Vesicular trafficking permits evasion of cGAS/STING surveillance during initial human papillomavirus infection

Oncogenic human papillomaviruses (HPVs) replicate in differentiating epithelium, causing 5% of cancers worldwide. Like most other DNA viruses, HPV infection initiates after trafficking viral genome (vDNA) to host cell nuclei. Cells possess innate surveillance pathways to detect microbial components or physiological stresses often associated with microbial infections. One of these pathways, cGAS/STING, induces IRF3-dependent antiviral interferon (IFN) responses upon detection of cytosolic DNA. Virion-associated vDNA can activate cGAS/STING during initial viral entry and uncoating/trafficking, and thus cGAS/STING is an obstacle to many DNA viruses. HPV has a unique vesicular trafficking pathway compared to many other DNA viruses. As the capsid uncoats within acidic endosomal compartments, minor capsid protein L2 protrudes across vesicular membranes to facilitate transport of vDNA to the Golgi. L2/vDNA resides within the Golgi lumen until G2/M, whereupon vesicular L2/vDNA traffics along spindle microtubules, tethering to chromosomes to access daughter cell nuclei. L2/vDNA-containing vesicles likely remain intact until G1, following nuclear envelope reformation. We hypothesize that this unique vesicular trafficking protects HPV from cGAS/STING surveillance. Here, we investigate cGAS/STING responses to HPV infection. DNA transfection resulted in acute cGAS/STING activation and downstream IFN responses. In contrast, HPV infection elicited minimal cGAS/STING and IFN responses. To determine the role of vesicular trafficking in cGAS/STING evasion, we forced premature viral penetration of vesicular membranes with membrane-perturbing cationic lipids. Such treatment renders a non-infectious trafficking-defective mutant HPV infectious, yet susceptible to cGAS/STING detection. Overall, HPV evades cGAS/STING by its unique subcellular trafficking, a property that may contribute to establishment of infection.     

Low modularity and specialization in a commensalistic epiphyte–phorophyte network in a tropical cloud forest

Species interactions can shape the structure of natural communities. Such sets of interactions have been described as complex ecological networks, an example of which is the commensal network formed by epiphyte–phorophyte interactions. Vascular epiphytes germinate and grow on phorophytes (support trees), assuming a horizontal distribution (among the phorophyte species) and a vertical distribution (from the base of the tree trunk to the crown of phorophytes, i.e., through ecological zones). Here, we investigated the organization of these structural dimensions of the epiphyte–phorophyte network in a Brazilian tropical montane cloud forest. The analyzed network, comprising 66 epiphyte species and 22 phorophyte species, exhibited a nested structure with a low degree of specialization, a typical pattern for epiphyte–phorophyte networks in forests. The network was slightly modular, with 65% of the species common to three modules, and had vertical structure corresponding to the vertical organization of the phorophytes. The size (diameter at breast height) of phorophyte individuals influenced the network structure, possibly due to the increase in habitat area, the time available for colonization by epiphytes, and a greater number of microenvironments. We found that the distribution of the epiphyte species differed between the phorophyte ecological zones, with greater richness in the lower portions and greater abundance in the upper portions of the phorophytes. The results provide relevant guidance for future research on the characteristics and the vertical and horizontal organization of vascular epiphyte and phorophyte networks. Abstract in Portuguese is available with online material.     

Food availability affects the strength of mutualistic host–microbiota interactions in Daphnia magna

The symbiotic gut microbial community is generally known to have a strong impact on the fitness of its host. Nevertheless, it is less clear how the impact of symbiotic interactions on the hosts'' fitness varies according to environmental circumstances such as changes in the diet. This study aims to get a better understanding of host–microbiota interactions under different levels of food availability. We conducted experiments with the invertebrate, experimental model organism Daphnia magna and compared growth, survival and reproduction of conventionalized symbiotic Daphnia with germ-free individuals given varying quantities of food. Our experiments revealed that the relative importance of the microbiota for the hosts'' fitness varied according to dietary conditions. The presence of the microbiota had strong positive effects on Daphnia when food was sufficient or abundant, but had weaker effects under food limitation. Our results indicate that the microbiota can be a potentially important factor in determining host responses to changes in dietary conditions. Characterization of the host-associated microbiota further showed that Aeromonas sp. was the most prevalent taxon in the digestive tract of Daphnia.     

Network Analysis of Differential Expression for the Identification of Disease-Causing Genes

Genetic studies (in particular linkage and association studies) identify chromosomal regions involved in a disease or phenotype of interest, but those regions often contain many candidate genes, only a few of which can be followed-up for biological validation. Recently, computational methods to identify (prioritize) the most promising candidates within a region have been proposed, but they are usually not applicable to cases where little is known about the phenotype (no or few confirmed disease genes, fragmentary understanding of the biological cascades involved). We seek to overcome this limitation by replacing knowledge about the biological process by experimental data on differential gene expression between affected and healthy individuals. Considering the problem from the perspective of a gene/protein network, we assess a candidate gene by considering the level of differential expression in its neighborhood under the assumption that strong candidates will tend to be surrounded by differentially expressed neighbors. We define a notion of soft neighborhood where each gene is given a contributing weight, which decreases with the distance from the candidate gene on the protein network. To account for multiple paths between genes, we define the distance using the Laplacian exponential diffusion kernel. We score candidates by aggregating the differential expression of neighbors weighted as a function of distance. Through a randomization procedure, we rank candidates by p-values. We illustrate our approach on four monogenic diseases and successfully prioritize the known disease causing genes.     

Expanding roles for AMP‐activated protein kinase in neuronal survival and autophagy

AMP‐activated protein kinase (AMPK) is an evolutionarily conserved cellular switch that activates catabolic pathways and turns off anabolic processes. In this way, AMPK activation can restore the perturbation of cellular energy levels. In physiological situations, AMPK senses energy deficiency (in the form of an increased AMP/ATP ratio), but it is also activated by metabolic insults, such as glucose or oxygen deprivation. Metformin, one of the most widely prescribed anti‐diabetic drugs, exerts its actions by AMPK activation. However, while the functions of AMPK as a metabolic regulator are fairly well understood, its actions in neuronal cells only recently gained attention. This review will discuss newly emerged functions of AMPK in neuroprotection and neurodegeneration. Additionally, recent views on the role of AMPK in autophagy, an important catabolic process that is also involved in neurodegeneration and cancer, will be highlighted.     

Context dependency of infectious disease: the cyanobacterium Microcystis aeruginosa decreases white bacterial disease in Daphnia magna

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Esa1, an Arabidopsis mutant with enhanced susceptibility to a range of necrotrophic fungal pathogens, shows a distorted induction of defense responses by reactive oxygen generating compounds

An Arabidopsis thaliana mutant, esa1, that shows enhanced susceptibility to the necrotrophic pathogens Alternaria brassicicola, Botrytis cinerea and Plectosphaerella cucumerina, but has wild-type levels of resistance to the biotrophic pathogens Pseudomonas syringae pv. tomato and Peronospora parasitica. The enhanced susceptibility towards necrotrophic pathogens correlated with a delayed induction of phytoalexin accumulation and delayed induction of the plant defensin gene PDF1.2 upon inoculation with pathogens. Two reactive oxygen generating compounds, paraquat and acifluorfen, were found to cause induction of both phytoalexin accumulation and PDF1.2 expression in wild-type plants, but this induction was almost completely abolished in esa1. This finding suggests that esa1 may somehow be involved in transduction of signals generated by reactive oxygen species.     

A clinical experience with perforator flaps in the coverage of extensive defects of the upper extremity

Traditional skin free flaps, such as radial arm, lateral arm, and scapular flaps, are rarely sufficient to cover large skin defects of the upper extremity because of the limitation of primary closure at the donor site. Muscle or musculocutaneous flaps have been used more for these defects. However, they preclude a sacrifice of a large amount of muscle tissue with the subsequent donor-site morbidity. Perforator or combined flaps are better alternatives to cover large defects. The use of a muscle as part of a combined flap is limited to very specific indications, and the amount of muscle required is restricted to the minimum to decrease the donor-site morbidity. The authors present a series of 12 patients with extensive defects of the upper extremity who were treated between December of 1999 and March of 2002. The mean defect was 21 x 11 cm in size. Perforator flaps (five thoracodorsal artery perforator flaps and four deep inferior epigastric perforator flaps) were used in seven patients. Combined flaps, which were a combination of two different types of tissue based on a single pedicle, were needed in five patients (scapular skin flap with a thoracodorsal artery perforator flap in one patient and a thoracodorsal artery perforator flap with a split latissimus dorsi muscle in four patients). In one case, immediate surgical defatting of a deep inferior epigastric perforator flap on a wrist was performed to immediately achieve thin coverage. The average operative time was 5 hours 20 minutes (range, 3 to 7 hours). All but one flap, in which the cutaneous part of a combined flap necrosed because of a postoperative hematoma, survived completely. Adequate coverage and complete wound healing were obtained in all cases. Perforator flaps can be used successfully to cover a large defect in an extremity with minimal donor-site morbidity. Combined flaps provide a large amount of tissue, a wide range of mobility, and easy shaping, modeling, and defatting.     

Defining a holoprosencephaly locus on human chromosome 14q13 and characterization of potential candidate genes

Holoprosencephaly (HPE) is the most common developmental field defect in patterning of the human prosencephalon and associated craniofacial structures. The genetics is complex, with 12 loci defined on 11 chromosomes. We defined a locus for HPE (HPE8) on human chromosome 14q13 between markers D14S49 and AFM205XG5, by mapping deletion intervals of affected subjects with proximal chromosome 14q interstitial cytogenetic deletions. A 35-BAC contig was built by chromosome walking. By annotation of the 2.82-Mb minimal critical region, we identified 28 possible genes. Seven genes were expressed in human fetal brain: NPAS3, SNX6, C14ORF11, C14ORF10, PAX9, NKX2.1, and C14ORF19, the last an apparent gene fragment. Molecular embryology, animal modeling, and human mutation studies were reported elsewhere for PAX9 and NKX2.1. We focused on three genes, SNX6, NPAS3, and C14ORF11, as potential candidates for HPE. Genomic structure, human expression patterns, protein cellular localization, and embryonic expression patterns of orthologous murine genes were determined, showing that the three genes have properties similar to those of known HPE genes.