The 2b protein of Cucumber mosaic virus has a role in nearly all steps of the viral cycle including cell-to-cell movement, symptom induction and suppression of antiviral RNA silencing. Previous ...studies demonstrated the presence of 2b protein in the nucleus and in cytoplasm as well. Phosphorylation site of 2b protein is conserved in all CMV isolates, including proposed constitute motifs for casein kinase II and cyclin-dependent kinase 2. To discern the impact of 2b protein phosphorylation, we created eight different mutants to mimic the non-phosporylated (serine to alanine) as well as the phosphorylated state (serine to aspartic acid) of the protein. We compared these mutants to the wild-type (Rs-CMV) virus in terms of symptom induction, gene silencing suppressor activity as well as in cellular localization. Here, in this study we confirmed the phosphorylation of 2b protein in vivo, both in infected N. benthamiana and in infiltrated patches. Mutants containing aspartic acid in the phosphorylation site accumulated only in the cytoplasm indicating that phosphorylated 2b protein could not enter the nucleus. We identified a conserved dual phosphorylation switch in CMV 2b protein, which equilibrates the shuttling of the 2b protein between the nucleus and the cytoplasm, and regulates the suppressor activity of the 2b protein.
During the early Cold War, it was difficult for American intelligence to penetrate the Iron Curtain but a potential solution soon arose: émigré intelligence groups such as the Magyar Harcosok ...Bajtársi Közössége (MHBK) or 'Association of Hungarian Veterans'. This group, however, turned out to be an intelligence 'paper mill'. Attempts at trans-Atlantic cooperation with the MHBK and similar groups failed as they lost most of their good sources and were penetrated by communist security services. By the mid-1950s, US intelligence cut these groups off, took over their good sources, and established a source registry to prevent recurrence of the problem.
Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the ...massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs;
< 1 × 10
) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci,
,
,
,
,
, and
associated with MM risk (
= 4.47 × 10
-5.79 × 10
). Mechanistically, we found that the
SNP correlated with circulating concentrations of vitamin D3 (
= 4.0 × 10
), whereas the
SNP correlated with the number of transitional CD24
CD38
B cells (
= 4.8 × 10
) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (
= 3.6 × 10
). We also found that the
SNP correlated with numbers of CD19
B cells, CD19
CD3
B cells, CD5
IgD
cells, IgM
cells, IgD
IgM
cells, and CD4
CD8
PBMCs (
= 4.9 × 10
-8.6 × 10
) and circulating concentrations of interleukin (IL)-20 (
= 0.00082). Finally, we observed that the
SNP correlated with levels of CD4
EMCD45RO
CD27
cells (
= 9.3 × 10
). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3
, MCP-2
, and IL20-dependent pathways.
There is overwhelming epidemiologic evidence that the risk of multiple myeloma (MM) has a solid genetic background. Genome-wide association studies (GWAS) have identified 23 risk loci that contribute ...to the genetic susceptibility of MM, but have low individual penetrance. Combining the SNPs in a polygenic risk score (PRS) is a possible approach to improve their usefulness. Using 2361 MM cases and 1415 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, we computed a weighted and an unweighted PRS. We observed associations with MM risk with OR = 3.44, 95% CI 2.53-4.69, p = 3.55 × 10
for the highest vs. lowest quintile of the weighted score, and OR = 3.18, 95% CI 2.1 = 34-4.33, p = 1.62 × 10
for the highest vs. lowest quintile of the unweighted score. We found a convincing association of a PRS generated with 23 SNPs and risk of MM. Our work provides additional validation of previously discovered MM risk variants and of their combination into a PRS, which is a first step towards the use of genetics for risk stratification in the general population.
Telomeres are involved in processes like cellular growth, chromosomal stability, and proper segregation to daughter cells. Telomere length measured in leukocytes (LTL) has been investigated in ...different cancer types, including multiple myeloma (MM). However, LTL measurement is prone to heterogeneity due to sample handling and study design (retrospective vs. prospective). LTL is genetically determined; genome-wide association studies identified 11 SNPs that, combined in a score, can be used as a genetic instrument to measure LTL and evaluate its association with MM risk. This approach has been already successfully attempted in various cancer types but never in MM. We tested the "teloscore" in 2407 MM patients and 1741 controls from the International Multiple Myeloma rESEarch (IMMeNSE) consortium. We observed an increased risk for longer genetically determined telomere length (gdTL) (OR = 1.69; 95% CI 1.36-2.11; P = 2.97 × 10
for highest vs. lowest quintile of the score). Furthermore, in a subset of 1376 MM patients we tested the relationship between the teloscore and MM patients survival, observing a better prognosis for longer gdTL compared with shorter gdTL (HR = 0.93; 95% CI 0.86-0.99; P = 0.049). In conclusion, we report convincing evidence that longer gdTL is a risk marker for MM risk, and that it is potentially involved in increasing MM survival.
Tibor Eckhardt, a Hungarian émigré, was a key player in American intelligence operations regarding Hungary during World War II and the early Cold War. He worked closely with a secretive American ...intelligence organization headed by John Grombach, an American intelligence officer who was a vehement opponent of the CIA. Though Eckhardt and Grombach shared concerns about the CIA, they were also forced to cooperate with it. Eckhardt's endeavors and those of the many Hungarians whose intelligence work he coordinated were ultimately futile. Hence, they were representative of the efforts of freedom-loving Hungarians to liberate their country during the Cold War.
Abstract Allelic distribution of −308 G > A ( TNF 1/2) polymorphism of the TNF-alpha , and the +252 A > G promoter polymorphism of the LT-alpha gene, the 1267 A > G polymorphism of the HSP70-2 gene ...as well as the −429 T > C promoter polymorphism of the RAGE gene were tested in 94 MM cases and 141 controls. Significantly less MM patients than controls carried the TNF2 allele ( p = 0.018) and the TNF2-LTA 252G haplotype ( p = 0.025). The difference was, however, restricted to the females, as well as the relatively young (<69 years) subjects. By contrast, we did not find differences with the other SNPs tested.
Los autores han estudiado peso de recién nacidos y placentas de embarazos de Puno, Perú, a una altitud de 3.850 m .; se han estudiado 46 embarazos normales de diferentes hospitales desde 46 grupo ...control normaI que Lima a 150 m. Los pesos de los recién nacidos fueron similares en ambos lugares, sin embargo, el peso de la placenta y el volumen fueron mayores en Puno, por lo que el coeficiente de la placenta fue mayor en altura. El análisis macroscópico en términos de parénquima y tejido no parénquima no fue diferente en ambos grupos, pero el análisis microscópico mostró capilaridad más rica con vellosidades disminuido en Puno. No se apreciaron diferencias en la proporción de ephithelium trofoblástica. El área total de la superficie de las vellosidades y capilar corial fueron significativamente mayor en altura. Los autores postulan estos cambios morfológicos favorecen el intercambio placentario metabólica en el ambiente hipóxico de gran altura.
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► Modeling the full length Cucumber mosaic virus (CMV) 2b protein–siRNA complex structure. ► The C-terminal domain is proved to be partially unstructured during MD simulation. ► We ...performed divalent metal ion screens seeking for metal ion binding site. ► A putative divalent binding site was found on the C-terminal domain of the CMV 2b protein. ► Plant experiments confirmed that a simple quadruple alanine mutation disrupted the divalent metal ion binding ability.
The main function of the 2b protein of Cucumber mosaic virus (CMV) is binding permanently the double stranded siRNA molecules in the suppression process of post-transcriptional gene silencing (PTGS). The crystal structure of the homologue Tomato aspermy virus (TAV) 2b protein is known, but without the C-terminal domain. The biologically active form is a tetramer: four 2b protein molecules and two siRNA duplexes. Regarding the complete 2b protein structure, we performed a molecular dynamics (MD) simulation of the whole siRNA–2b ribonucleoprotein complex. Unfortunately, the C-terminal domain is proved to be partially unstructured. Multiple sequence alignment showed a well conserved motif between residues 94 and 105. The negatively charged residues of the C-terminal domain are supposed to take part in coordination of a divalent metal ion and stabilize the three-dimensional structure of the C-terminal domain. MD simulations were performed on the detached C-terminal domains (aa 65–110). 0.15M MgCl2, CaCl2, FeCl2 and ZnCl2 salt concentrations were used in the screening simulations. Among the tested divalent metal ions Mg2+ proved to be very successful because Asp95, Asp96 and Asp98 forms a quasi-permanent Mg2+ binding site. However the control computations have resulted in any (at least) divalent metal ion remains in the binding site after replacement of the bound Mg2+ ion. A quadruple mutation (Rs2DDTD/95–98/AAAA) was introduced into the position of the putative divalent metal ion binding site to analyze the biological relevance of molecular modeling derived hypothesis. The plant inoculation experiments proved that the movement of the mutant virus is slower and the symptoms are milder comparing to the wild type virus. These results demonstrate that the quadruple mutation weakens the stability of the 2b protein tetramer–siRNA ribonucleoprotein complex.
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