‘Rules that apply in times of crisis’: time,agency, and norm‐remaking during Nepal's People's War

This article explores how people in the former Maoist heartland of Nepal adopted previously transgressive norms and practices during the decade of the People's War (1996‐2006). By examining the rise in practices of beef‐eating and inter‐caste commensality, this article suggests that the temporal dimension of wartime ‘when different rules apply’ was crucial in making people accept new ideas and break established norms on a scale atypical for the ‘normal’ times of peace. Analysing the agency of Maoist activists, who self‐consciously tried to implement a project of radical social transformation, and those people who were caught in the midst of the Maoist transformative endeavour, this article argues that the contours of the ‘new society’ emerged not only due to revolutionaries’ intentional actions but also because of the ‘exceptional’ nature of wartime, which forced people to radically re‐create their daily lives. By transgressing social norms, ‘ordinary’ people did not deliberately undermine the normative order, but rather responded to the constraints of wartime, when people's agency and ethical choices were mostly driven by the need to secure the survival of their families and ensure the continuity of life itself.     

De novo methylation in male germ cells of the common marmoset monkey occurs during postnatal development and is maintained in vitro

The timing of de novo DNA methylation in male germ cells during human testicular development is yet unsolved. Apart from that, the stability of established imprinting patterns in vitro is controversially discussed. This study aimed at determining the timing of DNA de novo methylation and at assessing the stability of the methylation status in vitro. We employed the marmoset monkey (Callithrix jacchus) as it is considered the best non-human primate model for human testicular development. We selected neonatal, pre-pubertal, pubertal, and adult animals (n = 3, each) and assessed germ cell global DNA methylation levels by 5-methyl cytosine staining, and Alu elements and gene-specific methylation (H19, LIT1, SNRPN, MEST, OCT4, MAGE-A4, and DDX-4) by pyrosequencing. De novo methylation is progressively established during postnatal primate development and continues until adulthood, a process that is different in most other species. Importantly, once established, methylation patterns remained stable, as demonstrated using in vitro cultures. Thus, the marmoset monkey is a unique model for the study of postnatal DNA methylation mechanisms in germ cells and for the identification of epimutations and their causes.     

Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports Pseudomonas aeruginosa-driven pathology

Regulated cell necrosis supports immune and anti-infectious strategies of the body; however, dysregulation of these processes drives pathological organ damage. Pseudomonas aeruginosa expresses a phospholipase, ExoU that triggers pathological host cell necrosis through a poorly characterized pathway. Here, we investigated the molecular and cellular mechanisms of ExoU-mediated necrosis. We show that cellular peroxidised phospholipids enhance ExoU phospholipase activity, which drives necrosis of immune and non-immune cells. Conversely, both the endogenous lipid peroxidation regulator GPX4 and the pharmacological inhibition of lipid peroxidation delay ExoU-dependent cell necrosis and improve bacterial elimination in vitro and in vivo. Our findings also pertain to the ExoU-related phospholipase from the bacterial pathogen Burkholderia thailandensis, suggesting that exploitation of peroxidised phospholipids might be a conserved virulence mechanism among various microbial phospholipases. Overall, our results identify an original lipid peroxidation-based virulence mechanism as a strong contributor of microbial phospholipase-driven pathology.     

Downregulation of mitochondrial biogenesis by virus infection triggers antiviral responses by cyclic GMP-AMP synthase

In general, in mammalian cells, cytosolic DNA viruses are sensed by cyclic GMP-AMP synthase (cGAS), and RNA viruses are recognized by retinoic acid-inducible gene I (RIG-I)-like receptors, triggering a series of downstream innate antiviral signaling steps in the host. We previously reported that measles virus (MeV), which possesses an RNA genome, induces rapid antiviral responses, followed by comprehensive downregulation of host gene expression in epithelial cells. Interestingly, gene ontology analysis indicated that genes encoding mitochondrial proteins are enriched among the list of downregulated genes. To evaluate mitochondrial stress after MeV infection, we first observed the mitochondrial morphology of infected cells and found that significantly elongated mitochondrial networks with a hyperfused phenotype were formed. In addition, an increased amount of mitochondrial DNA (mtDNA) in the cytosol was detected during progression of infection. Based on these results, we show that cytosolic mtDNA released from hyperfused mitochondria during MeV infection is captured by cGAS and causes consequent priming of the DNA sensing pathway in addition to canonical RNA sensing. We also ascertained the contribution of cGAS to the in vivo pathogenicity of MeV. In addition, we found that other viruses that induce downregulation of mitochondrial biogenesis as seen for MeV cause similar mitochondrial hyperfusion and cytosolic mtDNA-priming antiviral responses. These findings indicate that the mtDNA-activated cGAS pathway is critical for full innate control of certain viruses, including RNA viruses that cause mitochondrial stress.     

Alpha(+)-thalassaemia and malarial anaemia

The mechanisms by which alpha(+)-thalassaemia protects against severe malaria, and severe malarial anaemia in particular, are poorly understood. A recent report proposes that the increased count of microcytic and hypochromic erythrocytes in alpha(+)-thalassaemia reduces the haemoglobin decline during acute malaria and, thus, reduces the risk of anaemia. This mechanism might add to further alpha(+)-thalassaemic attributes that are involved in the attenuation of anaemia caused by both acute and chronic Plasmodium infections.     

Water dispersal as an additional pathway to invasions by the primarily wind-dispersed tree <Emphasis Type="Italic">Ailanthus altissima</Emphasis>

Long-distance dispersal is a key process in biological invasions. Previous research has emphasized the role of nonstandard dispersal vectors, but consequences of a change in dispersal vector for the establishment of invasive plant species have received less attention. We analyzed how water-mediated dispersal rather than the more expected wind-mediated dispersal can affect the establishment of the invasive tree Ailanthus altissima in riparian corridors by changing the germination rate and velocity and by providing the option of a new pathway of vegetative propagation. We analyzed the potential of different types of propagules (fruits that have floated or been submerged, current- and second-year stem fragments) to establish new individuals after contact with water for 0, 3, 10, and 20 days. Length and type of seed contact with water led to divergent germination responses. Seeds that had floated for 3 days had an increased level of seed germination (87%), while a 20-day stay in water water-curbed germination to 32% compared to 53% in control. After floatation, the maximum number of emerged seedlings was achieved more than 3 weeks earlier than in all other treatments. In general, the germination was enhanced in floating compared to submerged fruits. Experiments with stem fragments revealed the option of a novel pathway for long-distance dispersal in river corridors: Except for stem fragments that floated for 20 days, 33–75% of buried stem fragments produced adventitious shoots, 10% also set roots. The results suggest that both generative and vegetative propagules of A. altissima can be dispersed at regional scales in river corridors. Hence, water as an additional dispersal vector is expected to enhance invasions by species with wind-dispersed seeds. Our findings suggest the importance of control of initial colonizations in riparian habitats and emphasize the need to include consequences of secondary dispersal when modeling the spread of invasive species.     

The novel sorting nexin SNX33 interferes with cellular PrP formation by modulation of PrP shedding

The cellular prion protein (PrP^c) is a glycosyl-phosphatidylinositol (GPI)-anchored protein trafficking in the secretory and endocytic pathway and localized mainly at the plasma membrane. Conversion of PrP^c into its pathogenic isoform PrP^Sc is associated with pathogenesis and transmission of prion diseases. Intramolecular cleavage in the middle, the extreme C-terminal part or within the GPI anchor and shedding of PrP^c modulate this conversion process by reducing the substrate for prion formation. These phenomena provide similarities with the processing of amyloid precursor protein in Alzheimer's disease. Sorting nexins are a family of proteins with important functions in protein trafficking. In this study, we investigated the role of the newly described sorting nexin 33 (SNX33) in trafficking and processing of PrP^c. We found that overexpression of SNX33 in neuronal and non-neuronal cell lines resulted in increased shedding of full-length PrP^c from the plasma membrane and modulated the rate of PrP^c endocytosis. This was paralleled by reduction of PrP^Sc formation in persistently and newly infected cells. Using deletion mutants, we demonstrate that production of PrP fragment N1 is not influenced by SNX33. Our data provide new insights into the cellular mechanisms of PrP^c shedding and show how this can affect cellular PrP^Sc conversion.     

Bayesian QTL mapping using skewed Student-t distributions

In most QTL mapping studies, phenotypes are assumed to follow normal distributions. Deviations from this assumption may lead to detection of false positive QTL. To improve the robustness of Bayesian QTL mapping methods, the normal distribution for residuals is replaced with a skewed Student-t distribution. The latter distribution is able to account for both heavy tails and skewness, and both components are each controlled by a single parameter. The Bayesian QTL mapping method using a skewed Student-t distribution is evaluated with simulated data sets under five different scenarios of residual error distributions and QTL effects.