HIV-1 DIS stem loop forms an obligatory bent kissing intermediate in the dimerization pathway.

The HIV-1 dimerization initiation sequence (DIS) is a conserved palindrome in the apical loop of a conserved hairpin motif in the 5′-untranslated region of its RNA genome. DIS hairpin plays an important role in genome dimerization by forming a ‘kissing complex’ between two complementary hairpins. Understanding the kinetics of this interaction is key to exploiting DIS as a possible human immunodeficiency virus (HIV) drug target. Here, we present a single-molecule Förster resonance energy transfer (smFRET) study of the dimerization reaction kinetics. Our data show the real-time formation and dissociation dynamics of individual kissing complexes, as well as the formation of the mature extended duplex complex that is ultimately required for virion packaging. Interestingly, the single-molecule trajectories reveal the presence of a previously unobserved bent intermediate required for extended duplex formation. The universally conserved A272 is essential for the formation of this intermediate, which is stabilized by Mg(2+), but not by K(+) cations. We propose a 3D model of a possible bent intermediate and a minimal dimerization pathway consisting of three steps with two obligatory intermediates (kissing complex and bent intermediate) and driven by Mg(2+) ions

Finite dimensional quantizations of the (q,p) plane : new space and momentum inequalities

We present a N-dimensional quantization a la Berezin-Klauder or frame quantization of the complex plane based on overcomplete families of states (coherent states) generated by the N first harmonic oscillator eigenstates. The spectra of position and momentum operators are finite and eigenvalues are equal, up to a factor, to the zeros of Hermite polynomials. From numerical and theoretical studies of the large $N$ behavior of the product $\lambda\_m(N) \lambda\_M(N)$ of non null smallest positive and largest eigenvalues, we infer the inequality $\delta\_N(Q) \Delta\_N(Q) = \sigma\_N \overset{<}{\underset{N \to \infty}{\to}} 2 \pi$ (resp. $\delta\_N(P) \Delta\_N(P) = \sigma\_N \overset{<}{\underset{N \to \infty}{\to}} 2 \pi$) involving, in suitable units, the minimal ($\delta\_N(Q)$) and maximal ($\Delta\_N(Q)$) sizes of regions of space (resp. momentum) which are accessible to exploration within this finite-dimensional quantum framework. Interesting issues on the measurement process and connections with the finite Chern-Simons matrix model for the Quantum Hall effect are discussed

The see-saw mechanism: neutrino mixing, leptogenesis and lepton flavor violation

The see-saw mechanism to generate small neutrino masses is reviewed. After summarizing our current knowledge about the low energy neutrino mass matrix we consider reconstructing the see-saw mechanism. Low energy neutrino physics is not sufficient to reconstruct see-saw, a feature which we refer to as ``see-saw degeneracy''. Indirect tests of see-saw are leptogenesis and lepton flavor violation in supersymmetric scenarios, which together with neutrino mass and mixing define the framework of see-saw phenomenology. Several examples are given, both phenomenological and GUT-related. Variants of the see-saw mechanism like the type II or triplet see-saw are also discussed. In particular, we compare many general aspects regarding the dependence of LFV on low energy neutrino parameters in the extreme cases of a dominating conventional see-saw term or a dominating triplet term. For instance, the absence of mu -> e gamma or tau -> e gamma in the pure triplet case means that CP is conserved in neutrino oscillations. Scanning models, we also find that among the decays mu -> e gamma, tau -> e gamma and tau -> mu gamma the latter one has the largest branching ratio in (i) SO(10) type I see-saw models and in (ii) scenarios in which the triplet term dominates in the neutrino mass matrix.Comment: 26 pages, 7 figures. Expanded version of talk given at 10th Workshop In High Energy Physics Phenomenology (WHEPP 10), January 2008, Chennai, India. Typos corrected, comments and references adde

Origin and putative colonization routes for invasive rodent taxa in the democratic Republic of Congo

The threat posed by biological invasions is well established. An important consideration in preventing the spread of invasives and also subsequent introductions lies in understanding introduction pathways. The Democratic Republic of the Congo (DRC) houses a large percentage of the world's biodiversity, yet no national strategy exists to deal with the growing number of invasive alien species. Amongst these are the house mouse and ship and Norwegian rats. By comparing our result to published data, we show that species were possibly introduced into the DRC via two routes. The first is via the western seaport at Kinshasa where specimens of M. m. domesticus and R. rattus on the western and northwestern side of the DRC show ties with European haplotypes. The second is via the east where specimens of R. rattus appear linked to Arab and southeast Asian haplotypes. Future work should consider more comprehensive sampling throughout the DRC to more accurately investigate the occurrence of invasive species throughout the country as well as extend sampling to other African countries

Nucleic Acids Res

The HIV-1 dimerization initiation sequence (DIS) is a conserved palindrome in the apical loop of a conserved hairpin motif in the 5'-untranslated region of its RNA genome. DIS hairpin plays an important role in genome dimerization by forming a 'kissing complex' between two complementary hairpins. Understanding the kinetics of this interaction is key to exploiting DIS as a possible human immunodeficiency virus (HIV) drug target. Here, we present a single-molecule Förster resonance energy transfer (smFRET) study of the dimerization reaction kinetics. Our data show the real-time formation and dissociation dynamics of individual kissing complexes, as well as the formation of the mature extended duplex complex that is ultimately required for virion packaging. Interestingly, the single-molecule trajectories reveal the presence of a previously unobserved bent intermediate required for extended duplex formation. The universally conserved A272 is essential for the formation of this intermediate, which is stabilized by Mg2+, but not by K+ cations. We propose a 3D model of a possible bent intermediate and a minimal dimerization pathway consisting of three steps with two obligatory intermediates (kissing complex and bent intermediate) and driven by Mg2+ ions

The immunopeptidome landscape associated with T cell infiltration, inflammation and immune editing in lung cancer.

One key barrier to improving efficacy of personalized cancer immunotherapies that are dependent on the tumor antigenic landscape remains patient stratification. Although patients with CD3 &lt;sup&gt;+&lt;/sup&gt; CD8 &lt;sup&gt;+&lt;/sup&gt; T cell-inflamed tumors typically show better response to immune checkpoint inhibitors, it is still unknown whether the immunopeptidome repertoire presented in highly inflamed and noninflamed tumors is substantially different. We surveyed 61 tumor regions and adjacent nonmalignant lung tissues from 8 patients with lung cancer and performed deep antigen discovery combining immunopeptidomics, genomics, bulk and spatial transcriptomics, and explored the heterogeneous expression and presentation of tumor (neo)antigens. In the present study, we associated diverse immune cell populations with the immunopeptidome and found a relatively higher frequency of predicted neoantigens located within HLA-I presentation hotspots in CD3 &lt;sup&gt;+&lt;/sup&gt; CD8 &lt;sup&gt;+&lt;/sup&gt; T cell-excluded tumors. We associated such neoantigens with immune recognition, supporting their involvement in immune editing. This could have implications for the choice of combination therapies tailored to the patient's mutanome and immune microenvironment

RPL5 on 1p22.1 is recurrently deleted in multiple myeloma and its expression is linked to bortezomib response

Chromosomal region 1p22 is deleted in 6520% of multiple myeloma (MM) patients, suggesting the presence of an unidentified tumor suppressor. Using high-resolution genomic profiling, we delimit a 58 kb minimal deleted region (MDR) on 1p22.1 encompassing two genes: ectopic viral integration site 5 (EVI5) and ribosomal protein L5 (RPL5). Low mRNA expression of EVI5 and RPL5 was associated with worse survival in diagnostic cases. Patients with 1p22 deletion had lower mRNA expression of EVI5 and RPL5, however, 1p22 deletion status is a bad predictor of RPL5 expression in some cases, suggesting that other mechanisms downregulate RPL5 expression. Interestingly, RPL5 but not EVI5 mRNA levels were significantly lower in relapsed patients responding to bortezomib and; both in newly diagnosed and relapsed patients, bortezomib treatment could overcome their bad prognosis by raising their progression-free survival to equal that of patients with high RPL5 expression. In conclusion, our genetic data restrict the MDR on 1p22 to EVI5 and RPL5 and although the role of these genes in promoting MM progression remains to be determined, we identify RPL5 mRNA expression as a biomarker for initial response to bortezomib in relapsed patients and subsequent survival benefit after long-term treatment in newly diagnosed and relapsed patients