibitor was identified (compound 31) that crosses the blood-brain barrier. Compound 31 demonstrated proof of concept by successfully reducing brain Htt levels following oral dosing in rats.

Objective: To increase conception rates in lactating dairy cows by the application of a gonadotropin-releasing-hormone (GnRH)-agonist after insemination., Material and Methods: A total of 3125 inseminations of 1634 cows were included in this study. The animals were randomized into three groups at the time of insemination (day 0) using the final numeral of the ear-tag number: The cows of the GnRH0 group were treated using 100 μg gonadorelin[6-D-Phe] intramuscularly immediately after insemination (day 0), while those of the GnRH12 group were treated similarly at day 12. The cows of the control group received no hormonal treatment after insemination. An examination for pregnancy was performed at day 28 using transrectal ultrasonography. Analysis of the data sets was conducted for the number of inseminations (NI) 1-4 and for the last observed insemination of the respective cow during the experimental period, respectively. In a second step, statistical analysis was performed for the first service of cows with a lactation number of 1 versus > 1, with emphasis on the daily milk yield. In addition, a metritis diagnosed after the previous parturition was investigated as a possible factor influencing NI 1., Results: Pregnancy risk at day 28 was decreased for NI 2 (n = 792) in the GnRH0 group compared to the control group (odds ratio [OR] = 0.69; 95% confidence interval [CI95] = 0.5-1.0; p = 0.04). A similar observation was found for NI 3 (n = 495) for the GnRH12 group (OR = 0.54; CI95 = 0.3-0.9; p = 0.01). In contrast, the pregnancy risk was increased for cows with a lactation number ≥ 2 and with a daily milk yield ≥ 42.5 kg (7-day-mean at day 0) at the first service (n = 364) by treatment with gonadorelin immediately after insemination (OR = 2.0; CI95 = 1.2-3.4; p = 0.01). No significant differences in the pregnancy risk were observed for the remaining analysed classes., Conclusion: An increased conception rate was only achieved for the first service of high-yield dairy cows (lactation number ≥ 2) by gonadorelin treatment at day 0. Presumably, the higher incidence of delayed ovulations in this group was treated successfully by gona- dorelin administration.

HSP90 continues to be a target of interest for neurodegeneration indications. Selective knockdown of the HSP90 cytosolic isoforms α and β is sufficient to reduce mutant huntingtin protein levels in vitro. Chemotype-dependent binding conformations of HSP90α/β appear to strongly influence isoform selectivity. The rational design of HSP90α/β inhibitors selective versus the mitochondrial (TRAP1) and endoplasmic reticulum (GRP94) isoforms offers a potential mitigating strategy for mechanism-based toxicities. Better tolerated HSP90 inhibitors would be attractive for targeting chronic neurodegenerative diseases such as Huntington's disease., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Isolating high-priority segments of genomes greatly enhances the efficiency of next-generation sequencing (NGS) by allowing researchers to focus on their regions of interest. For the 2010-11 DNA Sequencing Research Group (DSRG) study, we compared outcomes from two leading companies, Agilent Technologies (Santa Clara, CA, USA) and Roche NimbleGen (Madison, WI, USA), which offer custom-targeted genomic enrichment methods. Both companies were provided with the same genomic sample and challenged to capture identical genomic locations for DNA NGS. The target region totaled 3.5 Mb and included 31 individual genes and a 2-Mb contiguous interval. Each company was asked to design its best assay, perform the capture in replicates, and return the captured material to the DSRG-participating laboratories. Sequencing was performed in two different laboratories on Genome Analyzer IIx systems (Illumina, San Diego, CA, USA). Sequencing data were analyzed for sensitivity, specificity, and coverage of the desired regions. The success of the enrichment was highly dependent on the design of the capture probes. Overall, coverage variability was higher for the Agilent samples. As variant discovery is the ultimate goal for a typical targeted sequencing project, we compared samples for their ability to sequence single-nucleotide polymorphisms (SNPs) as a test of the ability to capture both chromosomes from the sample. In the targeted regions, we detected 2546 SNPs with the NimbleGen samples and 2071 with Agilent's. When limited to the regions that both companies included as baits, the number of SNPs was ∼1000 for each, with Agilent and NimbleGen finding a small number of unique SNPs not found by the other.

Selected Reaction Monitoring (SRM) is a method of choice for accurate quantitation of low-abundance proteins in complex backgrounds. This strategy is, however, sensitive to interference from other components in the sample that have the same precursor and fragment masses as the monitored transitions. We present here an approach to detect interference by using the expected relative intensity of SRM transitions. We also designed an algorithm to automatically detect the linear range of calibration curves. These approaches were applied to the experimental data of Clinical Proteomic Tumor Analysis Consortium (CPTAC) Verification Work Group Study 7 and show that the corrected measurements provide more accurate quantitation than the uncorrected data., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)

Progressive nodular histiocytosis (PNH) represents a very rare type of non-Langerhans cell histiocytosis (NLCH). It can be distinguished from other types by the occurrence of yellow to red-brown papules and nodules measuring a few centimeters in size. Histologically the nodules represent spindle-cell xanthogranulomas. We report on two new cases of PNH with novel clinical symptoms. In the first case, the patient had microcytic anemia due to massive iron deposition in the nodules and a progressively worsening limp due to involvement of the soles. The complex therapeutic challenge was effectively managed by successive surgical ablation of all visible lesions. The second patient had epibulbar infiltrates. The clinical variability of PNH leads to considerable overlap with other forms of NLCH., (© The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin.)

Hyaluronan-linked protein 1 (HAPLN1) which has been shown to be highly expressed in malignant pleural mesotheliomas (MPM), was detected in serum using an electrochemical surface-imprinting method. First, the detection method was optimized using Bovine serum albumin (BSA) as a model protein to mimic the optimal conditions required to imprint the similar molecular weight protein HAPLN1. BSA was imprinted on the gold electrode with hydroxyl terminated alkane thiols, which formed a self-assembled monolayer (SAM) around BSA. The analyte (BSA) was then washed away and its imprint (empty cavity with shape-memory) was used for detection of BSA in a solution, using electrochemical open-circuit potential method, namely potentiometry. Factors considered to optimize the conditions include incubation time, protein concentration, limit of detection and size of electrode. Matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) was used to confirm selectivity of imprints. With the obtained imprinting control parameters, HAPLN1 was imprinted in duplicate and the detection of spiked HAPLN1 was successfully conducted in serum.

The goal of this study was to investigate plantar foot sensitivity and balance control of ADHD (n=21) impaired children compared to age-matched healthy controls (n=25). Thresholds were measured at 200 Hz at three anatomical locations of the plantar foot area of both feet (hallux, first metatarsal head (METI) and heel). Body balance was quantified using the length, area and velocity described by the center of pressure (COP) during two-legged as well as one-legged stand (right and left legs). The comparison of vibration thresholds showed no differences between ADHD and healthy children at all anatomical locations of both feet. Whereas COP excursion and area were significantly lower in ADHD subjects compared to the healthy controls during two-legged stand, no differences were found in those variables when balancing on one leg. No differences in COP velocity between ADHD and healthy children were found in any analyzed conditions. The results indicate that the unusual and simple test situation may have increased the perception of vibration stimuli by the ADHD children. Furthermore, ADHD subjects seem to be less variable when performing simple tasks than healthy controls., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Bowen's disease (squamous cell carcinoma in situ) has a 3%-5% risk to develop into invasive squamous cell carcinoma. Non-melanoma skin cancer is the most common cancer among Caucasians and its incidence has increased during the last decades dramatically. Multiple treatment options for Bowen's disease have been described and are established with advantages and disadvantages. Bowen's disease occurs more often in elderly patients (with a higher risk of comorbidities) and is frequently located on body sites with poor wound healing. Therefore there is need for non-invasive/non-destructive but effective treatment options.We would like to give an overview of established therapies and more detailed information about the newer treatment options for Bowen's disease with topical diclofenac, topical imiquimod and photodynamic therapy.

Introduction: Daily change of breathing circuits in the operating theatre requires a lot of resources and is time and labour consuming. The extended use of breathing circuits could reduce the workload of the staff and health care costs. The aim of the present study was to evaluate the contamination rate of anaesthesia breathing circuits changed after 24, 48 or 72 h of use., Materials: The study was performed as an experimental observational study. Microbiological samples were taken from 112 breathing systems including both parts of the ventilator circuit (inspiration and expiration) and analysed using microbiological standard techniques. Breathing circuits were changed according to three different schedules. In the 24-h group, breathing circuits were changed every day, whereas in the 48-h group changing of the circuits took place on Mondays, Wednesdays and Fridays. A period of 72 h operating use was tested on weekends., Results: A total of 112 breathing systems comprised of 224 samples from the ventilator circuit were tested for bacteria and yeast contamination. A non-significant increase in the contamination rate was observed with the extended use for breathing circuits (24 h: 3.33%, 48 h: 4.35% and 72 h: 5.56%; P for trend=0.66). Similarly, no significant increase in contamination rate could be observed at the sample level (24 h: 1.67%, 48 h: 3.26% and 72 h: 2.78%; P for trend=0.71)., Conclusion: The extended use of breathing circuits for 48 and 72 h does not increase significantly the risk of contamination, provided that HME filters are changed separately for every patient.

The improvement of surgical skills of trainees in Germany often occurs solely in the operating room. In recent years, several countries have established surgical skills labs as an essential part of surgical education, with the goal of improving and refining surgical skills before clinical application. Several years ago, training units were established by the industry wherein the curricula focused on products of the respective company. Selected training courses are still offered in a few clinics. Presently, laboratories which train the surgical skills of novices in an individually adapted form are lacking. A surgical skills lab with a comprehensive curriculum of training courses was introduced at the University Hospital of Marburg in 2005. The present article describes the development and introduction of such facilities. The authors are convinced that surgical skills labs will become increasingly important in German surgical education for improving patient safety in the operating room.

Introduction: Subjective experiences of patients during their stay in the intensive care unit (ICU) have so far rarely been described. The aim of this study was to analyze the experiences of patients during their stay in the ICU., Methods: In a prospective study, 100 general surgical ICU patients were recorded consecutively. A questionnaire that covered a broad range of possible ICU experiences was handed out to patients shortly following their stay in ICU. At the same time, a questionnaire was given to the personnel of the ICU to investigate how well nurses and doctors were able to adopt the patients' perspectives of the ICU experience., Results: Concerning the physical symptoms, insomnia was to the fore (67% of patients). Despite pain medication, 25% of patients reported severe pain. The main psychological symptom was a feeling of helplessness (29% of patients). As a general cause for concern, 48% of patients complained about limited mobility. The patients were critical of the presence of severely ill patients. The standards of nursing and medical attention, however, were judged very positively. The evaluation of the staff differed from the patients' experiences in many respects; the clearest differences concerned the items of pain, sleeping disorders and the observance of privacy., Conclusions: The study results led to several practical consequences in the quality of management procedure (e.g., the introduction of a thorough night's rest at the ICU, optimized information for patients). Additionally, we initiated further studies concerning the quality of life of ICU patients.

Antagonist-like engagement of the TCR has been proposed to induce T cell selection in the thymus. However, no natural TCR ligand with TCR antagonist activity is presently known. Using a combination of bioinformatics and functional testing we identified the first self-peptide that can both deliver antagonist-like signals and promote T cell selection in the thymus. The peptide is presented by appropriate MHC class I molecules in vivo. Thus, endogenous antagonist peptides exist and may be involved in TCR repertoire selection.

Familial British dementia (FBD) is an early onset inherited disorder that, like familial Alzheimer's disease (FAD), is characterized by progressive dementia, amyloid deposition in the brain, and neurofibrillary degeneration of limbic neurons. The primary structure of the amyloid subunit (ABri) extracted from FBD brain tissues (Vidal, R., Frangione, B., Rostagno, A., Mead, S., Revesz, T., Plant, G., and Ghiso, J. (1999) Nature 399, 776-781) is entirely different and unrelated to any previously known amyloid protein. Patients with FBD have a single nucleotide substitution at codon 267 in the BRI2 gene, resulting in an arginine replacing the stop codon and a longer open reading frame of 277 amino acids instead of 266. The ABri peptide comprises the 34 C-terminal residues of the mutated precursor ABriPP-277 and is generated via furin-like proteolytic processing. Here we report that carriers of the Stop-to-Arg mutation have a soluble form of the amyloid peptide (sABri) in the circulation with an estimated concentration in the range of 20 ng/ml, several fold higher than that of soluble Abeta. In addition, ABri species identical to those identified in the brain were also found as fibrillar components of amyloid deposits predominantly in the blood vessels of several peripheral tissues, including pancreas and myocardium. We hypothesize that the high concentration of the soluble de novo created amyloidogenic peptide and/or the insufficient tissue clearance are the main causative factors for the formation of amyloid deposits outside the brain. Thus, FBD constitutes the first documented cerebral amyloidosis associated with neurodegeneration and dementia in which the amyloid deposition is also systemic.

Purification from calf thymus of a DNA N-glycosylase activity (HMUDG) that released 5-hydroxymethyluracil (5hmUra) from the DNA of Bacillus subtilis phage SPO1 was undertaken. Analysis of the most purified fraction by SDS-polyacrylamide gel electrophoresis revealed a multiplicity of protein species making it impossible to identify HMUDG by inspection. Therefore, we renatured the enzyme after SDS-polyacrylamide gel electrophoresis and assayed slices of the gel for DNA N-glycosylase activity directed against 5hmUra. Maximum enzymatic activity was identified between molecular mass markers 30 and 34 kDa. Protein was extracted from gel slices and subjected to tryptic digestion and analysis by mass spectrometry. Analysis revealed the presence of 11 peptides that were homologous or identical to the sequence of the recently characterized human single-stranded monofunctional uracil DNA N-glycosylase (hSMUG1). The cDNA of hSMUG1 was isolated and expressed as a recombinant glutathione S-transferase fusion protein that was shown to release 5hmUra with 20x the specific activity of the most purified bovine fraction. We conclude that hSMUG1 and HMUDG are the same protein.

The binding of uropathogenic Escherichia coli to the urothelial surface is a crucial initial event for establishing urinary tract infection because it allows the bacteria to gain a foothold on the urothelial surface, thus preventing them from being removed by micturition. In addition, it triggers bacterial invasion as well as host urothelial defense. This binding is mediated by the FimH adhesin located at the tip of the bacterial type 1-fimbrium, a filamentous attachment apparatus, and its urothelial receptor. We have prepared a biotinylated, recombinant FimH-FimC adhesin:chaperone complex and used it to identify its mouse urothelial receptor. The FimH-FimC complex binds specifically to a single 24 kDa major mouse urothelial plaque protein, which we identified as uroplakin Ia by mass spectrometry, cDNA cloning and immunoreactivity. The terminal mannosyl moieties on Asn-169 of uroplakin Ia are responsible for FimH as well as concanavalin A binding. Although FimH binds to uroplakin Ia with only moderate strength (K(d) approximately 100 nM between pH 4 and 9), the binding between multiple fimbriae of a bacterium and the crystalline array of polymerized uroplakin receptors should achieve high avidity and stable bacterial attachment. The FimH-FimC complex binds preferentially to the mouse urothelial umbrella cells in a pattern similar to uroplakin staining. Our results indicate that the structurally related uroplakins Ia and Ib are glycosylated differently, that uroplakin Ia serves as the urothelial receptor for the type 1-fimbriated E. coli, and that the binding of uropathogenic bacteria to uroplakin Ia may play a key role in mediating the urothelial responses to bacterial attachment.