The global prevalence of Huntington’s disease: a systematic review and discussion

The ascertained prevalence of Huntington's disease (HD) increased significantly following the provision of diagnostic testing. A systematic review was conducted to estimate the prevalence of HD in the post-diagnostic testing era. Twenty-two studies with original data pertaining to the prevalence of HD (1993–2015) were included and analyzed. A global meta-analysis was not performed due to heterogeneity in study methods and geographical variation. The prevalence of HD is significantly lower in Asian populations compared with western Europe, North America and Australia. The global variation in HD prevalence is partly explained by the average CAG repeat lengths and frequency of different HTT gene haplotypes in the general population. Understanding the prevalence of HD has significant implications for healthcare resource planning

DREB/CBF expression in wheat and barley using the stress-inducible promoters of HD-Zip I genes: impact on plant development, stress tolerance and yield

Networks of transcription factors regulate diverse physiological processes in plants to ensure that plants respond to abiotic stresses rapidly and efficiently. In this study, expression of two DREB/CBF genes, TaDREB3 and TaCBF5L, was modulated in transgenic wheat and barley, by using stress‐responsive promoters HDZI‐3 and HDZI‐4. The promoters were derived from the durum wheat genes encoding the γ‐clade TFs of the HD‐Zip class I subfamily. The activities of tested promoters were induced by drought and cold in leaves of both transgenic species. Differences in sensitivity of promoters to drought strength were dependent on drought tolerance levels of cultivars used for generation of transgenic lines. Expression of the DREB/CBF genes under both promoters improved drought and frost tolerance of transgenic barley, and frost tolerance of transgenic wheat seedlings. Expression levels of the putative TaCBF5L downstream genes in leaves of transgenic wheat seedlings were up‐regulated under severe drought, and up‐ or down‐regulated under frost, compared to those of control seedlings. The application of TaCBF5L driven by the HDZI‐4 promoter led to the significant increase of the grain yield of transgenic wheat, compared to that of the control wild‐type plants, when severe drought was applied during flowering; although no yield improvements were observed when plants grew under well‐watered conditions or moderate drought. Our findings suggest that the studied HDZI promoters combined with the DREB/CBF factors could be used in transgenic cereal plants for improvement of abiotic stress tolerance, and the reduction of negative influence of transgenes on plant development and grain yields

Gene expression profiling reveals different pathways related to Abl and other genes that cooperate with c-Myc in a model of plasma cell neoplasia

<p>Abstract</p> <p>Background</p> <p>To elucidate the genes involved in the neoplastic transformation of B cells, global gene expression profiles were generated using Affymetrix U74Av2 microarrays, containing 12,488 genes, for four different groups of mouse B-cell lymphomas and six subtypes of pristane-induced mouse plasma cell tumors, three of which developed much earlier than the others.</p> <p>Results</p> <p>Unsupervised hierarchical cluster analysis exhibited two main sub-clusters of samples: a B-cell lymphoma cluster and a plasma cell tumor cluster with subclusters reflecting mechanism of induction. This report represents the first step in using global gene expression to investigate molecular signatures related to the role of cooperating oncogenes in a model of Myc-induced carcinogenesis. Within a single subgroup, e.g., ABPCs, plasma cell tumors that contained typical T(12;15) chromosomal translocations did not display gene expression patterns distinct from those with variant T(6;15) translocations, in which the breakpoint was in the <it>Pvt-1 </it>locus, 230 kb 3' of c-<it>Myc</it>, suggesting that c-<it>Myc </it>activation was the initiating factor in both. When integrated with previously published Affymetrix array data from human multiple myelomas, the IL-6-transgenic subset of mouse plasma cell tumors clustered more closely with MM1 subsets of human myelomas, slow-appearing plasma cell tumors clustered together with MM2, while plasma cell tumors accelerated by v-Abl clustered with the more aggressive MM3-MM4 myeloma subsets. Slow-appearing plasma cell tumors expressed <it>Socs1 </it>and <it>Socs2 </it>but v-<it>Abl</it>-accelerated plasma cell tumors expressed 4–5 times as much. Both v-<it>Abl</it>-accelerated and non-v-<it>Ab</it>l-associated tumors exhibited phosphorylated STAT 1 and 3, but only v-Abl-accelerated plasma cell tumors lost viability and STAT 1 and 3 phosphorylation when cultured in the presence of the v-Abl kinase inhibitor, STI-571. These data suggest that the Jak/Stat pathway was critical in the transformation acceleration by v-Abl and that v-Abl activity remained essential throughout the life of the tumors, not just in their acceleration. A different pathway appears to predominate in the more slowly arising plasma cell tumors.</p> <p>Conclusion</p> <p>Gene expression profiling differentiates not only B-cell lymphomas from plasma cell tumors but also distinguishes slow from accelerated plasma cell tumors. These data and those obtained from the sensitivity of v-Abl-accelerated plasma cell tumors and their phosphorylated STAT proteins indicate that these similar tumors utilize different signaling pathways but share a common initiating genetic lesion, a c-<it>Myc</it>-activating chromosome translocation.</p

Eef1a2 Promotes Cell Growth, Inhibits Apoptosis and Activates JAK/STAT and AKT Signaling in Mouse Plasmacytomas

The canonical function of EEF1A2, normally expressed only in muscle, brain, and heart, is in translational elongation, but recent studies suggest a non-canonical function as a proto-oncogene that is overexpressed in a variety of solid tumors including breast and ovary. Transcriptional profiling of a spectrum of primary mouse B cell lineage neoplasms showed that transcripts encoding EEF1A2 were uniquely overexpressed in plasmacytomas (PCT), tumors of mature plasma cells. Cases of human multiple myeloma expressed significantly higher levels of EEF1A2 transcripts than normal bone marrow plasma cells. High-level expression was also a feature of a subset of cell lines developed from mouse PCT and from the human MM.Heightened expression of EEF1A2 was not associated with increased copy number or coding sequence mutations. shRNA-mediated knockdown of Eef1a2 transcripts and protein was associated with growth inhibition due to delayed G1-S progression, and effects on apoptosis that were seen only under serum-starved conditions. Transcriptional profiles and western blot analyses of knockdown cells revealed impaired JAK/STAT and PI3K/AKT signaling suggesting their contributions to EEF1A2-mediated effects on PCT induction or progression.EEF1A2 may play contribute to the induction or progression of some PCT and a small percentage of MM. Eef1a2 could also prove to be a useful new marker for a subset of MM and, ultimately, a possible target for therapy

Challenges in QCD matter physics - The Compressed Baryonic Matter experiment at FAIR

Substantial experimental and theoretical efforts worldwide are devoted to explore the phase diagram of strongly interacting matter. At LHC and top RHIC energies, QCD matter is studied at very high temperatures and nearly vanishing net-baryon densities. There is evidence that a Quark-Gluon-Plasma (QGP) was created at experiments at RHIC and LHC. The transition from the QGP back to the hadron gas is found to be a smooth cross over. For larger net-baryon densities and lower temperatures, it is expected that the QCD phase diagram exhibits a rich structure, such as a first-order phase transition between hadronic and partonic matter which terminates in a critical point, or exotic phases like quarkyonic matter. The discovery of these landmarks would be a breakthrough in our understanding of the strong interaction and is therefore in the focus of various high-energy heavy-ion research programs. The Compressed Baryonic Matter (CBM) experiment at FAIR will play a unique role in the exploration of the QCD phase diagram in the region of high net-baryon densities, because it is designed to run at unprecedented interaction rates. High-rate operation is the key prerequisite for high-precision measurements of multi-differential observables and of rare diagnostic probes which are sensitive to the dense phase of the nuclear fireball. The goal of the CBM experiment at SIS100 (sqrt(s_NN) = 2.7 - 4.9 GeV) is to discover fundamental properties of QCD matter: the phase structure at large baryon-chemical potentials (mu_B > 500 MeV), effects of chiral symmetry, and the equation-of-state at high density as it is expected to occur in the core of neutron stars. In this article, we review the motivation for and the physics programme of CBM, including activities before the start of data taking in 2022, in the context of the worldwide efforts to explore high-density QCD matter.Comment: 15 pages, 11 figures. Published in European Physical Journal

Kidins220/ARMS is an essential modulator of cardiovascular and nervous system development

The growth factor family of neurotrophins has major roles both inside and outside the nervous system. Here, we report a detailed histological analysis of key phenotypes generated by the ablation of the Kinase D interacting substrate of 220 kDa/Ankyrin repeat-rich membrane spanning (Kidins220/ARMS) protein, a membrane-anchored scaffold for the neurotrophin receptors Trk and p75NTR. Kidins220 is important for heart development, as shown by the severe defects in the outflow tract and ventricle wall formation displayed by the Kidins220 mutant mice. Kidins220 is also important for peripheral nervous system development, as the loss of Kidins220 in vivo caused extensive apoptosis of DRGs and other sensory ganglia. Moreover, the neuronal-specific deletion of this protein leads to early postnatal death, showing that Kidins220 also has a critical function in the postnatal brain

Stromal Interferon-γ Signaling and Cross-Presentation Are Required to Eliminate Antigen-Loss Variants of B Cell Lymphomas in Mice

To study mechanisms of T cell-mediated rejection of B cell lymphomas, we developed a murine lymphoma model wherein three potential rejection antigens, human c-MYC, chicken ovalbumin (OVA), and GFP are expressed. After transfer into wild-type mice 60–70% of systemically growing lymphomas expressing all three antigens were rejected; lymphomas expressing only human c-MYC protein were not rejected. OVA expressing lymphomas were infiltrated by T cells, showed MHC class I and II upregulation, and lost antigen expression, indicating immune escape. In contrast to wild-type recipients, 80–100% of STAT1-, IFN-γ-, or IFN-γ receptor-deficient recipients died of lymphoma, indicating that host IFN-γ signaling is critical for rejection. Lymphomas arising in IFN-γ- and IFN-γ-receptor-deficient mice had invariably lost antigen expression, suggesting that poor overall survival of these recipients was due to inefficient elimination of antigen-negative lymphoma variants. Antigen-dependent eradication of lymphoma cells in wild-type animals was dependent on cross-presentation of antigen by cells of the tumor stroma. These findings provide first evidence for an important role of the tumor stroma in T cell-mediated control of hematologic neoplasias and highlight the importance of incorporating stroma-targeting strategies into future immunotherapeutic approaches

Synergistic Activation of Dopamine D1 and TrkB Receptors Mediate Gain Control of Synaptic Plasticity in the Basolateral Amygdala

Fear memory formation is thought to require dopamine, brain-derived neurotrophic factor (BDNF) and zinc release in the basolateral amygdala (BLA), as well as the induction of long term potentiation (LTP) in BLA principal neurons. However, no study to date has shown any relationship between these processes in the BLA. Here, we have used in vitro whole-cell patch clamp recording from BLA principal neurons to investigate how dopamine, BDNF, and zinc release may interact to modulate the LTP induction in the BLA. LTP was induced by either theta burst stimulation (TBS) protocol or spaced 5 times high frequency stimulation (5xHFS). Significantly, both TBS and 5xHFS induced LTP was fully blocked by the dopamine D1 receptor antagonist, SCH23390. LTP induction was also blocked by the BDNF scavenger, TrkB-FC, the zinc chelator, DETC, as well as by an inhibitor of matrix metalloproteinases (MMPs), gallardin. Conversely, prior application of the dopamine reuptake inhibitor, GBR12783, or the D1 receptor agonist, SKF39393, induced robust and stable LTP in response to a sub-threshold HFS protocol (2xHFS), which does not normally induce LTP. Similarly, prior activation of TrkB receptors with either a TrkB receptor agonist, or BDNF, also reduced the threshold for LTP-induction, an effect that was blocked by the MEK inhibitor, but not by zinc chelation. Intriguingly, the TrkB receptor agonist-induced reduction of LTP threshold was fully blocked by prior application of SCH23390, and the reduction of LTP threshold induced by GBR12783 was blocked by prior application of TrkB-FC. Together, our results suggest a cellular mechanism whereby the threshold for LTP induction in BLA principal neurons is critically dependent on the level of dopamine in the extracellular milieu and the synergistic activation of postsynaptic D1 and TrkB receptors. Moreover, activation of TrkB receptors appears to be dependent on concurrent release of zinc and activation of MMPs

An Epstein-Barr Virus Anti-Apoptotic Protein Constitutively Expressed in Transformed Cells and Implicated in Burkitt Lymphomagenesis: The Wp/BHRF1 Link

Two factors contribute to Burkitt lymphoma (BL) pathogenesis, a chromosomal translocation leading to c-myc oncogene deregulation and infection with Epstein-Barr virus (EBV). Although the virus has B cell growth–transforming ability, this may not relate to its role in BL since many of the transforming proteins are not expressed in the tumor. Mounting evidence supports an alternative role, whereby EBV counteracts the high apoptotic sensitivity inherent to the c-myc–driven growth program. In that regard, a subset of BLs carry virus mutants in a novel form of latent infection that provides unusually strong resistance to apoptosis. Uniquely, these virus mutants use Wp (a viral promoter normally activated early in B cell transformation) and express a broader-than-usual range of latent antigens. Here, using an inducible system to express the candidate antigens, we show that this marked apoptosis resistance is mediated not by one of the extended range of EBNAs seen in Wp-restricted latency but by Wp-driven expression of the viral bcl2 homologue, BHRF1, a protein usually associated with the virus lytic cycle. Interestingly, this Wp/BHRF1 connection is not confined to Wp-restricted BLs but appears integral to normal B cell transformation by EBV. We find that the BHRF1 gene expression recently reported in newly infected B cells is temporally linked to Wp activation and the presence of W/BHRF1-spliced transcripts. Furthermore, just as Wp activity is never completely eclipsed in in vitro–transformed lines, low-level BHRF1 transcripts remain detectable in these cells long-term. Most importantly, recognition by BHRF1-specific T cells confirms that such lines continue to express the protein independently of any lytic cycle entry. This work therefore provides the first evidence that BHRF1, the EBV bcl2 homologue, is constitutively expressed as a latent protein in growth-transformed cells in vitro and, in the context of Wp-restricted BL, may contribute to virus-associated lymphomagenesis in vivo

Activation-Induced Cytidine Deaminase Expression in CD4+ T Cells is Associated with a Unique IL-10-Producing Subset that Increases with Age

Activation-induced cytidine deaminase (AID), produced by the Aicda gene, is essential for the immunoglobulin gene (Ig) alterations that form immune memory. Using a Cre-mediated genetic system, we unexpectedly found CD4+ T cells that had expressed Aicda (exAID cells) as well as B cells. ExAID cells increased with age, reaching up to 25% of the CD4+ and B220+ cell populations. ExAID B cells remained IgM+, suggesting that class-switched memory B cells do not accumulate in the spleen. In T cells, AID was expressed in a subset that produced IFN-γ and IL-10 but little IL-4 or IL-17, and showed no evidence of genetic mutation. Interestingly, the endogenous Aicda expression in T cells was enhanced in the absence of B cells, indicating that the process is independent from the germinal center reaction. These results suggest that in addition to its roles in B cells, AID may have previously unappreciated roles in T-cell function or tumorigenesis