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Background Human T-lymphotropic virus type 1 (HTLV-1)–associated myelopathy (HAM) is an inflammatory condition characterized by severe disability and high levels of infected white blood cells. The circulating cellular inflammatory changes that distinguish this condition from asymptomatic infection are not well understood. Methods To investigate the immune characteristics of individuals with low or high HTLV-1 proviral load (pVL), symptomatic disease, and the impact of immunosuppressive therapy, 38 women living with HTLV-1 infection, at a median age of 59 (52–68) years, were studied. Nineteen were asymptomatic carriers with low or high pVL; 19 were diagnosed with HAM, with 10 receiving anti-inflammatory therapy. Peripheral blood mononuclear cells were stained and analyzed for frequency distribution and activation of innate and adaptive immune cell subsets using multiparameter flow cytometry. Results Inflation of the CD4:CD8 ratio (>2) was observed among all groups irrespective of pVL. The frequency of naive CD4+ T cells correlated inversely with HTLV-1 pVL (rs = –0.344, P = .026). Mature T effector memory TEM CD4+ T cells were expanded in patients with untreated HAM compared with asymptomatic carriers (P < .001) but less so in those on therapy. High levels of exhausted (PD-1+) and senescent (CD28null) CD4+ and CD8+ T cells were observed in all individuals, particularly in those with HAM, while monocytes showed increased aggregation and CD14+CD56- monocytes were less frequent. Conclusions CD4:CD8 ratio inflation is a feature of HTLV-1 infection, whereas enhanced CD4+ T cell maturation and monocyte aggregation are features of HAM, reflecting widespread inflammatory change, which may be detectable presymptomatically and be amenable to anti-inflammatory treatment.

Sertoli cells have dual roles during the cells’ lifetime. In the juvenile mammal, Sertoli cells proliferate and create the structure of the testis, and during puberty they cease to proliferate and take on the adult role of supporting germ cells through spermatogenesis. Accordingly, many genes expressed in Sertoli cells during testis formation are repressed during spermatogenesis. 5-Hydroxymethylcytosine (5hmC) is a DNA modification enzymatically generated from 5mC and present in all investigated mammalian tissues at varying levels. Using mass spectrometry and immunofluorescence staining we identified a substantial Sertoli cell-specific global 5hmC increase during rat puberty. Chemical labeling, pull-down and sequencing of 5hmC-containing genomic DNA from juvenile and adult rat Sertoli cells revealed that genes that lose or gain 5hmC belong to different functional pathways and mirror the functions of the cells in the two different states. Loss of 5hmC is associated with genes involved in development and cell structure, whereas gain of 5hmC is associated with genes involved in cellular pathways pertaining to the function of the adult Sertoli cells. This redistribution during maturation shows that 5hmC is a dynamic nucleotide modification, correlated to gene expression. © The Author(s) 2017. This work is licensed under a Creative Commons Attribution 4.0 International License.

Adult-born granule cells (ABGCs) are involved in certain forms of hippocampus-dependent learning and memory. It has been proposed that young but functionally integrated ABGCs (4-weeks-old) specifically contribute to pattern separation functions of the dentate gyrus due to their heightened excitability, whereas old ABGCs (>8 weeks old) lose these capabilities. Measuring multiple cellular and integrative characteristics of 3- 10-week-old individual ABGCs, we show that ABGCs consist of two functionally distinguishable populations showing highly distinct input integration properties (one group being highly sensitive to narrow input intensity ranges while the other group linearly reports input strength) that are largely independent of the cellular age and maturation stage, suggesting that ‘classmate’ cells (born during the same period) can contribute to the network with fundamentally different functions. Thus, ABGCs provide two temporally overlapping but functionally distinct neuronal cell populations, adding a novel level of complexity to our understanding of how life-long neurogenesis contributes to adult brain function. DOI: http://dx.doi.org/10.7554/eLife.03104.001, eLife digest Remembering what happened on different occasions involves a process in the brain called pattern separation, which allows us to separate and distinguish our memories. One part of the brain where pattern separation occurs is called the dentate gyrus, which sits in the hippocampus—the brain region that is in charge of certain forms of learning and memory. Neurons called granule cells are thought to play a central role in hippocampal pattern separation. These cells, unlike the majority of nerve cells, can form at any time, and those that form in the mature brain are called adult born granule cells (ABGCs). Although it usually takes 10 weeks for these cells to fully mature, they are capable of communicating with each other about 3–4 weeks after being generated. Previously, it had been reported that while young, 4-week-old ABGCs are required for pattern separation, slightly older (8 week old) ABGCs are not. What intrinsic properties make ABGCs capable of contributing to pattern separation? Is this property defined by the fate (i.e. a predetermined program) of the cell, or by the cell's experiences and activities? To investigate these questions, Brunner et al. labeled ABGCs with a fluorescent tag when these neurons were born in adult male rats. Then, when the tagged cells were aged between 3 and 10 weeks old, the electrical properties of the labeled cells were measured from thin brain slices. Brunner et al. found that ABGCs respond to input signals with two different levels of sensitivity. The youngest cells (3–5 weeks old) are exceptionally sensitive to a narrow range of input signal strengths, which is useful for pattern separation. The oldest investigated cells (10 weeks old), on the other hand, respond incrementally to a wide range of different input signal strengths. Under these experimental conditions, the cells changed how they respond to input signals some time between 5 and 9 weeks after being born. However, they either behaved like the youngest or like the oldest cells: no intermediate behavior was seen. Unexpectedly, the switch is not directly related to the age of the cells: cells born at the same time don't necessarily change behavior at the same time, and cells born at different times may behave similarly. Thus, Brunner et al. suggest that it is the experience of the cells, and not their fate, that determines how they help the dentate gyrus function during the investigated period. DOI: http://dx.doi.org/10.7554/eLife.03104.002

This review surveys immunocytochemical and histochemical markers of neuronal lineage for application to tissue sections of fetal and neonatal brain. They determine maturation of individual nerve cells as the tissue progresses to mature architecture. From a developmental perspective, neuronal markers are all about timing. These diverse cellular labels may be classified in two ways: 1) time of onset of expression (early; intermediate; late); 2) labeling of subcellular structures or metabolic functions (nucleoproteins; synaptic vesicle proteins; enolases; cytoskeletal elements; calcium-binding; nucleic acids; mitochondria). Apart from these positive markers of maturation, other negative markers are expressed in primitive neuroepithelial cells and early stages of neuroblast maturation, but no longer are demonstrated after initial stages of maturation. These examinations are relevant for studies of normal neuroembryology at the cellular level. In fetal and perinatal neuropathology they provide control criteria for application to malformations of the brain, inborn metabolic disorders and acquired fetal insults in which neuroblastic maturation may be altered. Disorders, in which cells differentiate abnormally, as in tuberous sclerosis and hemimegalencephaly, pose another yet aspect of mixed cellular lineage. The measurement in living patients, especially neonates, of serum and CSF levels of enolases, chromogranins and S-100 proteins as biomarkers of brain damage may potentially be correlated with their corresponding tissue markers at autopsy in infants who do not survive. The neuropathological markers here described can be performed in ordinary hospital laboratories, not just research facilities, and offer another dimension of diagnostic precision in interpreting abnormally developed fetal and postnatal brains.

During heart development, cells from the proepicardial organ spread over the naked heart tube to form the epicardium. From here, epicardium-derived cells (EPDCs) migrate into the myocardium. EPDCs proved to be indispensable for the formation of the ventricular compact zone and myocardial maturation, by largely unknown mechanisms. In this study we investigated in vitro how EPDCs affect cardiomyocyte proliferation, cellular alignment and contraction, as well as the expression and cellular distribution of proteins involved in myocardial maturation. Embryonic quail EPDCs induced proliferation of neonatal mouse cardiomyocytes. This required cell-cell interactions, as proliferation was not observed in transwell cocultures. Western blot analysis showed elevated levels of electrical and mechanical junctions (connexin43, N-cadherin), sarcomeric proteins (Troponin-I, alpha-actinin), extracellular matrix (collagen I and periostin) in cocultures of EPDCs and cardiomyocytes. Immunohistochemistry indicated more membrane-bound expression of Cx43, N-cadherin, the mechanotransduction molecule focal adhesion kinase, and higher expression of the sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a). Newly developed software for analysis of directionality in immunofluorescent stainings showed a quantitatively determined enhanced cellular alignment of cardiomyocytes. This was functionally related to increased contraction. The in vitro effects of EPDCs on cardiomyocytes were confirmed in three reciprocal in vivo models for EPDC-depletion (chicken and mice) in which downregulation of myocardial N-cadherin, Cx43, and FAK were observed. In conclusion, direct interaction of EPDCs with cardiomyocytes induced proliferation, correct mechanical and electrical coupling of cardiomyocytes. ECM-deposition and concurrent establishment of cellular array. These findings implicate that EPDCs are ideal candidates as adjuvant cells for cardiomyocyte integration during cardiac (stem) cell therapy. (c) 2010 Elsevier Ltd. All rights reserved.