PATTERNS OF OSSIFICATION IN SOUTHERN VERSUS NORTHERN PLACENTAL MAMMALS

Consensus on placental mammal phylogeny is fairly recent compared to that for vertebrates as a whole. A stable phylogenetic hypothesis enables investigation into the possibility that placental clades differ from one another in terms of their development. Here, we focus on the sequence of skeletal ossification as a possible source of developmental distinctiveness in “northern” (Laurasiatheria and Euarchontoglires) versus “southern” (Afrotheria and Xenarthra) placental clades. We contribute data on cranial and postcranial ossification events during growth in Afrotheria, including elephants, hyraxes, golden moles, tenrecs, sengis, and aardvarks. We use three different techniques to quantify sequence heterochrony: continuous method, sequence‐ANOVA (analysis of variance) and event‐paring/Parsimov. We show that afrotherians significantly differ from other placentals by an early ossification of the orbitosphenoid and caudal vertebrae. Our analysis also suggests that both southern placental groups show a greater degree of developmental variability; however, they rarely seem to vary in the same direction, especially regarding the shifts that differ statistically. The latter observation is inconsistent with the Atlantogenata hypothesis in which afrotherians are considered as the sister clade of xenarthrans. Interestingly, ancestral nodes for Laurasiatheria and Euarchontoglires show very similar trends and our results suggest that developmental homogeneity in some ossification sequences may be restricted to northern placental mammals (Boreoeutheria).     

Anthocyanins Double the Shelf Life of Tomatoes by Delaying Overripening and Reducing Susceptibility to Gray Mold

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Community-wide plasmid gene mobilization and selection

Plasmids have long been recognized as an important driver of DNA exchange and genetic innovation in prokaryotes. The success of plasmids has been attributed to their independent replication from the host''s chromosome and their frequent self-transfer. It is thought that plasmids accumulate, rearrange and distribute nonessential genes, which may provide an advantage for host proliferation under selective conditions. In order to test this hypothesis independently of biases from culture selection, we study the plasmid metagenome from microbial communities in two activated sludge systems, one of which receives mostly household and the other chemical industry wastewater. We find that plasmids from activated sludge microbial communities carry among the largest proportion of unknown gene pools so far detected in metagenomic DNA, confirming their presumed role of DNA innovators. At a system level both plasmid metagenomes were dominated by functions associated with replication and transposition, and contained a wide variety of antibiotic and heavy metal resistances. Plasmid families were very different in the two metagenomes and grouped in deep-branching new families compared with known plasmid replicons. A number of abundant plasmid replicons could be completely assembled directly from the metagenome, providing insight in plasmid composition without culturing bias. Functionally, the two metagenomes strongly differed in several ways, including a greater abundance of genes for carbohydrate metabolism in the industrial and of general defense factors in the household activated sludge plasmid metagenome. This suggests that plasmids not only contribute to the adaptation of single individual prokaryotic species, but of the prokaryotic community as a whole under local selective conditions.     

TGF‐β induces SOX2 expression in a time‐dependent manner in human melanoma cells

The sry‐related high‐mobility box (SOX)‐2 protein has recently been proven to play a significant role in progression, metastasis, and clinical prognosis spanning several cancer types. Research on the role of SOX2 in melanoma is limited and currently little is known about the mechanistic function of this gene in this context. Here, we observed high expression of SOX2 in both human melanoma cell lines and primary melanomas in contrast to melanocytic nevi. This overexpression in melanoma can, in part, be explained by extra gene copy numbers of SOX2 in primary samples. Interestingly, we were able to induce SOX2 expression, mediated by SOX4, via TGF‐β1 stimulation in a time‐dependent manner. Moreover, the knockdown of SOX2 impaired TGF‐β‐induced invasiveness. This phenotype switch can be explained by SOX2‐mediated cross talk between TGF‐β and non‐canonical Wnt signaling. Thus, we propose that SOX2 is involved in the critical TGF‐β signaling pathway, which has been shown to correlate with melanoma aggressiveness and metastasis. In conclusion, we have identified a novel downstream factor of TGF‐β signaling in melanoma, which may have further implications in the clinic.     

Signal Intensities in Preoperative MRI Do Not Reflect Proliferative Activity in Meningioma

BACKGROUND: Identification of high-grade meningiomas in preoperative magnetic resonance imaging (MRI) is important for optimized surgical strategy and best possible resection. Numerous studies investigated subjectively determined morphological features as predictors of tumor biology in meningiomas. The aim of this study was to identify the predictive value of more reliable, quantitatively measured signal intensities in MRI for differentiation of high- and low-grade meningiomas and identification of meningiomas with high proliferation rates, respectively. PATIENTS AND METHODS: Sixty-six patients (56 World Health Organization [WHO] grade I, 9 WHO grade II, and 1 WHO grade I) were included in the study. Preoperative MRI signal intensities (fluid-attenuated inversion recovery [FLAIR], T1 precontrast, and T1 postcontrast as genuine and normalized values) were correlated with Ki-67 expression in tissue sections of resected meningiomas. Differences between the groups (analysis of variance) and Spearman rho correlation were computed using SPSS 22. RESULTS: Mean values of genuine signal intensities of meningiomas in FLAIR, T1 native, and T1 postcontrast were 323.9 ± 59, 332.8 ± 67.9, and 768.5 ± 165.3. Mean values of normalized (to the contralateral white matter) signal intensities of meningiomas in FLAIR, T1 native, and T1 postcontrast were 1.5 ± 0.3, 0.8 ± 0.1, and 1.9 ± 0.4. There was no significant correlation between MRI signal intensities and WHO grade or Ki-67 expression. Signal intensities did not differ significantly between WHO grade I and II/III meningiomas. Ki-67 expression was significantly increased in high-grade meningiomas compared with low-grade meningiomas (P < 0.01). Objectively measured values of MRI signal intensities (FLAIR, T1 precontrast, and T1 postcontrast enhancement) did not distinguish between high-grade and low-grade meningiomas. Furthermore, there was no association between MRI signal intensities and Ki-67 expression representing proliferative activity.Meningiomas are among the most common brain tumors. Their incidence is about 1%, and they account for almost one third of all primary intracranial masses. The majority of meningiomas are very slowly growing and nonsymptomatic or minimally symptomatic entities, discovered as incidental findings on neuroimaging [1]. The World Health Organization (WHO) classification system distinguishes 3 histological grades and 15 subtypes and is a well-accepted tool for prediction of prognosis. Although most meningiomas are benign masses, certain histological subtypes reveal very high recurrence rates despite the tumors’ seemingly total removal. Grade II (atypical) and grade III (anaplastic) meningiomas are associated with an increased risk of recurrence, are more aggressive, and show invasive behavior [2]. Grade I meningiomas are generally considered as benign tumors, but recent studies indicate substantial neurological deficits and impaired long-term survival due to tumor recurrence and stroke despite their low histopathological grading in a considerable proportion of cases [3], [4]. Increased mitotic activity (more than 4 mitoses per 10 high-power fields) and elevated Ki-67 expression (Ki-67 index of more than 5% of nuclei) are reliable histopathological markers for tumor recurrence [2].Because histopathological grading alone does not predict outcome satisfyingly, numerous studies investigated the value of preoperative magnetic resonance imaging (MRI) for prognostics. For example, Liu et al. demonstrated that hyperintensity on diffusion-weighted imaging, heterogeneous gadolinium enhancement, disruption of the arachnoid at brain tumor interface, T2 hyperintense peritumoral edema, and irregular tumor shape were independent predictors of non–grade I meningioma [5]. Other works produced comparable results, although some of these studies underline the importance of positive capsular enhancement [6], [7], whereas others emphasize the predictive value of peritumoral edema [5], [8]. All the above-cited works investigated morphological features of meningiomas summarized in subjective scoring systems, but not one of the studies objectively analyzed values of SIs in commonly used preoperative MRI sequences.Therefore, the aim of this study was to investigate the predictive value of genuine and normalized SIs of standardized preoperative MRI (T1 pre- and postcontrast, T2, and fluid-attenuated inversion recovery [FLAIR]) as in vivo predictors of proliferative activity of meningiomas.     

Metabolomics-Based Discovery of Small Molecule Biomarkers in Serum Associated with Dengue Virus Infections and Disease Outcomes

Background

Epidemic dengue fever (DF) and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) are overwhelming public health capacity for diagnosis and clinical care of dengue patients throughout the tropical and subtropical world. The ability to predict severe dengue disease outcomes (DHF/DSS) using acute phase clinical specimens would be of enormous value to physicians and health care workers for appropriate triaging of patients for clinical management. Advances in the field of metabolomics and analytic software provide new opportunities to identify host small molecule biomarkers (SMBs) in acute phase clinical specimens that differentiate dengue disease outcomes.

Methodology/Principal Findings

Exploratory metabolomic studies were conducted to characterize the serum metabolome of patients who experienced different dengue disease outcomes. Serum samples from dengue patients from Nicaragua and Mexico were retrospectively obtained, and hydrophilic interaction liquid chromatography (HILIC)-mass spectrometry (MS) identified small molecule metabolites that were associated with and statistically differentiated DHF/DSS, DF, and non-dengue (ND) diagnosis groups. In the Nicaraguan samples, 191 metabolites differentiated DF from ND outcomes and 83 differentiated DHF/DSS and DF outcomes. In the Mexican samples, 306 metabolites differentiated DF from ND and 37 differentiated DHF/DSS and DF outcomes. The structural identities of 13 metabolites were confirmed using tandem mass spectrometry (MS/MS). Metabolomic analysis of serum samples from patients diagnosed as DF who progressed to DHF/DSS identified 65 metabolites that predicted dengue disease outcomes. Differential perturbation of the serum metabolome was demonstrated following infection with different DENV serotypes and following primary and secondary DENV infections.

Conclusions/Significance

These results provide proof-of-concept that a metabolomics approach can be used to identify metabolites or SMBs in serum specimens that are associated with distinct DENV infections and disease outcomes. The differentiating metabolites also provide insights into metabolic pathways and pathogenic and immunologic mechanisms associated with dengue disease severity.