Spatial dysregulation of T follicular helper cells impairs vaccine responses in aging.

The magnitude and quality of the germinal center (GC) response decline with age, resulting in poor vaccine-induced immunity in older individuals. A functional GC requires the co-ordination of multiple cell types across time and space, in particular across its two functionally distinct compartments: the light and dark zones. In aged mice, there is CXCR4-mediated mislocalization of T follicular helper (TFH) cells to the dark zone and a compressed network of follicular dendritic cells (FDCs) in the light zone. Here we show that TFH cell localization is critical for the quality of the antibody response and for the expansion of the FDC network upon immunization. The smaller GC and compressed FDC network in aged mice were corrected by provision of TFH cells that colocalize with FDCs using CXCR5. This demonstrates that the age-dependent defects in the GC response are reversible and shows that TFH cells support stromal cell responses to vaccines

A probable case of diffuse idiopathic skeletal hyperostosis from an early modern crypt in Eastern Germany

Diffuse idiopathic skeletal hyperostosis (DISH) is a non-inflammatory joint disease mainly characterised by the ossification of the right anterior longitudinal ligament and the presence of enthesopathies. Studies have shown that the disease typically affects malesof advanced age. This is a case report of a female individual, aged between 40-60 years, dating to 1472-1635 AD and found in Eastern Germany. A differential diagnosis was completedfollowing macroscopic examination and radiographicimaging of the affected bones. The resultsshowseveral pathological features that resemble skeletal characteristicsof DISH, besides other diseases. Therefore, we discuss DISH and provide a differential diagnosis of additional pathologies. Our case is particularly important becauseancient female DISH cases are underrepresented and the burial location indicatesa possible noble or monastic context, both linkedwith a lifestyle knownto be related to DISH

Antibodies inhibit transmission and aggregation of <em>C9orf72</em> poly-GA dipeptide repeat proteins.

Cell-to-cell transmission of protein aggregates is an emerging theme in neurodegenerative disease. Here, we analyze the dipeptide repeat (DPR) proteins that form neuronal inclusions in patients with hexanucleotide repeat expansion C9orf72, the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Sense and antisense transcripts of the (G4C2)n repeat are translated by repeat-associated non-ATG (RAN) translation in all reading frames into five aggregating DPR proteins. We show that the hydrophobic DPR proteins poly-GA, poly-GP, and poly-PA are transmitted between cells using co-culture assays and cell extracts. Moreover, uptake or expression of poly-GA induces nuclear RNA foci in (G4C2)80-expressing cells and patient fibroblasts, suggesting an unexpected positive feedback loop. Exposure to recombinant poly-GA and cerebellar extracts of C9orf72 patients increases repeat RNA levels and seeds aggregation of all DPR proteins in receiver cells expressing (G4C2)80 Treatment with anti-GA antibodies inhibits intracellular poly-GA aggregation and blocks the seeding activity of C9orf72 brain extracts. Poly-GA-directed immunotherapy may thus reduce DPR aggregation and disease progression in C9orf72 ALS/FTD

Roquin suppresses the PI3K-mTOR signaling pathway to inhibit T helper cell differentiation and conversion of treg to Tfr cells.

Roquin proteins preclude spontaneous T cell activation and aberrant differentiation of T follicular helper (Tfh) or T helper 17 (Th17) cells. Here we showed that deletion of Roquin-encoding alleles specifically in regulatory T (Treg) cells also caused the activation of conventional T cells. Roquin-deficient Treg cells downregulated CD25, acquired a follicular Treg (Tfr) cell phenotype, and suppressed germinal center reactions but could not protect from colitis. Roquin inhibited the PI3K-mTOR signaling pathway by upregulation of Pten through interfering with miR-17 92 binding to an overlapping cis-element in the Pten 3&#39; UTR, and downregulated the Foxo1-specific E3 ubiquitin ligase Itch. Loss of Roquin enhan ced Akt-mTOR signaling and protein synthesis, whereas inhibition of PI3K or mTOR in Roquin-deficient T cells corrected enhanced Tfh and Th17 or reduced iTreg cell differentiation. Thereby, Roquin-mediated control of PI3K-mTOR signaling prevents autoimmunity by restraining activation and differentiation of conventional T cells and specialization of Treg cells. Essig et al. show that spontaneous activation and aberrant differentiation of Roquin-deficient T cells involves cell-intrinsic causes in not only conventional T cells but also impaired Treg cell function. In both cell types, Roquin inhibits the PI3K-mTOR signaling pathway at several levels, thereby controlling protein biosynthesis and limiting differentiation toward Th17 and Tfh cells as well as preventing the conversion and functional specialization of Treg into Tfr cells

Phylogeography of the second plague pandemic revealed through analysis of historical Yersinia pestis genomes

© 2019, The Author(s). The second plague pandemic, caused by Yersinia pestis, devastated Europe and the nearby regions between the 14th and 18th centuries AD. Here we analyse human remains from ten European archaeological sites spanning this period and reconstruct 34 ancient Y. pestis genomes. Our data support an initial entry of the bacterium through eastern Europe, the absence of genetic diversity during the Black Death, and low within-outbreak diversity thereafter. Analysis of post-Black Death genomes shows the diversification of a Y. pestis lineage into multiple genetically distinct clades that may have given rise to more than one disease reservoir in, or close to, Europe. In addition, we show the loss of a genomic region that includes virulence-related genes in strains associated with late stages of the pandemic. The deletion was also identified in genomes connected with the first plague pandemic (541–750 AD), suggesting a comparable evolutionary trajectory of Y. pestis during both events

Phylogeography of the second plague pandemic revealed through analysis of historical Yersinia pestis genomes

© 2019, The Author(s). The second plague pandemic, caused by Yersinia pestis, devastated Europe and the nearby regions between the 14th and 18th centuries AD. Here we analyse human remains from ten European archaeological sites spanning this period and reconstruct 34 ancient Y. pestis genomes. Our data support an initial entry of the bacterium through eastern Europe, the absence of genetic diversity during the Black Death, and low within-outbreak diversity thereafter. Analysis of post-Black Death genomes shows the diversification of a Y. pestis lineage into multiple genetically distinct clades that may have given rise to more than one disease reservoir in, or close to, Europe. In addition, we show the loss of a genomic region that includes virulence-related genes in strains associated with late stages of the pandemic. The deletion was also identified in genomes connected with the first plague pandemic (541–750 AD), suggesting a comparable evolutionary trajectory of Y. pestis during both events

The Woman from Leuk (Switzerland)—Discovery, Conservation, and Interdisciplinary Investigations of a Seventeenth-Century Mummy

During the excavation of St. Stephan’s Church in Leuk (Switzerland) in the 1980s, a wellpreserved mummy with clothing and shoes was found in a wooden coffin. Subsequently, the Mummy underwent restoration, but the observations have never been published. Therefore, an interdisciplinary Investigation was recently organized that included a thorough archaeological and anthropological documentation in collaboration with specialists in costume history and leatherworking. The aim was to gather evidence for the dating and preservation mechanism, as well as to determine the biological profile of the individual. The investigation was accompanied by a noninvasive examination with a mobile x-ray device, which enabled identification of sex, age, Body height, and pathologies. The clothing (cape, blouse, skirt, drawers) and the shoes were subjected to a detailed stylistic and technological examination. The individual is female, aged 45–60 years, with foot deformities that might be related to constricting footwear. Stylistic details of the shoes indicate that the burial dates from the first half of the 17th century, more precisely to the 1630s. Despite her simple clothing, the burial location attests to her respected position in society

Troubles in Tuva: Patterns of perimortem trauma in a nomadic community from Southern Siberia (second to fourth c. CE

Objectives: Warfare is assumed to be one of the defining cultural characteristics of steppe nomads in Eastern Eurasia. For the first-centuries CE, a period of political turmoil in Northern China and Southern Siberia, relatively few data are, however, available about the degree and variability of violence in these communities. Here, we provide new data on violence among steppe nomads during the firstcenturies CE by analyzing the type, anatomical distribution, and demographic distribution of perimortem trauma at Tunnug1 (Tuva, Southern Siberia—second to fourth c. CE). Materials and Methods: Perimortem traumas were assessed on 87 individuals representing both sexes and different age classes. The timing of the lesions was assessed based on morphological criteria, including the absence and presence of bone reactive processes and the relative plasticity of the bone at the moment of impact. The distribution by age, sex, and anatomical location of trauma was analyzed by means of logistic models, Fisher's exact tests, and 3D visualizations. Results: A total of 130 perimortem traumas, including chop marks, slice marks, penetrating lesions, and blunt traumas were identified on 22 individuals. Chop marks were mostly at the level of the skull and vertebrae and were likely caused by bladed weapons. Slice marks were found on the cervical vertebrae and cranium and may be the result of throat slitting and scalping by means of smaller bladed implements. Traumas were more frequent in males, and their presence is not correlated with age. Discussion: This study adds new data to the few available regarding violence among steppe nomadic cultures and provides new insights about the effects of political instability on the life of the people inhabiting Eastern Eurasia during the early centuries CE