Chronic Opisthorchis felineus infection attenuates atherosclerosis – An autopsy study

Previously, we proposed a hypothesis that chronic helminthic infection may have beneficial effects on the development of atherosclerosis. The aim of this study was to investigate an association between Opisthorchis felineus chronic helminthic infections with aortic atherosclerosis and serum total cholesterol. A series of medico-legal autopsy specimens collected in Khanty-Mansiisk (the region in Russia endemic for O. felineus) were studied to assess O. felineus worm burden in cadaver livers. The areas of atherosclerotic lesions in the cadaver aortas were measured by visual planimetry. A family history of cardiovascular disease, smoking, hypertension or diabetes was elicited, and serum total cholesterol levels examined. Three hundred and nineteen cadavers (280 (87.8%) males and 39 (12.2%) females) aged 20–72 years were divided into five age groups: (i) 20–29, (ii) 30–39, (iii) 40–49, (iv) 50–59 and (v) >60 years old. The O. felineus mean worm burden was 257 ± 312 worms/liver. Infected subjects were categorised into three subgroups depending on the worm burden: mild (<100 worms), moderate (100–500 worms) and severe (>500 worms). Infected subjects had lower serum total cholesterol (mild worm burden, 186.4 ± 25.6 mg/dl; moderate worm burden, 183.4 ± 23.1 mg/dl, P = 0.002; severe worm burden, 170.6 ± 25.1 mg/dl, P < 0.001) than non-infected subjects (201.1 ± 21.2 mg/dl). The average percentage of aortic surface covered by fatty streaks, fibrotic plaques and complicated lesions was negatively related to worm burden in the infected subjects. Chronic helminthic infections was a negative predictor of aortic atherosclerosis; with an odds ratio of 1.72 (1.02–2.91), P = 0.041 for all subjects; and 3.19 (1.35–7.58), P = 0.008 for subjects aged >40 years old. Opisthorchis felineus chronic helminthic infectionswas found to be associated with lower serum total cholesterol levels and a significant attenuation of atherosclerosis.     

RANKL/RANK – From bone physiology to breast cancer

RANK and its ligand RANKL are key molecules in bone metabolism and are critically involved in pathologic bone disorders. Deregulation of the RANK/RANKL system is for example a main reason for the development of postmenopausal osteoporosis, which affects millions of women worldwide. Another essential function of RANK and RANKL is the development of a functional lactating mammary gland during pregnancy. Sex hormones, in particular progesterone, induce RANKL expression resulting in proliferation of mammary epithelial cells. Moreover, RANK and RANKL have been shown to regulate mammary epithelial stem cells. RANK and RANKL were also identified as critical mechanism in the development of hormone-induced breast cancer and metastatic spread to bone. In this review, we will focus on the various RANK/RANKL functions ranging from bone physiology, immune regulation, and initiation of breast cancer.     

S1P-lyase deficiency uncouples ganglioside formation – Potential contribution to tumorigenic capacity

Sphingosine-1-phosphate (S1P) is not only a catabolic intermediate of all sphingolipids but also an evolutionary conserved bioactive lipid with critical functions in cell survival, differentiation, and migration as well as in immunity and angiogenesis. S1P-lyase (SGPL1) irreversibly cleaves S1P in the final step of sphingolipid catabolism. As sphingoid bases and their 1-phosphates are not only metabolic intermediates but also highly bioactive lipids that modulate a wide range of physiological processes, it would be predicted that their elevation might induce adjustments in other facets of sphingolipid metabolism and/or alter cell behavior. We actually found in a previous study that in terminally differentiated neurons SGPL1 deficiency increases sphingolipid formation via recycling at the expense of de novo synthesis. We now investigated whether and how SGPL1 deficiency affects the metabolism of (glyco)sphingolipids in mouse embryonic fibroblasts (MEFs). According to our previous experiments in neurons, we found a strong accumulation of S1P in SGPL1-deficient MEFs. Surprisingly, a completely different situation arose as we analyzed sphingolipid metabolism in this non-differentiated cell type. The production of biosynthetic precursors of complex glycosphingolipids including ceramide, glucosylceramide and also ganglioside GM3 via de novo synthesis and recycling pathway was substantially increased whereas the amount of more complex gangliosides dropped significantly.     

Articulospora – Phylogeny vs morphology

The taxonomy of the aquatic hyphomycete genus Articulospora (Ascomycota, Pezizomycotima, Leotiales, Helotiaceae) is based on the morphology of the generative phase of its lifecycle. The type species is Articulospora tetracladia, which is distributed worldwide. Its most frequent populations in nature have dimorphic conidia, differing by the extent of conidial branching (i.e., one or two levels of branching). Some strains, stable in culture, produce exclusively conidia of one type. With the molecular analyses employed here and the relatively low number of available isolates (20), separation based on branching of conidia has not been fully supported. Therefore we propose to retain the broad concept of A. tetracladia with dimorphic conidia. Among the three gene sequences tested as potential barcodes, the internal transcribed spacer (ITS) gene was the most promising region. All strains yielded amplifiable DNA which provided adequate resolution, according to accepted ranges in inter/intraspecific differences, to differentiate among the three Articulospora and two Fontanospora species that were tested (Articulospora atra, Articulospora proliferata, A. tetracladia, Fontanospora eccentrica, Fontanospora fusiramosa). D1/D2 primers also permitted amplification in all strains, however without much resolution. Amplification of the COX1 gene sequence was least consistent.     

PKCι regulates the expression of PDL1 through multiple pathways to modulate immune suppression of pancreatic cancer cells

To investigate the impact of oncogenic protein kinase C isoform ι (PKCι) on the microenvironment and the immunogenic properties of pancreatic tumors, we prohibit PKCι activity in various pancreatic ductal adenocarcinoma (PDAC) cell lines and co-culture them with human natural killer NK92 cells. The results demonstrate that PKCι suppression enhances the susceptibility of PDAC to NK cytotoxicity and promotes the degranulation and cytolytic activity of co-cultured NK92 cells. Mechanistic studies pinpoint that downstream of KRAS, both YAP1 and STAT3 are recruited by oncogenic PKCι to elevate the expression of PDL1, contributing to constitute an immune suppressive microenvironment in PDAC. Co-culture with NK92 further induces PDL1 upregulation via STAT3 to stimulate immune escape of PDAC cells. Subsequently, inhibition of PKCι in PDAC alleviates the immune suppression and enhances the cytotoxicity of NK92 towards PDAC through restraining PDL1 overexpression. Combined with PD1/PDL1 blocker, PKCι inhibitor remarkably elevates the cytotoxicity of NK92 against PDAC cells in vitro, establishing PKCι inhibitor as a promising candidate for boosting the immunotherapy of PDAC.     

Drugs to cure avian influenza infection – multiple ways to prevent cell death

New treatments and new drugs for avian influenza virus (AIV) infection are developed continually, but there are still high mortality rates. The main reason may be that not all cell death pathways induced by AIV were blocked by the current therapies. In this review, drugs for AIV and associated acute respiratory distress syndrome (ARDS) are summarized. The roles of antioxidant (vitamin C) and multiple immunomodulators (such as Celecoxib, Mesalazine and Eritoran) are discussed. The clinical care of ARDS may result in ischemia reperfusion injury to poorly ventilated alveolar cells. Cyclosporin A should effectively inhibit this kind of damages and, therefore, may be the key drug for the survival of patients with virus-induced ARDS. Treatment with protease inhibitor Ulinastatin could also protect lysosome integrity after the infection. Through these analyses, a large drug combination is proposed, which may hypothetically greatly reduce the mortality rate.     

The Angiomotins – From discovery to function

Angiomotins were originally identified as angiostatin binding proteins and implicated in the regulation of endothelial cell migration. Recent studies have shed light on the role of Angiomotins and other members of the Motin protein family in epithelial cells and in pathways directly linked to the pathogenesis of cancer. In particular, Motins have been shown to play a role in signaling pathways regulated by small G-proteins and the Hippo–YAP pathway. In this review the role of the Motin protein family in these signaling pathways will be described and open questions will be discussed.     

The βγ-crystallins: Native state stability and pathways to aggregation

The βγ-crystallins are among the most stable and long-lived proteins in the human body. With increasing age, however, they transform to high molecular weight light-scattering aggregates, resulting in cataracts. This occurs despite the presence in the lens of high concentrations of the a-crystallin chaperones. Aggregation of crystallins can be induced in vitro by a variety of stresses, including acidic pH, ultraviolet light, oxidative damage, heating or freezing, and specific amino acid substitutions. Accumulating evidence points to the existence of specific biochemical pathways of protein: protein interaction and polymerization. We review the methods used for studying crystallin stability and aggregation and discuss the sometimes counterintuitive relationships between factors that favor native state stability and those that favor non-native aggregation. We discuss the behavior of βγ-crystallins in mixtures and their chaperone ability; the consequences of missense mutations and covalent damage to the side-chains; and the evolutionary strategies that have shaped these proteins. Efforts are ongoing to reveal the nature of cataractous crystallin aggregates and understand the mechanisms of aggregation in the context of key models of protein polymerization: amyloid, native-state, and domain-swapped. Such mechanistic understanding is likely to be of value for the development of therapeutic interventions and draw attention to unanswered questions about the relationship between a protein’s native state stability and its transformation to an aggregated state.     

From open areas to forests? The evolutionary history of Philodendron subgenus Meconostigma (Araceae) using morphological data

Due to its wide distribution covering three of the largest Neotropical biomes, Philodendron subgenus Meconostigma is an interesting model to discuss the diversification of Neotropical plants. The aim of this study was to test a previous hypothesis that the Eastern and Southern species of P. subg. Meconostigma have plesiomorphic gynoecial structure while in Amazonian species they are apomorphic. To this end, we conducted an analysis of maximum parsimony with generalized frequency coding method using a matrix with 59 morphological characters and 90% of the species of P. subg. Meconostigma. The phylogenetic reconstruction suggests that the subgenus is monophyletic and originates from open areas of Cerrado. Four morphological synapomorphies support the monophyly of the subgenus and seven synapomorphies support four minor clades within it. Our results also include characterization of three new gynoecial subtypes (A1, A2 and A3) within the subgenus. Subtype A2 (undeveloped stylar body with long stylar canals, absent central stylar dome, shallow compitum) is basal and represents the ancestral gynoecium in the group. These findings suggest that the balance between pollen uptake and accessibility of the locules were decisive to drive gynoecium evolution in the subgenus Meconostigma.     

Germ lineage properties in the urochordate Botryllus schlosseri – From markers to temporal niches

The primordial germ cells (PGCs) in the colonial urochordate Botryllus schlosseri are sequestered in late embryonic stage. PGC-like populations, located at any blastogenic stage in specific niches, inside modules with curtailed lifespan, survive throughout the life of the colony by repeated weekly migration to newly formed buds. This cyclical migration and the lack of specific markers for PGC-like populations are obstacles to the study on PGCs. For that purpose, we isolated the Botryllus DDX1 (BS-DDX1) and characterized it by normal expression patterns and by specific siRNA knockdown experiments. Expression of BS-DDX1 concurrent with BS-Vasa, γ-H2AX, BS-cadherin and phospho-Smad1/5/8, demarcate PGC cells from soma cells and from more differentiated germ cells lineages, which enabled the detection of additional putative transient niches in zooids. Employing BS-cadherin siRNA knockdown, retinoic acid (RA) administration or β-estradiol administration affirmed the BS-Vasa⁺BS-DDX1⁺BS-cadherin⁺γ-H2AX⁺phospho-Smad1/5/8⁺ population as the B. schlosseri PGC-like cells. By striving to understand the PGC-like cells trafficking between transient niches along blastogenic cycles, CM-DiI-stained PGC-like enriched populations from late blastogenic stage D zooids were injected into genetically matched colonial ramets at blastogenic stages A or C and their fates were observed for 9 days. Based on the accumulated data, we conceived a novel network of several transient and short lived ‘germ line niches’ that preserve PGCs homeostasis, protecting these cells from the weekly astogenic senescence processes, thus enabling the survival of the PGCs throughout the organism's life.     

En route to a genome-based classification of Archaea and Bacteria?

Given the considerable promise whole-genome sequencing offers for phylogeny and classification, it is surprising that microbial systematics and genomics have not yet been reconciled. This might be due to the intrinsic difficulties in inferring reasonable phylogenies from genomic sequences, particularly in the light of the significant amount of lateral gene transfer in prokaryotic genomes. However, recent studies indicate that the species tree and the hierarchical classification based on it are still meaningful concepts, and that state-of-the-art phylogenetic inference methods are able to provide reliable estimates of the species tree to the benefit of taxonomy. Conversely, we suspect that the current lack of completely sequenced genomes for many of the major lineages of prokaryotes and for most type strains is a major obstacle in progress towards a genome-based classification of microorganisms. We conclude that phylogeny-driven microbial genome sequencing projects such as the Genomic Encyclopaedia of Archaea and Bacteria (GEBA) project are likely to rectify this situation.     

The histone deacetylase inhibitor vorinostat prevents TNFα-induced necroptosis by regulating multiple signaling pathways

Histone deacetylase (HDAC) inhibitors are novel anticancer reagents that have recently been reported to have anti-inflammatory and neuroprotective effects; however, the mechanisms underlying their activities are largely undefined. The data from this study show that the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) can protect L929 cells from TNFα-induced necroptosis. This effect involves multiple mechanisms, including the upregulation of cFLIP_L expression, the enhanced activation of NFκB and p38 MAPK, and the inactivation of JNK. In addition, SAHA could initiate cell autophagy by inhibiting Akt and mTOR, which also play important roles in protecting cells from necroptosis. Because cell necroptosis is important for inflammation-related deterioration and neurodegenerative disease, our results indicate that preventing cell necrosis may be an important mechanism through which HDAC inhibitor compounds exert their anti-inflammatory or neuroprotective effects.     

Are the diatoms Navicula sp. and Thalassiosira fluviatilis suitable to be fed to the benthic harpacticoid copepod Tisbe biminiensis?

The objective of this study was to compare the influence of the diets of two diatoms, Navicula sp. (benthic) and Thalassiosira fluviatilis (planctonic), on the development, fecundity and survival of the harpacticoid copepod Tisbe biminiensis. In order to determine the optimal concentration of food, 35 egg-bearing females were submitted to six algal concentrations and controls (without food). After 24 h, the content of the recipients was fixed with 4% formalin and then fecal pellets produced by each female were counted and measured. The larval development was studied by surveying 50 nauplii on each diet individually until the adult stage, at intervals of 6 h. The cast exoskeletons were removed to count the number of segments and for measurement. The fecundity was obtained counting the naupliar production every 48 h of groups containing 10 females in different algal concentrations in both diets. The diet influence on fecundity was tested by submitting four groups of 10 females fed on optimal algal concentrations based on the fecal pellet experiments. In the Navicula sp. concentration of 0.4 μg Chl-a/ml, considered to be optimal for fecal pellets production, the diatoms were shown toxic, resulting in a low survival rate and inhibiting the egg production of copepods. The optimal concentration considering fecundity was estimated to be 0.1 μg Chl-a/ml for both diets. Copepods fed on Navicula sp. presented a faster development rate and higher naupliar production compared to copepods fed on T. fluviatilis. Size and survival did not vary significantly among diets. The algal concentration interfered significantly in the reproductive success of females. Both very low and very high algal concentrations reduced reproductive success. Concluding, the benthic diatom Navicula sp. was more favorable to the copepod T. biminiensis than the planktonic diatom T. fluviatilis.     

Polynucleotide kinase–phosphatase enables neurogenesis via multiple DNA repair pathways to maintain genome stability

Polynucleotide kinase–phosphatase (PNKP) is a DNA repair factor possessing both 5′-kinase and 3′-phosphatase activities to modify ends of a DNA break prior to ligation. Recently, decreased PNKP levels were identified as the cause of severe neuropathology present in the human microcephaly with seizures (MCSZ) syndrome. Utilizing novel murine Pnkp alleles that attenuate expression and a T424GfsX48 frame-shift allele identified in MCSZ individuals, we determined how PNKP inactivation impacts neurogenesis. Mice with PNKP inactivation in neural progenitors manifest neurodevelopmental abnormalities and postnatal death. This severe phenotype involved defective base excision repair and non-homologous end-joining, pathways required for repair of both DNA single- and double-strand breaks. Although mice homozygous for the T424GfsX48 allele were lethal embryonically, attenuated PNKP levels (akin to MCSZ) showed general neurodevelopmental defects, including microcephaly, indicating a critical developmental PNKP threshold. Directed postnatal neural inactivation of PNKP affected specific subpopulations including oligodendrocytes, indicating a broad requirement for genome maintenance, both during and after neurogenesis. These data illuminate the basis for selective neural vulnerability in DNA repair deficiency disease.     

The tumorigenic potential of pluripotent stem cells: What can we do to minimize it?

Human pluripotent stem cells (hPSCs) have the potential to fundamentally change the way that we go about treating and understanding human disease. Despite this extraordinary potential, these cells also have an innate capability to form tumors in immunocompromised individuals when they are introduced in their pluripotent state. Although current therapeutic strategies involve transplantation of only differentiated hPSC derivatives, there is still a concern that transplanted cell populations could contain a small percentage of cells that are not fully differentiated. In addition, these cells have been frequently reported to acquire genetic alterations that, in some cases, are associated with certain types of human cancers. Here, we try to separate the panic from reality and rationally evaluate the true tumorigenic potential of these cells. We also discuss a recent study examining the effect of culture conditions on the genetic integrity of hPSCs. Finally, we present a set of sensible guidelines for minimizing the tumorigenic potential of hPSC‐derived cells. © 2016 The Authors. Inside the Cell published by Wiley Periodicals, Inc.