Interferometric, modulation-free laser stabilization.
We demonstrate novel modulation-free frequency locking of a diode laser, utilizing a simple Sagnac interferometer to create an error signal from saturated-absorption spectroscopy. The interference condition at the output of the Sagnac is strongly affected by the sharp dispersion feature near an atomic resonance. Slight misalignment of the interferometer and subsequent spatially selective, or tilt, detection allows this phase change to be converted into an error signal. Tilt locking has significant advantages over previously described methods, as it requires only a small number of low-cost optical components and a detector. In addition, the system has the potential to be constructed as a plug-and-play fiber-coupled monolithic device to provide submegahertz stability for lasers in the commercial market.


Cervical Conization and the Risk of Preterm Birth: A Population-Based Multicentric Trial of Turkish Cohort.
Cold Knife Conization (CKC) is one of the most effective methods for the treatment of Cervical Intraepithelial Neoplasia (CIN). Some studies showed a relation between preterm birth and the treatment of CIN; on the other hand, other studies do not show such a relationship. The present study was conducted with the aim to investigate the pregnancy outcomes of Turkish women regarding demographic characteristics, obstetric history, removed tissue, and residual cervical length after CKC and to determine the effect of removed cervical tissue volume and height on preterm birth. This study was a population-based, multicenter trial that was conducted on singleton pregnancies between January 2007 and December 2013. The control group comprised of 38,892 patients who gave birth during this period. On the other hand, patients who conceived after CKC during this period were invited to the hospital and included in the case group (n=20). The course of pregnancy following CKC was studied. Preterm birth rates, risk factors for preterm birth, conisation age, cervical smear and colposcopic biopsy results and the volume and height of the removed cervical tissue of those patients were evaluated. There was no statistically significant difference in preterm birth rates between the case and the control groups. None of our cases had any identified preterm birth risk factor except for one case. The average height of removed cervical tissue was 12.6±5.4 mm and the average length of the residual cervix after birth was 28.7±4.3 mm. Removal of cervical tissue of 12.6±5.4 mm in height and 2.35±2.27 cm3 in volume will not increase the risk of preterm birth of women who do not have any other preterm birth risk factors. If there is no other preterm birth risk factors, term birth is most probably possible after conisation.


Epac mediates cyclic AMP-dependent axon growth, guidance and regeneration.
A decline in developing neuronal cAMP levels appears to render mammalian axons susceptible to growth inhibitory factors in the damaged CNS. cAMP elevation enhances axon regeneration, but the cellular mechanisms involved have yet to be fully elucidated. Epac has been identified as a signaling protein that can be activated by cAMP independently of PKA, but little is known of its expression or role in the nervous system. We report that Epac expression is developmentally regulated in the rat nervous system, and that activation of Epac promotes DRG neurite outgrowth and is as effective as cAMP elevation in promoting neurite regeneration on spinal cord tissue. Additionally, siRNA mediated knockdown of Epac reduces DRG neurite outgrowth, prevents the increased growth promoted by cAMP elevation and also diminishes the ability of embryonic neurons to grow processes on spinal cord tissue. Furthermore, we show that asymmetric activation of Epac promotes attractive growth cone turning in a similar manner to cAMP activation. We propose that Epac plays a role in mediating cAMP-dependent axon growth and guidance, and may provide an important target for inducing axon regeneration in vivo.


Effect of acute augmented feedback on between limb asymmetries and eccentric knee flexor strength during the Nordic hamstring exercise.
Hamstring strain injuries (HSI) are one of the most prevalent and serious injuries affecting athletes, particularly those in team ball sports or track and field. Recent evidence demonstrates that eccentric knee flexor weakness and between limb asymmetries are possible risk factors for HSIs. While eccentric hamstring resistance training, e.g. the Nordic hamstring exercise (NHE) significantly increases eccentric hamstring strength and reduces HSI risk, little research has examined whether between limb asymmetries can be reduced with training. As augmented feedback (AF) can produce significant acute and chronic increases in muscular strength and reduce injury risk, one way to address the limitation in the eccentric hamstring training literature may be to provide athletes real-time visual AF of their NHE force outputs with the goal to minimise the between limb asymmetry. Using a cross over study design, 44 injury free, male cricket players from two skill levels performed two NHE sessions on a testing device. The two NHE sessions were identical with the exception of AF, with the two groups randomised to perform the sessions with and without visual feedback of each limb's force production in real-time. When performing the NHE with visual AF, the participants were provided with the following instructions to 'reduce limb asymmetries as much as possible using the real-time visual force outputs displayed in front them'. Between limb asymmetries and mean peak force outputs were compared between the two feedback conditions (FB1 and FB2) using independent t-tests to ensure there was no carryover effect, and to determine any period and treatment effects. The magnitude of the differences in the force outputs were also examined using Cohen d effect size. There was a significant increase in mean peak force production when feedback was provided (mean difference, 21.7 N; 95% CI [0.2-42.3 N]; P = 0.048; d = 0.61) and no significant difference in between limb asymmetry for feedback or no feedback (mean difference, 5.7%; 95% CI [-2.8% to 14.3%]; P = 0.184; d = 0.41). Increases in force production under feedback were a result of increased weak limb (mean difference, 15.0 N; 95% CI [1.6-28.5 N]; P = 0.029; d = 0.22) force contribution compared to the strong limb. The results of this study further support the potential utility of AF in improving force production and reducing risk in athletic populations. While there are currently some financial limitations to the application of this training approach, even in high-performance sport, such an approach may improve outcomes for HSI prevention programs. Further research with more homogenous populations over greater periods of time that assess the chronic effect of such training practices on injury risk factors and injury rates are also recommended.


Cross-cultural evaluation of the Parkinson's Disease Questionnaire: tests of data quality, score reliability, response rate, and scaling assumptions in the United States, Canada, Japan, Italy, and Spain.
Health status measures, used to measure the subjective functioning and well-being of respondents, are increasingly being used in trials of treatments that are undertaken in a variety of countries. To assess comparability of results gained from such cross-cultural studies, it is important for researchers to know the comparability of instruments across cultures. One measure widely used in cross-cultural studies is the Parkinson's Disease Questionnaire (PDQ-39). We evaluated response rate, data quality, score reliability, and scaling assumptions of the instrument in the United States, Canada, Spain, Italy, and Japan. Our data were gained from the Global Parkinson's Disease Survey, a cross-national survey, in which the PDQ-39 was interviewer administered to respondents. Our data suggest that the PDQ-39 is, for the most part, a valid and reliable measure that can be appropriately and meaningfully used in cross-cultural studies. However, one of the dimensions of the measure, Social Support, may not be sufficiently reliable to be used as a primary endpoint in trials. The PDQ-39 seems to be sufficiently robust to be used in trials and surveys in cross-cultural studies.


Circular RNAs are down-regulated in KRAS mutant colon cancer cells and can be transferred to exosomes.
Recent studies have shown that circular RNAs (circRNAs) are abundant, widely expressed in mammals, and can display cell-type specific expression. However, how production of circRNAs is regulated and their precise biological function remains largely unknown. To study how circRNAs might be regulated during colorectal cancer progression, we used three isogenic colon cancer cell lines that differ only in KRAS mutation status. Cellular RNAs from the parental DLD-1 cells that contain both wild-type and G13D mutant KRAS alleles and isogenically-matched derivative cell lines, DKO-1 (mutant KRAS allele only) and DKs-8 (wild-type KRAS allele only) were analyzed using RNA-Seq. We developed a bioinformatics pipeline to identify and evaluate circRNA candidates from RNA-Seq data. Hundreds of high-quality circRNA candidates were identified in each cell line. Remarkably, circRNAs were significantly down-regulated at a global level in DLD-1 and DKO-1 cells compared to DKs-8 cells, indicating a widespread effect of mutant KRAS on circRNA abundance. This finding was confirmed in two independent colon cancer cell lines HCT116 (KRAS mutant) and HKe3 (KRAS WT). In all three cell lines, circRNAs were also found in secreted extracellular-vesicles, and circRNAs were more abundant in exosomes than cells. Our results suggest that circRNAs may serve as promising cancer biomarkers.


First record of the mosquito control potentiality of Stigmatogobius sadanundio (F. Hamilton, 1822) Gobiidae, Perciformes in laboratory condition.
In recent years, resurgence of mosquito-borne diseases has become a serious health problem in India. In the present study, Stigmatogobius sadanundio, a common indigenous fish, has been tested for its biocontrol potentiality for controlling Culex quinquefasciatus larvae. This small larvivorous fish can consume large number of Culex larvae even in the presence of alternate prey. This is the first report on the mosquito control ability of this fish. Experimental fishes were captured from tidal canals of Rupnarayan River in Purba Medinipur district, West Bengal. Mosquito larvae, pupae, and chironomid larvae were collected from Tamralipta municipality drainage system. Predation efficacy of the fish was evaluated on C. quinquefasciatus larvae and pupae as well as on Chironomus ramosus larvae which were collected from the drainage system of Tamralipta municipality and reared in the laboratory maintaining similar water parameters. Prey were offered to the fish separately and in paired combination to study its dietary preference. S. sadanundio is a diurnal predator consuming significantly large number of prey during daytime. It prefers mosquito and chironomid larvae over mosquito pupae. The rate of predation was very high during 1st h of predation. It consumed more chironomid larvae in the presence of mosquito larvae during daytime but consumed large number of mosquito larvae as compared to other larvivorous fish. S. sadanundio, an indigenous fish, is an effective biocontrol agent for the larvae of C. quinquefasciatus in laboratory condition. Even though the presence of alternate prey chironomid larvae influences the predation rate, it consumed large number of mosquito larvae. However, careful controlled field trials must be conducted before this fish is used as a biocontrol agent.


Cut-off values for Gaussian first-trimester screening for early-onset preeclampsia with maternal history, biochemical markers and uterine artery Doppler.
Several algorithms for first-trimester screening for preeclampsia are available; however, the Gaussian model algorithm is more likely to match the characteristics of different populations. It is recommended to validate a screening strategy before being implemented in clinical practice; unfortunately, the validation process might not be feasible in all settings. Thus, the aim of this study was to provide cut-off values for the Gaussian model for its use in clinical practice. This prospective cohort study was conducted at Vall d'Hebron University Hospital (Barcelona) from October 2015 to September 2017. A total of 2641 women with singleton pregnancies were recruited. Recorded at the first-trimester scan were demographic characteristics, maternal obstetric history, maternal history, uterine artery Doppler and arterial blood pressure. Serum concentrations of pregnancy-associated plasma protein-A and placental growth factor were assessed from the first-trimester blood test. Detection rates and cut-off values for fixed 5%, 10 %, 15 %, 20 %, 25 % and 30 % false-positive rates were calculated for all combinations of markers. Ninety (3.41 %) of the 2641 women developed preeclampsia, which was early-onset in 11 (0.42 %). The cut-off values and their respective detection rates, for the screening of early-onset PE by all possible combinations of markers involved in this model, are provided. When external validation of first-trimester screening for preeclampsia before its clinical implementation is not feasible, the cut-off values from the Gaussian model algorithm provided in this study could be used and median values corrected prospectively if necessary.


Simple all-PM-fiber laser mode-locked with a nonlinear loop mirror.
In this Letter, we present a figure-eight all-PM-fiber laser oscillator design with a nonlinear optical loop mirror as an artificial saturable absorber. Unlike previous constructions using the same mode-locking technique, our cavity is constructed entirely of polarization-maintaining (PM) fibers, making the oscillator more resistant to thermal and mechanical perturbations. Two simple and robust laser configurations that differ by the output coupling ratio (70% or 30%) are presented. The first configuration delivers high energy pulses of 3.5 nJ, and the second configuration delivers pulses of 1.6 nJ at a common repetition rate of 15 MHz. In either configuration, the pulsed operation is stable, and the laser operates in a single pulse train regime, even for pump powers approaching twice the power required for mode-locking. We have also observed that, at higher intracavity powers, stimulated Raman scattering plays a significant role.


Clinical and angiographic long-term follow-up of completely coiled intracranial aneurysms using endovascular technique.
The anatomical evolution and clinical outcome of completely coiled intracranial aneurysms after endovascular embolization have rarely been studied separately. From their prospective database, the authors reviewed follow-up angiography and clinical outcome of 87 patients whose aneurysms were designated as 100% obliterated on immediate postembolization angiography. Ninety-one aneurysms (56 ruptured and 35 unruptured) in 87 patients were included in this study. Clinical outcome was evaluated using the Glasgow Outcome Scale. Follow-up angiographic findings were assessed and categorized as 1 of the following: no recanalization, recanalization with a neck remnant, or recanalization with a body remnant. For statistical analysis, the recanalization rate was correlated with: clinical presentation; the largest aneurysm diameter, aneurysm neck size, and dome-to-neck ratio; aneurysm location; and use of special techniques such as usage of a surface modified coil, balloon remodeling technique, or stent. At the latest clinical evaluation (mean 34.3 months), 81 (93.1%) of the 87 patients (91 aneurysms) had good clinical outcomes (Glasgow Outcome Scale Score 5). The procedure-related morbidity rate (permanent neurological deficit) was 2.3% (2 of 87), and there were no procedure-related deaths. On the latest follow-up angiography (mean 26.4 months), the recanalization rate was 26.4% (24 of 91 aneurysms): 16 (17.6%) with neck remnants and 8 (8.8%) with body remnants. The neck size of the recanalized aneurysms was statistically significantly larger than that of the nonrecanalized aneurysms (p = 0.006), and aneurysms with wide necks (> or = 4 mm) had a higher recanalization rate than those with a narrow neck (< 4 mm) (p = 0.002). There was no bleeding after endovascular treatment during the follow-up period. Completely coiled aneurysms after endovascular embolization demonstrated good clinical outcome, and there was no bleeding episode after endovascular treatment; however, there was a relatively high recanalization rate.


Biomimetic crystalline actuators: structure-kinematic aspects of the self-actuation and motility of thermosalient crystals.
While self-actuation and motility are habitual for humans and nonsessile animals, they are hardly intuitive for simple, lifeless, homogeneous objects. Among mechanically responsive materials, the few accidentally discovered examples of crystals that when heated suddenly jump, propelling themselves to distances that can reach thousands of times their own size in less than 1 ms, provide the most impressive display of the conversion of heat into mechanical work. Such thermosalient crystals are biomimetic, nonpolymeric self-actuators par excellence. Yet, due to the exclusivity and incongruity of the phenomenon, as well as because of the unavailability of ready analytical methodology for its characterization, the reasons behind this colossal self-actuation remain unexplained. Aimed at unraveling the mechanistic aspects of the related processes, herein we establish the first systematic assessment of the interplay among the thermodynamic, kinematic, structural, and macroscopic factors driving the thermosalient phenomenon. The collective results are consistent with a latent but very rapid anisotropic unit cell deformation in a two-stage process that ultimately results in crystal explosion, separation of debris, or crystal reshaping. The structural perturbations point to a mechanism similar to phase transitions of the martensitic family.


Pro-Oxidant Activity of Amine-Pyridine-Based Iron Complexes Efficiently Kills Cancer and Cancer Stem-Like Cells.
Differential redox homeostasis in normal and malignant cells suggests that pro-oxidant-induced upregulation of cellular reactive oxygen species (ROS) should selectively target cancer cells without compromising the viability of untransformed cells. Consequently, a pro-oxidant deviation well-tolerated by nonmalignant cells might rapidly reach a cell-death threshold in malignant cells already at a high setpoint of constitutive oxidative stress. To test this hypothesis, we took advantage of a selected number of amine-pyridine-based Fe(II) complexes that operate as efficient and robust oxidation catalysts of organic substrates upon reaction with peroxides. Five of these Fe(II)-complexes and the corresponding aminopyridine ligands were selected to evaluate their anticancer properties. We found that the iron complexes failed to display any relevant activity, while the corresponding ligands exhibited significant antiproliferative activity. Among the ligands, none of which were hemolytic, compounds 1, 2 and 5 were cytotoxic in the low micromolar range against a panel of molecularly diverse human cancer cell lines. Importantly, the cytotoxic activity profile of some compounds remained unaltered in epithelial-to-mesenchymal (EMT)-induced stable populations of cancer stem-like cells, which acquired resistance to the well-known ROS inducer doxorubicin. Compounds 1, 2 and 5 inhibited the clonogenicity of cancer cells and induced apoptotic cell death accompanied by caspase 3/7 activation. Flow cytometry analyses indicated that ligands were strong inducers of oxidative stress, leading to a 7-fold increase in intracellular ROS levels. ROS induction was associated with their ability to bind intracellular iron and generate active coordination complexes inside of cells. In contrast, extracellular complexation of iron inhibited the activity of the ligands. Iron complexes showed a high proficiency to cleave DNA through oxidative-dependent mechanisms, suggesting a likely mechanism of cytotoxicity. In summary, we report that, upon chelation of intracellular iron, the pro-oxidant activity of amine-pyrimidine-based iron complexes efficiently kills cancer and cancer stem-like cells, thus providing functional evidence for an efficient family of redox-directed anti-cancer metallodrugs.


Contribution of Germline Predisposition Gene Mutations to Breast Cancer Risk in African American Women.
The risks of breast cancer in African American (AA) women associated with inherited mutations in breast cancer predisposition genes are not well defined. Thus, whether multigene germline hereditary cancer testing panels are applicable to this population is unknown. We assessed associations between mutations in panel-based genes and breast cancer risk in 5054 AA women with breast cancer and 4993 unaffected AA women drawn from 10 epidemiologic studies. Germline DNA samples were sequenced for mutations in 23 cancer predisposition genes using a QIAseq multiplex amplicon panel. Prevalence of mutations and odds ratios (ORs) for associations with breast cancer risk were estimated with adjustment for study design, age, and family history of breast cancer. Pathogenic mutations were identified in 10.3% of women with estrogen receptor (ER)-negative breast cancer, 5.2% of women with ER-positive breast cancer, and 2.3% of unaffected women. Mutations in BRCA1, BRCA2, and PALB2 were associated with high risks of breast cancer (OR = 47.55, 95% confidence interval [CI] = 10.43 to >100; OR = 7.25, 95% CI = 4.07 to 14.12; OR = 8.54, 95% CI = 3.67 to 24.95, respectively). RAD51D mutations were associated with high risk of ER-negative disease (OR = 7.82, 95% CI = 1.61 to 57.42). Moderate risks were observed for CHEK2, ATM, ERCC3, and FANCC mutations with ER-positive cancer, and RECQL mutations with all breast cancer. The study identifies genes that predispose to breast cancer in the AA population, demonstrates the validity of current breast cancer testing panels for use in AA women, and provides a basis for increased referral of AA patients for cancer genetic testing.


Identification of residues in the human respiratory syncytial virus fusion protein that modulate fusion activity and pathogenesis.
Human respiratory syncytial virus (RSV) lower respiratory tract infection can result in inflammation and mucus plugging of airways. RSV strain A2-line19F induces relatively high viral load and mucus in mice. The line 19 fusion (F) protein harbors five unique residues compared to the non-mucus-inducing strains A2 and Long, at positions 79, 191, 357, 371, and 557. We hypothesized that differential fusion activity is a determinant of pathogenesis. In a cell-cell fusion assay, line 19 F was more fusogenic than Long F. We changed the residues unique to line 19 F to the corresponding residues in Long F and identified residues 79 and 191 together as responsible for high fusion activity. Surprisingly, mutation of residues 357 or 357 with 371 resulted in gain of fusion activity. Thus, we generated RSV F mutants with a range of defined fusion activity and engineered these into recombinant viruses. We found a clear, positive correlation between fusion activity and early viral load in mice; however, we did not detect a correlation between viral loads and levels of airway mucin expression. The F mutant with the highest fusion activity, A2-line19F-K357T/Y371N, induced high viral loads, severe lung histopathology, and weight loss but did not induce high levels of airway mucin expression. We defined residues 79/191 as critical for line 19 F fusion activity and 357/371 as playing a role in A2-line19F mucus induction. Defining the molecular basis of the role of RSV F in pathogenesis may aid vaccine and therapeutic strategies aimed at this protein. Human respiratory syncytial virus (RSV) is the most important lower respiratory tract pathogen of infants for which there is no vaccine. Elucidating mechanisms of RSV pathogenesis is important for rational vaccine and drug design. We defined specific amino acids in the fusion (F) protein of RSV strain line 19 critical for fusion activity and elucidated a correlation between fusion activity and viral load in mice. Further, we identified two distinct amino acids in F as contributing to the mucogenic phenotype of the A2-line19F virus. Taken together, these results illustrate a role for RSV F in virulence.


What is the overlap between HIV and shigellosis epidemics in England: further evidence of MSM transmission?
Evidence suggests that sexual transmission between men has replaced foreign travel as the predominant mode of Shigella transmission in England. However, sexuality and HIV status are not routinely recorded for laboratory-reported Shigella, and the role of HIV in the Shigella epidemic is not well understood. The Modular Open Laboratory Information System containing all Shigella cases reported to Public Health England (PHE) and the PHE HIV and AIDS Reporting System holding all adults living with diagnosed HIV in England were matched using a combination of Soundex code, date of birth and gender. From 2004 to 2015, 88 664 patients were living with HIV, and 10 269 Shigella cases were reported in England; 9% (873/10 269) of Shigella cases were diagnosed with HIV, of which 93% (815/873) were in men. Shigella cases without reported travel history were more likely to be living with HIV than those who had travelled (14% (751/5427) vs 3% (134/4854); p<0.01). From 2004 to 2015, the incidence of Shigella in men with HIV rose from 47/100 000 to 226/100 000 (p<0.01) peaking in 2014 at 265/100 000, but remained low in women throughout the study period (0-24/100 000). Among Shigella cases without travel and with HIV, 91% (657/720) were men who have sex with men (MSM). HIV preceded Shigella diagnosis in 86% (610/720), and 65% (237/362) had an undetectable viral load (<50 copies/mL). We observed a sustained increase in the national rate of shigellosis in MSM with HIV, who may experience more serious clinical disease. Sexual history, HIV status and STI risk might require sensitive investigation in men presenting with gastroenteritis.


Aerobic TCE degradation by encapsulated toluene-oxidizing bacteria, Pseudomonas putida and Bacillus spp.
The degradation rates of toluene and trichloroethylene (TCE) by Pseudomonas putida and Bacillus spp. that were encapsulated in polyethylene glycol (PEG) polymers were evaluated in comparison with the results of exposure to suspended cultures. PEG monomers were polymerized together with TCE-degrading microorganisms, such that the cells were encapsulated in and protected by the matrices of the PEG polymers. TCE concentrations were varied from 0.1 to 1.5 mg/L. In the suspended cultures of P. putida, the TCE removal rate decreased as the initial TCE concentration increased, revealing TCE toxicity or a limitation of reducing power, or both. When the cells were encapsulated, an initial lag period of about 10-20 h was observed for toluene degradation. Once acclimated, the encapsulated P. putida cultures were more tolerant to TCE at an experimental range of 0.6-1.0 mg/L and gave higher transfer efficiencies (mass TCE transformed/mass toluene utilized). When the TCE concentration was low (e.g., 0.1 mg/L) the removal of TCE per unit mass of cells (specific removal) was significantly lower, probably due to a diffusion limitation into the PEG pellet. Encapsulated Bacillus spp. were able to degrade TCE cometabolically. The encapsulated Bacillus spp. gave significantly higher values than did P. putida in the specific removal and the transfer efficiency, particularly at relatively high TCE concentration of approximately 1.0±0.5 mg/L. The transfer efficiency by encapsulated Bacillus spp. in this study was 0.27 mgTCE/mgToluene, which was one to two orders of magnitude greater than the reported values.


Samarium hexaboride is a trivial surface conductor.
SmB6 is predicted to be the first member of the intersection of topological insulators and Kondo insulators, strongly correlated materials in which the Fermi level lies in the gap of a many-body resonance that forms by hybridization between localized and itinerant states. While robust, surface-only conductivity at low temperature and the observation of surface states at the expected high symmetry points appear to confirm this prediction, we find both surface states at the (100) surface to be topologically trivial. We find the [Formula: see text] state to appear Rashba split and explain the prominent [Formula: see text] state by a surface shift of the many-body resonance. We propose that the latter mechanism, which applies to several crystal terminations, can explain the unusual surface conductivity. While additional, as yet unobserved topological surface states cannot be excluded, our results show that a firm connection between the two material classes is still outstanding.


Plant Hosts of Xylella fastidiosa In and Near Southern California Vineyards.
Xylella fastidiosa is a xylem-limited bacterium that causes Pierce's disease (PD) of grapevines. A variety of plant species found near a severe outbreak of PD in vineyards in the Temecula Valley of California were tested using enzyme-linked immunosorbent assay, culture on media, and polymerase chain reaction to identify potential inoculum sources in the area. Species that consistently tested positive for X. fastidiosa were the known hosts, grape, almond, and oleander, and two new hosts, Spanish broom (Spartium junceum) and wild mustard (Brassica spp). Sequence analysis of the 16S-23S rRNA spacer region found that strains isolated from grapevine, Spanish broom, wild mustard, and almond clustered with previously sequenced PD strains. Thus, these species could serve as sources of inoculum for infection of grapevines and should be removed or monitored for signs of infection. Sequences from oleander isolates from Temecula formed another cluster with a previously published oleander strain sequence. Oleander strains do not infect grapevines and thus do not appear to cause a direct threat to grapevines. Two additional isolates from almond were determined to be genetically different from PD strains, and the ability of these strains to infect grapevine is not known. Greenhouse transmission studies indicate that the glassy-winged sharpshooter was able to transmit a PD strain of X. fastidiosa to Spanish broom, black mustard, and other hosts.


A photo- and electrochemically-active porphyrin-fullerene dyad electropolymer.
A hole- and electron-conducting polymer has been prepared by electropolymerization of a porphyrin-fullerene monomer. The porphyrin units are linked by aminophenyl groups to form a linear chain in which the porphyrin is an integral part of the polymer backbone. The absorption spectrum of a film formed on indium-tin-oxide-coated glass resembles that of a model porphyrin-fullerene dyad, but with significant peak broadening. The film demonstrates a first oxidation potential of 0.75 V vs. SCE, corresponding to oxidation of the porphyrin polymer, and a first reduction potential of -0.63 V vs. SCE, corresponding to fullerene reduction. Time-resolved fluorescence studies show that the porphyrin first excited singlet state is strongly quenched by photoinduced electron transfer to fullerene. Transient absorption investigations reveal that excitation generates mobile charge carriers that recombine by both geminate and nongeminate pathways over a large range of time scales. Similar studies on a related polymer that lacks the fullerene component show complex, laser-intensity-dependent photoinduced electron transfer behavior. The properties of the porphyrin-fullerene electropolymer suggest that it may be useful in organic photovoltaic applications, wherein light absorption leads to charge separation within picoseconds in a "molecular heterojunction" with no requirement for exciton migration.


Evidence that proteolysis of Gal4 cannot explain the transcriptional effects of proteasome ATPase mutations.
The Gal system of Saccharomyces cerevisiae is a paradigm for eukaryotic gene regulation. Expression of genes required for growth on galactose is regulated by the transcriptional activator Gal4. The activation function of Gal4 has been localized to 34 amino acids near the C terminus of the protein. The gal4D allele of GAL4 encodes a truncated protein in which only 14 amino acids of the activation domain remain. Expression of GAL genes is dramatically reduced in gal4D strains and these strains are unable to grow on galactose as the sole carbon source. Overexpression of gal4D partially relieves the defect in GAL gene expression and allows growth on galactose. A search for extragenic suppressors of gal4D identified recessive mutations in the SUG1 and SUG2 genes, which encode ATPases of the 19S regulatory complex of the proteasome. The proteasome is responsible for the ATP-dependent degradation of proteins marked for destruction by the ubiquitin system. It has been commonly assumed that effects of SUG1 and SUG2 mutations on transcription are explained by alterations in the proteolysis of gal4D protein. We have investigated this assumption. Surprisingly, we find that SUG1 and SUG2 alleles that are unable to suppress gal4D cause a larger increase in gal4D protein levels than do suppressing alleles. In addition, mutations in genes encoding subunits of the proteolytic 20S sub-complex of the proteasome increase the levels of gal4D protein but do not rescue its transcriptional activity. Therefore, an alteration in the proteolysis of gal4D by the proteasome cannot explain the effects of mutations in SUG1 and SUG2 on expression of GAL genes. These findings suggest that the 19S regulatory complex may play a more direct role in transcription.


Appendicitis risk prediction models in children presenting with right iliac fossa pain (RIFT study): a prospective, multicentre validation study.
Acute appendicitis is the most common surgical emergency in children. Differentiation of acute appendicitis from conditions that do not require operative management can be challenging in children. This study aimed to identify the optimum risk prediction model to stratify acute appendicitis risk in children. We did a rapid review to identify acute appendicitis risk prediction models. A prospective, multicentre cohort study was then done to evaluate performance of these models. Children (aged 5-15 years) presenting with acute right iliac fossa pain in the UK and Ireland were included. For each model, score cutoff thresholds were systematically varied to identify the best achievable specificity while maintaining a failure rate (ie, proportion of patients identified as low risk who had acute appendicitis) less than 5%. The normal appendicectomy rate was the proportion of resected appendixes found to be normal on histopathological examination. 15 risk prediction models were identified that could be assessed. The cohort study enrolled 1827 children from 139 centres, of whom 630 (34·5%) underwent appendicectomy. The normal appendicectomy rate was 15·9% (100 of 630 patients). The Shera score was the best performing model, with an area under the curve of 0·84 (95% CI 0·82-0·86). Applying score cutoffs of 3 points or lower for children aged 5-10 years and girls aged 11-15 years, and 2 points or lower for boys aged 11-15 years, the failure rate was 3·3% (95% CI 2·0-5·2; 18 of 539 patients), specificity was 44·3% (95% CI 41·4-47·2; 521 of 1176), and positive predictive value was 41·4% (38·5-44·4; 463 of 1118). Positive predictive value for the Shera score with a cutoff of 6 points or lower (72·6%, 67·4-77·4) was similar to that of ultrasound scan (75·0%, 65·3-83·1). The Shera score has the potential to identify a large group of children at low risk of acute appendicitis who could be considered for early discharge. Risk scoring does not identify children who should proceed directly to surgery. Medium-risk and high-risk children should undergo routine preoperative ultrasound imaging by operators trained to assess for acute appendicitis, and MRI or low-dose CT if uncertainty remains. None.


Biofilm formation enhances fomite survival of Streptococcus pneumoniae and Streptococcus pyogenes.
Both Streptococcus pyogenes and Streptococcus pneumoniae are widely thought to rapidly die outside the human host, losing infectivity following desiccation in the environment. However, to date, all literature investigating the infectivity of desiccated streptococci has used broth-grown, planktonic populations. In this study, we examined the impact of biofilm formation on environmental survival of clinical and laboratory isolates of S. pyogenes and S. pneumoniae as both organisms are thought to colonize the human host as biofilms. Results clearly demonstrate that while planktonic cells that are desiccated rapidly lose viability both on hands and abiotic surfaces, such as plastic, biofilm bacteria remain viable over extended periods of time outside the host and remain infectious in a murine colonization model. To explore the level and extent of streptococcal fomite contamination that children might be exposed to naturally, direct bacteriologic cultures of items in a day care center were conducted, which demonstrated high levels of viable streptococci of both species. These findings raise the possibility that streptococci may survive in the environment and be transferred from person to person via fomites contaminated with oropharyngeal secretions containing biofilm streptococci.


Gowers' Queen Square case notes on chorea: a 21st century re-appraisal.
To analyze the case notes of 127 patients with chorea admitted to the National Hospital at Queen Square, London, under the care of William Richard Gowers and review his contribution to the study of choreas. We consulted the case books available at the Queen Square Library, from 1878 to 1911, comprising 42 volumes. 97 patients (76.3%) were female and the age of presentation ranged from 4 to 60 years (mean 14.3). 43 patients (33.8%) experienced recurrent attacks of chorea. 29 patients (22.8%) had a family history of chorea. Past history of rheumatic fever was observed in 46 patients (36.2%). 54 patients (42.5%) had speech impairment while a similar number had a cardiac murmur. Generalized chorea occurred in 87.4% and hemichorea in 11.8%. Gowers diagnosed different forms of chorea: Huntington's disease, paralytic, persistent, recurrent, tetanoid, functional, maniacal, hemichorea and chorea gravidarum. Gowers was one of the pioneers in recognizing chorea as a physical sign found in a myriad of etiologies. He also provided a comprehensive description of the clinical features and natural history of Sydenham's chorea in his work.


Folate status and aberrant DNA methylation are associated with HPV infection and cervical pathogenesis.
Aberrant DNA methylation is a recognized feature of human cancers, and folate is directly involved in DNA methylation via one-carbon metabolism. Previous reports also suggest that folate status is associated with the natural history of human papillomavirus (HPV) infection. A cross-sectional study was conducted to test the hypothesis that folate status and aberrant DNA methylation show a progressive change across stages of cervical pathology from normal cells to cervical cancer. Additionally, we postulated that a gene-specific hypermethylation profile might be used as a predictive biomarker of cervical cancer risk. DNA hypermethylation of seven tumor suppressor genes, global DNA hypomethylation, systemic folate status, and HPV status were measured in 308 women with a diagnosis of normal cervix (n = 58), low-grade cervical intraepithelial neoplasia (CIN1; n = 68), high-grade cervical intraepithelial neoplasia (CIN2, n = 56; and CIN3, n = 76), or invasive cervical cancer (ICC; n = 50). Lower folate status was associated with high-risk HPV infection (P = 0.031) and with a diagnosis of cervical intraepithelial neoplasia or invasive cervical cancer (P < 0.05). Global DNA hypomethylation was greater in women with invasive cervical cancer than all other groups (P < 0.05). A cluster of three tumor suppressor genes, CDH1, DAPK, and HIC1, displayed a significantly increased frequency of promoter methylation with progressively more severe cervical neoplasia (P < 0.05). These findings are compatible with a role for folate in modulating the risk of cervical cancer, possibly through an influence over high-risk HPV infection. DAPK, CDH1, and HIC1 genes are potential biomarkers of cervical cancer risk.


Catalyst-Directed Diastereoselective Isomerization of Allylic Alcohols for the Stereoselective Construction of C(20) in Steroid Side Chains: Scope and Topological Diversification.
The stereoselective construction of C20 in steroidal derivatives by a highly diastereoselective Ir-catalyzed isomerization of primary allylic alcohols is reported. A key aspect of this strategy is a straightforward access to geometrically pure steroidal enol tosylate and enol triflate intermediates for subsequent high yielding stereoretentive Negishi cross-coupling reactions to allow structural diversity to be introduced. A range of allylic alcohols participates in the diastereoselective isomerization under the optimized reaction conditions. Electron-rich and electron-poor aryl or heteroaryl substituents are particularly well-tolerated, and the stereospecific nature of the reaction provides indifferently access to the natural C20-(R) and unnatural C20-(S) configurations. Alkyl containing substrates are more challenging as they affect regioselectivity of iridium-hydride insertion. A rationale for the high diastereoselectivities observed is proposed for aryl containing precursors. The scope of our method is further highlighted through topological diversification in the side chain and within the polycyclic domain of advanced and complex steroidal architectures. These findings have the potential to greatly simplify access to epimeric structural analogues of important steroid scaffolds for applications in biological, pharmaceutical, and medical sciences.


Pilot Study of the Effects of High-Protein Meals During Hemodialysis on Intradialytic Hypotension in Patients Undergoing Maintenance Hemodialysis.
Patients undergoing hemodialysis (HD) have high protein and energy requirements, and protein-energy wasting is common and associated with poor outcomes. Eating during dialysis may improve nutritional status by counteracting the catabolic effects of HD treatment; but eating during HD may be discouraged because of concerns of postprandial hypotension. However, little data are available to support this practice. In this study, we hypothesized that high-protein meals during HD do not lead to symptomatic intradialytic hypotension events. A 9-week, nonrandomized, parallel-arm study. A single in-center HD clinic. Eighteen patients undergoing HD from 2 shifts completed the study. Patients were aged 62 ± 16 years with dialysis vintage of 3.4 ± 2.6 years. Patients in the intervention group (n = 9) undergoing HD received meals of ∼30 g protein and ∼1/3 daily recommended intakes of sodium, potassium, phosphorus, and fluid during dialysis for 25 consecutive HD sessions. The control group (n = 9) completed all aspects of the study including a visit by study personnel but were not given meals. The 25 consecutive sessions before the start of the intervention/control phase were used as a baseline comparison for each patient. Symptomatic hypotension event frequency. In the intervention arm, there were 19 symptomatic hypotension events in 5 patients prestudy and 18 events in 6 patients during the study. In the control arm, there were 16 events in 7 patients prestudy and 13 events in 7 patients during the study. Change in the frequency of symptomatic hypotension events from prestudy to during study was not different between groups (P = .71). There was no effect of meals on nutritional status, but patients reported positive attitudes toward receiving meals during dialysis. High-protein meals during HD did not increase symptomatic hypotension events. Larger, longer term studies are needed to confirm these results and evaluate whether high-protein meals on dialysis benefit nutritional status and clinical outcomes.


Long-Term Incubation PrPCWD with Soils Affects Prion Recovery but Not Infectivity.
Chronic wasting disease (CWD) is a contagious prion disease of cervids. The infectious agent is shed from animals at the preclinical and clinical stages of disease where it persists in the environment as a reservoir of CWD infectivity. In this study, we demonstrate that long-term incubation of CWD prions (generated from tg-mice infected with deer or elk prions) with illite, montmorillonite (Mte) and whole soils results in decreased recovery of PrPCWD, suggesting that binding becomes more avid and irreversible with time. This continual decline of immunoblot PrPCWD detection did not correlate with prion infectivity levels. Bioassay showed no significant differences in incubation periods between mice inoculated with 1% CWD brain homogenate (BH) and with the CWD-BH pre-incubated with quartz or Luvisolic Ae horizon for 1 or 30 weeks. After 55 weeks incubation with Chernozem and Luvisol, bound PrPCWD was not detectable by immunoblotting but remained infectious. This study shows that although recovery of PrPCWD bound to soil minerals and whole soils with time become more difficult, prion infectivity is not significantly altered. Detection of prions in soil is, therefore, not only affected by soil type but also by length of time of the prion-soil interaction.


Taking climate change seriously: An analysis of op-ed articles in Spanish press.
In this article, we study the evolution of opinion genres regarding climate change in three Spanish newspapers ( El País, El Mundo, and ABC). Analyzing the op-ed articles in these newspapers, we observe a significant change in the evolution of opinion. While denialism was very present in conservative press in 2007, 7 years later it is almost absent from El Mundo, and its presence in ABC is much lower and inactive: this shows that scientific consensus has prevailed over time and Spanish denialism has weakened, exclusively supported by political arguments by the most conservative parties.


Schizophrenia interactome with 504 novel protein-protein interactions.
Genome-wide association studies of schizophrenia (GWAS) have revealed the role of rare and common genetic variants, but the functional effects of the risk variants remain to be understood. Protein interactome-based studies can facilitate the study of molecular mechanisms by which the risk genes relate to schizophrenia (SZ) genesis, but protein-protein interactions (PPIs) are unknown for many of the liability genes. We developed a computational model to discover PPIs, which is found to be highly accurate according to computational evaluations and experimental validations of selected PPIs. We present here, 365 novel PPIs of liability genes identified by the SZ Working Group of the Psychiatric Genomics Consortium (PGC). Seventeen genes that had no previously known interactions have 57 novel interactions by our method. Among the new interactors are 19 drug targets that are targeted by 130 drugs. In addition, we computed 147 novel PPIs of 25 candidate genes investigated in the pre-GWAS era. While there is little overlap between the GWAS genes and the pre-GWAS genes, the interactomes reveal that they largely belong to the same pathways, thus reconciling the apparent disparities between the GWAS and prior gene association studies. The interactome including 504 novel PPIs overall, could motivate other systems biology studies and trials with repurposed drugs. The PPIs are made available on a webserver, called Schizo-Pi at http://severus.dbmi.pitt.edu/schizo-pi with advanced search capabilities.


Cell-intrinsic signals that regulate adult neurogenesis in vivo: insights from inducible approaches.
The process by which adult neural stem cells generate new and functionally integrated neurons in the adult mammalian brain has been intensely studied, but much more remains to be discovered. It is known that neural progenitors progress through distinct stages to become mature neurons, and this progression is tightly controlled by cell-cell interactions and signals in the neurogenic niche. However, less is known about the cell-intrinsic signaling required for proper progression through stages of adult neurogenesis. Techniques have recently been developed to manipulate genes specifically in adult neural stem cells and progenitors in vivo, such as the use of inducible transgenic mice and viral-mediated gene transduction. A critical mass of publications utilizing these techniques has been reached, making it timely to review which molecules are now known to play a cell-intrinsic role in regulating adult neurogenesis in vivo. By drawing attention to these isolated molecules (e.g. Notch), we hope to stimulate a broad effort to understand the complex and compelling cascades of intrinsic signaling molecules important to adult neurogenesis. Understanding this process opens the possibility of understanding brain functions subserved by neurogenesis, such as memory, and also of harnessing neural stem cells for repair of the diseased and injured brain.


The social mission of medical education: ranking the schools.
The basic purpose of medical schools is to educate physicians to care for the national population. Fulfilling this goal requires an adequate number of primary care physicians, adequate distribution of physicians to underserved areas, and a sufficient number of minority physicians in the workforce. To develop a metric called the social mission score to evaluate medical school output in these 3 dimensions. Secondary analysis of data from the American Medical Association (AMA) Physician Masterfile and of data on race and ethnicity in medical schools from the Association of American Medical Colleges and the Association of American Colleges of Osteopathic Medicine. U.S. medical schools. 60 043 physicians in active practice who graduated from medical school between 1999 and 2001. The percentage of graduates who practice primary care, work in health professional shortage areas, and are underrepresented minorities, combined into a composite social mission score. The contribution of medical schools to the social mission of medical education varied substantially. Three historically black colleges had the highest social mission rankings. Public and community-based medical schools had higher social mission scores than private and non-community-based schools. National Institutes of Health funding was inversely associated with social mission scores. Medical schools in the northeastern United States and in more urban areas were less likely to produce primary care physicians and physicians who practice in underserved areas. The AMA Physician Masterfile has limitations, including specialty self-designation by physicians, inconsistencies in reporting work addresses, and delays in information updates. The public good provided by medical schools may include contributions not reflected in the social mission score. The study was not designed to evaluate quality of care provided by medical school graduates. Medical schools vary substantially in their contribution to the social mission of medical education. School rankings based on the social mission score differ from those that use research funding and subjective assessments of school reputation. These findings suggest that initiatives at the medical school level could increase the proportion of physicians who practice primary care, work in underserved areas, and are underrepresented minorities.


Full-genome next-generation sequencing of hepatitis C virus to assess the accuracy of genotyping by the commercial assay LiPA and the prevalence of resistance-associated substitutions in a Belgian cohort.
Although most currently used regimens for Hepatitis C virus (HCV) infections can be initiated without prior knowledge of genotype and subtype, genotyping is still useful to identify patients who might benefit from a personalized treatment due to resistance to direct-acting antivirals (DAA). To assess the utility of full-genome next-generation sequencing (FG-NGS) for HCV genotyping. 138 HCV plasma samples previously genotyped by VERSANT HCV Genotype Assay (LiPA) were subjected to FG-NGS and phylogenetically genotyped Genome Detective. Consensuses were analysed by HCV-GLUE for resistance-associated substitutions (RASs) and their impact on treatment response was investigated. 102/138 (73.9%) samples were sequenced to a genome coverage and depth of >90% of the HCV open reading frame covered by >100 reads/site. Concordant genotype and subtype results were assigned in 97.1% and 79.4% of samples, respectively. FG-NGS resolved the subtype of 13.7% samples that had ambiguous calls by LiPA and identified one dual infection and one recombinant strain. At least one RAS was found for the HCV genes NS3, NS5A, and NS5B in 2.91%, 36.98% and 27.3% samples, respectively. Irrespective of the observed RAS, all patients responded well to DAA treatment, except for HCV1b-infected patients treated with Zepatier (33.3% failure rate (5/15)). While LiPA and FG-NGS showed overall good concordance, FG-NGS improved specificity for subtypes, recombinant and mixed infections. FG-NGS enabled the detection of RAS, but its predictive value for treatment outcome in DAA-naïve patients remains uncertain. With additional refinements, FG-NGS may be the way forward for HCV genotyping.


2D affine-invariant contour matching using B-spline model.
This paper presents a new affine-invariant matching algorithm based on B-Spline modeling, which solves the problem of the non-uniqueness of B-Spline in curve matching. This method first smoothes the B-Spline curve by increasing the degree of the curve. It is followed by a reduction of the curve degree using the Least Square Error (LSE) approach to construct the Curvature Scale Space (CSS) image. CSS matching is then carried out. Our method combines the advantages of B-Spline that are continuous curve representation and the robustness of CSS matching with respect to noise and affine transformation. It avoids the need for other matching algorithms that have to use the re-sampled points on the curve. Thus, the curve matching error is reduced. The proposed algorithm has been tested by matching similar shapes from a prototype database. The experimental results showed the robustness and accuracy of the proposed method in B-Spline curve matching.


Global school-based childhood obesity interventions: a review.
The issue of childhood overweight and obesity has become a global public health crisis. School-based interventions have been developed and implemented to combat this growing concern. The purpose of this review is to compare and contrast U.S. and international school-based obesity prevention interventions and highlight efficacious strategies. A systematic literature review was conducted utilizing five relevant databases. Inclusion criteria were: (1) primary research; (2) overweight or obesity prevention interventions; (3) school-based; (4) studies published between 1 January 2002 through 31 December 2013; (5) published in the English language; (6) child-based interventions, which could include parents; and (7) studies that reported outcome data. A total of 20 interventions met the inclusion criteria. Ten interventions each were implemented in the U.S. and internationally. International interventions only targeted elementary-aged students, were less likely to target low-income populations, and were less likely to be implemented for two or more years in duration. However, they were more likely to integrate an environmental component when compared to U.S. interventions. Interventions implemented in the U.S. and internationally resulted in successful outcomes, including positive changes in student BMI. Yet, varying approaches were used to achieve success, reinforcing the fact that a one-size-fits-all approach is not necessary to impact childhood obesity. However, building on successful interventions, future school-based obesity prevention interventions should integrate culturally specific intervention strategies, aim to incorporate an environmental component, and include parents whenever possible. Consideration should be given to the potential impact of long-term, frequent dosage interventions, and subsequent follow-up should be given attention to determine long-term efficacy.


Principal Component Analysis from Mass Spectrometry Data Combined to a Sensory Evaluation as a Suitable Method for Assessing Bitterness of Enzymatic Hydrolysates Produced from Micellar Casein Proteins.
Enzymatic hydrolysis of food proteins generally changes the techno-functional, nutritional, and organoleptic properties of hydrolyzed proteins. As a result, protein hydrolysates have an important interest in the food industries. However, they tend to be characterized by a bitter taste and some off-flavors, which limit their use in the food industry. These tastes and aromas come from peptides, amino acids, and volatile compounds generated during hydrolysis. In this article, sixteen more or less bitter enzymatic hydrolysates produced from a milk protein liquid fraction enriched in micellar caseins using commercially available, food-grade proteases were subjected to a sensory analysis using a trained and validated sensory panel combined to a peptidomics approach based on the peptide characterization by reverse-phase high-performance liquid chromatography, high-resolution mass spectrometry, and bioinformatics software. The comparison between the sensory characteristics and the principal components of the principal component analysis (PCA) of mass spectrometry data reveals that peptidomics constitutes a convenient, valuable, fast, and economic intermediate method to evaluating the bitterness of enzymatic hydrolysates, as a trained sensory panel can do it.


Performance of 4 Immunohistochemical Phosphohistone H3 Antibodies for Marking Mitotic Figures in Breast Cancer.
Phosphohistone H3 (PHH3) has been suggested to facilitate and improve mitotic activity assessment in breast cancer and other tumor entities, but the reliability of respective immunohistochemical antibodies has not yet been compared for routine purposes. Our aim was to test the performance of 4 different PHH3 antibodies on a series of highly proliferating breast cancers with good preservation of morphology. Four commercially available PHH3 antibodies were tested on 9 grade 3 invasive breast cancers processed in the same batch. We analyzed the number of antibody stained and nonstained mitotic figures as well as the total of cells observed in 10 high power fields per tumor to calculate sensitivity, specificity, and accuracy of the respective antibodies for staining mitotic figures, taking morphologically defined mitotic figures as gold standard. Sensitivity, specificity, and accuracy of the respective PHH3 antibodies for staining mitotic figures were 54.51%, 99.98%, and 98.79% for Cell Marque, 87.48%, 67.62%, and 67.47% for Epitomics, 98.62%, 99.73%, and 99.49% for Merck 06-570, and 99.74%, 99.52%, and 99.51% for Merck 09-797, respectively. Sensitivity was lowest for telophase. In statistical analysis, the Cell Marque antibody demonstrated significantly lower sensitivity and Epitomics substantially lower sensitivity and specificity than Merck 06-570 and Merck 09-797 antibodies (P<0.0001, respectively). Performance and reliability varied significantly between the 4 tested antibodies. For faster identification of mitotic hot spots and as potential marker in digital image analysis, the Merck antibodies seem to be most suitable.


Dermatoglyphic asymmetry and testosterone levels in normal males.
Dermatoglyphic prints and salivary samples were taken on a sample of 39 adult males. A statistical relationship between dermatoglyphic asymmetry and adult testosterone levels as measured in saliva was examined for seven dermatoglyphic variables by means of correlation, regression, and analysis of covariance, controlling for age and stature when necessary. The first two types of analyses indicated a significant effect of testosterone level upon the asymmetry of three dermatoglyphic variables: a-b ridge count, palmar pattern intensity, and the combined pattern intensity of palm and digits. Analysis of covariance, which examined the effect of testosterone level as a categorical variable, while holding age or stature constant, demonstrated the asymmetry of five variables to be significantly affected by testosterone level: radial digital count, digital pattern intensity, palmar pattern intensity, total digital ridge count, and the combined palmar and digital intensity. Although there is as yet only associational evidence linking levels of prenatal and secondary testosterone, the results of the present study lend support to the hypothesis that prenatal testosterone levels may have a significant effect on the development of dermatoglyphics.


Disposal of medical waste: a legal perspective.
The Constitution of the Republic of South Africa provides that everyone has the right to an environment that is not harmful to their health and well-being. The illegal dumping of hazardous waste poses a danger to the environment when pollutants migrate into water sources and ultimately cause widespread infection or toxicity, endangering the health of humans who might become exposed to infection and toxins. To give effect to the Constitution, the safe disposal of hazardous waste is governed by legislation in South Africa. Reports of the illegal disposal of waste suggest a general lack of awareness and training in regard to the safe disposal of medical waste.


Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1.5 current in calmodulin binding-deficient channels.
The Ca2+-binding protein calmodulin has emerged as a pivotal player in tuning Na+ channel function, although its impact in vivo remains to be resolved. Here, we identify the role of calmodulin and the NaV1.5 interactome in regulating late Na+ current in cardiomyocytes. We created transgenic mice with cardiac-specific expression of human NaV1.5 channels with alanine substitutions for the IQ motif (IQ/AA). The mutations rendered the channels incapable of binding calmodulin to the C-terminus. The IQ/AA transgenic mice exhibited normal ventricular repolarization without arrhythmias and an absence of increased late Na+ current. In comparison, transgenic mice expressing a lidocaine-resistant (F1759A) human NaV1.5 demonstrated increased late Na+ current and prolonged repolarization in cardiomyocytes, with spontaneous arrhythmias. To determine regulatory factors that prevent late Na+ current for the IQ/AA mutant channel, we considered fibroblast growth factor homologous factors (FHFs), which are within the NaV1.5 proteomic subdomain shown by proximity labeling in transgenic mice expressing NaV1.5 conjugated to ascorbate peroxidase. We found that FGF13 diminished late current of the IQ/AA but not F1759A mutant cardiomyocytes, suggesting that endogenous FHFs may serve to prevent late Na+ current in mouse cardiomyocytes. Leveraging endogenous mechanisms may furnish an alternative avenue for developing novel pharmacology that selectively blunts late Na+ current.


Mutation-Enrichment Next-Generation Sequencing for Quantitative Detection of KRAS Mutations in Urine Cell-Free DNA from Patients with Advanced Cancers.
Purpose: Tumor-derived cell-free DNA (cfDNA) from urine of patients with cancer offers noninvasive biological material for detection of cancer-related molecular abnormalities such as mutations in Exon 2 of KRASExperimental Design: A quantitative, mutation-enrichment next-generation sequencing test for detecting KRASG12/G13 mutations in urine cfDNA was developed, and results were compared with clinical testing of archival tumor tissue and plasma cfDNA from patients with advanced cancer.Results: With 90 to 110 mL of urine, the KRASG12/G13 cfDNA test had an analytical sensitivity of 0.002% to 0.006% mutant copies in wild-type background. In 71 patients, the concordance between urine cfDNA and tumor was 73% (sensitivity, 63%; specificity, 96%) for all patients and 89% (sensitivity, 80%; specificity, 100%) for patients with urine samples of 90 to 110 mL. Patients had significantly fewer KRASG12/G13 copies in urine cfDNA during systemic therapy than at baseline or disease progression (P = 0.002). Compared with no changes or increases in urine cfDNA KRASG12/G13 copies during therapy, decreases in these measures were associated with longer median time to treatment failure (P = 0.03).Conclusions: A quantitative, mutation-enrichment next-generation sequencing test for detecting KRASG12/G13 mutations in urine cfDNA had good concordance with testing of archival tumor tissue. Changes in mutated urine cfDNA were associated with time to treatment failure. Clin Cancer Res; 23(14); 3657-66. ©2017 AACR.


Potent simian immunodeficiency virus-specific cellular immune responses in the breast milk of simian immunodeficiency virus-infected, lactating rhesus monkeys.
Breast milk transmission of HIV is a leading cause of infant HIV/AIDS in the developing world. Remarkably, only a small minority of breastfeeding infants born to HIV-infected mothers contract HIV via breast milk exposure, raising the possibility that immune factors in the breast milk confer protection to the infants who remain uninfected. To model HIV-specific immunity in breast milk, lactation was pharmacologically induced in Mamu-A*01(+) female rhesus monkeys. The composition of lymphocyte subsets in hormone-induced lactation breast milk was found to be similar to that in natural lactation breast milk. Hormone-induced lactating monkeys were inoculated i.v. with SIVmac251 and CD8(+) T lymphocytes specific for two immunodominant SIV epitopes, Gag p11C and Tat TL8, and SIV viral load were monitored in peripheral blood and breast milk during acute infection. The breast milk viral load was 1-2 logs lower than plasma viral load through peak and set point of viremia. Surprisingly, whereas the kinetics of the SIV-specific cellular immunity in breast milk mirrored that of the blood, the peak magnitude of the SIV-specific CD8(+) T lymphocyte response in breast milk was more than twice as high as the cellular immune response in the blood. Furthermore, the appearance of the SIV-specific CD8(+) T lymphocyte response in breast milk was associated with a reduction in breast milk viral load, and this response remained higher than that in the blood after viral set point. This robust viral-specific cellular immune response in breast milk may contribute to control of breast milk virus replication.


Demographic, behavioral, and health correlates of complementary and alternative medicine and prayer use among midlife women: 2002.
This study investigated the demographic, behavioral, and health correlates of the most frequently used types of complementary and alternative medicine (CAM) therapy and the use of prayer for health among midlife women. We also examined the extent to which women used CAM for treatment of health conditions, including menopausal symptoms, and for general health and well-being. Data from the 2002 National Health Interview Survey (NHIS), a cross-sectional, household survey representative of the U.S. civilian adult population, were used. Midlife women aged 40-59 years (n = 5849) were analyzed. Bivariate prevalence estimates were obtained, and binomial logistic regression models were estimated; all analyses were weighted. Overall, 46% of midlife women used any type of CAM in the past 12 months, and 54% reported using prayer for health reasons. The top five specific CAM therapies used were herbs and natural products; relaxation techniques; chiropractic care; yoga, tai chi, or qi gong; and massage. Multivariate results demonstrated different patterns of association between demographic, health, and behavioral characteristics and specific CAM therapies. A higher percentage of women used chiropractic care for an existing health condition than those using relaxation techniques, and few women used CAM specifically for menopausal symptoms. CAM and prayer are frequently used by midlife women, and herbs and natural supplements are the mostly frequently used. The findings underscore the importance, particularly in the clinical setting, of asking women about their use of individual CAM therapies. Such clinical assessment is also important because of the potential for interactions of CAM therapies with prescribed therapies.


Evaluation of liver regeneration by modulation with ischemic preconditioning after ischemia and reperfusion and partial hepatectomy.
To evaluate liver regeneration modulated by ischemic preconditioning after ischemia, reperfusion and partial hepatectomy. We used 24 Wistar rats of 12 weeks of age, which were randomly assigned into four groups: control (SHAM), hepatectomy (HEP), ischemia and reperfusion (IRG) and Ischemic Preconditioning (SRG). Analyses were made on liver enzymes ALT and AST, assessment of regeneration through the initial and final weight of the liver and the proliferation of hepatocytes by immunohistochemical analysis with Proliferating Cell Nuclear Antigen (PCNA). In all groups there was liver regeneration, with no statistically significant difference between them. There were significant differences in ALT and AST between groups HEP and SHAM, PRE and GIR, GIR and SHAM and PRE and SHAM (p <0.05). There were also significant differences in the PCNA labeling of the SHAM group as compared to other groups (p <0.05). The ischemic preconditioning decreased liver injury, but did not influence the regeneration up to 48 hours.


Lineage relationship of Gleason patterns in Gleason score 7 prostate cancer.
Gleason score 7 (GS7) prostate cancer [tumors with both Gleason patterns 3 (GP3) and 4 (GP4)] portends a significantly more aggressive tumor than Gleason score 6 (GS6). It is, therefore, critical to understand the molecular relationship of adjacent GP3 and GP4 tumor cell populations and relate molecular abnormalities to disease progression. To decipher molecular relatedness, we used laser capture microdissection (LCM) and whole-genome amplification (WGA) to separately collect and amplify DNA from adjacent GP3 and GP4 cell populations from 14 cases of GS7 prostate cancer. We then carried out massively parallel mate-pair next generation sequencing (NGS) to examine the landscape of large chromosomal alterations. We identified four to 115 DNA breakpoints in GP3 and 17 to 480 in GP4. Our findings indicate that while GP3 and GP4 from the same tumor each possess unique breakpoints, they also share identical ones, indicating a common origin. Approximately 300 chromosomal breakpoints were localized to the regions affected in at least two tumors, whereas more than 3,000 were unique within the set of 14 tumors. TMPRSS2-ERG was the most recurrent rearrangement present in eight cases, in both GP3 and GP4. PTEN rearrangements were found in five of eight TMPRSS2-ERG fusion-positive cases in both GP3 and GP4. Hierarchical clustering analysis revealed that GP3 has greater breakpoint similarity to its partner GP4 compared with GP3 from different patients. We show evidence that LCM, WGA, and NGS of adjacent tumor regions provide an important tool in deciphering lineage relationships and discovering chromosomal alterations associated with tumor progression.


Why are stroke patients excluded from TPA therapy? An analysis of patient eligibility.
Thrombolytic therapy for acute stroke (<3 hours) will not have a major impact on death and dependency unless it is accessible to more patients. To determine why patients with ischemic stroke did not receive IV TPA and assess the availability of this therapy to patients with ischemic stroke. Consecutive patients with acute ischemic stroke were prospectively identified at a university teaching hospital between October 1996 and December 1999. Additional patients with ischemic stroke were identified that were admitted to one of three other hospitals in the Calgary region during the study period. The Oxford Community Stroke Programme Classification was used to record type and side of stroke. Of 2165 stroke patients presenting to the university hospital, 1168 (53.9%) were diagnosed with ischemic stroke, 31.8% with intracranial hemorrhage (intracerebral, subarachnoid, or subdural), and 13.9% with TIA. Delay in presentation to emergency department beyond 3 hours excluded 73.1% (854/1168). Major reasons for delay included uncertain time of onset (24.2%), patients waited to see if symptoms would improve (29%), delay caused by transfer from an outlying hospital (8.9%), and inaccessibility of treating hospital (5.7%). Twenty-seven percent of patients with ischemic stroke (314/1168) were admitted within 3 hours of sympton onset and of these 84 (26.7%) patients received IV TPA. The major reasons for exclusion in this group of patients (<3 hours) were mild stroke (13.1%), clinical improvement (18.2%), perceived protocol exclusions (13.6%), emergency department referral delay (8.9%), and significant comorbidity (8.3%). Of those patients who were considered too mild or were documented to have had significant improvement, 32% either remained dependent at hospital discharge or died during hospital admission. Throughout the region there was a total of 1806 ischemic stroke patients (admitted to all four Calgary hospitals). During this study period, 4.7% received IV TPA. The majority of patients are unable to receive TPA for acute ischemic stroke because they do no not reach the hospital soon enough. Of those patients presenting within 3 hours, 27% received the therapy but a further 31% were excluded because their symptoms were either considered too mild or were rapidly improving. Subsequently, a third of these patients were left either dependent or dead, bringing into question the initial decision not to treat.


Effects of Noise and Chemical Exposure on Peripheral and Central Auditory Pathways in Normal-hearing Workers.
To assess the effects of noise and chemical exposure on peripheral and central auditory pathways in normal-hearing workers exposed to chemicals or high noise levels and compare the groups with each other and with workers not exposed to either of these agents. A total of 54 normal-hearing workers were divided into three groups (chemical, noise, control) and submitted to the following assessments: conventional and extended high-frequency pure-tone audiometry; transient and distortion-product otoacoustic emissions, the inhibitory effect of the efferent auditory pathway; and Staggered Spondaic Word (SSW) and Pitch Pattern Sequence (PPS) test. There were no significant differences between the groups in extended high-frequency hearing thresholds. Significantly lower amplitudes were observed in the noise group for otoacoustic emissions. There were significantly more absences of the inhibitory effect of the efferent system in the noise group. There was no difference between the groups in the SSW test, while in PPS, the noise group performed worse than the control group. These findings suggest that noise exposure produced deleterious effects on the workers' peripheral and central auditory systems, despite their normal hearing thresholds. The chemical group did not have significantly different results from those of the control group. It is important that individuals exposed to noise or chemicals have their auditory pathways monitored with complementary assessments.


Challenges Faced by Healthcare Professionals During the COVID-19 Pandemic: A Qualitative Inquiry From Bangladesh.
Background: The coronavirus disease 2019 (COVID-19) pandemic has caused increasing challenges for healthcare professionals globally. However, there is a dearth of information about these challenges in many developing countries, including Bangladesh. This study aims to explore the challenges faced by healthcare professionals (doctors and nurses) during COVID-19 in Bangladesh. Methods: We conducted qualitative research among healthcare professionals of different hospitals and clinics in Khulna and Dhaka city of Bangladesh from May 2020 to August 2020. We conducted 15 in-depth telephone interviews using a snowball sampling technique. We used an in-depth interview guide as data were collected, audiotaped, and transcribed. The data were analyzed both manually and using QDA Miner software as we used thematic analysis for this study. Results: Seven themes emerged from the study. Participants experienced higher workload, psychological distress, shortage of quality personal protective equipment (PPE), social exclusion/stigmatization, lack of incentives, absence of coordination, and proper management during their service. These healthcare professionals faced difficulty coping with these challenges due to situational and organizational factors. They reported of faith in God and mutual support to be the keys to adapt to adversities. Adequate support to address the difficulties faced by healthcare professionals is necessary for an overall improved health outcome during the pandemic. Conclusion: The findings highlight the common challenges faced by healthcare professionals during the COVID-19 outbreak. This implies the need to support adequate safety kits, protocols, and support for both physical and mental health of the healthcare professionals.


Assessment of Heparanase-Mediated Angiogenesis Using Microvascular Endothelial Cells: Identification of λ-Carrageenan Derivative as a Potent Anti Angiogenic Agent.
Heparanase is overexpressed by tumor cells and degrades the extracellular matrix proteoglycans through cleavage of heparan sulfates (HS), allowing pro-angiogenic factor release and thus playing a key role in tumor angiogenesis and metastasis. Here we propose new HS analogs as potent heparanase inhibitors: Heparin as a positive control, Dextran Sulfate, λ-Carrageenan, and modified forms of them obtained by depolymerization associated to glycol splitting (RD-GS). After heparanase activity assessment, 11 kDa RD-GS-λ-Carrageenan emerged as the most effective heparanase inhibitor with an IC50 of 7.32 ng/mL compared to 10.7 ng/mL for the 16 kDa unfractionated heparin. The fractionated polysaccharides were then tested in a heparanase-rich medium-based in vitro model, mimicking tumor microenvironment, to determine their effect on microvascular endothelial cells (HSkMEC) angiogenesis. As a preliminary study, we identified that under hypoxic and nutrient poor conditions, MCF-7 cancer cells released much more mature heparanase in their supernatant than in normal conditions. Then a MatrigelTM assay using HSkMEC cultured under hypoxic conditions in the presence (or not) of this heparanase-rich supernatant was realized. Adding heparanase-rich media strongly enhanced angiogenic network formation with a production of twice more pseudo-vessels than with the control. When sulfated polysaccharides were tested in this angiogenesis assay, RD-GS-λ-Carrageenan was identified as a promising anti-angiogenic agent.


Multi-walled carbon nanotube-induced inflammatory response and oxidative stress in a dynamic cell growth environment.
Rapid increase in multi-walled carbon nanotube (MWCNT) production for their industrial and biomedical applications has led to concerns over the effects of MWCNTs on human health and the environment. Both animal and in vitro studies have provided important findings about MWCNT-induced effects on the lung cells or tissues. In vitro studies have provided a considerable amount of fundamental information on MWCNT-induced effects on the specific lung cells. However, the cell culture systems used in those studies were limited by the absence of dynamic nature of lung tissues. We hypothesized that MWCNT-induced cellular responses such as proliferation, inflammation, and oxidative stress under dynamic cell growth environment may differ from those under static cell growth environment. In this study, we used a dynamic cell growth condition to mimic mechanically dynamic environment of the lung and characterized interleukin 8 (IL-8), reactive oxygen species (ROS), glutathione (GSH), and cell proliferation for three days following exposure of MWCNTs at different concentrations (5, 10, and 20 μg/ml) to A549 cell monolayer under both static and dynamic cell growth conditions. Our results demonstrated the distinct differences in the levels of inflammatory response and oxidative stress between static and dynamic cell growth conditions. In conclusion, the dynamic cell growth system used in this study provided important changes in cellular responses that were not found in the static cell growth system and were similar to animal studies. The dynamic cell growth system can be considered as a viable alternative to in vivo test system in combination with existing in vitro static cell growth systems to evaluate the effect of MWCNTs on cellular responses in the respiratory system.


Evaluating revascularization and flap survival using vascular endothelial growth factor in an irradiated rat model.
To evaluate the role of vascular endothelial growth factor (VEGF) plasmid DNA (pDNA) in improving flap revascularization in a previously developed rat model. Our hypothesis was that the uptake and expression of VEGF pDNA in the wound bed would improve revascularization and flap viability. Twenty-eight male Sprague-Dawley rats received a total dose of 40 Gy electron beam radiation to the ventral abdominal wall. After a recovery period, they underwent a ventral fasciocutaneous flap procedure with a 2-hour ischemia period. Group 1 (n = 14) received topical VEGF pDNA, in vivo cationic polymer, and fibrin sealant. Group 2 (n = 14) received topical cationic polymer and fibrin sealant only. Seven of the rats from each group underwent pedicle ligation at 8 or 14 days. The primary outcome measure was percentage of flap revascularization 5 days after pedicle ligation. Rats receiving VEGF pDNA had a significantly higher rate of flap revascularization (90.8% vs 79.8%) after pedicle ligation at 14 days (P = .045). At 8 days, rats receiving VEGF pDNA (group 1) had an increased rate of flap revascularization (58.2% vs 42.8%) that approached significance (P = .11). This study demonstrates the potential of VEGF pDNA to improve revascularization and flap viability in previously irradiated tissue.


Progressive transmission of images over fading channels using rate-compatible LDPC codes.
In this paper, we propose a combined source/channel coding scheme for transmission of images over fading channels. The proposed scheme employs rate-compatible low-density parity-check codes along with embedded image coders such as JPEG2000 and set partitioning in hierarchical trees (SPIHT). The assignment of channel coding rates to source packets is performed by a fast trellis-based algorithm. We examine the performance of the proposed scheme over correlated and uncorrelated Rayleigh flat-fading channels with and without side information. Simulation results for the expected peak signal-to-noise ratio of reconstructed images, which are within 1 dB of the capacity upper bound over a wide range of channel signal-to-noise ratios, show considerable improvement compared to existing results under similar conditions. We also study the sensitivity of the proposed scheme in the presence of channel estimation error at the transmitter and demonstrate that under most conditions our scheme is more robust compared to existing schemes.


Larch Wood Residues Valorization through Extraction and Utilization of High Value-Added Products.
Many of current bio-based materials are not fully or partly used for material utilization, as the composition of their raw materials and/or possible applications are unknown. This study deals with the analysis of the wood extractives from three different tissue of larch wood: Sapwood mainly from outer part of the log, and sound knotwood as well as dead knotwood. The extractions were performed with an accelerated solvent extractor (ASE) using hexane and acetone/water. The obtained extracts were analyzed by gas chromatography coupled to mass spectrometry (GC-MS). Three various vibrational spectroscopy (FT-RAMAN, FT-IR and FT-NIR) methods reflect the information from the extracts to the chemical composition of the types of wood before the extraction processes. Multivariate data analysis of the spectra was used to obtain a better insight into possible classification methods. Taxifolin and kaempferol were found in larger amount in sound knotwood samples compared to larch wood with high percentage of sapwood and dead knotwood samples. While the extractions of dead knotwood samples yielded more larixol and resin acids than the other larch wood samples used. Based on the chemical composition, three lead compounds were defined for the classification of the different wood raw materials. The vibrational spectroscopy methods were applied to show their potential for a possible distinction of the three types of larch wood tissue. This new insight into the different larch wood extracts will help in the current efforts to use more environmentally friendly raw materials for innovative applications. The connection between the raw materials and extraction yields of the target values is important to transform the results from the laboratory to industry and consumer applications.


Mindfulness for female outpatients with chronic primary headaches: an internet-based bibliotherapy.
Our aim was to investigate effectiveness of mindfulness by bibliotherapy on disability, distress, perceived pain and mindfulness in women with tension headaches and migraines. Primary headaches have been of great interest to mental health researchers because of the high prevalence, as well as significant disability and distress in the affected people. Despite the promising results of in-person treatment and some limitations that such interventions may cause, patients may be encountered with problems when using health care services. The present study is a quasi-experimental randomized design with pre-test, post-test, and control group. The study population consisted of 1396 women with migraine headache referring to headache clinic of Baqiyatallah Hospital in Tehran. Of these, 30 patients (including tboh experimental and control group) were selected by objective sampling method and were randomly assigned to the two groups. The experimental group, in addition to medical treatment as usual, was treated for a period of 8 sessions by Mindfulness-based Stress Reduction Internet-based Bibliotherapy, but the control group used only the medical treatment. The sample had no attritions. Data were collected by the four scales of (DASS-21), Migraine Disability Assessment Test (MIDAS), McGill's Short Form Questionnaire (MPQ-SF), and Mindfulness Inventory (MAAS). We used covariance analysis to analyze the findings in the measured scales. MBSR-IBB treatment had no significant effect on pain sensory dimension (P <0.44), despite improvement of mindfulness (P <0.0001). In contrast, the greatest effect was on the level of disability (P <0.0001). We observed also a significant improvement in distress (P <0.0001). In conclusion, in spite of the presence of headaches, the mindfulness improved the quality of life and reduced the level of mental distress. In addition, using the Internet-based bibliotherapy method, these services can be used with easier access, lower cost, and more flexibility.


Methodologies for assessing telemedicine: a systematic review of reviews.
Previous reviews have expressed concerns about the quality of telemedicine studies. There is debate about shortcomings and appropriate methodologies. The aim of this review of systematic reviews of telemedicine is to summarize methodologies used in telemedicine research, discuss knowledge gaps and recommendations and suggest methodological approaches for further research. We conducted a review of systematic reviews of telemedicine according to a protocol listing explicit methods, selection criteria, data collection and quality assessment procedures. We included reviews where authors explicitly addressed and made recommendations for assessment methodologies. We did a qualitative analysis of the reviews included, sensitized by two broad methodological positions; positivist and naturalistic approaches. The analysis focused on methodologies used in the primary studies included in the reviews as reported by the review authors, and methodological recommendations made by the review authors. We identified 1593 titles/abstracts. We included 50 reviews that explicitly addressed assessment methodologies. One group of reviews recommended larger and more rigorously designed controlled studies to assess the impacts of telemedicine; a second group proposed standardisation of populations, and/or interventions and outcome measures to reduce heterogeneity and facilitate meta-analysis; a third group recommended combining quantitative and qualitative research methods; and others applying different naturalistic approaches including methodologies addressing mutual adaptations of services and users; politically driven action research and formative research aimed at collaboration to ensure capacity for improvement of services in natural settings. Larger and more rigorous studies are crucial for the production of evidence of effectiveness of unambiguous telemedicine services for pre defined outcome measures. Summative methodologies acknowledging telemedicine as complex innovations and outcomes as partly contingent on values, meanings and contexts are also important. So are formative, naturalistic methodologies that acknowledge telemedicine as ongoing collaborative achievements and engage with stakeholders, including patients to produce and conceptualise new and effective telemedicine innovations.


Temporal interactions in the cat visual system. II. Suppressive and facilitatory effects in the lateral geniculate nucleus.
Extracellular responses were recorded from single neurons in the lateral geniculate nucleus (LGN) of the cat during presentation of pairs of brief visual stimuli identical to those that produce orientation-selective paired-pulsed suppression in the visual cortex. LGN neurons also show paired-pulse suppression, but the suppression is not orientation selective, and it occurs only for short interstimulus intervals (ISIs; usually less than 200 msec). At longer ISIs, most LGN neurons show a period of facilitation. Thus, the paired-pulse suppression in the LGN cannot account for that seen in the visual cortex. Paired-pulse suppression in the LGN was found to be enhanced by stimulation of the receptive field surround. LGN neurons also showed a second type of suppression, termed "offset suppression," which consisted of a more long-lasting suppression of spontaneous activity following the offset of an excitatory visual stimulus. The suppression of spontaneous activity was accompanied by a reduction of the antidromic excitability, assessed by stimulating LGN axons within the cortex or optic radiation. Unlike paired-pulsed suppression, offset suppression was not enhanced by increased stimulation of the receptive field surround. Paired-pulse suppression and offset suppression are most likely due to different mechanisms because they have different time courses and depend differently on the spatial properties of the stimuli. Functionally, paired-pulse suppression may be related to the reduced visual sensitivity that accompanies eye movements, while offset suppression may serve to enhance temporal contrast.


The role of nanoparticle shapes and deterministic aperiodicity for the design of nanoplasmonic arrays.
In this paper, we study the role of nanoparticle shape and aperiodic arrangement in the scattering and spatial localization properties of plasmonic modes in deterministic-aperiodic (DA) arrays of metal nanoparticles. By using an efficient coupled-dipole model for the study of the electromagnetic response of large arrays excited by an external field, we demonstrate that DA structures provide enhanced spatial localization of plasmonic modes and a higher density of enhanced field states with respect to their periodic counterparts. Finally, we introduce and discuss specific design rules for the engineering and optimization of field enhancement and localization in DA arrays. Our results, which we fully validated by rigorous Generalized Mie Theory (GMT) and transition matrix (T-matrix) theory, demonstrate that DA arrays provide a robust platform for the design of a variety of novel optical devices with enhanced and controllable plasmonic fields.


Crystal structures and superconductivity of technetium hydrides under pressure.
Guided by a simple strategy in search of new superconducting materials, we have performed extensive simulations on crystal structures and electronic properties of Tc-H compounds at high pressures. Three stoichiometries, namely TcH, TcH2, and TcH3, were predicted to be stable under high pressure. The chemical bonding characters of Tc-H compounds were investigated by introducing the electron localization function and electronic projected density of states, which show that the stable Tc-H compounds including TcH, TcH2 and TcH3 are all classified as ionic crystals as a result of Tc → H charge transfer. Based on the Bardeen-Cooper-Schrieffer theory and estimated from the Allen-Dynes modified McMillan equation, the superconducting critical temperature (Tc) values of the I4/mmm phase for TcH2 are 5 K at 100 GPa and 11 K at 200 GPa. Moreover, it is found that Cmcm-TcH2 and P42/mmc-TcH3 at 300 GPa have Tc values of 9 K and 10 K, respectively. Our current results significantly enrich the crystal structures of the Tc-H system and provide a further understanding of their structural features and physical properties.


Investigating the impact of bank branch closures on access to financial services in the early stages of the COVID-19 pandemic.
There is a longstanding policy interest in understanding the impacts of changes in access to public and private services in rural areas. To date much of the empirical analysis concerning changing patterns of accessibility has been predicated on assumptions regarding the mode of transport used to access such facilities. The availability of new and open sources of data, and the increasing sophistication of spatial analytical tools, has enabled alternative transportation modes to be included when investigating the impact of service changes. In this study a nationwide analysis of changes in public transport provision and bank closures has enabled the identification of those parts of Wales that were disproportionally impacted by the loss of financial services during the early years of the COVID-19 pandemic. Drawing on local scenarios which show the combined impact of such changes, the findings demonstrate how temporal variations in accessibility can be used to examine potential patterns of exclusion that arise from the loss of key services. We conclude by suggesting that any assessment of changes in accessibility needs a holistic approach that considers changes in the transport infrastructure alongside other facets of service provision to understand the full impact of such closures on rural communities.


Suppression of estrogen biosynthesis by procyanidin dimers in red wine and grape seeds.
In breast cancer, in situ estrogen production has been demonstrated to play a major role in promoting tumor growth. Aromatase is the enzyme responsible for the conversion of androgen substrates into estrogens. This enzyme is highly expressed in breast cancer tissue compared with normal breast tissue. A wine extract fraction was recently isolated from red wine that exhibited a potent inhibitory action on aromatase activity. Using UV absorbance analysis, high-performance liquid chromatography profiling, accurate mass-mass spectrometry, and nanospray tandem mass spectrometry, most of the compounds in our red wine fraction were identified as procyanidin B dimers that were shown to be aromatase inhibitors. These chemicals have been found in high levels in grape seeds. Inhibition kinetic analysis on the most potent procyanidin B dimer has revealed that it competes with the binding of the androgen substrate with a K(i) value of 6 micro M. Because mutations at Asp-309, Ser-378, and His-480 of aromatase significantly affected the binding of the procyanidin B dimer, these active site residues are thought to be important residues that interact with this phytochemical. The in vivo efficacy of procyanidin B dimers was evaluated in an aromatase-transfected MCF-7 breast cancer xenograft model. The procyanidin B dimers were able to reduce androgen-dependent tumor growth, indicating that these chemicals suppress in situ estrogen formation. These in vitro and in vivo studies demonstrated that procyanidin B dimers in red wine and grape seeds could be used as chemopreventive agents against breast cancer by suppressing in situ estrogen biosynthesis.


Structural and mechanistic insight into Holliday-junction dissolution by topoisomerase IIIα and RMI1.
Repair of DNA double-strand breaks via homologous recombination can produce double Holliday junctions (dHJs) that require enzymatic separation. Topoisomerase IIIα (TopIIIα) together with RMI1 disentangles the final hemicatenane intermediate obtained once dHJs have converged. How binding of RMI1 to TopIIIα influences it to behave as a hemicatenane dissolvase, rather than as an enzyme that relaxes DNA topology, is unknown. Here, we present the crystal structure of human TopIIIα complexed to the first oligonucleotide-binding domain (OB fold) of RMI1. TopIII assumes a toroidal type 1A topoisomerase fold. RMI1 attaches to the edge of the gate in TopIIIα through which DNA passes. RMI1 projects a 23-residue loop into the TopIIIα gate, thereby influencing the dynamics of its opening and closing. Our results provide a mechanistic rationale for how RMI1 stabilizes TopIIIα-gate opening to enable dissolution and illustrate how binding partners modulate topoisomerase function.