Structure and Segmental Motions in a Substituted Polythiophene: A Solid‐State NMR Study

Thermochromic poly[3‐(2‐methyl‐1‐butoxy)‐4‐methylthiophene] has been investigated in the solid state. Some important changes have been observed by UV‐Vis absorption and XRD measurements. Solid‐state NMR spectroscopy, which has the ability to provide information about the structure and dynamics of polymers over a wide range of length scales and time scales, has been utilized to better understand the motion of polythiophene chains during this thermochromic transition. Different solid‐state NMR analyses led to the determination of the relaxation rates for the main chain and the side chain as well as to the characterization of a twisting of the conjugated backbone chain during the thermochromic transition.

     

Split-hand/foot malformation with long-bone deficiency and BHLHA9 duplication: Two cases and expansion of the phenotype to radial agenesis

Split-hand/foot malformation (SHFM) with long-bone deficiency (SHFLD, MIM#119100) is a rare condition characterised by SHFM associated with long-bone malformation usually involving the tibia. Previous published data reported several unrelated patients with 17p13.3 duplication and SHFLD. Recently, BHLHA9 has been proposed to be the major candidate gene responsible for this limb malformation. Here we report two new patients affected with ectrodactyly harbouring a 17p13.3 duplication detected by array-CGH. Both duplications contain 3 genes including BHLHA9 and are inherited from an unaffected parent. One of the patients presents a complete radial agenesis, expanding the phenotype of SHFLD3.     

T-cell recognition of the HspX protein of Mycobacterium tuberculosis correlates with latent M. tuberculosis infection but not with M. bovis BCG vaccination

During stationary growth or in vitro conditions mimicking relevant aspects of latency, the HspX protein (Rv2031c) is specifically upregulated by Mycobacterium tuberculosis. In this study we compared T-cell responses against HspX and the secreted M. tuberculosis protein Ag85B (Rv1886c) in tuberculosis (TB) patients, tuberculin skin test-positive individuals, M. bovis BCG-vaccinated individuals, and healthy negative controls. Gamma interferon responses to HspX were significantly higher in M. tuberculosis-exposed individuals than in M. tuberculosis-unexposed BCG vaccinees. In contrast, no such differences were found with respect to T-cell responses against Ag85B. Therefore, BCG-based vaccines containing relevant fragments of HspX may induce improved responses against this TB latency antigen. To identify relevant major histocompatibility complex class I- and class II-restricted HspX-specific T-cell epitopes, we immunized HLA-A2/K(b) and HLA-DR3.Ab(0) transgenic (tg) mice with HspX. Two new T-cell epitopes were identified, p91-105 and p31-50, restricted via HLA-A*0201 and HLA-DRB1*0301, respectively. These epitopes were recognized by human T cells as well, underlining the relevance of HspX T-cell recognition both in vivo and in vitro. In line with the data in humans, BCG immunization of both tg strains did not lead to T-cell responses against HspX-derived epitopes, whereas nonlatency antigens were efficiently recognized. These data support the notion that BCG vaccination per se does not induce T-cell responses against the latency antigen, HspX. Thus, we suggest that subunit vaccines incorporating HspX and/or other latency antigens, as well as recombinant BCG strains expressing latency antigens need to be considered as new vaccines against TB.     

Abnormal retinal thickness in patients with mild cognitive impairment and Alzheimer's disease

In Alzheimer's disease (AD), brain lesions are marked by severe neuronal loss and retinal degeneration was previously mentioned in affected patients. Mild cognitive impairment (MCI) is a clinical syndrome that could be an early phase of AD. In this study, using optical coherence tomography (OCT), the retinal nerve fiber layer (RNFL) thickness was assessed in patients with mild AD, moderate to severe AD, amnestic MCI and control subjects. The results show that RNFL thickness is statistically reduced in patients with MCI, mild AD or moderate to severe AD compared to controls. In addition, no statistical difference was found between the results in MCI patients and mild AD patients. The RNFL seems to be involved early during the course of amnestic MCI and OCT tests could be carried out in patients with cognitive troubles.     

Association of the proprotein convertase subtilisin/kexin-type 2 (PCSK2) gene with type 2 diabetes in an African American population

In a genome-wide scan for type 2 diabetes (T2DM) in African American (AA) families, ordered subsets analysis (OSA) provided evidence for linkage to chromosome 20p in a subset with later age at diagnosis (max LOD 2.57, P=0.008). The proprotein convertase subtilisin/kexin-type 2 (PCSK2) gene is within the LOD-1 interval of this linkage peak. Twenty-nine single nucleotide polymorphisms (SNPs) were genotyped across this gene in 380 unrelated AA individuals with T2DM and end-stage renal disease (T2DM-ESRD), 278 AA controls, 96 European Americans (EA) and 120 Yoruba Nigerian (YRI) controls. In addition, 22 ancestry-informative markers (AIMs) were genotyped in all AA subjects, 120 YRI, and 282 EA controls. ADMIXMAP was used to model the distributions of admixture and generate score tests of allelic and haplotypic association. Association with T2DM was observed among 4 SNPs: rs2021785 (admixture-adjusted Pa=0.00014), rs1609659 (Pa=0.028), rs4814597 (Pa=0.039) and rs2269023 (Pa=0.043). None of the PCSK2 SNPs were associated with age at T2DM diagnosis. A variant in the PCKS2 gene, rs2021785, appears to play a role in susceptibility to T2DM in this AA population.     

A large genomic deletion in the PDHX gene caused by the retrotranspositional insertion of a full-length LINE-1 element

The long interspersed element-1 (LINE-1 or L1) retrotransposition has altered the human genome in many ways. In particular, recent in vitro studies have demonstrated that the retrotranspositional insertion of L1 elements has resulted in significant genomic deletions. Here we provide evidence for its operation in the human genome by identifying a approximately 46-kb pathological genomic deletion in the PDHX gene directly linked to the insertion of a full-length L1 element, in a patient with pyruvate dehydrogenase complex (PDHc) deficiency. Both the deduced bottom and top strand cleavage sites in the PDHX gene coincide with the consensus L1 endonuclease (EN) target sequence 5'-TTTT/A-3', while the full-length L1 element is followed by a 67-bp poly(A) tail. Interestingly, two hairpin structures, potentially formed by the inverted repeats present immediately 5' to the top strand nick site and 3' to the bottom strand nick site, may have facilitated the accessibility of L1 EN to the target sequences and also brought the two otherwise distantly located sequences into close proximity. Since the L1 element inserted in the PDHX gene is full-length, we favor the model of the template jumping as opposed to that of the microhomology-mediated end-joining for linking the 5' end of the nascent L1 copy to its genomic target. Our finding not only serves as an important complement to the in vitro approaches to studying L1 retrotransposition, but also reveals a novel mechanism causing human genetic disease.     

Calibration of an amorphous-silicon flat panel portal imager for exit-beam dosimetry

Amorphous-silicon flat panel detectors are currently used to acquire digital portal images with excellent image quality for patient alignment before external beam radiation therapy. As a first step towards interpreting portal images acquired during treatment in terms of the actual dose delivered to the patient, a calibration method is developed to convert flat panel portal images to the equivalent water dose deposited in the detector plane and at a depth of 1.5 cm. The method is based on empirical convolution models of dose deposition in the flat panel detector and in water. A series of calibration experiments comparing the response of the flat panel imager and ion chamber measurements of dose in water determines the model parameters. Kernels derived from field size measurements account for the differences in the production and detection of scattered radiation in the two systems. The dissimilar response as a function of beam energy spectrum is characterized from measurements performed at various off-axis positions and for increasing attenuator thickness in the beam. The flat panel pixel inhomogeneity is corrected by comparing a large open field image with profiles measured in water. To verify the accuracy of the calibration method, calibrated flat panel profiles were compared with measured dose profiles for fields delivered through solid water slabs, a solid water phantom containing an air cavity, and an anthropomorphic head phantom. Open rectangular fields of various sizes and locations as well as a multileaf collimator-shaped field were delivered. For all but the smallest field centered about the central axis, the calibrated flat panel profiles matched the measured dose profiles with little or no systematic deviation and approximately 3% (two standard deviations) accuracy for the in-field region. The calibrated flat panel profiles for fields located off the central axis showed a small -1.7% systematic deviation from the measured profiles for the in-field region. Out of the field, the differences between the calibrated flat panel and measured profiles continued to be small, approximately 0%-2% of the mean in-field dose. Further refinement of the calibration model should increase the accuracy of the procedure. This calibration method for flat panel portal imagers may be used as part of a validation scheme to verify the dose delivered to the patient during treatment.