Geographical distribution of selected and putatively neutral SNPs in Southeast Asian malaria parasites.

Loci targeted by directional selection are expected to show elevated geographical population structure relative to neutral loci, and a flurry of recent papers have used this rationale to search for genome regions involved in adaptation. Studies of functional mutations that are known to be under selection are particularly useful for assessing the utility of this approach. Antimalarial drug treatment regimes vary considerably between countries in Southeast Asia selecting for local adaptation at parasite loci underlying resistance. We compared the population structure revealed by 10 nonsynonymous mutations (nonsynonymous single-nucleotide polymorphisms [nsSNPs]) in four loci that are known to be involved in antimalarial drug resistance, with patterns revealed by 10 synonymous mutations (synonymous single-nucleotide polymorphisms [sSNPs]) in housekeeping genes or genes of unknown function in 755 Plasmodium falciparum infections collected from 13 populations in six Southeast Asian countries. Allele frequencies at known nsSNPs underlying resistance varied markedly between locations (F(ST) = 0.18-0.66), with the highest frequencies on the Thailand-Burma border and the lowest frequencies in neighboring Lao PDR. In contrast, we found weak but significant geographic structure (F(ST) = 0-0.14) for 8 of 10 sSNPs. Importantly, all 10 nsSNPs showed significantly higher F(ST) (P < 8 x 10(-5)) than simulated neutral expectations based on observed F(ST) values in the putatively neutral sSNPs. This result was unaffected by the methods used to estimate allele frequencies or the number of populations used in the simulations. Given that dense single-nucleotide polymorphism (SNP) maps and rapid SNP assay methods are now available for P. falciparum, comparing genetic differentiation across the genome may provide a valuable aid to identifying parasite loci underlying local adaptation to drug treatment regimes or other selective forces. However, the high proportion of polymorphic sites that appear to be under balancing selection (or linked to selected sites) in the P. falciparum genome violates the central assumption that selected sites are rare, which complicates identification of outlier loci, and suggests that caution is needed when using this approach

Bloch-Wall Phase Transition in the Spherical Model

The temperature-induced second-order phase transition from Bloch to linear (Ising-like) domain walls in uniaxial ferromagnets is investigated for the model of D-component classical spin vectors in the limit D \to \infty. This exactly soluble model is equivalent to the standard spherical model in the homogeneous case, but deviates from it and is free from unphysical behavior in a general inhomogeneous situation. It is shown that the thermal fluctuations of the transverse magnetization in the wall (the Bloch-wall order parameter) result in the diminishing of the wall transition temperature T_B in comparison to its mean-field value, thus favouring the existence of linear walls. For finite values of T_B an additional anisotropy in the basis plane x,y is required; in purely uniaxial ferromagnets a domain wall behaves like a 2-dimensional system with a continuous spin symmetry and does not order into the Bloch one.Comment: 16 pages, 2 figure

Aldosterone and the mineralocorticoid receptor in renal injury: A potential therapeutic target in feline chronic kidney disease

There is a growing body of experimental and clinical evidence supporting mineralocorticoid receptor (MR) activation as a powerful mediator of renal damage in laboratory animals and humans. Multiple pathophysiological mechanisms are proposed, with the strongest evidence supporting aldosterone‐induced vasculopathy, exacerbation of oxidative stress and inflammation, and increased growth factor signalling promoting fibroblast proliferation and deranged extracellular matrix homeostasis. Further involvement of the MR is supported by extensive animal model experiments where MR antagonists (such as spironolactone and eplerenone) abrogate renal injury, including ischaemia‐induced damage. Additionally, clinical trials have shown MR antagonists to be beneficial in human chronic kidney disease (CKD) in terms of reducing proteinuria and cardiovascular events, though current studies have not evaluated primary end points which allow conclusions to made about whether MR antagonists reduce mortality or slow CKD progression. Although differences between human and feline CKD exist, feline CKD shares many characteristics with human disease including tubulointerstitial fibrosis. This review evaluates the evidence for the role of the MR in renal injury and summarizes the literature concerning aldosterone in feline CKD. MR antagonists may represent a promising therapeutic strategy in feline CKD

Valence bond solids for SU(n) spin chains: exact models, spinon confinement, and the Haldane gap

To begin with, we introduce several exact models for SU(3) spin chains: (1) a translationally invariant parent Hamiltonian involving four-site interactions for the trimer chain, with a three-fold degenerate ground state. We provide numerical evidence that the elementary excitations of this model transform under representation 3bar of SU(3) if the original spins of the model transform under rep. 3. (2) a family of parent Hamiltonians for valence bond solids of SU(3) chains with spin reps. 6, 10, and 8 on each lattice site. We argue that of these three models, only the latter two exhibit spinon confinement and hence a Haldane gap in the excitation spectrum. We generalize some of our models to SU(n). Finally, we use the emerging rules for the construction of VBS states to argue that models of antiferromagnetic chains of SU(n) spins in general possess a Haldane gap if the spins transform under a representation corresponding to a Young tableau consisting of a number of boxes \lambda which is divisible by n. If \lambda and n have no common divisor, the spin chain will support deconfined spinons and not exhibit a Haldane gap. If \lambda and n have a common divisor different from n, it will depend on the specifics of the model including the range of the interaction.Comment: 26 pages two-column style, 15 figures, revtex4; references adde

Massive IIA flux compactifications and U-dualities

We attempt to find a rigorous formulation for the massive type IIA orientifold compactifications of string theory introduced in hep-th/0505160. An approximate double T-duality converts this background into IIA string theory on a twisted torus, but various arguments indicate that the back reaction of the orientifold on this geometry is large. In particular, an AdS calculation of the entropy suggests a scaling appropriate for N M2-branes, in a certain limit of the compactification, though not the one studied in hep-th/0505160. The M-theory lift of this specific regime is not 4 dimensional. We suggest that the generic limit of the background corresponds to a situation analogous to F-theory, where the string coupling is small in some regions of a compact geometry, and large in others, so that neither a long wavelength 11D SUGRA expansion, nor a world sheet expansion exists for these compactifications. We end with a speculation on the nature of the generic compactification.Comment: JHEP3 LaTeX - 34 pages - 3 figures; v2: Added references; v3: mistake in entropy scaling corrected, major changes in conclusions; v4: changed claims about original DeWolfe et al. setup, JHEP versio

Rationale, design, and results of the first screening round of a comprehensive, register-based, Chlamydia screening implementation programme in the Netherlands

<p>Abstract</p> <p>Background</p> <p>Implementing <it>Chlamydia trachomatis </it>screening in the Netherlands has been a point of debate for several years. The National Health Council advised against implementing nationwide screening until additional data collected from a pilot project in 2003 suggested that screening by risk profiles could be effective. A continuous increase in infections recorded in the national surveillance database affirmed the need for a more active approach. Here, we describe the rationale, design, and implementation of a <it>Chlamydia </it>screening demonstration programme.</p> <p>Methods</p> <p>A systematic, selective, internet-based <it>Chlamydia </it>screening programme started in April 2008. Letters are sent annually to all 16 to 29-year-old residents of Amsterdam, Rotterdam, and selected municipalities of South Limburg. The letters invite sexually active persons to login to <url>http://www.chlamydiatest.nl</url> with a personal code and to request a test kit. In the lower prevalence area of South Limburg, test kits can only be requested if the internet-based risk assessment exceeds a predefined value.</p> <p>Results</p> <p>We sent invitations to 261,025 people in the first round. One-fifth of the invitees requested a test kit, of whom 80% sent in a sample for testing. The overall positivity rate was 4.2%.</p> <p>Conclusions</p> <p>This programme advances <it>Chlamydia </it>control activities in the Netherlands. Insight into the feasibility, effectiveness, cost-effectiveness, and impact of this large-scale screening programme will determine whether the programme will be implemented nationally.</p

Clues For Genetic Anticipation In Multiple Endocrine Neoplasia Type 1

CONTEXT: Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant hereditary disease caused by the loss of function of the MEN1 gene, a tumor-suppressor gene that encodes the protein menin. It is characterized by the occurrence of primary hyperparathyroidism (pHPT), duodenopancreatic neuroendocrine tumors (dpNET), pituitary tumors (PIT), adrenal adenomas, and bronchopulmonary (bp-NET), thymic, and gastric neuroendocrine tumors. More insight into factors influencing the age-related penetrance of MEN1 manifestations could provide clues for more personalized screening programs. OBJECTIVE: To investigate whether genetic anticipation plays a role in the largest known MEN1 families in the Netherlands. METHODS: All Dutch MEN1 families with ≥ 10 affected members in ≥ 2 successive generations were identified. Age at detection of the different MEN1-related manifestations were compared among generations using regression analyses adjusted for competing risks. To correct for the beneficial effect of being under surveillance, manifestations occurring during surveillance were also separately compared. RESULTS: A total of 152 MEN1 patients from 10 families were included. A significantly decreased age at detection of pHPT, dpNET, PIT, and bp-NET was found in successive generations (P < 0.0001). Adjusted analyses led to the same results. CONCLUSIONS: These results suggest the presence of genetic anticipation. However, due to a risk of residual bias, the results must be interpreted with caution. After independent validation in other cohorts and further translational research investigating the molecular mechanisms explaining this phenomenon in MEN1, the results might add to future, more personalized, screening protocols and earlier screening for future generations of MEN1 patients

Keeping participants on board: increasing uptake by automated respondent reminders in an Internet-based Chlamydia Screening in the Netherlands

<p>Abstract</p> <p>Background</p> <p>Effectiveness of Chlamydia screening programs is determined by an adequate level of participation and the capturing of high-risk groups. This study aimed to evaluate the contribution of automated reminders by letter, email and short message service (SMS) on package request and sample return in an Internet-based Chlamydia screening among people aged 16 to 29 years in the Netherlands.</p> <p>Methods</p> <p>Individuals not responding to the invitation letter received a reminder letter after 1 month. Email- and SMS-reminders were sent to persons who did not return their sample. It was examined to what extent reminders enhanced the response rate (% of package requests) and participation rate (% of sample return). Sociodemographic and behavioural correlates of providing a cell phone number and participation after the reminder(s) were studied by logistic regression models.</p> <p>Results</p> <p>Of all respondents (screening round 1: 52,628, round 2: 41,729), 99% provided an email address and 72% a cell phone number. Forty-two percent of all package requests were made after the reminder letter. The proportion of invitees returning a sample increased significantly from 10% to 14% after email/SMS reminders (round 2: from 7% to 10%). Determinants of providing a cell-phone number were younger age (OR in 25-29 year olds versus 16-19 year olds = 0.8, 95%CI 0.8-0.9), non-Dutch (OR in Surinam/Antillean versus Dutch = 1.3, 95%CI 1.2-1.4, Turkish/Moroccan: 1.1, 95%CI 1.0-1.2, Sub Sahara African: 1.5, 95%CI 1.3-1.8, non-Western other 1.1, 95%CI 1.1-1.2), lower educational level (OR in high educational level versus low level = 0.8, 95%CI 0.7-0.9), no condom use during the last contact with a casual partner (OR no condom use versus condom use 1.2, 95%CI 1.1-1.3), younger age at first sexual contact (OR 19 years or older versus younger than 16: 0.7, 95%CI 0.6-0.8). Determinants for requesting a test-package after the reminder letter were male gender (OR female versus male 0.9 95%CI 0.8-0.9), non-Dutch (OR in Surinam/Antillean versus Dutch 1.3, 95%CI 1.2-1.4, Turkish/Moroccan: 1.4, 95%CI 1.3-1.5, Sub Sahara African: 1.4, 95%CI 1.2-1.5, non-Western other: 1.2, 95%CI 1.1-1.2), having a long-term steady partnership (long-term versus short-term.1.2 95%CI 1.1-1.3). Email/SMS reminders seem to have resulted in more men and people aged 25-29 years returning a sample.</p> <p>Conclusions</p> <p>Nearly all respondents (99.5%) were reachable by modern communication media. Response and participation rates increased significantly after the reminders. The reminder letters also seemed to result in reaching more people at risk. Incorporation of automated reminders in Internet-based (<b>C</b>hlamydia) screening programs is strongly recommended.</p

Spin-Gap Phases in Tomonaga-Luttinger Liquids

We give the details of the analysis for critical properties of spin-gap phases in one-dimensional lattice electron models. In the Tomonaga-Luttinger (TL) liquid theory, the spin-gap instability occurs when the backward scattering changes from repulsive to attractive. This transition point is shown to be equivalent to that of the level-crossing of the singlet and the triplet excitation spectra, using the c=1 conformal field theory and the renormalization group. Based on this notion, the transition point between the TL liquid and the spin-gap phases can be determined with high-accuracy from the numerical data of finite-size clusters. We also discuss the boundary conditions and discrete symmetries to extract these excitation spectra. This technique is applied to the extended Hubbard model, the t-J model, and the t-J-J' model, and their phase diagrams are obtained. We also discuss the relation between our results and analytical solutions in weak-coupling and low-density limits.Comment: 14 pages(REVTeX), 9 figures(EPS), 1 table, To appear in PRB, Detailed paper of PRL 79 (1997) 3214 and JPSJ 67 (1998) 71