BMP-2 induces ATF4 phosphorylation in chondrocytes through a COX-2/PGE2 dependent signaling pathway

SummaryObjectiveBone morphogenic protein (BMP)-2 is approved for fracture non-union and spine fusion. We aimed to further dissect its downstream signaling events in chondrocytes with the ultimate goal to develop novel therapeutics that can mimic BMP-2 effect but have less complications.MethodsBMP-2 effect on cyclooxygenase (COX)-2 expression was examined using Real time quantitative PCR (RT-PCR) and Western blot analysis. Genetic approach was used to identify the signaling pathway mediating the BMP-2 effect. Similarly, the pathway transducing the PGE2 effect on ATF4 was investigated. Immunoprecipitation (IP) was performed to assess the complex formation after PGE2 binding.ResultsBMP-2 increased COX-2 expression in primary mouse costosternal chondrocytes (PMCSC). The results from the C9 Tet-off system demonstrated that endogenous BMP-2 also upregulated COX-2 expression. Genetic approaches using PMCSC from ALK2fx/fx, ALK3fx/fx, ALK6−/−, and Smad1fx/fx mice established that BMP-2 regulated COX-2 through activation of ALK3–Smad1 signaling. PGE-2 EIA showed that BMP-2 increased PGE2 production in PMCSC. ATF4 is a transcription factor that regulates bone formation. While PGE2 did not have significant effect on ATF4 expression, it induced ATF4 phosphorylation. In addition to stimulating COX-2 expression, BMP-2 also induced phosphorylation of ATF4. Using COX-2 deficient chondrocytes, we demonstrated that the BMP-2 effect on ATF4 was COX-2-dependent. Tibial fracture samples from COX-2−/− mice showed reduced phospho-ATF4 immunoreactivity compared to wild type (WT) ones. PGE2 mediated ATF4 phosphorylation involved signaling primarily through the EP2 and EP4 receptors and PGE2 induced an EP4-ERK1/2-RSK2 complex formation.ConclusionsBMP-2 regulates COX-2 expression through ALK3–Smad1 signaling, and PGE2 induces ATF4 phosphorylation via EP4-ERK1/2-RSK2 axis

The time-dependent expression of keratins 5 and 13 during the reepithelialization of human skin wounds

The time-dependent reepithelialization of 55 human surgical skin wounds with a wound age between 8h and more than 2 months was investigated by the immunohistochemical localization of cytokeratins 5 and 13. A complete, rebuilt epidermal layer over the wound area was first detectable in a 5-day-old wound, while all wounds of more than 18 days duration contained a completely reepithelialized wound area. Between 5 and 18 days the basal layer of keratinocytes showed — in contrast to normal skin — only some cells positive for cytokeratin 5. In some, but not all lesions with a wound age of 13 days or more, a basal cell layer completely staining for cytokeratin 5 was demonstrable. This staining pattern was found in all skin wounds with a wound age of more than 23 days. The immunohistochemical detection of cytokeratin 13 which can be observed regularly in non-cornifying squamous epithelia provides no information for the time-estimation of human skin wounds, since no significant temporary expression of this polypeptide seems to occur during the healing of human skin wounds

Impoundment increases methane emissions in Phragmites‐invaded coastal wetlands

© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Sanders‐DeMott, R., Eagle, M., Kroeger, K., Wang, F., Brooks, T., Suttles, J., Nick, S., Mann, A., & Tang, J. Impoundment increases methane emissions in Phragmites‐invaded coastal wetlands. Global Change Biology, 28(15), (2022): 4539– 4557. https://doi.org/10.1111/gcb.16217.Saline tidal wetlands are important sites of carbon sequestration and produce negligible methane (CH4) emissions due to regular inundation with sulfate-rich seawater. Yet, widespread management of coastal hydrology has restricted tidal exchange in vast areas of coastal wetlands. These ecosystems often undergo impoundment and freshening, which in turn cause vegetation shifts like invasion by Phragmites, that affect ecosystem carbon balance. Understanding controls and scaling of carbon exchange in these understudied ecosystems is critical for informing climate consequences of blue carbon restoration and/or management interventions. Here, we (1) examine how carbon fluxes vary across a salinity gradient (4–25 psu) in impounded and natural, tidally unrestricted Phragmites wetlands using static chambers and (2) probe drivers of carbon fluxes within an impounded coastal wetland using eddy covariance at the Herring River in Wellfleet, MA, United States. Freshening across the salinity gradient led to a 50-fold increase in CH4 emissions, but effects on carbon dioxide (CO2) were less pronounced with uptake generally enhanced in the fresher, impounded sites. The impounded wetland experienced little variation in water-table depth or salinity during the growing season and was a strong CO2 sink of −352 g CO2-C m−2 year−1 offset by CH4 emission of 11.4 g CH4-C m−2 year−1. Growing season CH4 flux was driven primarily by temperature. Methane flux exhibited a diurnal cycle with a night-time minimum that was not reflected in opaque chamber measurements. Therefore, we suggest accounting for the diurnal cycle of CH4 in Phragmites, for example by applying a scaling factor developed here of ~0.6 to mid-day chamber measurements. Taken together, these results suggest that although freshened, impounded wetlands can be strong carbon sinks, enhanced CH4 emission with freshening reduces net radiative balance. Restoration of tidal flow to impounded ecosystems could limit CH4 production and enhance their climate regulating benefits.This project was supported by USGS-NPS Natural Resources Preservation Program #2021-07, U.S. Geological Survey Coastal & Marine Hazards and Resources Program and the USGS Land Change Science Program's LandCarbon program, and NOAA National Estuarine Research Reserve Science Collaborative NA14NOS4190145. R Sanders-DeMott was supported by a USGS Mendenhall Fellowship and partnership with Restore America's Estuaries

Cyber security fear appeals:unexpectedly complicated

Cyber security researchers are starting to experiment with fear appeals, with a wide variety of designs and reported efficaciousness. This makes it hard to derive recommendations for designing and deploying these interventions. We thus reviewed the wider fear appeal literature to arrive at a set of guidelines to assist cyber security researchers. Our review revealed a degree of dissent about whether or not fear appeals are indeed helpful and advisable. Our review also revealed a wide range of fear appeal experimental designs, in both cyber and other domains, which confirms the need for some standardized guidelines to inform practice in this respect. We propose a protocol for carrying out fear appeal experiments, and we review a sample of cyber security fear appeal studies, via this lens, to provide a snapshot of the current state of play. We hope the proposed experimental protocol will prove helpful to those who wish to engage in future cyber security fear appeal research

The role of ongoing dendritic oscillations in single-neuron dynamics

The dendritic tree contributes significantly to the elementary computations a neuron performs while converting its synaptic inputs into action potential output. Traditionally, these computations have been characterized as temporally local, near-instantaneous mappings from the current input of the cell to its current output, brought about by somatic summation of dendritic contributions that are generated in spatially localized functional compartments. However, recent evidence about the presence of oscillations in dendrites suggests a qualitatively different mode of operation: the instantaneous phase of such oscillations can depend on a long history of inputs, and under appropriate conditions, even dendritic oscillators that are remote may interact through synchronization. Here, we develop a mathematical framework to analyze the interactions of local dendritic oscillations, and the way these interactions influence single cell computations. Combining weakly coupled oscillator methods with cable theoretic arguments, we derive phase-locking states for multiple oscillating dendritic compartments. We characterize how the phase-locking properties depend on key parameters of the oscillating dendrite: the electrotonic properties of the (active) dendritic segment, and the intrinsic properties of the dendritic oscillators. As a direct consequence, we show how input to the dendrites can modulate phase-locking behavior and hence global dendritic coherence. In turn, dendritic coherence is able to gate the integration and propagation of synaptic signals to the soma, ultimately leading to an effective control of somatic spike generation. Our results suggest that dendritic oscillations enable the dendritic tree to operate on more global temporal and spatial scales than previously thought

Hippocampus Leads Ventral Striatum in Replay of Place-Reward Information

While the brain is asleep, the hippocampus plays first fiddle in the orchestra of memory; spatial information is reactivated in the hippocampus shortly in advance of emotional memory traces in the vental striatum

Similarity in cognitive complexity and attraction to friends and lovers: Experimental and correlational studies

Abstract OnlyTwo studies are reported examining whether similarities in cognitive complexity foster different forms of interpersonal attraction. Study 1 provided an experimental test of the hypothesis that perceivers would be more attracted to targets with similar levels of complexity than to targets with dissimilar levels of complexity. Participants read interpersonal impressions reflecting low and high levels of cognitive complexity and completed 3 assessments of attraction (social, task, and intellectual) to the source of the impressions. As predicted, there were significant interactions between perceiver complexity and target complexity such that high-complexity perceivers were more attracted to high-complexity targets than were low-complexity perceivers, whereas low-complexity perceivers were more attracted to low-complexity targets than were high-complexity perceivers. Unexpectedly, however, low-complexity perceivers were more attracted to a high-complexity target than a low-complexity target. Study 2 examined the effects of similarities in cognitive complexity on attraction among 126 pairs of dating partners. Partners having similar levels of cognitive complexity expressed significantly greater intellectual attraction to one another than partners having dissimilar levels of cognitive complexity

Quantum saturation and condensation of excitons in Cu2_2O: a theoretical study

Recent experiments on high density excitons in Cu$_2$O provide evidence for degenerate quantum statistics and Bose-Einstein condensation of this nearly ideal gas. We model the time dependence of this bosonic system including exciton decay mechanisms, energy exchange with phonons, and interconversion between ortho (triplet-state) and para (singlet-state) excitons, using parameters for the excitonic decay, the coupling to acoustic and low-lying optical phonons, Auger recombination, and ortho-para interconversion derived from experiment. The single adjustable parameter in our model is the optical-phonon cooling rate for Auger and laser-produced hot excitons. We show that the orthoexcitons move along the phase boundary without crossing it (i.e., exhibit a ``quantum saturation''), as a consequence of the balance of entropy changes due to cooling of excitons by phonons and heating by the non-radiative Auger two-exciton recombination process. The Auger annihilation rate for para-para collisions is much smaller than that for ortho-para and ortho-ortho collisions, explaining why, under the given experimental conditions, the paraexcitons condense while the orthoexcitons fail to do so.Comment: Revised to improve clarity and physical content 18 pages, revtex, figures available from G. Kavoulakis, Physics Department, University of Illinois, Urban

Grifonin-1: A Small HIV-1 Entry Inhibitor Derived from the Algal Lectin, Griffithsin

Background: Griffithsin, a 121-residue protein isolated from a red algal Griffithsia sp., binds high mannose N-linked glycans of virus surface glycoproteins with extremely high affinity, a property that allows it to prevent the entry of primary isolates and laboratory strains of T- and M-tropic HIV-1. We used the sequence of a portion of griffithsin's sequence as a design template to create smaller peptides with antiviral and carbohydrate-binding properties. Methodology/Results: The new peptides derived from a trio of homologous β-sheet repeats that comprise the motifs responsible for its biological activity. Our most active antiviral peptide, grifonin-1 (GRFN-1), had an EC50 of 190.8±11.0 nM in in vitro TZM-bl assays and an EC50 of 546.6±66.1 nM in p24gag antigen release assays. GRFN-1 showed considerable structural plasticity, assuming different conformations in solvents that differed in polarity and hydrophobicity. Higher concentrations of GRFN-1 formed oligomers, based on intermolecular β-sheet interactions. Like its parent protein, GRFN-1 bound viral glycoproteins gp41 and gp120 via the N-linked glycans on their surface. Conclusion: Its substantial antiviral activity and low toxicity in vitro suggest that GRFN-1 and/or its derivatives may have therapeutic potential as topical and/or systemic agents directed against HIV-1