New unusual pregnane glycosides with antiproliferative activity from Solenostemma argel

Seven new 15-keto pregnane glycosides, namely Stemmosides E--K, were isolated from Solenostemma argel. Stemmosides E--J are characterized by the occurrence of an uncommon 14 beta proton configuration while stemmosides E and F possess in addition a rare enolic function in C-16. On the other hand, stemmosides G-J display an unusual C-17 alpha side chain. Their structures were established by ESI-MS and NMR experiments. Moreover, the effect of these compounds on the VEGF-induced in Kaposi's sarcoma cell proliferation was tested. Results indicated that all the compounds reduced the cell proliferation in a dose dependent manner.     

Right Occipital Cortex Activation Correlates with Superior Odor Processing Performance in the Early Blind

Using functional magnetic resonance imaging (fMRI) in ten early blind humans, we found robust occipital activation during two odor-processing tasks (discrimination or categorization of fruit and flower odors), as well as during control auditory-verbal conditions (discrimination or categorization of fruit and flower names). We also found evidence for reorganization and specialization of the ventral part of the occipital cortex, with dissociation according to stimulus modality: the right fusiform gyrus was most activated during olfactory conditions while part of the left ventral lateral occipital complex showed a preference for auditory-verbal processing. Only little occipital activation was found in sighted subjects, but the same right-olfactory/left-auditory-verbal hemispheric lateralization was found overall in their brain. This difference between the groups was mirrored by superior performance of the blind in various odor-processing tasks. Moreover, the level of right fusiform gyrus activation during the olfactory conditions was highly correlated with individual scores in a variety of odor recognition tests, indicating that the additional occipital activation may play a functional role in odor processing.     

Dipeptidyl-Peptidase IV Activity Is Correlated with Colorectal Cancer Prognosis

Background

Dipeptidyl-peptidase IV (EC 3.4.14.5) (DPPIV) is a serine peptidase involved in cell differentiation, adhesion, immune modulation and apoptosis, functions that control neoplastic transformation. Previous studies have demonstrated altered expression and activity of tissue and circulating DPPIV in several cancers and proposed its potential usefulness for early diagnosis in colorectal cancer (CRC).

Methods and principal findings

The activity and mRNA and protein expression of DPPIV was prospectively analyzed in adenocarcinomas, adenomas, uninvolved colorectal mucosa and plasma from 116 CRC patients by fluorimetric, quantitative RT-PCR and immunohistochemical methods. Results were correlated with the most important classic pathological data related to aggressiveness and with 5-year survival rates. Results showed that: 1) mRNA levels and activity of DPPIV increased in colorectal neoplasms (Kruskal-Wallis test, p<0.01); 2) Both adenomas and CRCs displayed positive cytoplasmic immunostaining with luminal membrane reinforcement; 3) Plasmatic DPPIV activity was lower in CRC patients than in healthy subjects (Mann-U test, p<0.01); 4) Plasmatic DPPIV activity was associated with worse overall and disease-free survivals (log-rank p<0.01, Cox analysis p<0.01).

Conclusion/significance

1) Up-regulation of DPPIV in colorectal tumors suggests a role for this enzyme in the neoplastic transformation of colorectal tissues. This finding opens the possibility for new therapeutic targets in these patients. 2) Plasmatic DPPIV is an independent prognostic factor in survival of CRC patients. The determination of DPPIV activity levels in the plasma may be a safe, minimally invasive and inexpensive way to define the aggressiveness of CRC in daily practice.     

A Context-Aware Delayed Agglomeration Framework for Electron Microscopy Segmentation

Electron Microscopy (EM) image (or volume) segmentation has become significantly important in recent years as an instrument for connectomics. This paper proposes a novel agglomerative framework for EM segmentation. In particular, given an over-segmented image or volume, we propose a novel framework for accurately clustering regions of the same neuron. Unlike existing agglomerative methods, the proposed context-aware algorithm divides superpixels (over-segmented regions) of different biological entities into different subsets and agglomerates them separately. In addition, this paper describes a “delayed” scheme for agglomerative clustering that postpones some of the merge decisions, pertaining to newly formed bodies, in order to generate a more confident boundary prediction. We report significant improvements attained by the proposed approach in segmentation accuracy over existing standard methods on 2D and 3D datasets.     

Detecting Falls as Novelties in Acceleration Patterns Acquired with Smartphones

Despite being a major public health problem, falls in the elderly cannot be detected efficiently yet. Many studies have used acceleration as the main input to discriminate between falls and activities of daily living (ADL). In recent years, there has been an increasing interest in using smartphones for fall detection. The most promising results have been obtained by supervised Machine Learning algorithms. However, a drawback of these approaches is that they rely on falls simulated by young or mature people, which might not represent every possible fall situation and might be different from older people''s falls. Thus, we propose to tackle the problem of fall detection by applying a kind of novelty detection methods which rely only on true ADL. In this way, a fall is any abnormal movement with respect to ADL. A system based on these methods could easily adapt itself to new situations since new ADL could be recorded continuously and the system could be re-trained on the fly. The goal of this work is to explore the use of such novelty detectors by selecting one of them and by comparing it with a state-of-the-art traditional supervised method under different conditions. The data sets we have collected were recorded with smartphones. Ten volunteers simulated eight type of falls, whereas ADL were recorded while they carried the phone in their real life. Even though we have not collected data from the elderly, the data sets were suitable to check the adaptability of novelty detectors. They have been made publicly available to improve the reproducibility of our results. We have studied several novelty detection methods, selecting the nearest neighbour-based technique (NN) as the most suitable. Then, we have compared NN with the Support Vector Machine (SVM). In most situations a generic SVM outperformed an adapted NN.     

A customized pigmentation SNP array identifies a novel SNP associated with melanoma predisposition in the SLC45A2 gene

As the incidence of Malignant Melanoma (MM) reflects an interaction between skin colour and UV exposure, variations in genes implicated in pigmentation and tanning response to UV may be associated with susceptibility to MM. In this study, 363 SNPs in 65 gene regions belonging to the pigmentation pathway have been successfully genotyped using a SNP array. Five hundred and ninety MM cases and 507 controls were analyzed in a discovery phase I. Ten candidate SNPs based on a p-value threshold of 0.01 were identified. Two of them, rs35414 (SLC45A2) and rs2069398 (SILV/CKD2), were statistically significant after conservative Bonferroni correction. The best six SNPs were further tested in an independent Spanish series (624 MM cases and 789 controls). A novel SNP located on the SLC45A2 gene (rs35414) was found to be significantly associated with melanoma in both phase I and phase II (P<0.0001). None of the other five SNPs were replicated in this second phase of the study. However, three SNPs in TYR, SILV/CDK2 and ADAMTS20 genes (rs17793678, rs2069398 and rs1510521 respectively) had an overall p-value<0.05 when considering the whole DNA collection (1214 MM cases and 1296 controls). Both the SLC45A2 and the SILV/CDK2 variants behave as protective alleles, while the TYR and ADAMTS20 variants seem to function as risk alleles. Cumulative effects were detected when these four variants were considered together. Furthermore, individuals carrying two or more mutations in MC1R, a well-known low penetrance melanoma-predisposing gene, had a decreased MM risk if concurrently bearing the SLC45A2 protective variant. To our knowledge, this is the largest study on Spanish sporadic MM cases to date.     

Human Indoleamine 2,3-Dioxygenase Is a Catalyst of Physiological Heme Peroxidase Reactions: IMPLICATIONS FOR THE INHIBITION OF DIOXYGENASE ACTIVITY BY HYDROGEN PEROXIDE*

The heme enzyme indoleamine 2,3-dioxygenase (IDO) is a key regulator of immune responses through catalyzing l-tryptophan (l-Trp) oxidation. Here, we show that hydrogen peroxide (H₂O₂) activates the peroxidase function of IDO to induce protein oxidation and inhibit dioxygenase activity. Exposure of IDO-expressing cells or recombinant human IDO (rIDO) to H₂O₂ inhibited dioxygenase activity in a manner abrogated by l-Trp. Dioxygenase inhibition correlated with IDO-catalyzed H₂O₂ consumption, compound I-mediated formation of protein-centered radicals, altered protein secondary structure, and opening of the distal heme pocket to promote nonproductive substrate binding; these changes were inhibited by l-Trp, the heme ligand cyanide, or free radical scavengers. Protection by l-Trp coincided with its oxidation into oxindolylalanine and kynurenine and the formation of a compound II-type ferryl-oxo heme. Physiological peroxidase substrates, ascorbate or tyrosine, enhanced rIDO-mediated H₂O₂ consumption and attenuated H₂O₂-induced protein oxidation and dioxygenase inhibition. In the presence of H₂O₂, rIDO catalytically consumed nitric oxide (NO) and utilized nitrite to promote 3-nitrotyrosine formation on IDO. The promotion of H₂O₂ consumption by peroxidase substrates, NO consumption, and IDO nitration was inhibited by l-Trp. This study identifies IDO as a heme peroxidase that, in the absence of substrates, self-inactivates dioxygenase activity via compound I-initiated protein oxidation. l-Trp protects against dioxygenase inactivation by reacting with compound I and retarding compound II reduction to suppress peroxidase turnover. Peroxidase-mediated dioxygenase inactivation, NO consumption, or protein nitration may modulate the biological actions of IDO expressed in inflammatory tissues where the levels of H₂O₂ and NO are elevated and l-Trp is low.     

Implications of bacterial,viral and mycotic microorganisms in vultures for wildlife conservation,ecosystem services and public health

The effects that microorganisms (bacteria, viruses and fungi) have on their hosts remain unexplored for most vulture species. This is especially relevant for vultures, as their diet consists of carcasses in various stages of decomposition, which are breeding grounds for potentially pathogenic microorganisms. Here we review current knowledge of bacterial, viral and mycotic microorganisms present in wild vultures. We consider their potential to cause disease in vultures and whether this poses any population-level threats. Furthermore, we address the question of whether vultures may act as disease spreaders or mitigators. We found 76 articles concerning bacterial, viral and mycotic microorganisms present in 13 vulture species, 57 evaluating bacteria, 13 evaluating viruses and six evaluating mycotic microorganisms. These studies come from all continents where vultures are present, but mainly from Europe and North America, and the most studied species was the Griffon Vulture Gyps fulvus. We found that vultures are colonized by zoonotic pathogens, and even host-specific human pathogens. Some recorded bacteria showed multi-antibiotic resistance, especially those that can be associated with anthropogenic food subsides such as supplementary feeding stations. We found evidence that vulture health can be affected by some microorganisms, producing a wide array of clinical alterations that have the potential to influence mortality risk and fitness. We did not find clear scientific evidence that vultures play an epidemiological role spreading microorganisms to humans and other species. However, there is evidence that vultures could prevent the spread of infectious diseases through their removal of decomposing organic material. The evaluation of vulture exposure to microorganisms is of fundamental importance to design better conservation policies for this threatened group, which may serve a key role as ecosystem cleaners.