Synaptic inhibition critically influences sensory processing throughout the mammalian brain, including the main olfactory bulb (MOB), the first station of sensory processing in the olfactory system. ...Decades of research across numerous laboratories have established a central role for granule cells (GCs), the most abundant GABAergic interneuron type in the MOB, in the precise regulation of principal mitral and tufted cell (M/TC) firing rates and synchrony through lateral and recurrent inhibitory mechanisms. In addition to GCs, however, the MOB contains a vast diversity of other GABAergic interneuron types, and recent findings suggest that, while fewer in number, these oft-ignored interneurons are just as important as GCs in shaping odor-evoked M/TC activity. Here I challenge the prevailing centrality of GCs. In this review, I first outline the specific properties of each GABAergic interneuron type in the rodent MOB, with particular emphasis placed on direct interneuron recordings and cell type-selective manipulations. On the basis of these properties, I then critically reevaluate the contribution of GCs vs. other interneuron types to the regulation of odor-evoked M/TC firing rates and synchrony via lateral, recurrent, and other inhibitory mechanisms. This analysis yields a novel model in which multiple interneuron types with distinct abundances, connectivity patterns, and physiologies complement one another to regulate M/TC activity and sensory processing.
Oncogenic RAS promotes production of reactive oxygen species (ROS), which mediate pro-malignant signaling but can also trigger DNA damage-induced tumor suppression. Thus RAS-driven tumor cells ...require redox-protective mechanisms to mitigate the damaging aspects of ROS. Here, we show that MutT Homolog 1 (MTH1), the mammalian 8-oxodGTPase that sanitizes oxidative damage in the nucleotide pool, is important for maintaining several KRAS-driven pro-malignant traits in a nonsmall cell lung carcinoma (NSCLC) model. MTH1 suppression in KRAS-mutant NSCLC cells impairs proliferation and xenograft tumor formation. Furthermore, MTH1 levels modulate KRAS-induced transformation of immortalized lung epithelial cells. MTH1 expression is upregulated by oncogenic KRAS and correlates positively with high KRAS levels in NSCLC human tumors. At a molecular level, in p53-competent KRAS-mutant cells, MTH1 loss provokes DNA damage and induction of oncogene-induced senescence. In p53-nonfunctional KRAS-mutant cells, MTH1 suppression does not produce DNA damage but reduces proliferation and leads to an adaptive decrease in KRAS expression levels. Thus, MTH1 not only enables evasion of oxidative DNA damage and its consequences, but can also function as a molecular rheostat for maintaining oncogene expression at optimal levels. Accordingly, our results indicate MTH1 is a novel and critical component of oncogenic KRAS-associated malignancy and its inhibition is likely to yield significant tumor-suppressive outcomes in KRAS-driven tumors.
Nanoparticulate mackinawite (FeS) can be an important host-phase for arsenic (As) in sulfidic, subsurface environments. Although not previously investigated, phosphate (PO43−) may compete with As for ...available sorption sites on FeS, thereby enhancing As mobility in FeS-bearing soils, sediments and groundwater systems. In this study, we examine the effect of PO43− on sorption of arsenate (As(V)) and arsenite (As(III)) to nanoparticulate FeS at pH 6, 7 and 9. Results show that PO43− (at 0.01–1.0 mM P) did not significantly affect sorption of either As(V) or As(III) to nanoparticulate FeS at initial aqueous As concentrations ranging from 0.01 to 1.0 mM. At pH 9 and 7, sorption of both As(III) and As(V) to nanoparticulate FeS was similar, with distribution coefficient (Kd) values spanning 0.76–15 L g−1 (which corresponds to removal of 87–98% of initial aqueous As(III) and As(V) concentrations). Conversely, at pH 6, the sorption of As(III) was characterized by substantially higher Kd values (6.3–93.4 L g−1) than those for As(V) (Kd = 0.21–0.96 L g−1). Arsenic K-edge X-ray absorption near edge structure (XANES) spectroscopy indicated that up to 52% of the added As(V) was reduced to As(III) in As(V) sorption experiments, as well as the formation of minor amounts of an As2S3-like species. In As(III) sorption experiments, XANES spectroscopy also demonstrated the formation of an As2S3-like species and the partial oxidation of As(III) to As(V) (despite the strictly O2-free experimental conditions). Overall, the XANES data indicate that As sorption to nanoparticulate FeS involves several redox transformations and various sorbed species, which display a complex dependency on pH and As loading but that are not influenced by the co-occurrence of PO43−. This study shows that nanoparticulate FeS can help to immobilize As(III) and As(V) in sulfidic subsurface environments where As co-exists with PO43−.
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•A competitive effect of PO43− was examined on sorption of As(V) and As(III) to nanoparticulate FeS.•PO43− did not affect sorption of either As(V) or As(III) to nanoparticulate FeS at pH 6, 7 and 9.•XANES spectroscopy indicated the involvement of several As redox transformations and formation of sorbed species.•Nanoparticulate FeS immobilized 99% As in sulfidic reduced environments, in the presence of PO43−.
Our findings reveal that the nanoparticulate FeS can remove As(III) and As(V) in reduced sulfidic environments in the presence of PO43−.
Acid sulfate soils (ASS) contain substantial quantities of iron sulfide minerals or the oxidation reaction products of these sulfidic minerals. Transformation of iron (Fe) and sulfur (S) bearing ...minerals is an important process in ASS wetlands with fluctuating redox conditions. A range of potentially toxic metals and metalloids can either be adsorbed on or incorporated into the structure of Fe and S bearing minerals. Therefore, transformation of these minerals as affected by dynamic redox conditions may regulate the mobility and bioavailability of associated metals/metalloids. Better understanding of the interaction between Fe/S biogeochemistry and trace metal/metalloid mobility under fluctuating redox conditions is important for assessing contaminant risk to the environment. This review paper provides an overview of current knowledge regarding cycling of Fe, S and selected trace metal/metalloids in ASS wetlands under fluctuating redox conditions and outlines future research challenges and directions on this subject.
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•Potential acid sulfate soils (PASS) contain substantial quantities of sulfidic minerals.•Oxidation of sulfidic minerals in ASS environments generates acidity and secondary Fe(III) minerals.•Seasonal redox oscillations can affect Fe and S speciation in ASS environments.•Transformation of Fe and S mineral phases may regulate metalloids mobility in ASS environments.•Dynamic redox can drive complex biogeochemical processes in freshwater re-flooded ASS.
In floodplain soils, As may be released during flooding-induced soil anoxia, with the degree of mobilization being affected by microbial redox processes such as the reduction of As(V), Fe(III), and ...SO4 2–. Microbial SO4 2– reduction may affect both Fe and As cycling, but the processes involved and their ultimate consequences on As mobility are not well understood. Here, we examine the effect of microbial SO4 2 reduction on solution dynamics and solid-phase speciation of As during flooding of an As-contaminated soil. In the absence of significant levels of microbial SO4 2– reduction, flooding caused increased Fe(II) and As(III) concentrations over a 10 week period, which is consistent with microbial Fe(III)- and As(V)-reduction. Microbial SO4 2– reduction leads to lower concentrations of porewater Fe(II) as a result of FeS formation. Scanning electron microscopy with energy dispersive X-ray fluorescence spectroscopy revealed that the newly formed FeS sequestered substantial amounts of As. Bulk and microfocused As K-edge X-ray absorption near-edge structure spectroscopy confirmed that As(V) was reduced to As(III) and showed that in the presence of FeS, solid-phase As was retained partly via the formation of an As2S3-like species. High resolution transmission electron microscopy suggested that this was due to As retention as an As2S3-like complex associated with mackinawite (tetragonal FeS) rather than as a discrete As2S3 phase. This study shows that mackinawite formation in contaminated floodplain soil can help mitigate the extent of arsenic mobilization during prolonged flooding.
Experiments are conducted to examine the mechanisms behind the coupling between corner separation and separation away from the corner when holding a high-Mach-number
${M}_{\infty } = 1. 5$
normal ...shock in a rectangular channel. The ensuing shock wave interaction with the boundary layer on the wind tunnel floor and in the corners was studied using laser Doppler anemometry, Pitot probe traverses, pressure sensitive paint and flow visualization. The primary mechanism explaining the link between the corner separation size and the other areas of separation appears to be the generation of compression waves at the corner, which act to smear the adverse pressure gradient imposed upon other parts of the flow. Experimental results indicate that the alteration of the
$\lambda $
-region, which occurs in the supersonic portion of the shock wave/boundary layer interaction (SBLI), is more important than the generation of any blockage in the subsonic region downstream of the shock wave.
Lipids are essential for physiological processes such as maintaining membrane integrity, providing a source of energy and acting as signalling molecules to control processes including cell ...proliferation, metabolism, inflammation and apoptosis. Disruption of lipid homeostasis can promote pathological changes that contribute towards biological ageing and age-related diseases. Several age-related diseases have been associated with altered lipid metabolism and an elevation in highly damaging lipid peroxidation products; the latter has been ascribed, at least in part, to mitochondrial dysfunction and elevated ROS formation. In addition, senescent cells, which are known to contribute significantly to age-related pathologies, are also associated with impaired mitochondrial function and changes in lipid metabolism. Therapeutic targeting of dysfunctional mitochondrial and pathological lipid metabolism is an emerging strategy for alleviating their negative impact during ageing and the progression to age-related diseases. Such therapies could include the use of drugs that prevent mitochondrial uncoupling, inhibit inflammatory lipid synthesis, modulate lipid transport or storage, reduce mitochondrial oxidative stress and eliminate senescent cells from tissues. In this review, we provide an overview of lipid structure and function, with emphasis on mitochondrial lipids and their potential for therapeutic targeting during ageing and age-related disease.
Realizing a large tunneling electroresistance (TER) effect is crucial for device application of ferroelectric tunnel junctions (FTJs). FTJs are typically composed of a thin ferroelectric layer ...sandwiched by two metallic electrodes, where TER generally results from the dependence of the effective tunneling barrier height on the ferroelectric polarization. Since the resistance depends exponentially not only on barrier height but also on barrier width, TER is expected to be greatly enhanced when one of the electrodes is a semiconductor where the depletion region near the interface can be controlled via ferroelectric polarization. To explore this possibility, we perform studies of SrRuO_{3}/BaTiO_{3}/n-SrTiO_{3} FTJs, where n-SrTiO_{3} is an electron doped SrTiO_{3} electrode, using first-principles density functional theory. Our studies reveal that, in addition to modulation of the depletion region in n-SrTiO_{3}, the BaTiO_{3} barrier layer becomes conducting near the interface for polarization pointing into n-SrTiO_{3}, leading to dramatic enhancement of TER. The effect is controlled by the band alignment between the semiconductor and the ferroelectric insulator and opens the way for experimental realization of enhanced TER in FTJs through the choice of a semiconducting electrode and interface engineering.
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