The growth threshold conjecture: a theoretical framework for understanding T-cell tolerance

Adaptive immune responses depend on the capacity of T cells to target specific antigens. As similar antigens can be expressed by pathogens and host cells, the question naturally arises of how can T cells discriminate friends from foes. In this work, we suggest that T cells tolerate cells whose proliferation rates remain below a permitted threshold. Our proposal relies on well-established facts about T-cell dynamics during acute infections: T-cell populations are elastic (they expand and contract) and they display inertia (contraction is delayed relative to antigen removal). By modelling inertia and elasticity, we show that tolerance to slow-growing populations can emerge as a population-scale feature of T cells. This result suggests a theoretical framework to understand immune tolerance that goes beyond the self versus non-self dichotomy.M.A.H. has been partially supported by MINECO grant no. MTM2014-53156. The rest of the authors have not received any particular financial support for this work

Metabarcoding of insect-associated fungal communities: a comparison of internal transcribed spacer (ITS) and large-subunit (LSU) rRNA markers

Full taxonomic characterisation of fungal communities is necessary for establishing ecological associations and early detection of pathogens and invasive species. Complex communities of fungi are regularly characterised by metabarcoding using the Internal Transcribed Spacer (ITS) and the Large-Subunit (LSU) gene of the rRNA locus, but reliance on a single short sequence fragment limits the confidence of identification. Here we link metabarcoding from the ITS2 and LSU D1-D2 regions to characterise fungal communities associated with bark beetles (Scolytinae), the likely vectors of several tree pathogens. Both markers revealed similar patterns of overall species richness and response to key variables (beetle species, forest type), but identification against the respective reference databases using various taxonomic classifiers revealed poor resolution towards lower taxonomic levels, especially the species level. Thus, Operational Taxonomic Units (OTUs) could not be linked via taxonomic classifiers across ITS and LSU fragments. However, using phylogenetic trees (focused on the epidemiologically important Sordariomycetes) we placed OTUs obtained with either marker relative to reference sequences of the entire rRNA cistron that includes both loci and demonstrated the largely similar phylogenetic distribution of ITS and LSU-derived OTUs. Sensitivity analysis of congruence in both markers suggested the biologically most defensible threshold values for OTU delimitation in Sordariomycetes to be 98% for ITS2 and 99% for LSU D1-D2. Studies of fungal communities using the canonical ITS barcode require corroboration across additional loci. Phylogenetic analysis of OTU sequences aligned to the full rRNA cistron shows higher success rate and greater accuracy of species identification compared to probabilistic taxonomic classifiers

Genome-wide association study of regional brain volume suggests involvement of known psychiatry candidate genes, identified new candidates for psychiatric disorders and points to potential modes of their action

Though most psychiatric disorders are highly heritable, it has been hard to identify genetic risk factors involved, which are most likely of small individual effect size. A possible way to aid identification of risk genes is the use of intermediate phenotypes. These are supposed to be closer to the biological substrate(s) of the disorder than psychiatric diagnoses, and therefore less genetically complex. Intermediate phenotypes can be defined e. g. at the level of brain function and of regional brain structure. Both are highly heritable, and regional brain structure is linked to brain function. Within the Brain Imaging Genetics (BIG) study at the Radboud University Nijmegen (Medical Centre) we performed a genome-wide association study (GWAS) in 1000 of the currently 1400 healthy study participants. For all BIG participants, structural MRI brain images were available. Gray and white matter volumes were determined by brain segmentation using SPM software. FSL-FIRST was used to assess volumes of specific brain structures. Genotyping was performed on Affymetrix 6.0 arrays. Results implicate known candidates from earlier GWAS and candidate gene studies in mental disorders in the regulation of regional brain structure. E. g. polymorphisms in CDH13, featuring among the top-findings of GWAS in disorders including ADHD, addiction and schizophrenia, were found associated with amygdala volume. The ADHD candidate gene SNAP25 was found associated with total brain volume. In conclusion, the use of intermediate phenotypes based on (subcortical) brain volumes may shed more light on pathways from genes to diseases, but can also be expected to facilitate gene identification in psychiatric disorders

Asylum seeker’s ‘brain death’ shows failure of care and of democracy

The news that Hamid Kehazaei, a 24-year-old Iranian asylum seeker detained on Manus Island, has been diagnosed as brain dead following his transfer to the Mater Hospital in Brisbane is a tragedy. That it is a tragedy for this young man and his family is unquestionable – but the extent of this tragedy may be much more pervasive than we realise. If the emerging details of his case are correct, Kehazaei developed septicaemia as a complication of cellulitis (skin and soft-tissue infection) arising from a cut in his foot. This, in itself, is disturbing. Severe infection can result in brain death – either from infection of the brain itself (meningitis, encephalitis or brain abscess), or from brain injury due to a lack of oxygen resulting from cardiac arrest (as appears to be the case here), or from reduced blood supply to the brain. Yet it is very uncommon, especially in a young, previously healthy man. Such a case could occur in Australia and has been described in 2012 in young Indigenous adults in Central Australia. Nevertheless, severe sepsis resulting from a foot infection is preventable. And a case like this occurring in an Australian national would raise serious questions about the appropriateness of the antibiotics used and the timeliness of care. Most cases of brain death result from traumatic brain injury, stroke or lack of oxygen to the brain following asphyxia, near-drowning, or prolonged cardiopulmonary resuscitation. What happened to Hamid Kehazaei raises concerns about the adequacy of care provided to him during initial treatment, including wound care and antibiotics, and how soon he was transferred to expert medical care, first to Port Moresby and subsequently to Brisbane. If this young man became ill and had his brain die while seeking asylum in Australia and while in our care, then we must examine the details of his case and ask ourselves not only whether it was preventable but whether our policies and processes actually contributed to his death

The Proteasomal Deubiquitinating Enzyme PSMD14 Regulates Macroautophagy by Controlling Golgi-to-ER Retrograde Transport

Ubiquitination regulates several biological processes, however the role of specific members of the ubiquitinome on intracellular membrane trafficking is not yet fully understood. Here, we search for ubiquitin-related genes implicated in protein membrane trafficking performing a High-Content siRNA Screening including 1187 genes of the human “ubiquitinome” using amyloid precursor protein (APP) as a reporter. We identified the deubiquitinating enzyme PSMD14, a subunit of the 19S regulatory particle of the proteasome, specific for K63-Ub chains in cells, as a novel regulator of Golgi-to-endoplasmic reticulum (ER) retrograde transport. Silencing or pharmacological inhibition of PSMD14 with Capzimin (CZM) caused a robust increase in APP levels at the Golgi apparatus and the swelling of this organelle. We showed that this phenotype is the result of rapid inhibition of Golgi-to-ER retrograde transport, a pathway implicated in the early steps of the autophagosomal formation. Indeed, we observed that inhibition of PSMD14 with CZM acts as a potent blocker of macroautophagy by a mechanism related to the retention of Atg9A and Rab1A at the Golgi apparatus. As pharmacological inhibition of the proteolytic core of the 20S proteasome did not recapitulate these effects, we concluded that PSMD14, and the K63-Ub chains, act as a crucial regulatory factor for macroautophagy by controlling Golgi-to-ER retrograde transport

TECHNIQUES FOR THE STUDY OF THE STRUCTURAL PROPERTIES.

The evolution of our understanding of the behavior of oxide nanostructures depends heavily on the structural information obtained from a wide range of physical methods traditionally used in solid state physics, surface science and inorganic chemistry. In this chapter, we describe several techniques that are useful for the characterization of the structural properties of oxide nanostructures: X-ray diffraction (XRD) and scattering, X-ray absorption fine structure (XAFS), Raman spectroscopy, transmission electron microscopy (TEM), scanning tunneling microscopy (STM) and atomic force microscopy (AFM). The ultimate goal is to obtain information about the spatial arrangement of atoms in the nanostructures with precise interatomic distances and bond angles. This may not be possible for complex systems and one may get only partial information about the local geometry or morphology