The voltage‐dependent potassium channel Kv1.3 has been implicated in proliferation in many cell types, based on the observation that Kv1.3 blockers inhibited proliferation. By modulating membrane ...potential, cell volume, and/or Ca2+ influx, K+ channels can influence cell cycle progression. Also, noncanonical channel functions could contribute to modulate cell proliferation independent of K+ efflux. The specificity of the requirement of Kv1.3 channels for proliferation suggests the involvement of molecule‐specific interactions, but the underlying mechanisms are poorly identified. Heterologous expression of Kv1.3 channels in HEK cells has been shown to increase proliferation independently of K+ fluxes. Likewise, some of the molecular determinants of Kv1.3‐induced proliferation have been located in the C‐terminus region, where individual point mutations of putative phosphorylation sites (Y447A and S459A) abolished Kv1.3‐induced proliferation. Here, we investigated the mechanisms linking Kv1.3 channels to proliferation exploring the correlation between Kv1.3 voltage‐dependent molecular dynamics and cell cycle progression. Using transfected HEK cells, we analyzed both the effect of changes in resting membrane potential on Kv1.3‐induced proliferation and the effect of mutated Kv1.3 channels with altered voltage dependence of gating. We conclude that voltage‐dependent transitions of Kv1.3 channels enable the activation of proliferative pathways. We also found that Kv1.3 associated with IQGAP3, a scaffold protein involved in proliferation, and that membrane depolarization facilitates their interaction. The functional contribution of Kv1.3‐IQGAP3 interplay to cell proliferation was demonstrated both in HEK cells and in vascular smooth muscle cells. Our data indicate that voltage‐dependent conformational changes of Kv1.3 are an essential element in Kv1.3‐induced proliferation.
Ion channels have been involved in proliferation in many tissues, but the underlying mechanisms remain unclear. Here, the authors demonstrate a link between Kv1.3 conformational changes and proliferation, and conclude that voltage‐dependent transitions of the channel regulate cell cycle progression.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Kv1.3 channels are involved in the switch to proliferation of normally quiescent cells, being implicated in the control of cell cycle in many different cell types and in many different ways. They ...modulate membrane potential controlling K
fluxes, sense changes in potential, and interact with many signaling molecules through their intracellular domains. From a mechanistic point of view, we can describe the role of Kv1.3 channels in proliferation with at least three different models. In the "membrane potential model," membrane hyperpolarization resulting from Kv1.3 activation provides the driving force for Ca
influx required to activate Ca
-dependent transcription. This model explains most of the data obtained from several cells from the immune system. In the "voltage sensor model," Kv1.3 channels serve mainly as sensors that transduce electrical signals into biochemical cascades, independently of their effect on membrane potential. Kv1.3-dependent proliferation of vascular smooth muscle cells (VSMCs) could fit this model. Finally, in the "channelosome balance model," the master switch determining proliferation may be related to the control of the Kv1.3 to Kv1.5 ratio, as described in glial cells and also in VSMCs. Since the three mechanisms cannot function independently, these models are obviously not exclusive. Nevertheless, they could be exploited differentially in different cells and tissues. This large functional flexibility of Kv1.3 channels surely gives a new perspective on their functions beyond their elementary role as ion channels, although a conclusive picture of the mechanisms involved in Kv1.3 signaling to proliferation is yet to be reached.
This volume, dedicated to Bruno J. Müller, a renowned algebraist, is a collection of papers that provide a snapshot of the diversity of themes and applications that interest algebraists today.The ...papers highlight the latest progress in ring and module research and present work done on the frontiers of the topics discussed.In addition, selected expository articles are included to give algebraists and other mathematicians, including graduate students, an accessible introduction to areas that may be outside their own expertise.
Climate change will affect semiarid ecosystems through severe droughts that increase the competition for resources in plant and microbial communities. In these habitats, adaptations to climate change ...may consist of thinning—that reduces competition for resources through a decrease in tree density and the promotion of plant survival. We deciphered the functional and phylogenetic responses of the microbial community to 60 years of drought induced by rainfall exclusion and how forest management affects its resistance to drought, in a semiarid forest ecosystem dominated by Pinus halepensis Mill. A multiOMIC approach was applied to reveal novel, community‐based strategies in the face of climate change. The diversity and the composition of the total and active soil microbiome were evaluated by 16S rRNA gene (bacteria) and ITS (fungal) sequencing, and by metaproteomics. The microbial biomass was analyzed by phospholipid fatty acids (PLFAs), and the microbially mediated ecosystem multifunctionality was studied by the integration of soil enzyme activities related to the cycles of C, N, and P. The microbial biomass and ecosystem multifunctionality decreased in drought‐plots, as a consequence of the lower soil moisture and poorer plant development, but this decrease was more notable in unthinned plots. The structure and diversity of the total bacterial community was unaffected by drought at phylum and order level, but did so at genus level, and was influenced by seasonality. However, the total fungal community and the active microbial community were more sensitive to drought and were related to ecosystem multifunctionality. Thinning in plots without drought increased the active diversity while the total diversity was not affected. Thinning promoted the resistance of ecosystem multifunctionality to drought through changes in the active microbial community. The integration of total and active microbiome analyses avoids misinterpretations of the links between the soil microbial community and climate change.
A multiOMIC approach was applied to understand the responses of soil microbial communities to drought and how forest management modulates the resistance of soil microbiome. Metaproteomics revealed that the active microbial community was highly sensitive to drought.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The central nervous system (CNS) is one of the most frequent metastatic sites of various cancers, including lung cancer, breast cancer and melanoma. The development of brain metastases requires a ...specific therapeutic approach and is associated with high mortality and morbidity in cancer patients. Advances in precision medicine and the introduction in recent years of new drugs, such as immunotherapy, have made it possible to improve the prognosis of these patients by improving survival and quality of life. New diagnostic techniques such as liquid biopsy allow real-time monitoring of tumor evolution, providing molecular information on prognostic and predictive biomarkers of response to treatment in blood or other fluids. In this review, we perform an exhaustive update of the clinical trials that demonstrate the utility of immunotherapy in patients with brain metastases and the potential of circulating biomarkers to improving the results of efficacy and toxicity in this subgroup of patients.
We demonstrate the feasibility and potential of using large integral field spectroscopic surveys to investigate the prevalence of galactic-scale outflows in the local Universe. Using integral field ...data from the Sydney-AAO Multi-object Integral field spectrograph (SAMI) and the Wide Field Spectrograph, we study the nature of an isolated disc galaxy, SDSS J090005.05+000446.7 (z = 0.053 86). In the integral field data sets, the galaxy presents skewed line profiles changing with position in the galaxy. The skewed line profiles are caused by different kinematic components overlapping in the line-of-sight direction. We perform spectral decomposition to separate the line profiles in each spatial pixel as combinations of (1) a narrow kinematic component consistent with H ii regions, (2) a broad kinematic component consistent with shock excitation, and (3) an intermediate component consistent with shock excitation and photoionization mixing. The three kinematic components have distinctly different velocity fields, velocity dispersions, line ratios, and electron densities. We model the line ratios, velocity dispersions, and electron densities with our mappings iv shock and photoionization models, and we reach remarkable agreement between the data and the models. The models demonstrate that the different emission line properties are caused by major galactic outflows that introduce shock excitation in addition to photoionization by star-forming activities. Interstellar shocks embedded in the outflows shock-excite and compress the gas, causing the elevated line ratios, velocity dispersions, and electron densities observed in the broad kinematic component. We argue from energy considerations that, with the lack of a powerful active galactic nucleus, the outflows are likely to be driven by starburst activities. Our results set a benchmark of the type of analysis that can be achieved by the SAMI Galaxy Survey on large numbers of galaxies.
Technological approaches which enable the effective utilization of CO2 for manufacturing value-added chemicals and fuels can help to solve environmental problems derived from large CO2 emissions ...associated with the use of fossil fuels. One of the most interesting products that can be synthesized from CO2 is methanol, since it is an industrial commodity used in several chemical products and also an efficient transportation fuel. In this review, we highlight the recent advances in the development of heterogeneous catalysts and processes for the direct hydrogenation of CO2 to methanol. The main efforts focused on the improvement of conventional Cu/ZnO based catalysts and the development of new catalytic systems targeting the specific needs for CO2 to methanol reactions (unfavourable thermodynamics, production of high amount of water and high methanol selectivity under high or full CO2 conversion). Major studies on the development of active and selective catalysts based on thermodynamics, mechanisms, nano-synthesis and catalyst design (active phase, promoters, supports, etc.) are highlighted in this review. Finally, a summary concerning future perspectives on the research and development of efficient heterogeneous catalysts for methanol synthesis from CO2 will be presented.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Aims
Twenty‐five enological yeasts belonging to nine different species (Candida zeylanoides, Cryptococcus uzbekistanensis, Debaryomyces hansenii, Lachancea thermotolerans, Metschnikowia pulcherrima, ...Torulaspora delbrueckii, Williopsis pratensis, Zygosaccharomyces bailii and Saccharomyces cerevisiae) were screened for aroma formation and fermentative behaviour as part of a non‐Saccharomyces yeast selection programme.
Methods and Results
Pure cultures were inoculated in pasteurized grape juice in order to perform alcoholic fermentations. Some non‐Saccharomyces species did not ferment, others did not get established and none of them completed alcoholic fermentations. The physico‐chemical parameters of the wines and the abundance of aromatic compounds at the end of alcoholic fermentation highlighted the notable differences in the aroma‐forming ability and fermentative behaviour of the different non‐Saccharomyces species, but not within clones.
Conclusions
Lower diversity was detected within non‐Saccharomyces species than that reported in S. cerevisiae with regard to enological behaviour and aromatic profiles. Metschnikowia pulcherrima and L. thermotolerans are the two species with higher possibilities to become an inoculum.
Significance and Impact of the Study
Few significant differences were found within clones of the same species, but very important parameters in wine quality, such as volatile acidity, ethyl acetate and acetoin, which would justify selection programmes within those species. The results also demonstrated that T. delbrueckii and L. thermotolerans are two close species in their aromatic profiles.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Increasing evidence demonstrate that the electron transfer chain plays a critical role in controlling the effector functions of macrophages. In this work, we have generated a Ndufs4-/- murine ...macrophage cell lines. The Ndufs4 gene, which encodes a supernumerary subunit of complex I, is a mutational hotspot in Leigh syndrome patients. Ndufs4-/- macrophages showed decreased complex I activity, altered complex I assembly, and lower levels of maximal respiration and ATP production. These mitochondrial respiration alterations were associated with a shift towards a pro-inflammatory cytokine profile after lipopolysaccharide challenge and improved ability to phagocytose Gram-negative bacteria.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
State-of-the-art optical clocks
achieve precisions of 10
or better using ensembles of atoms in optical lattices
or individual ions in radio-frequency traps
. Promising candidates for use in atomic ...clocks are highly charged ions
(HCIs) and nuclear transitions
, which are largely insensitive to external perturbations and reach wavelengths beyond the optical range
that are accessible to frequency combs
. However, insufficiently accurate atomic structure calculations hinder the identification of suitable transitions in HCIs. Here we report the observation of a long-lived metastable electronic state in an HCI by measuring the mass difference between the ground and excited states in rhenium, providing a non-destructive, direct determination of an electronic excitation energy. The result is in agreement with advanced calculations. We use the high-precision Penning trap mass spectrometer PENTATRAP to measure the cyclotron frequency ratio of the ground state to the metastable state of the ion with a precision of 10
-an improvement by a factor of ten compared with previous measurements
. With a lifetime of about 130 days, the potential soft-X-ray frequency reference at 4.96 × 10
hertz (corresponding to a transition energy of 202 electronvolts) has a linewidth of only 5 × 10
hertz and one of the highest electronic quality factors (10
) measured experimentally so far. The low uncertainty of our method will enable searches for further soft-X-ray clock transitions
in HCIs, which are required for precision studies of fundamental physics
.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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