Gap junction channels facilitate the intercellular exchange of ions and small molecules. While this process is critical to all multicellular organisms, the proteins that form gap junction channels ...are not conserved. Vertebrate gap junctions are formed by connexins, while invertebrate gap junctions are formed by innexins. Interestingly, vertebrates and lower chordates contain innexin homologs, the pannexins, which also form channels, but rarely (if ever) make intercellular channels. While the connexin and the innexin/pannexin polypeptides do not share significant sequence similarity, all three of these protein families share a similar membrane topology and some similarities in quaternary structure. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve.
•The proteins that form gap junction channels are not conserved.•Vertebrate gap junctions are formed by connexins.•Invertebrate gap junctions are formed by innexins.•Vertebrates also contain innexin homologs called pannexins.•Pannexins form channels, but may not make intercellular channels.
During the last decades an increasing area of drained peatlands has been rewetted. Especially in Germany, rewetting is the principal treatment on cutover sites when peat extraction is finished. The ...objectives are bog restoration and the reduction of greenhouse gas (GHG) emissions. The first sites were rewetted in the 1980s. Thus, there is a good opportunity to study long-term effects of rewetting on greenhouse gas exchange, which has not been done so far on temperate cutover peatlands. Moreover, Sphagnum cultivating may become a new way to use cutover peatlands and agriculturally used peatlands as it permits the economical use of bogs under wet conditions. The climate impact of such measures has not been studied yet. We conducted a field study on the exchange of carbon dioxide, methane and nitrous oxide at three rewetted sites with a gradient from dry to wet conditions and at a Sphagnum cultivation site in NW Germany over the course of more than 2 years. Gas fluxes were measured using transparent and opaque closed chambers. The ecosystem respiration (CO2) and the net ecosystem exchange (CO2) were modelled at a high temporal resolution. Measured and modelled values fit very well together. Annually cumulated gas flux rates, net ecosystem carbon balances (NECB) and global warming potential (GWP) balances were determined. The annual net ecosystem exchange (CO2) varied strongly at the rewetted sites (from −201.7 ± 126.8 to 29.7± 112.7g CO2-C m−2 a−1) due to differing weather conditions, water levels and vegetation. The Sphagnum cultivation site was a sink of CO2 (−118.8 ± 48.1 and −78.6 ± 39.8 g CO2-C m−2 a−1). The annual CH4 balances ranged between 16.2 ± 2.2 and 24.2 ± 5.0g CH4-C m−2 a−1 at two inundated sites, while one rewetted site with a comparatively low water level and the Sphagnum farming site show CH4 fluxes close to 0. The net N2O fluxes were low and not significantly different between the four sites. The annual NECB was between −185.5 ± 126.9 and 49.9 ± 112.8 g CO2-C m−2 a−1 at the rewetted sites and −115.8 ± 48.1 and −77 ± 39.8 g CO2-C m−2 a−1 at the Sphagnum cultivating site. The annual GWP100 balances ranged from −280.5 ± 465.2 to 644.5 ± 413.6 g CO2-eq. m−2 a−1 at the rewetted sites. In contrast, the Sphagnum farming site had a cooling impact on the climate in both years (−356.8 ± 176.5 and −234.9 ± 145.9 g CO2-C m−2 a−1). If the carbon exported through the harvest of the Sphagnum biomass and the additional CO2 emission from the decay of the organic material is considered, the NECB and GWP100 balances are near neutral. Peat mining sites are likely to become net carbon sinks and a peat accumulating ("growing") peatland within 30 years of rewetting, but the GWP100 balance may still be positive. A recommended measure for rewetting is to achieve a water level of a few centimetres below ground. Sphagnum farming is a climate-friendly alternative to conventional commercial use of bogs. A year-round constant water level of a few centimetres below ground level should be maintained.
Thermodynamic parameters have been calibrated for a geobarometer suitable for use on eclogitic mantle xenoliths. The barometer is based on the incorporation of tetrahedrally coordinated aluminum in ...clinopyroxene coexisting with garnet and has been calibrated using the results of piston cylinder and multi-anvil experiments performed between pressures of 3 and 7 GPa and temperatures from 1,200 to 1,550 °C. Starting materials were hydrous and anhydrous synthetic mixtures of basaltic bulk compositions that yielded homogeneous bimineralic garnet–clinopyroxene phase assemblages. The experimental data set was expanded by employing results from previous experimental studies conducted in eclogitic systems, which widened the range of applicable conditions and compositions. The calibration reproduces experimental pressures of bimineralic eclogite assemblages, in addition to SiO
2
-saturated and kyanite-bearing eclogites, to within 0.4 GPa at the 95 % confidence interval. The barometer was then used to examine equilibration pressures recorded by natural mantle eclogites from various xenolith locations covering a wide pressure, temperature, and compositional range.
Background and Purpose
Modulation of the sphingosine 1‐phosphate receptor is an approved treatment for relapsing multiple sclerosis because of its anti‐inflammatory effect of retaining lymphocytes ...within the lymph nodes. Here, we evaluated the potential of an agonist at this receptor, FTY720 (fingolimod), to activate the promyelinating pathways within the brain to encourage remyelination and neuroprotection.
Experimental Approach
In this study, we used the cuprizone model in male C57BL/6 mice and tested the promyelinating and neuroprotective effects of FTY720 after acute and chronic toxin‐induced experimental demyelination. We used histological, immunohistochemical and gene expression methods.
Key Results
The midline of the corpus callosum was severely demyelinated after acute and chronic cuprizone‐induced demyelination. Robust endogenous remyelination was evident after acute, but impaired after chronic, demyelination. FTY720 treatment modestly accelerated myelin recovery after acute but not chronic cuprizone exposure. Markers of gliosis (astrocyte and microglia activation) were not affected by FTY720 treatment. Remarkably, the accumulation of amyloid precursor protein‐positive spheroids in axons was less distinct in FTY720‐treated animals, indicating that this compound alleviated ongoing axonal damage.
Conclusions and Implications
We show that even during endogenous remyelination, axonal degeneration continued at a low level, accumulating over time. This continuous neurodegenerative process was ameliorated by FTY720 treatment. FTY720 preserved CNS integrity by direct interaction with brain resident cells, the actions of which are still to be defined.
Base‐metal sulfur liquids (mattes) play a crucial role as metasomatic agents and carriers of highly siderophile elements (HSE) within the Earth's mantle. Prior research has predominantly focused on ...sulfur‐poor metallic liquids involved in core formation scenarios. We conducted high‐pressure experiments using a multi‐anvil apparatus to investigate the effects of pressure, non‐ferrous compounds in mattes, and the mineral composition of the silicate host on matte wetting properties. Specifically, we explored conditions representing both the lithospheric (6 and 7 GPa) and sub‐lithospheric Earth's mantle (13 GPa). We characterized the experiments using the distribution of the dihedral angle in backscattered‐electron sections and the sphericity and network topology of the mattes in tomography scans. Our findings reveal distinct behaviors: while the matte in olivine‐dominated samples exhibited behaviors consistent with previous studies, such as high dihedral angle values (94° and 100°), the majorite‐bearing sample run at 13 GPa formed a disseminated network with a mean dihedral angle of 43°, below the connectivity threshold of 60°. Furthermore, in an experiment involving a garnet‐bearing silicate host, we observed a decrease in the matte's dihedral angle to 72°. Our results suggest that pressure within mafic hosts contributes to increased matte mobility in the sub‐lithospheric Earth's mantle, especially inasmuch as the stability of garnet phases is concerned. Consequently, mattes within subducted oceanic crusts may efficiently transport HSE into surrounding lithologies, while mattes within depleted, more harzburgitic lithologies and the ambient mantle may remain trapped within the silicate host at low melt fractions.
Plain Language Summary
Our study focused on how sulfur‐rich liquids percolate in Earth's mantle and carry important elements. Previous research mostly studied how metallic liquids, which are sulfur‐poor, form planetary cores. We did experiments under high pressure and high temperature to see how different factors affect the mobility of sulfur‐bearing liquids in the deep Earth's mantle. We found that the type of rock and pressure levels affect how mattes spread. When rocks contained the high‐pressure polymorph of garnet, called majorite, mattes moved differently compared to rocks that mostly contain the mineral olivine. Our results show that rocks and pressure levels influence matte movement in regions of Earth's mantle that are comprised of subducted oceanic crust. This helps us understand how elements move inside the Earth, especially when oceanic crust sinks into the mantle.
Key Points
The mobility of mattes is enhanced by majoritic garnet at sub‐lithospheric depths
The combination of 2D and 3D methods improves our understanding of liquid percolation in the Earth's mantle
Increased vascular permeability causes pulmonary edema that impairs arterial oxygenation and thus contributes to morbidity and mortality associated with Acute Respiratory Distress Syndrome and ...sepsis. Although components of intercellular adhesive and tight junctions are critical for maintaining the endothelial barrier, there has been limited study of the roles of gap junctions and their component proteins (connexins). Since connexins can modulate inflammatory signaling in other systems, we hypothesized that connexins may also regulate pulmonary endothelial permeability. The relationships between connexins and the permeability response to inflammatory stimuli were studied in cultured human pulmonary endothelial cells. Prolonged treatment with thrombin, lipopolysaccharide, or pathological cyclic stretch increased levels of mRNA and protein for the major connexin, connexin43 (Cx43). Thrombin and lipopolysaccharide both increased intercellular communication assayed by transfer of microinjected Lucifer yellow. Although thrombin decreased transendothelial resistance in these cells, the response was attenuated by pretreatment with the connexin inhibitor carbenoxolone. Additionally, the decreases of transendothelial resistance produced by either thrombin or lipopolysaccharide were attenuated by reducing Cx43 expression by siRNA knockdown. Both carbenoxolone and Cx43 knockdown also abrogated thrombin-induced phosphorylation of myosin light chain. Taken together, these data suggest that increased lung vascular permeability induced by inflammatory conditions may be amplified via increased expression of Cx43 and intercellular communication among pulmonary endothelial cells.
Departamento de Ciencias Fisiológicas, Pontificia Universidad Católica de Chile, Santiago, Chile; and Department of Pediatrics, University of Chicago, Chicago, Illinois
Sáez, Juan C., Viviana M. ...Berthoud, María C. Brañes, Agustín D. Martínez, and Eric C. Beyer. Plasma Membrane Channels Formed by Connexins: Their Regulation and Functions. Physiol Rev 83: 1359-1400, 2003; 10.1152/physrev.00007.2003.Members of the connexin gene family are integral membrane proteins that form hexamers called connexons. Most cells express two or more connexins. Open connexons found at the nonjunctional plasma membrane connect the cell interior with the extracellular milieu. They have been implicated in physiological functions including paracrine intercellular signaling and in induction of cell death under pathological conditions. Gap junction channels are formed by docking of two connexons and are found at cell-cell appositions. Gap junction channels are responsible for direct intercellular transfer of ions and small molecules including propagation of inositol trisphosphate-dependent calcium waves. They are involved in coordinating the electrical and metabolic responses of heterogeneous cells. New approaches have expanded our knowledge of channel structure and connexin biochemistry (e.g., protein trafficking/assembly, phosphorylation, and interactions with other connexins or other proteins). The physiological role of gap junctions in several tissues has been elucidated by the discovery of mutant connexins associated with genetic diseases and by the generation of mice with targeted ablation of specific connexin genes. The observed phenotypes range from specific tissue dysfunction to embryonic lethality.
Address for reprint requests and other correspondence: J. C. Sáez, Departamento de Ciencias Fisiológicas, Pontificia Universidad Católica de Chile, Alameda 340, Santiago, Chile (E-mail: jsaez{at}genes.bio.puc.cl ).
K2SiH6, crystallizing in the cubic K2PtCl6 structure type (Fm3̅m), features unusual hypervalent SiH6 2– complexes. Here, the formation of K2SiH6 at high pressures is revisited by in situ synchrotron ...diffraction experiments, considering KSiH3 as a precursor. At the investigated pressures, 8 and 13 GPa, K2SiH6 adopts the trigonal (NH4)2SiF6 structure type (P3̅m1) upon formation. The trigonal polymorph is stable up to 725 °C at 13 GPa. At room temperature, the transition into an ambient pressure recoverable cubic form occurs below 6.7 GPa. Theory suggests the existence of an additional, hexagonal, variant in the pressure interval 3–5 GPa. According to density functional theory band structure calculations, K2SiH6 is a semiconductor with a band gap around 2 eV. Nonbonding H-dominated states are situated below and Si–H anti-bonding states are located above the Fermi level. Enthalpically feasible and dynamically stable metallic variants of K2SiH6 may be obtained when substituting Si partially by Al or P, thus inducing p- and n-type metallicity, respectively. Yet, electron–phonon coupling appears weak, and calculated superconducting transition temperatures are <1 K.
Intracellular accumulations of mutant, misfolded proteins are major pathological hallmarks of amyotrophic lateral sclerosis (ALS) and related disorders. Recently, mutations in Sigma receptor 1 ...(SigR1) have been found to cause a form of ALS and frontotemporal lobar degeneration (FTLD). Our goal was to pinpoint alterations and modifications of SigR1 in ALS and to determine how these changes contribute to the pathogenesis of ALS. In the present study, we found that levels of the SigR1 protein were reduced in lumbar ALS patient spinal cord. SigR1 was abnormally accumulated in enlarged C-terminals and endoplasmic reticulum (ER) structures of alpha motor neurons. These accumulations co-localized with the 20s proteasome subunit. SigR1 accumulations were also observed in SOD1 transgenic mice, cultured ALS-8 patient's fibroblasts with the P56S-VAPB mutation and in neuronal cell culture models. Along with the accumulation of SigR1 and several other proteins involved in protein quality control, severe disturbances in the unfolded protein response and impairment of protein degradation pathways were detected in the above-mentioned cell culture systems. Furthermore, shRNA knockdown of SigR1 lead to deranged calcium signaling and caused abnormalities in ER and Golgi structures in cultured NSC-34 cells. Finally, pharmacological activation of SigR1 induced the clearance of mutant protein aggregates in these cells. Our results support the notion that SigR1 is abnormally modified and contributes to the pathogenesis of ALS.
Neuroinflammation is a devastating pathophysiological process that results in brain damage and neuronal death. Pathogens, cell fragments and cellular dysfunction trigger inflammatory responses. ...Irrespective of the cause, inflammasomes are key intracellular multiprotein signalling platforms that sense neuropathological conditions. The activation of inflammasomes leads to the auto‐proteolytic cleavage of caspase‐1, resulting in the proteolysis of the pro‐inflammatory cytokines interleukin (IL)1β and IL18 into their bioactive forms. It also initiates pyroptosis, a type of cell death. The two cytokines contribute to the pathogenesis in acute and chronic brain diseases and also play a central role in human aging and psychiatric disorders. Sex steroids, in particular oestrogens, are well‐described neuroprotective agents in the central nervous system. Oestrogens improve the functional outcome after ischaemia and traumatic brain injury, reduce neuronal death in Parkinson′s and Alzheimer′s disease, as well as in amyotrophic lateral sclerosis, attenuate glutamate excitotoxicity and the formation of radical oxygen species, and lessen the spread of oedema after damage. Moreover, oestrogens alleviate menopause‐related depressive symptoms and have a positive influence on depressive disorders probably by influencing growth factor production and serotonergic brain circuits. Recent evidence also suggests that inflammasome signalling affects anxiety‐ and depressive‐like behaviour and that oestrogen ameliorates depression‐like behaviour through the suppression of inflammasomes. In the present review, we highlight the most recent findings demonstrating that oestrogens selectively suppress the activation of the neuroinflammatory cascade in the brain in acute and chronic brain disease models. Furthermore, we aim to describe putative regulatory signalling pathways involved in the control of inflammasomes. Finally, we consider that psychiatric disorders such as depression also contain an inflammatory component that could be modulated by oestrogen.
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