Treg and Oligoclonal Expansion of Terminal Effector CD8+ T Cell as Key Players in Multiple Myeloma

The classical paradigm of host-tumor interaction, i.e. elimination, equilibrium, and escape (EEE), is reflected in the clinical behavior of myeloma which progresses from the premalignant condition, Monoclonal Gammopathy of Unknown Significance (MGUS). Despite the role of other immune cells, CD4+ regulatory T cells (Treg) and cytotoxic CD8+ T cells have emerged as the dominant effectors of host control of the myeloma clone. Progression from MGUS to myeloma is associated with alterations in Tregs and terminal effector CD8+ T cells (TTE). These changes involve CD39 and CD69 expression, affecting the adenosine pathway and residency in the bone marrow (BM) microenvironment, together with oligoclonal expansion within CD8+ TTE cells. In this mini-review article, in the context of earlier data, we summarize our recent understanding of Treg involvement in the adenosine pathway, the significance of oligoclonal expansion within CD8+ TTE cells and BM-residency of CD8+ TTE cells in MGUS and newly diagnosed multiple myeloma patients

Turnip mosaic potyvirus probably first spread to Eurasian brassica crops from wild orchids about 1000 years ago

Turnip mosaic potyvirus (TuMV) is probably the most widespread and damaging virus that infects cultivated brassicas worldwide. Previous work has indicated that the virus originated in western Eurasia, with all of its closest relatives being viruses of monocotyledonous plants. Here we report that we have identified a sister lineage of TuMV-like potyviruses (TuMV-OM) from European orchids. The isolates of TuMV-OM form a monophyletic sister lineage to the brassica-infecting TuMVs (TuMV-BIs), and are nested within a clade of monocotyledon-infecting viruses. Extensive host-range tests showed that all of the TuMV-OMs are biologically similar to, but distinct from, TuMV-BIs and do not readily infect brassicas. We conclude that it is more likely that TuMV evolved from a TuMV-OM-like ancestor than the reverse. We did Bayesian coalescent analyses using a combination of novel and published sequence data from four TuMV genes [helper component-proteinase protein (HC-Pro), protein 3(P3), nuclear inclusion b protein (NIb), and coat protein (CP)]. Three genes (HC-Pro, P3, and NIb), but not the CP gene, gave results indicating that the TuMV-BI viruses diverged from TuMV-OMs around 1000 years ago. Only 150 years later, the four lineages of the present global population of TuMV-BIs diverged from one another. These dates are congruent with historical records of the spread of agriculture in Western Europe. From about 1200 years ago, there was a warming of the climate, and agriculture and the human population of the region greatly increased. Farming replaced woodlands, fostering viruses and aphid vectors that could invade the crops, which included several brassica cultivars and weeds. Later, starting 500 years ago, inter-continental maritime trade probably spread the TuMV-BIs to the remainder of the world

The frequency of osteogenic activities and the pattern of intermittence between periods of physical activity and sedentary behaviour affects bone mineral content: the cross-sectional NHANES study

BACKGROUND: Sedentary behaviours, defined as non exercising seated activities, have been shown to have deleterious effects on health. It has been hypothesised that too much sitting time can have a detrimental effect on bone health in youth. The aim of this study is to test this hypothesis by exploring the association between objectively measured volume and patterns of time spent in sedentary behaviours, time spent in specific screen-based sedentary pursuits and bone mineral content (BMC) accrual in youth. METHODS: NHANES 2005–2006 cycle data includes BMC of the femoral and spinal region via dual-energy X-ray absorptiometry (DEXA), assessment of physical activity and sedentary behaviour patterns through accelerometry, self reported time spent in screen based pursuits (watching TV and using a computer), and frequency of vigorous playtime and strengthening activities. Multiple regression analysis, stratified by gender was performed on N = 671 males and N = 677 females aged from 8 to 22 years. RESULTS: Time spent in screen-based sedentary behaviours is negatively associated with femoral BMC (males and females) and spinal BMC (females only) after correction for time spent in moderate and vigorous activity. Regression coefficients indicate that an additional hour per day of screen-based sitting corresponds to a difference of −0.77 g femoral BMC in females [95% CI: -1.31 to −0.22] and of −0.45 g femoral BMC in males [95% CI: -0.83 to −0.06]. This association is attenuated when self-reported engagement in regular (average 5 times per week) strengthening exercise (for males) and vigorous playing (for both males and females) is taken into account. Total sitting time and non screen-based sitting do not appear to have a negative association with BMC, whereas screen based sedentary time does. Patterns of intermittence between periods of sitting and moderate to vigorous activity appears to be positively associated with bone health when activity is clustered in time and inter-spaced with long continuous bouts of sitting. CONCLUSIONS: Some specific sedentary pursuits (screen-based) are negatively associated with bone health in youth. This association is specific to gender and anatomical area. This relationship between screen-based time and bone health is independent of the total amount of physical activity measured objectively, but not independent of self-reported frequency of strengthening and vigorous play activities. The data clearly suggests that the frequency, rather than the volume, of osteogenic activities is important in counteracting the effect of sedentary behaviour on bone health. The pattern of intermittence between sedentary periods and activity also plays a role in bone accrual, with clustered short bouts of activity interspaced with long periods of sedentary behaviours appearing to be more beneficial than activities more evenly spread in time

Cooling of Dark-Matter Admixed Neutron Stars with density-dependent Equation of State

We propose a dark-matter (DM) admixed density-dependent equation of state where the fermionic DM interacts with the nucleons via Higgs portal. Presence of DM can hardly influence the particle distribution inside neutron star (NS) but can significantly affect the structure as well as equation of state (EOS) of NS. Introduction of DM inside NS softens the equation of state. We explored the effect of variation of DM mass and DM Fermi momentum on the NS EOS. Moreover, DM-Higgs coupling is constrained using dark matter direct detection experiments. Then, we studied cooling of normal NSs using APR and DD2 EOSs and DM admixed NSs using dark-matter modified DD2 with varying DM mass and Fermi momentum. We have done our analysis by considering different NS masses. Also DM mass and DM Fermi momentum are varied for fixed NS mass and DM-Higgs coupling. We calculated the variations of luminosity and temperature of NS with time for all EOSs considered in our work and then compared our calculations with the observed astronomical cooling data of pulsars namely Cas A, RX J0822-43, 1E 1207-52, RX J0002+62, XMMU J17328, PSR B1706-44, Vela, PSR B2334+61, PSR B0656+14, Geminga, PSR B1055-52 and RX J0720.4-3125. It is found that APR EOS agrees well with the pulsar data for lighter and medium mass NSs but cooling is very fast for heavier NS. For DM admixed DD2 EOS, it is found that for all considered NS masses, all chosen DM masses and Fermi momenta agree well with the observational data of PSR B0656+14, Geminga, Vela, PSR B1706-44 and PSR B2334+61. Cooling becomes faster as compared to normal NSs in case of increasing DM mass and Fermi momenta. It is infered from the calculations that if low mass super cold NSs are observed in future that may support the fact that heavier WIMP can be present inside neutron stars.Comment: 24 Pages, 15 Figures and 2 Tables. Version accepted in The European Physical Journal

Inverse relationship between oligoclonal expanded CD69- TTE and CD69+ TTE cells in bone marrow of multiple myeloma patients.

CD8+CD57+ terminal effector T (TTE) cells are a component of marrow-infiltrating lymphocytes and may contribute to the altered immune responses in multiple myeloma (MM) patients. We analyzed TTE cells in the bone marrow (BM) and peripheral blood (PB) of age-matched controls and patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM), and newly diagnosed (ND) MM using flow cytometry, mass cytometry, and FlowSOM clustering. TTE cells are heterogeneous in all subjects, with BM containing both CD69- and CD69+ subsets, while only CD69- cells are found in PB. Within the BM-TTE compartment, CD69- and CD69+ cells are found in comparable proportions in controls, while CD69- cells are dominant in MGUS and SMM and predominantly either CD69- or CD69+ cells in NDMM. A positive relationship between CD69+TTE and CD69-TTE cells is observed in the BM of controls, lost in MGUS, and converted to an inverse relationship in NDMM. CD69-TTE cells include multiple oligoclonal expansions of T-cell receptor/Vβ families shared between BM and PB of NDMM. Oligoclonal expanded CD69-TTE cells from the PB include myeloma-reactive cells capable of killing autologous CD38hi plasma cells in vitro, involving degranulation and high expression of perforin and granzyme. In contrast to CD69-TTE cells, oligoclonal expansions are not evident within CD69+TTE cells, which possess low perforin and granzyme expression and high inhibitory checkpoint expression and resemble T resident memory cells. Both CD69-TTE and CD69+TTE cells from the BM of NDMM produce large amounts of the inflammatory cytokines interferon-γ and tumor necrosis factor α. The balance between CD69- and CD69+ cells within the BM-TTE compartment may regulate immune responses in NDMM and contribute to the clinical heterogeneity of the disease

Guillain-Barré syndrome: a century of progress

In 1916, Guillain, Barré and Strohl reported on two cases of acute flaccid paralysis with high cerebrospinal fluid protein levels and normal cell counts — novel findings that identified the disease we now know as Guillain–Barré syndrome (GBS). 100 years on, we have made great progress with the clinical and pathological characterization of GBS. Early clinicopathological and animal studies indicated that GBS was an immune-mediated demyelinating disorder, and that severe GBS could result in secondary axonal injury; the current treatments of plasma exchange and intravenous immunoglobulin, which were developed in the 1980s, are based on this premise. Subsequent work has, however, shown that primary axonal injury can be the underlying disease. The association of Campylobacter jejuni strains has led to confirmation that anti-ganglioside antibodies are pathogenic and that axonal GBS involves an antibody and complement-mediated disruption of nodes of Ranvier, neuromuscular junctions and other neuronal and glial membranes. Now, ongoing clinical trials of the complement inhibitor eculizumab are the first targeted immunotherapy in GBS

Developing a digital intervention for cancer survivors: an evidence-, theory- and person-based approach

This paper illustrates a rigorous approach to developing digital interventions using an evidence-, theory- and person-based approach. Intervention planning included a rapid scoping review which identified cancer survivors’ needs, including barriers and facilitators to intervention success. Review evidence (N=49 papers) informed the intervention’s Guiding Principles, theory-based behavioural analysis and logic model. The intervention was optimised based on feedback on a prototype intervention through interviews (N=96) with cancer survivors and focus groups with NHS staff and cancer charity workers (N=31). Interviews with cancer survivors highlighted barriers to engagement, such as concerns about physical activity worsening fatigue. Focus groups highlighted concerns about support appointment length and how to support distressed participants. Feedback informed intervention modifications, to maximise acceptability, feasibility and likelihood of behaviour change. Our systematic method for understanding user views enabled us to anticipate and address important barriers to engagement. This methodology may be useful to others developing digital interventions

miR-132/212 knockout mice reveal roles for these miRNAs in regulating cortical synaptic transmission and plasticity

miR-132 and miR-212 are two closely related miRNAs encoded in the same intron of a small non-coding gene, which have been suggested to play roles in both immune and neuronal function. We describe here the generation and initial characterisation of a miR-132/212 double knockout mouse. These mice were viable and fertile with no overt adverse phenotype. Analysis of innate immune responses, including TLR-induced cytokine production and IFNβ induction in response to viral infection of primary fibroblasts did not reveal any phenotype in the knockouts. In contrast, the loss of miR-132 and miR-212, while not overtly affecting neuronal morphology, did affect synaptic function. In both hippocampal and neocortical slices miR-132/212 knockout reduced basal synaptic transmission, without affecting paired-pulse facilitation. Hippocampal long-term potentiation (LTP) induced by tetanic stimulation was not affected by miR-132/212 deletion, whilst theta burst LTP was enhanced. In contrast, neocortical theta burst-induced LTP was inhibited by loss of miR-132/212. Together these results indicate that miR-132 and/or miR-212 play a significant role in synaptic function, possibly by regulating the number of postsynaptic AMPA receptors under basal conditions and during activity-dependent synaptic plasticity

Functional and Structural Insights Revealed by Molecular Dynamics Simulations of an Essential RNA Editing Ligase in Trypanosoma brucei

RNA editing ligase 1 (TbREL1) is required for the survival of both the insect and bloodstream forms of Trypanosoma brucei, the parasite responsible for the devastating tropical disease African sleeping sickness. The type of RNA editing that TbREL1 is involved in is unique to the trypanosomes, and no close human homolog is known to exist. In addition, the high-resolution crystal structure revealed several unique features of the active site, making this enzyme a promising target for structure-based drug design. In this work, two 20 ns atomistic molecular dynamics (MD) simulations are employed to investigate the dynamics of TbREL1, both with and without the ATP substrate present. The flexibility of the active site, dynamics of conserved residues and crystallized water molecules, and the interactions between TbREL1 and the ATP substrate are investigated and discussed in the context of TbREL1's function. Differences in local and global motion upon ATP binding suggest that two peripheral loops, unique to the trypanosomes, may be involved in interdomain signaling events. Notably, a significant structural rearrangement of the enzyme's active site occurs during the apo simulations, opening an additional cavity adjacent to the ATP binding site that could be exploited in the development of effective inhibitors directed against this protozoan parasite. Finally, ensemble averaged electrostatics calculations over the MD simulations reveal a novel putative RNA binding site, a discovery that has previously eluded scientists. Ultimately, we use the insights gained through the MD simulations to make several predictions and recommendations, which we anticipate will help direct future experimental studies and structure-based drug discovery efforts against this vital enzyme