Domain selection and familywise error rate for functional data: A unified framework

Functional data are smooth, often continuous, random curves, which can be seen as an extreme case of multivariate data with infinite dimensionality. Just as componentwise inference for multivariate data naturally performs feature selection, subsetwise inference for functional data performs domain selection. In this paper, we present a unified testing framework for domain selection on populations of functional data. In detail, p-values of hypothesis tests performed on pointwise evaluations of functional data are suitably adjusted for providing control of the familywise error rate (FWER) over a family of subsets of the domain. We show that several state-of-the-art domain selection methods fit within this framework and differ from each other by the choice of the family over which the control of the FWER is provided. In the existing literature, these families are always defined a priori. In this work, we also propose a novel approach, coined thresholdwise testing, in which the family of subsets is instead built in a data-driven fashion. The method seamlessly generalizes to multidimensional domains in contrast to methods based on a priori defined families. We provide theoretical results with respect to consistency and control of the FWER for the methods within the unified framework. We illustrate the performance of the methods within the unified framework on simulated and real data examples and compare their performance with other existing methods.     

Structural and enzymatic properties of Ageritin,a novel metal-dependent ribotoxin-like protein with antitumor activity

Ageritin has been recently described as the first ribotoxin-like from Basidiomycota division (mushroom Agrocybe aegerita) with known antitumor activity (BBA 2017, 1861: 1113-1121). By investigating structural, catalytic and binding properties, we demonstrate that Ageritin is a unique ribotoxin-like protein. Indeed, typical of the ribotoxin family, it shows the specific ribonucleolytic activity against the ribosomal Sarcin-Ricin Loop in a rabbit reticulocytes assay. However, it displays several elements of novelty, as this activity is strongly metal-dependent and completely suppressed in the presence of EDTA, different from other representative members of the ribotoxin family. Consistently, we prove that Ageritin is able to bind magnesium ions with low micromolar affinity. We also show that Ageritin is significantly more stable than other ribotoxins in thermal and chemical denaturation experiments. These peculiar features make Ageritin the prototype of a new ribotoxin-like family present in basidiomycetes. Finally, given its high stability, this enzyme is a promising candidate as a new tool in immunoconjugates and nanoconstructs.     

Effect of heliox on lung dynamic hyperinflation, dyspnea, and exercise endurance capacity in COPD patients.

We tested the hypothesis that heliox breathing, by reducing lung dynamic hyperinflation (DH) and dyspnea (Dys) sensation, may significantly improve exercise endurance capacity in patients with chronic obstructive pulmonary disease [n = 12, forced expiratory volume in 1 s = 1.15 (SD 0.32) liters]. Each subject underwent two cycle ergometer high-intensity constant work rate exercises to exhaustion, one on room air and one on heliox (79% He-21% O2). Minute ventilation (VE), carbon dioxide output, heart rate, inspiratory capacity (IC), Dys, and arterial partial pressure of CO2 were measured. Exercise endurance time increased significantly with heliox [9.0 (SD 4.5) vs. 4.2 (SD 2.0) min; P < 0.001]. This was associated with a significant reduction in lung DH at isotime (Iso), as reflected by the increase in IC [1.97 (SD 0.40) vs. 1.77 (SD 0.41) liters; P < 0.001] and a decrease in Dys [6 (SD 1) vs. 8 (SD 1) score; P < 0.001]. Heliox induced a state of relative hyperventilation, as reflected by the increase in VE [38.3 (SD 7.7) vs. 35.5 (SD 8.8) l/min; P < 0.01] and VE/carbon dioxide output [36.3 (SD 6.0) vs. 33.9 (SD 5.6); P < 0.01] at peak exercise and by the reduction in arterial partial pressure of CO2 at Iso [44 (SD 6) vs. 48 (SD 6) Torr; P < 0.05] and at peak exercise [46 (SD 6) vs. 48 (SD 6) Torr; P < 0.05]. The reduction in Dys at Iso correlated significantly (R = -0.75; P < 0.01) with the increase in IC induced by heliox. The increment induced by heliox in exercise endurance time correlated significantly with resting increment in resting forced expiratory in 1 s (R = 0.88; P < 0.01), increase in IC at Iso (R = 0.70; P < 0.02), and reduction in Dys at Iso (R = -0.71; P < 0.01). In chronic obstructive pulmonary disease, heliox breathing improves high-intensity exercise endurance capacity by increasing maximal ventilatory capacity and by reducing lung DH and Dys.     

A protective role for autophagy in vitiligo

A growing number of studies supports the existence of a dynamic interplay between energetic metabolism and autophagy, whose induction represents an adaptive response against several stress conditions. Autophagy is an evolutionarily conserved and a highly orchestrated catabolic recycling process that guarantees cellular homeostasis. To date, the exact role of autophagy in vitiligo pathogenesis is still not clear. Here, we provide the first evidence that autophagy occurs in melanocytes and fibroblasts from non-lesional skin of vitiligo patients, as a result of metabolic surveillance response. More precisely, this study is the first to reveal that induction of autophagy exerts a protective role against the intrinsic metabolic stress and attempts to antagonize degenerative processes in normal appearing vitiligo skin, where melanocytes and fibroblasts are already prone to premature senescence.Subject terms: Macroautophagy, Translational research     

Selective inhibition of carbonic anhydrase IX and XII by coumarin and psoralen derivatives

A small library of coumarin and their psoralen analogues EMAC10157a-b-d-g and EMAC10160a-b-d-g has been designed and synthesised to investigate the effect of structural modifications on their inhibition ability and selectivity profile towards carbonic anhydrase isoforms I, II, IX, and XII. None of the new compounds exhibited activity towards hCA I and II isozymes. Conversely, both coumarin and psoralen derivatives were active against tumour associated isoforms IX and XII in the low micromolar or nanomolar range of concentration. These data further corroborate our previous findings on analogous derivatives, confirming that both coumarins and psoralens are interesting scaffolds for the design of isozyme selective hCA inhibitors.     

Patterns of nucleotide and haplotype diversity at ICAM-1 across global human populations with varying levels of malaria exposure

Malaria is one of the strongest selective pressures in recent human evolution. African populations have been and continue to be at risk for malarial infections. However, few studies have re-sequenced malaria susceptibility loci across geographically and genetically diverse groups in Africa. We examined nucleotide diversity at Intercellular adhesion molecule-1 (ICAM-1), a malaria susceptibility candidate locus, in a number of human populations with a specific focus on diverse African ethnic groups. We used tests of neutrality to assess whether natural selection has impacted this locus and tested whether SNP variation at ICAM-1 is correlated with malaria endemicity. We observe differing patterns of nucleotide and haplotype variation in global populations and higher levels of diversity in Africa. Although we do not observe a deviation from neutrality based on the allele frequency distribution, we do observe several alleles at ICAM-1, including the ICAM-1 ^Kilifi allele, that are correlated with malaria endemicity. We show that the ICAM-1 ^Kilifi allele, which is common in Africa and Asia, exists on distinct haplotype backgrounds and is likely to have arisen more recently in Asia. Our results suggest that correlation analyses of allele frequencies and malaria endemicity may be useful for identifying candidate functional variants that play a role in malaria resistance and susceptibility.     

Presence of CTAK/CCL27, MCP-3/CCL7 and LIF in human colostrum and breast milk

Human colostrum and breast milk are known to contain high levels of cytokines and chemokines, which are thought to contribute to the development of the newborn. The aim of this study was to investigate the difference in the presence and levels of 21 soluble cytokines and chemokines in paired samples of human colostrum (day 2 after delivery) and breast milk (day 4–5 after delivery) by using the multiplex technology. Of the 21 cytokine investigated in 10 pairs of samples, only β-NGF was absent in both colostrum and milk, while INF-α2, SCF and TNF-β were present in colostrum but not in human milk. As a general rule, colostrum contained higher concentrations of cytokines and chemokines with respect to breast milk. The majority of cytokines, detected in colostrum alone or in colostrum and human milk (IL-1α, IL-2Rα, IL-3, IL-16, IL-18, GRO-α, HGF, IFN-α2, M-CSF, MIF, MIG, TNF-β, SDF-1α, TRAIL) have been described in previous studies, while for the first time we describe the presence of additional cytokines either in colostrum alone (SCF) or in both colostrum and breast milk (CTAK/CCL27, MCP-3/CCL7, LIF). Our data confirm and expand previous studies showing that some cytokines/chemokines, which might contribute to the development of the gastro-intestinal and nervous systems, are overexpressed in human colostrum and breast milk, and might contribute to the development of these systems.     

Hypothalamic bile acid-TGR5 signaling protects from obesity

1. Download : Download high-res image (167KB)
2. Download : Download full-size image