Identifying bioenergetics that facilitate the epithelial to mesenchymal transition (EMT) in breast cancer cells may uncover targets to treat incurable metastatic disease. Metastasis is the number one cause of cancer-related deaths; therefore, it is urgent to identify new treatment strategies to prevent the initiation of metastasis. To characterize the bioenergetics of EMT, we compared metabolic activities and gene expression in cells induced to differentiate into the mesenchymal state with their epithelial counterparts. We found that levels of GLS2, which encodes a glutaminase, are inversely associated with EMT. GLS2 down-regulation was correlated with reduced mitochondrial activity and glutamine independence even in low-glucose conditions. Restoration of GLS2 expression in GLS2-negative breast cancer cells rescued mitochondrial activity, enhanced glutamine utilization, and inhibited stem-cell properties. Additionally, inhibition of expression of the transcription factor FOXC2, a critical regulator of EMT in GLS2-negative cells, restored GLS2 expression and glutamine utilization. Furthermore, in breast cancer patients, high GLS2 expression is associated with improved survival. These findings suggest that epithelial cancer cells rely on glutamine and that cells induced to undergo EMT become glutamine independent. Moreover, the inhibition of EMT leads to a GLS2-directed metabolic shift in mesenchymal cancer cells, which may make these cells susceptible to chemotherapies. Full article

Sustainability scholars frame urbanization as a multidimensional concept with divergent environmental impacts. Through synthesizing recent quantitative studies of urbanization in criminology, we evaluated this multidimensional framework in a longitudinal, cross-national analysis of homicide rates for 217 countries between 2000 and 2015. For the analysis, we also highlighted the issue of missing data, a common concern for cross-national scholars in a variety of disciplines. While controlling for other relevant factors, we compared results from panel models that use the common technique of listwise deletion (n = 113) and from structural equation models (SEM) that handle missing values with full information maximum likelihood (n = 216). While the estimates for the control variables are non-significant in the SEM approach, the findings for the urbanization variables were robust and multidimensional. In particular, while the proportion of the population that is urban is positively related to homicide, the proportion of the population living in large cities of at least one million inhabitants is significantly and negatively related to homicide in all models. Given our focus on urbanization, we outline our contribution not only in the context of criminology but also the cross-national sustainability literature, which often uses similar variables with missing values. Full article

Flexible paper-based physiological sensor electrodes were developed using chemically-modified graphene (CG) and carboxylic-functionalized multiwalled carbon nanotube composites ([email protected]). A solvothermal process with additional treatment was conducted to synthesize CG and [email protected] to make [email protected] composites. The composite was sonicated in an appropriate solvent to make a uniform suspension, and then it was drop cast on a nylon membrane in a vacuum filter. A number of batches (0%~35% [email protected]) were prepared to investigate the performance of the physical characteristics. The 25% [email protected] composite showed the best adhesion on the paper substrate. The surface topography and chemical bonding of the proposed [email protected] electrodes were characterized by scanning electron microscopy (SEM) and Raman spectroscopy, respectively. The average sheet resistance of the 25% [email protected] electrode was determined to be 75 Ω/□, and it showed a skin contact impedance of 45.12 kΩ at 100 Hz. Electrocardiogram (ECG) signals were recorded from the chest and fingertips of healthy adults using the proposed electrodes. The [email protected] electrodes demonstrated comfortability and a high sensitivity for electrocardiogram signal detection. Full article

Malignant melanoma is often used as a model tumor for the establishment of novel therapies. It is known that two-dimensional (2D) culture methods are not sufficient to elucidate the various processes during cancer development and progression. Therefore, it is of major interest to establish defined biofabricated three-dimensional (3D) models, which help to decipher complex cellular interactions. To get an impression of their printability and subsequent behavior, we printed fluorescently labeled melanoma cell lines with Matrigel and two different types of commercially available bioinks, without or with modification (RGD (Arginine-Glycine-Aspartate)-sequence/laminin-mixture) for increased cell-matrix communication. In general, we demonstrated the printability of melanoma cells in all tested biomaterials and survival of the printed cells throughout 14 days of cultivation. Melanoma cell lines revealed specific differential behavior in the respective inks. Whereas in Matrigel, the cells were able to spread, proliferate and form dense networks throughout the construct, the cells showed no proliferation at all in alginate-based bioink. In gelatin methacrylate-based bioink, the cells proliferated in clusters. Surprisingly, the modifications of the bioinks with RGD or the laminin blend did not affect the analyzed cellular behavior. Our results underline the importance of precisely adapting extracellular matrices to individual requirements of specific 3D bioprinting applications. Full article

We asked whether the C-terminal repeat domain (CTD) kinase, CDK12/CyclinK, phosphorylates substrates in addition to the CTD of RPB1, using our CDK12^{analog-sensitive} HeLa cell line to investigate CDK12 activity-dependent phosphorylation events in human cells. Characterizing the phospho-proteome before and after selective inhibition of CDK12 activity by the analog 1-NM-PP1, we identified 5,644 distinct phospho-peptides, among which were 50 whose average relative amount decreased more than 2-fold after 30 min of inhibition (none of these derived from RPB1). Half of the phospho-peptides actually showed >3-fold decreases, and a dozen showed decreases of 5-fold or more. As might be expected, the 40 proteins that gave rise to the 50 affected phospho-peptides mostly function in processes that have been linked to CDK12, such as transcription and RNA processing. However, the results also suggest roles for CDK12 in other events, notably mRNA nuclear export, cell differentiation and mitosis. While a number of the more-affected sites resemble the CTD in amino acid sequence and are likely direct CDK12 substrates, other highly-affected sites are not CTD-like, and their decreased phosphorylation may be a secondary (downstream) effect of CDK12 inhibition. Full article

The scientific literature has demonstrated that glutamine is one of the main beneficial amino acids. It plays an important role in gut microbiota and immunity. This paper provides a critical overview of experimental studies (in vitro, in vivo, and clinical) investigating the efficacy of glutamine and its effect on gut microbiota. As a result of this review, we have summarized that glutamine could affect gut microbiota via different mechanisms including the reduction in the ratio of Firmicutes to Bacteroidetes, with the activation of NF-κB and PI3K-Akt pathways, reducing the intestinal colonization (Eimeria lesions) and bacterial overgrowth or bacterial translocation, increasing the production of secretory immunoglobulin A (SIgA) and immunoglobulin A+ (IgA⁺) cells in the intestinal lumen, and decreasing asparagine levels. The potential applications of glutamine on gut microbiota include, but are not limited to, the management of obesity, bacterial translocation and community, cytokines profiles, and the management of side effects during post-chemotherapy and constipation periods. Further studies and reviews are needed regarding the effects of glutamine supplementation on other conditions in humans. Full article

Leaves are initiated as lateral outgrowths from shoot apical meristems throughout the vegetative life of the plant. To achieve proper developmental patterning, cell-type specification and growth must occur in an organized fashion along the proximodistal (base-to-tip), mediolateral (central-to-edge), and adaxial–abaxial (top-bottom) axes of the developing leaf. Early studies of mutants with defects in patterning along multiple leaf axes suggested that patterning must be coordinated across developmental axes. Decades later, we now recognize that a highly complex and interconnected transcriptional network of patterning genes and hormones underlies leaf development. Here, we review the molecular genetic mechanisms by which leaf development is coordinated across leaf axes. Such coordination likely plays an important role in ensuring the reproducible phenotypic outcomes of leaf morphogenesis. Full article

Halophytic grasses have been recently targeted as possible sources of nutraceutical and medicinal compounds. Nonetheless, few studies have been conducted on the phytochemistry and biological activities of metabolites produced by these plants. Among these, Spartina maritima (Curtis) Fernald, Spartina patens (Aiton.) Muhl., and Puccinellia maritima (Hudson) Parl. are three halophytic grasses whose chemical composition and bioactivities are unknown. The present work broadens the knowledge on the polyphenolic and chlorophyll composition of these species identifying for the first time hydroxycinnamic acids and their derivatives, flavones, flavonols, lignans, as well as chlorophylls and xantophylls. The extracts were particularly rich in caffeic and ferulic acids as well as in trihydroxymethoxyflavone, apigenin and tricin derivatives. Interestingly, several of the identified compounds are relevant from a medicinal and nutraceutical point of view putting in evidence the potential of these species. Thus, the antioxidant, anti-acetylcholinesterase, antibacterial, and antifungal activities of the polyphenolic extracts were assessed as well as the photophysical properties of the chlorophyll-rich extracts. The results, herein presented for the first time, reinforce the nutritional and the medicinal potential of these halophytic grasses. Full article

Centaurium erythraea is recommended for the treatment of gastrointestinal disorders and to reduce hypercholesterolemia in ethno-medicinal practice. To perform a top-down study that could give some insight into the molecular basis of these bioactivities, decoctions from C. erythraea leaves were prepared and the compounds were identified by liquid chromatography-high resolution tandem mass spectrometry (LC–MS/MS). Secoiridoids glycosides, like gentiopicroside and sweroside, and several xanthones, such as di-hydroxy-dimethoxyxanthone, were identified. Following some of the bioactivities previously ascribed to C. erythraea, we have studied its antioxidant capacity and the ability to inhibit acetylcholinesterase (AChE) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR). Significant antioxidant activities were observed, following three assays: free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) reduction; lipoperoxidation; and NO radical scavenging capacity. The AChE and HMGR inhibitory activities for the decoction were also measured (56% at 500 μg/mL and 48% at 10 μg/mL, respectively). Molecular docking studies indicated that xanthones are better AChE inhibitors than gentiopicroside, while this compound exhibits a better shape complementarity with the HMGR active site than xanthones. To the extent of our knowledge, this is the first report on AChE and HMGR activities by C. erythraea decoctions, in a top-down analysis, complemented with in silico molecular docking, which aims to understand, at the molecular level, some of the biological effects ascribed to infusions from this plant. Full article

Microglia originate from yolk sac-primitive macrophages and auto-proliferate into adulthood without replacement by bone marrow-derived circulating cells. In inflammation, stroke, aging, or infection, microglia have been shown to contribute to brain pathology in both deleterious and beneficial ways, which have been studied extensively. However, less is known about their role in the healthy adult brain. Astrocytes and oligodendrocytes are widely accepted to strongly contribute to the maintenance of brain homeostasis and to modulate neuronal function. On the other hand, contribution of microglia to cognition and behavior is only beginning to be understood. The ability to probe their function has become possible using microglial depletion assays and conditional mutants. Studies have shown that the absence of microglia results in cognitive and learning deficits in rodents during development, but this effect is less pronounced in adults. However, evidence suggests that microglia play a role in cognition and learning in adulthood and, at a cellular level, may modulate adult neurogenesis. This review presents the case for repositioning microglia as key contributors to the maintenance of homeostasis and cognitive processes in the healthy adult brain, in addition to their classical role as sentinels coordinating the neuroinflammatory response to tissue damage and disease. Full article

Highly conserved α- and β-tubulin heterodimers assemble into dynamic microtubules and perform multiple important cellular functions such as structural support, pathway for transport and force generation in cell division. Tubulin exists in different forms of isotypes expressed by specific genes with spatially- and temporally-regulated expression levels. Some tubulin isotypes are differentially expressed in normal and neoplastic cells, providing a basis for cancer chemotherapy drug development. Moreover, specific tubulin isotypes are overexpressed and localized in the nuclei of cancer cells and/or show bioenergetic functions through the regulation of the permeability of mitochondrial ion channels. It has also become clear that tubulin isotypes are involved in multiple cellular functions without being incorporated into microtubule structures. Understanding the mutations of tubulin isotypes specifically expressed in tumors and their post-translational modifications might help to identify precise molecular targets for the design of novel anti-microtubular drugs. Knowledge of tubulin mutations present in tubulinopathies brings into focus cellular functions of tubulin in brain pathologies such as Alzheimer’s disease. Uncovering signaling pathways which affect tubulin functions during antigen-mediated activation of mast cells presents a major challenge in developing new strategies for the treatment of inflammatory and allergic diseases. γ-tubulin, a conserved member of the eukaryotic tubulin superfamily specialized for microtubule nucleation is a target of cell cycle and stress signaling. Besides its microtubule nucleation role, γ-tubulin functions in nuclear and cell cycle related processes. This special issue “Tubulin: Structure, Functions and Roles in Disease” contains eight articles, five of which are original research papers and three are review papers that cover diverse areas of tubulin biology and functions under normal and pathological conditions. Full article

A statistical modelling of PM10 concentration (2006–2015) is applied to understand the behaviour, to know the influence of the variables to exposure risk, to treat the missing data to evaluate air quality, and to estimate data for those sites where they are not available. The study area, Castellón region (Spain), is a strategic area in the framework of EU pollution control. A decrease of PM10 is observed for industrial and urban stations. In the case of rural stations, the levels remain constant throughout the study period. The contribution of anthropogenic sources has been estimated through the PM10 background of the study area. The behaviour of PM10 annual trend is tri-modal for industrial and urban stations and bi-modal in the case of rural stations. The EU Normative suggests that 90% of the data per year are necessary to control air quality. Thus, interpolation statistical methods are presented to fill missing data: Linear Interpolation, Exponential Interpolation, and Kalman Smoothing. This study also focuses on testing the goodness of these methods in order to find the ones that better approach the gaps. After analyzing graphically and using the RMSE the last method is confirmed to be the best option. Full article

The positioning accuracy is critical for satellite-based topographic modeling in cases of exterior orientation parameters with high uncertainty and scarce ground control data. The integration of multi-sensor data can help to ensure precision topographical modeling in such situations. Presently, research on the combined processing of optical camera images and laser altimeter data has focused on planetary observations, especially on the Moon and Mars. This study presents an endeavor to establish a combined adjustment model with one constraint in image space for integration of ZY3-02 stereo images and laser altimeter data for improved Earth topographic modeling. The geometric models for stereo images and laser altimeter data were built first, and then, the laser ranging information was introduced to construct a combined adjustment model on the basis of the block adjustment model. One constraint that minimized the back-projection discrepancies in image space was incorporated into the combined adjustment. Datasets in several areas were collected as experimental data for the validation work. Experimental results demonstrated that the inconsistencies between stereo images and laser altimeter data for the ZY3-02 satellite can be reduced, and the elevation accuracy of stereo images can be significantly improved after applying the proposed combined adjustment. Experiments further proved that the improved height accuracy is insensitive to the number and relative position of laser altimeter points (LAPs) in stereo images. Moreover, additional plane control points (PCPs) were incorporated to achieve better planimetric accuracy. Experimental results in the Dengfeng area showed that the adjustment results derived by using LAPs and additional four PCPs were only slightly lower than those for the block adjustment with four ground control points (GCPs). Generally, the proposed approach can effectively improve the quality of Earth topographic model. Full article

The new general theory dedicated to the stability for LTI MIMO, in particular nonsquare, fractional-order systems described by the Grünwald–Letnikov discrete-time state–space domain is presented in this paper. Such systems under inverse model control, principally MV/perfect control, represent a real research challenge due to an infinite number of solutions to the underlying inverse problem for nonsquare matrices. Therefore, the paper presents a new algorithm for fractional-order perfect control with corresponding stability formula involving recently given H- and $\sigma$ -inverse of nonsquare matrices, up to now applied solely to the integer-order plants. On such foundation a new set of stability-related tools is introduced, among them the key role played by so-called control zeros. Control zeros constitute an extension of transmission zeros for nonsquare fractional-order LTI MIMO systems under inverse model control. Based on the sets of stable control zeros a minimum-phase behavior is specified because of the stability of newly defined perfect control law described in the non-integer-order framework. The whole theory is complemented by pole-free fractional-order perfect control paradigm, a special case of fractional-order perfect control strategy. A significant number of simulation examples confirm the correctness and research potential proposed in the paper methodology. Full article