Effect of natural genetic variation on enhancer selection and function.

The mechanisms by which genetic variation affects transcription regulation and phenotypes at the nucleotide level are incompletely understood. Here we use natural genetic variation as an in vivo mutagenesis screen to assess the genome-wide effects of sequence variation on lineage-determining and signal-specific transcription factor binding, epigenomics and transcriptional outcomes in primary macrophages from different mouse strains. We find substantial genetic evidence to support the concept that lineage-determining transcription factors define epigenetic and transcriptomic states by selecting enhancer-like regions in the genome in a collaborative fashion and facilitating binding of signal-dependent factors. This hierarchical model of transcription factor function suggests that limited sets of genomic data for lineage-determining transcription factors and informative histone modifications can be used for the prioritization of disease-associated regulatory variants.

Self-organized assemblies of colloidal particles obtained from an aligned chromonic liquid crystal dispersion.

The behavior of mono-disperse colloidal particles in a chromonic liquid crystal was investigated. Poly(methyl methacrylate) spherical particles with three different functionalizations, with and without surface charges, were utilized in the nematic and columnar phases of disodium cromoglycate solutions. The nematic phase was completely aligned parallel to the glass substrates by a simple rubbing technique, and the columnar phase showed regions of similar alignment. The behavior of the colloidal particles in the chromonic liquid crystal depended critically on the functionality, with bromine functionalized particles not dispersing at all, and cationic trimethylammonium and epoxy functionalized particles dispersing well in the isotropic phase of the liquid crystal. At the transition to the nematic and especially the columnar phase, the colloidal particles were expelled into the remaining isotropic phase. Since the columnar phase grew in parallel ribbons, the colloidal particles ended up in chain-like assemblies. Such behavior opens the possibility of producing patterned assemblies of colloidal particles by taking advantage of the self-organized structure of chromonic liquid crystals.

Synthesis of liquid crystal silane-functionalized gold nanoparticles and their effects on the optical and electro-optic properties of a structurally related nematic liquid crystal.

Chemically and thermally robust liquid crystal silane-functionalized gold nanoparticles (i.e. AuNP1-AuNP3) were synthesized through silane conjugation. Colloidal dispersions of these particles with mesogenic ligands that are structurally identical (as in AuNP1, AuNP2) or compatible (as in AuNP3) with molecules of the nematic liquid crystal (N-LC) host showed superior colloidal stability and dispersibility. The thermal, optical, and electro-optic behaviors of the N-LC composites at different concentrations of each gold nanoparticle were investigated. All dispersions showed lower values for the rotational viscosity and elastic constant, but only AuNP3 with a dissimilar structure between the nanoparticle ligand and the host displayed the most drastic thermal effects and overall strongest impact on the electro-optic properties of the host. The observed results were explained considering both the structure and the density of the surface ligands of each gold nanoparticle.

Nanoparticle doping in nematic liquid crystals: distinction between surface and bulk effects by numerical simulations.

Doping nematic liquid crystals with small amounts of nanoparticles can significantly alter the electro-optic response of the nematic host. Some of these effects result from nanoparticles influencing the liquid crystal/substrate interface, while other effects are caused by nanoparticles in the bulk. So far, little attention has been paid to the influence of surface interactions on the determination of bulk properties. In the present study, these effects are investigated experimentally and confirmed by numerical simulations. The splay-type Fréedericksz-transition of the nematic liquid crystal 5CB doped with CdSe quantum dots is investigated, as these dispersions are known from earlier studies to affect the initial alignment layers. In comparison, dispersions of chemically and thermally stable silanized gold nanoparticles in the apolar nematic host FELIX-2900-03 are analyzed, which are expected to be bulk-active only. A data fitting routine is presented which allows a distinction between bulk and surface effects of nanoparticle doping. For the quantum dots, an increase of pretilt angle proportional to the doping concentration is found, as well as a slight decrease of the anchoring energy of molecules at the confining substrates. The silanized gold particles show no influence on the boundary conditions up to doping concentrations of 2.5 % (w). For higher concentrations an increase of pretilt angle is reported.

X-ray scattering of nematic liquid crystal nanodispersion with negative dielectric anisotropy [Invited].

A nematic liquid crystal (LC) mixture was doped with harvested ferroelectric BaTiO3 nanoparticles and investigated with wide- and small-angle x-ray scattering upon heating from the nematic to the isotropic phase. At moderate temperatures, colloidal crystallites were observed. LC test cells with homeotropic anchoring were placed in the x-ray beam and the realignment of the LC director was investigated upon applying an electric field.

Recommendations in Second Opinion Reports of Neurologic Head and Neck Imaging: Frequency, Referring Clinicians' Compliance, and Diagnostic Yield.

BACKGROUND AND PURPOSE: Second opinion reports of neurologic head and neck imaging are requested with increased regularity, and they may contain a recommendation to the clinician. Our aim was to investigate the frequency and determinants of the presence of a recommendation and the adherence by the referring physician to the recommendation in a second opinion neurology head and neck imaging report and the diagnostic yield of these recommendations. MATERIALS AND METHODS: This retrospective study included 994 consecutive second opinion reports of neurology head and neck imaging examinations performed at a tertiary care center. RESULTS: Of the 994 second opinion reports, 12.2% (121/994) contained a recommendation. An oncologic imaging indication was significantly (P = .030) associated with a lower chance of a recommendation in the second opinion report (OR = .67; 95% CI, 0.46-0.96). Clinicians followed 65.7% (88/134) of the recommendations. None of the investigated variables (patient age, sex, hospitalization status, indication for the second opinion report, experience of the radiologist who signed the second opinion report, strength of the recommendation, and whether the recommendation was made due to apparent quality issues of the original examination) were significantly associated with the compliance of the referring physician to this recommendation. The 134 individual recommendations eventually led to the establishment of 52 (38.2%) benign diagnoses and 28 (20.6%) malignant diagnoses, while no definitive diagnosis could be established in 56 (41.2%) cases. CONCLUSIONS: Recommendations are relatively common in second opinion reports of neurology head and neck imaging examinations, though less for oncologic indications. They are mostly followed by requesting physicians, thus affecting patient management. In most cases, they also lead to the establishment of a diagnosis, hence adding value to patient care.

Tuning quantum-dot based photonic devices with liquid crystals.

Microdisks made from GaAs with embedded InAs quantum dots are immersed in the liquid crystal 4-cyano-4'-pentylbiphenyl (5CB). The quantum dots serve as emitters feeding the optical modes of the photonic cavity. By changing temperature, the liquid crystal undergoes a phase transition from the isotropic to the nematic state, which can be used as an effective tuning mechanism of the photonic modes of the cavity. In the nematic state, the uniaxial electrical anisotropy of the liquid crystal molecules can be exploited for orienting the material in an electric field, thus externally controlling the birefringence of the material. Using this effect, an electric field induced tuning of the modes is achieved. Numerical simulations using the finite-differences time-domain (FDTD) technique employing an anisotropic dielectric medium allow to understand the alignment of the liquid crystal molecules on the surface of the microdisk resonator.

Indication of a deeply bound and compact K- pp state formed in the pp- -> pLambdaK+ reaction at 2.85 GeV.

We have analyzed data of the DISTO experiment on the exclusive pp --> pLambdaK+ reaction at 2.85 GeV to search for a strongly bound compact K- pp(approximately = X) state to be formed in the pp --> K+ + X reaction. The observed spectra of the K+ missing mass and the pLambda invariant-mass with high transverse momenta of p and K+ revealed a broad distinct peak of 26-sigma confidence with a mass M(X)=2267+/-3(stat)+/-5(syst) MeV/c2 and a width Gamma(X)=118+/-8(stat)+/-10(syst) MeV. The enormously large cross section indicates formation of a compact K- pp with a large binding energy of B(K)=103 MeV, which can be a possible gateway toward cold and dense kaonic nuclear matter.

Bilateral ovarian well-differentiated Sertoli-Leydig cell tumors with heterologous elements associated with unilateral serous cystadenoma--a case report.

Bilateral Sertoli-Leydig cell tumors (SLCTs) of the ovary, especially in association with a cystadenoma, are exceedingly rare. Some SLCTs, usually of poor differentiation, show heterologous elements. We present a case of a 61-year-old woman with bilateral well-differentiated SLCTs in which the Sertoli-Leydig cell component showed leiomyogenic (heterologous) differentiation. Furthermore, on the left side it also was associated with a serous cystadenoma.

DNA Origami Nano-Sheets and Nano-Rods Alter the Orientational Order in a Lyotropic Chromonic Liquid Crystal.

Rod-like and sheet-like nano-particles made of desoxyribonucleic acid (DNA) fabricated by the DNA origami method (base sequence-controlled self-organized folding of DNA) are dispersed in a lyotropic chromonic liquid crystal made of an aqueous solution of disodium cromoglycate. The respective liquid crystalline nanodispersions are doped with a dichroic fluorescent dye and their orientational order parameter is studied by means of polarized fluorescence spectroscopy. The presence of the nano-particles is found to slightly reduce the orientational order parameter of the nematic mesophase. Nano-rods with a large length/width ratio tend to preserve the orientational order, while more compact stiff nano-rods and especially nano-sheets reduce the order parameter to a larger extent. In spite of the difference between the sizes of the DNA nano-particles and the rod-like columnar aggregates forming the liquid crystal, a similarity between the shapes of the former and the latter seems to be better compatible with the orientational order of the liquid crystal.

Factor 5 mutation profile in German patients with homozygous and heterozygous factor V deficiency.

Coagulation factor V (FV) plays an important role in the blood coagulation cascade as part of the prothrombinase complex. FV deficiency is a rare autosomal recessive bleeding disorder with variable phenotypic expression. Thus, our study reports 39 patients with FV deficiency. In 36 cases, we were able to identify a causative mutation. Of these, 20 patients were heterozygous for the identified mutation, nine were homozygous, six were compound heterozygous and one proband was pseudohomozygous. In the remaining patients, no mutation was found. A total of 42 genetic alterations (of which 33 were uniquely different mutations), comprising 19 missense mutations, eight nonsense mutations, four small deletions and two splice site mutations, were identified by this study. Twenty-three of these were novel sequence variations not previously described in the literature. Interestingly, all changes found in exon 13 resulted in null alleles as either nonsense mutations or small deletions. The overall profile of these new mutations corresponds well with the data published in the F5 database. In those cases, where data were available, information on FV activity levels and/or bleeding history is given. Interestingly, some patients with mild FV deficiency (FV:C about 50% of normal) also exhibited bleeding episodes. Our data substantially contribute to the broadening and better understanding of the FV deficiency mutational spectrum. Identifying the molecular basis of mutations underlying this rare coagulation disorder will allow more insight into the mechanisms involved in the variable clinical phenotypes of patients with FV deficiency.

Breast metastasis 56 months before the diagnosis of primary ovarian cancer: a case study.

BACKGROUND: Breast metastasis of ovarian cancer is rare. A patient with a breast tumor which turned out to be a metastasis as the first clinical manifestation of a primary ovarian cancer diagnosed 56 months later is described. CASE REPORT: A 72-year-old patient presented with a palpable mass in the right breast. Lumpectomy was performed and primary breast cancer was excluded. Histology confirmed a poorly differentiated adenocarcinoma. However, further examination showed no evidence of extramammary primary malignancy. Fifty-six months later, a multicystic pelvic lesion with irregular septa was found. Laparotomy showed a tumor of the right adnexa. The final pathology confirmed the diagnosis of a primary serous ovarian carcinoma. The paraffin blocks of both tumors were reevaluated and showed that the cytological atypia and the immunohistochemical profiles [cytokeratin (CK) 5/6, CK 17, gross cystic disease fluid protein (GCDFP)-15 / BRST-2, estrogen- and progesterone receptor, cancer antigen (CA)125, Wilms tumor (WT-1), tumorsuppressor gene p53, MIB-1 (proliferation marker)] were similar in both the breast and the ovarian specimens. CONCLUSION: To our knowledge, this is the first report of a breast metastasis preceding the diagnosis of primary ovarian cancer by several years.

Recombinant expression of coagulation factor VIII in hepatic and non-hepatic cell lines stably transduced with third generation lentiviral vectors comprising the minimal factor VIII promoter.

BACKGROUND: Lentiviral vectors have the capacity to transduce stably non-dividing, differentiated and undifferentiated cells of various tissues, including liver. To obtain high-level expression of transgenes, vectors often rely on viral promoters. However, recent data suggest that the supraphysiologic expression from ubiquitous viral promoters may not be beneficial and harbor the risk of oncogene activation. Therefore this study explored the lentiviral-mediated expression of human coagulation factor VIII (FVIII) driven by the physiologic FVIII gene promoter (FVIII-p), the liver-specific human alpha-1-antitrypsin gene promoter (hAAT-p), the ubiquitous but non-viral EF1alpha promoter (EF1alpha-p) and the viral CMV promoter. METHODS: Hepatic and non-hepatic cell lines were stably transduced with lentiviral vectors encoding FVIIIdelB and EGFP. To compare the different promoters, lentiviral vectors were cloned to drive FVIII expression from FVIII-p, EF1alpha-p, hAAT-p and CMV-p. RESULTS: As expected, the strong viral CMV-p and the ubiquitous EF1alpha-p resulted in the highest FVIII expression in all cell lines tested (CMV-p 1.85 IU/mL/10(6) cells for 293T, 3.15 for HepG2, 5.03 for SK-Hep, 0.91 for Hepa1-6; EF1-alpha promoter 0.30 IU/mL/10(6) cells for 293T, 0.04 for HepG2, 2.75 for SK-Hep, 0.46 for Hepa1-6). While the hAAT-p resulted in low FVIII levels (0.10 IU/mL/10(6)cells in HepG2 and 0.04 in Hepa1-6), the FVIII promoter gave reasonable expression levels in hepatic cells (0.47 IU/mL/10(6)cells in Hepa1-6 and 0.44 in SK-Hep). DISCUSSION: These results indicate the potential usefulness of the FVIII-p for hemophilia A gene therapy.

Ferroelectric Liquid Crystals in Microcapillaries: Observation of Different Electro-optic Switching Mechanisms.

Ferroelectric liquid crystals (FLCs) can provide fast electro-optic switching effects in photonic crystal fibers, which are promising for developing integrated optical modulators to be used for optical telecommunication. The present study describes experiments on capillaries filled with FLCs, which pave the way toward application of FLCs in state-of-the-art solid core microstructured optical fibers. A method to achieve uniform alignment of the helix axis and the appearance of two different switching modes with switching times in the submillisecond range are found. An additional slow relaxation that was reported recently can be attributed to space charge fields, which may appear due to the migration of ions.

Influence of Proton and Salt Concentration on the Chromonic Liquid Crystal Phase Diagram of Disodium Cromoglycate Solutions: Prospects and Limitations of a Host for DNA Nanostructures.

Lyotropic chromonic liquid crystals have recently been suggested for use as a self-organized host for dispersing and aligning self-organized DNA origami nanostructures. However, an appropriate pH value and a suitable cation concentration are necessary to stabilize such nanostructures and to avoid unfolding of the DNA. The present study shows that the nematic and columnar liquid crystal phases appearing in aqueous solutions of disodium cromoglycate are robust against the replacement of deionized water by a neutral or alkaline buffer solution. However, disodium cromoglycate precipitates when an acidic buffer is used or when the concentration of magnesium cations exceeds a critical concentration of about 0.6-0.7 mmol/L.

[The Significance of Early Reposition in Patients with Visible Malposition of the Upper Ankle Joint]. / Stellenwert der frühzeitigen Reposition bei sichtbarer Luxation im oberen Sprunggelenk.

Background: Protracted dislocation of the upper ankle joint can lead to substantial damage to the surrounding soft tissue, possibly followed by local complications and longer hospitalisation. Although reposition is usually easy to conduct, it is commonly recommended that this should only be performed by an experienced specialist, as long as there is no neurovascular restriction. There are however no exact data or studies on this problem. The aim of the present study is to examine whether early reposition is of benefit for subsequent treatment. Methods: Retrospective study of all patients in a supra-regional trauma centre during the period from January 2009 to July 2015, with either prehospital reposition of the ankle joint because of visible malposition or documented visible malposition on arrival at hospital. Patients with relevant concomitant injuries elsewhere were excluded. Data on the duration of dislocation were matched with diagnostic findings at the time of hospital admission, the kind of primary care, local complications and the time of hospitalisation, using linear regression analysis and ANOVA calculations. Results: Of a total of 391 patients with a dislocation or a fracture dislocation of the ankle joint within this period, 132 fulfilled the inclusion criteria. These patients were divided into 5 groups on the basis of the time of dislocation. Time to reposition was less than one hour for 39 patients, between one and two hours for 29 patients, between two and six hours for 41 patients, between six and 24 hours for 13 patients and more than 24 hours for 10 patients, all with a visible dislocation. The results on admission showed a significant increase in skin bruises and tension bullae with increasing time of dislocation. A longer time of dislocation was associated with more two stage surgical procedures with external fixators and a decreasing number of single stage procedures. While there was immediate definitive treatment of 79.5 % of the patients in the first group, this figure decreased continuously to 10.0 % in the last group. The number of local complications increased significantly in every group with the duration of dislocation. In particular, the incidence of severe swelling, wound healing disorders, skin necrosis and the need for revision surgery and plastic reconstruction exhibit a significant linear increase within the groups (p < 0.05). The incidence of severe swelling rose from 10.3 % in the first group, to 31.0 % in the second group, to 100 % in the last group. The incidence of wound healing disorders rose from 7.7 to 13.8 to 80 % and the incidence of skin necrosis from 2.6 to 3.5 to 30.0 %. The duration of hospitalisation also exhibited a significant linear increase with group affiliation (p < 0.001), from 8.3 days in the first group to 12.5 days in the second group and 30.5 days in the last group. Conclusion: This study shows the importance of conducting reposition of the ankle joint as soon as possible if there is visible malposition, in order to avoid local complications and longer hospitalisation. If there is visible malposition of the ankle joint, the best procedure is immediate - ideally prehospital - reposition and in-axis splinting, in order to preserve soft tissue.

Hydrogen peroxide for prevention of bacterial growth on polymer biomaterials.

BACKGROUND: Despite widespread use of potent antibiotics, infections of artificial implants and catheters are of increasing concern. We tested whether local treatment with 3% hydrogen peroxide (H2O2), long known as an inexpensive wound disinfectant, could prevent or reduce bacterial growth on polymer biomaterials. METHODS: Two-centimeter-long pieces of polyurethane and silicone tubing were contaminated with a standardized solution of Staphylococcus epidermidis (10(5)/mL) and then rinsed and wiped with saline (0.9%) solution. Bacterial growth was assessed after incubation at 37 degrees C for 24 hours. Bacterial colonies were compared for the following treatments: wiping only with saline; wiping with 1.5%, 2%, or 3% H2O2; pretreating biomaterials with 3% H2O2 and subsequent contamination for 2 and 4 hours without treatment after contamination; and contamination of tubings 1 month after pretreatment with 3% H2O2. The effect of 3% H2O2 was also assessed on contamination with Escherichia coli. RESULTS: Bacterial growth was reduced by more than 99% when the contaminated tubes were treated with 3% H2O2 compared with saline control (p < 0.001). Lower concentrations of H2O2 were less effective. The length of the contamination period had no influence on the effectiveness of H2O2 when used on polyurethane but did with silicone tubings. Pretreatment with H2O2 1 month before contamination still reduced bacterial growth rate by 90% on polyurethane and by 75% on silicone tubings. Comparable effects on bacterial growth rate were observed for staphylococci (-90%, p < 0.001) and escherichiae (-90%, p < 0.001). CONCLUSIONS: Local treatment with 3% H2O2 significantly reduced bacterial growth on polymer biomaterials even for 1 month after treatment. This finding might influence clinical strategies of prevention of foreign body infection.

Does reducing capacitance have potential for further miniaturisation of implantable defibrillators?

OBJECTIVE: To determine whether considerably smaller capacitors could replace 125 microF capacitors as the standard for use in implantable defibrillators. METHODS: Measured energy, impedance, voltage, and current delivered were compared at defibrillation threshold in 10 mongrel dogs for defibrillation using 75 microF and 125 microF capacitors alternated randomly. Defibrillation was attempted with biphasic shocks of comparable tilt between an endocardial lead in the right ventricular apex and a "dummy" active can of an experimental implantable device placed in the subpectoral position. RESULTS: A reduction of capacitor size of 40% was associated with an increase in voltage of 21% and in current of 22%. With a 65% tilt, no significant differences were found between the two capacitances with respect to the impedance or energy required for defibrillation. CONCLUSIONS: Multiple advances in electrode material, electrode configuration, shock morphology, and shock polarity have reduced defibrillation energy requirements. Smaller capacitors could be used in implantable cardioverter/defibrillators without a major decrease in effectiveness.

Depth of nontarget processing in an attention task.

Two studies examined the effect of the sensory discriminability of targets from nontargets on depth of nontarget processing. Subjects shadowed target words that were binaurally presented with coincident nontarget words. Targets and nontargets were spoken in the same male voice under low sensory discriminability and in male and female voices, respectively under high sensory discriminability. Across the two studies, depth of nontarget processing was assessed in three ways: extent to which shadowing accuracy was disrupted by a semantic overlap between targets and nontargets, expenditure of capacity (reaction time to subsidiary light signals), and nontarget recall. All three possible measures of depth of nontarget processing decreased as sensory discriminability increased. The data support the assumption of multiple-loci theories of attention that nontargets can be perceptually inhibited; they contraindicate the assumption of late-selection theories that perceptual processing is automatic and irrepressible.