Quantitative SPECT/CT parameters of myocardial 99mTechnetium-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) uptake in suspected cardiac transthyretin amyloidosis

Background: 99mTc-labelled bisphosphonates are used for imaging assessment of patients with transthyretin cardiac amyloidosis (ATTR). Present study evaluates whether quantitative SPECT/CT measurement of absolute myocardial 99mTc-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid (Tc-DPD) uptake can diagnose patients with suspected ATTR. / Methods: Twenty-eight patients (25 male, age 80.03 ± 6.99 years) with suspected ATTR referred for Tc-DPD imaging had planar and SPECT/CT imaging of the chest. Three operators independently obtained Tc-DPD myocardial SUVmax and SUVmean above threshold (SMaT) (20, 40 and 60% of SUVmax), using a semi-automated threshold segmentation method. Results were compared to visual grading (0–3) of cardiac uptake. / Results: Twenty-two patients (78%) had cardiac uptake (2 grade 1, 15 grade 2, 5 grade 3). SUVmax and SMaT segmentation thresholds enabled separating grades 2/3 from 0/1 with excellent inter- and intra-reader correlation. Cut-off values 6.0, 2.5, 3 and 4 for SUVmax, SMaT20,40,60, respectively, separated between grades 2/3 and 0 /1 with PPV and NPV of 100%. SMaT20,40,60(cardiac)/SUVmean (liver) and SMaT20,40,60(cardiac)/SUVmean(liver/lung) separated grades 2 and 3. / Conclusion: Quantitative SPECT/CT parameters of cardiac Tc-DPD uptake are robust, enabling separation of patients with grades 2 and 3 cardiac uptake from grades 0 and 1. Larger patient cohorts will determine the incremental value of SPECT/CT quantification for ATTR management

Light Stop Decay in the MSSM with Minimal Flavour Violation

In supersymmetric scenarios with a light stop particle $\tilde{t}_1$ and a small mass difference to the lightest supersymmetric particle (LSP) assumed to be the lightest neutralino, the flavour changing neutral current decay $\tilde{t}_1 \to c \tilde{\chi}_1^0$ can be the dominant decay channel and can exceed the four-body stop decay for certain parameter values. In the framework of Minimal Flavour Violation (MFV) this decay is CKM-suppressed, thus inducing long stop lifetimes. Stop decay length measurements at the LHC can then be exploited to test models with minimal flavour breaking through Standard Model Yukawa couplings. The decay width has been given some time ago by an approximate formula, which takes into account the leading logarithms of the MFV scale. In this paper we calculate the exact one-loop decay width in the framework of MFV. The comparison with the approximate result exhibits deviations of the order of 10% for large MFV scales due to the neglected non-logarithmic terms in the approximate decay formula. The difference in the branching ratios is negligible. The large logarithms have to be resummed. The resummation is performed by the solution of the renormalization group equations. The comparison of the exact one-loop result and the tree level flavour changing neutral current decay, which incorporates the resummed logarithms, demonstrates that the resummation effects are important and should be taken into account.Comment: 29 page

Modification of the carboxy-terminal flanking region of a universal influenza epitope alters CD4+ T-cell repertoire selection

Human CD4+ αβ T cells are activated via T-cell receptor recognition of peptide epitopes presented by major histocompatibility complex (MHC) class II (MHC-II). The open ends of the MHC-II binding groove allow peptide epitopes to extend beyond a central nonamer core region at both the amino- and carboxy-terminus. We have previously found that these non-bound C-terminal residues can alter T cell activation in an MHC allele-transcending fashion, although the mechanism for this effect remained unclear. Here we show that modification of the C-terminal peptide-flanking region of an influenza hemagglutinin (HA305−320) epitope can alter T-cell receptor binding affinity, T-cell activation and repertoire selection of influenza-specific CD4+ T cells expanded from peripheral blood. These data provide the first demonstration that changes in the C-terminus of the peptide-flanking region can substantially alter T-cell receptor binding affinity, and indicate a mechanism through which peptide flanking residues could influence repertoire selection

Quantitative Genetics, Pleiotropy, and Morphological Integration in the Dentition of Papio hamadryas

Variation in the mammalian dentition is highly informative of adaptations and evolutionary relationships, and consequently has been the focus of considerable research. Much of the current research exploring the genetic underpinnings of dental variation can trace its roots to Olson and Miller's 1958 book Morphological Integration. These authors explored patterns of correlation in the post-canine dentitions of the owl monkey and Hyopsodus, an extinct condylarth from the Eocene. Their results were difficult to interpret, as was even noted by the authors, due to a lack of genetic information through which to view the patterns of correlation. Following in the spirit of Olson and Miller's research, we present a quantitative genetic analysis of dental variation in a pedigreed population of baboons. We identify patterns of genetic correlations that provide insight to the genetic architecture of the baboon dentition. This genetic architecture indicates the presence of at least three modules: an incisor module that is genetically independent of the post-canine dentition, and a premolar module that demonstrates incomplete pleiotropy with the molar module. We then compare this matrix of genetic correlations to matrices of phenotypic correlations between the same measurements made on museum specimens of another baboon subspecies and the Southeast Asian colobine Presbytis. We observe moderate significant correlations between the matrices from these three primate taxa. From these observations we infer similarity in modularity and hypothesize a common pattern of genetic integration across the dental arcade in the Cercopithecoidea

A Twist in the Dyon Partition Function

In four dimensional string theories with N=4 and N=8 supersymmetries one can often define twisted index in a subspace of the moduli space which captures additional information on the partition function than the ones contained in the usual helicity trace index. We compute several such indices in type IIB string theory on K3 x T^2 and T^6, and find that they share many properties with the usual helicity trace index that captures the spectrum of quarter BPS states in N=4 supersymmetric string theories. In particular the partition function is a modular form of a subgroup of Sp(2,Z) and the jumps across the walls of marginal stability are controlled by the residues at the poles of the partition function. However for large charges the logarithm of this index grows as 1/n times the entropy of a black hole carrying the same charges where n is the order of the symmetry generator that is used to define the twisted index. We provide a macroscopic explanation of this phenomenon using quantum entropy function formalism. The leading saddle point corresponding to the attractor geometry fails to contribute to the twisted index, but a Z_n orbifold of the attractor geometry produces the desired contribution.Comment: LaTeX file, 35 pages; v2: references adde

Estimated pre-morbid IQ effects on cognitive and functional outcomes in Alzheimer disease: a longitudinal study in a treated cohort

Abstract Background Cognitive reserve is thought to influence the degree of neuropathology needed for diagnosis of Alzheimer disease (AD). Cognitive reserve can be operationally defined as the hypothesized capacity of the mature adult brain to sustain the effects of disease or injury without manifesting clinical symptoms of AD, but sufficient to cause clinical dementia in an individual possessing less cognitive reserve. Its effect on the subsequent course of AD is less clear. Pre-morbid IQ is a useful measure of cognitive reserve. Methods We studied 659 consecutive patients with AD at a tertiary referral memory clinic. Patients were assessed on six cognitive tests at baseline. Activities of Daily Living (ADL) were measured on the Instrumental Activities of Daily Living (IADL) scale and Physical Self-Maintenance Scale (PSMS). The National Adult Reading Test (NART) was used to estimate pre-morbid IQ. Patients were followed up after starting a cholinesterase inhibitor over 78 weeks. Mixed general linear models estimated the effects of NART on cognition and ADL. Results Three hundred and fifty-five patients had NART scored with a mean estimated pre-morbid IQ of 104.7 (standard deviation 18.5). NART increased overall cognitive ability by 2.7% for every 10 IQ points (p Conclusion Our data support the hypothesis that cognitive reserve continues to have a limited influence on cognition after AD has been diagnosed and thus, indirectly, has an impact on ADL.</p

Characterization of Structural Features Controlling the Receptiveness of Empty Class II MHC Molecules

MHC class II molecules (MHC II) play a pivotal role in the cell-surface presentation of antigens for surveillance by T cells. Antigen loading takes place inside the cell in endosomal compartments and loss of the peptide ligand rapidly leads to the formation of a non-receptive state of the MHC molecule. Non-receptiveness hinders the efficient loading of new antigens onto the empty MHC II. However, the mechanisms driving the formation of the peptide inaccessible state are not well understood. Here, a combined approach of experimental site-directed mutagenesis and computational modeling is used to reveal structural features underlying “non-receptiveness.” Molecular dynamics simulations of the human MHC II HLA-DR1 suggest a straightening of the α-helix of the β1 domain during the transition from the open to the non-receptive state. The movement is mostly confined to a hinge region conserved in all known MHC molecules. This shift causes a narrowing of the two helices flanking the binding site and results in a closure, which is further stabilized by the formation of a critical hydrogen bond between residues αQ9 and βN82. Mutagenesis experiments confirmed that replacement of either one of the two residues by alanine renders the protein highly susceptible. Notably, loading enhancement was also observed when the mutated MHC II molecules were expressed on the surface of fibroblast cells. Altogether, structural features underlying the non-receptive state of empty HLA-DR1 identified by theoretical means and experiments revealed highly conserved residues critically involved in the receptiveness of MHC II. The atomic details of rearrangements of the peptide-binding groove upon peptide loss provide insight into structure and dynamics of empty MHC II molecules and may foster rational approaches to interfere with non-receptiveness. Manipulation of peptide loading efficiency for improved peptide vaccination strategies could be one of the applications profiting from the structural knowledge provided by this study

Anchor Side Chains of Short Peptide Fragments Trigger Ligand-Exchange of Class II MHC Molecules

Class II MHC molecules display peptides on the cell surface for the surveillance by CD4+ T cells. To ensure that these ligands accurately reflect the content of the intracellular MHC loading compartment, a complex processing pathway has evolved that delivers only stable peptide/MHC complexes to the surface. As additional safeguard, MHC molecules quickly acquire a ‘non-receptive’ state once they have lost their ligand. Here we show now that amino acid side chains of short peptides can bypass these safety mechanisms by triggering the reversible ligand-exchange. The catalytic activity of dipeptides such as Tyr-Arg was stereo-specific and could be enhanced by modifications addressing the conserved H-bond network near the P1 pocket of the MHC molecule. It affected both antigen-loading and ligand-release and strictly correlated with reported anchor preferences of P1, the specific target site for the catalytic side chain of the dipeptide. The effect was evident also in CD4+ T cell assays, where the allele-selective influence of the dipeptides translated into increased sensitivities of the antigen-specific immune response. Molecular dynamic calculations support the hypothesis that occupation of P1 prevents the ‘closure’ of the empty peptide binding site into the non-receptive state. During antigen-processing and -presentation P1 may therefore function as important “sensor” for peptide-load. While it regulates maturation and trafficking of the complex, on the cell surface, short protein fragments present in blood or lymph could utilize this mechanism to alter the ligand composition on antigen presenting cells in a catalytic way