Species- and sex-specific connectivity effects of habitat fragmentation in a suite of woodland birds.
Loss of functional connectivity following habitat loss and fragmentation could drive species declines. A comprehensive understanding of fragmentation effects on functional connectivity of an ecological assemblage requires investigation of multiple species with different mobilities, at different spatial scales, for each sex, and in different landscapes. Based on published data on mobility and ecological responses to fragmentation of 10 woodland-dependent birds, and using simulation studies, we predicted that (1) fragmentation would impede dispersal and gene flow of eight "decliners" (species that disappear from suitable patches when landscape-level tree cover falls below species-specific thresholds), but not of two "tolerant" species (whose occurrence in suitable habitat patches is independent of landscape tree cover); and that fragmentation effects would be stronger (2) in the least mobile species, (3) in the more philopatric sex, and (4) in the more fragmented region. We tested these predictions by evaluating spatially explicit isolation-by-landscape-resistance models of gene flow in fragmented landscapes across a 50 x 170 km study area in central Victoria, Australia, using individual and population genetic distances. To account for sex-biased dispersal and potential scale- and configuration-specific effects, we fitted models specific to sex and geographic zones. As predicted, four of the least mobile decliners showed evidence of reduced genetic connectivity. The responses were strongly sex specific, but in opposite directions in the two most sedentary species. Both tolerant species and (unexpectedly) four of the more mobile decliners showed no reduction in gene flow. This is unlikely to be due to time lags because more mobile species develop genetic signatures of fragmentation faster than do less mobile ones. Weaker genetic effects were observed in the geographic zone with more aggregated vegetation, consistent with gene flow being unimpeded by landscape structure. Our results indicate that for all but the most sedentary species in our system, the movement of the more dispersive sex (females in most cases) maintains overall genetic connectivity across fragmented landscapes in the study area, despite some small-scale effects on the more philopatric sex for some species. Nevertheless, to improve population viability for the less mobile bird species, structural landscape connectivity must be increased.


Optical manipulation of single flux quanta.
Magnetic field can penetrate into type II superconductors in the form of Abrikosov vortices, which are magnetic flux tubes surrounded by circulating supercurrents often trapped at defects referred to as pinning sites. Although the average properties of the vortex matter in superconductors can be tuned with magnetic fields, temperature or electric currents, handling of individual Abrikosov vortices remains challenging and has been demonstrated only with sophisticated scanning local probe microscopies. Here we introduce a far-field optical method based on local heating of the superconductor with a focused laser beam to realize a fast and precise manipulation of individual vortices, in the same way as with optical tweezers. This simple approach provides the perfect basis for sculpting the magnetic flux profile in superconducting devices like a vortex lens or a vortex cleaner, without resorting to static pinning or ratchet effects.


Diversity has stronger top-down than bottom-up effects on decomposition.
The flow of energy and nutrients between trophic levels is affected by both the trophic structure of food webs and the diversity of species within trophic levels. However, the combined effects of trophic structure and diversity on trophic transfer remain largely unknown. Here we ask whether changes in consumer diversity have the same effect as changes in resource diversity on rates of resource consumption. We address this question by focusing on consumer-resource dynamics for the ecologically important process of decomposition. This study compares the top-down effect of consumer (detritivore) diversity on the consumption of dead organic matter (decomposition) with the bottom-up effect of resource (detrital) diversity, based on a compilation of 90 observations reported in 28 studies. We did not detect effects of either detrital or consumer diversity on measures of detrital standing stock, and effects on consumer standing stock were equivocal. However, our meta-analysis indicates that reductions in detritivore diversity result in significant reductions in the rate of decomposition. Detrital diversity has both positive and negative effects on decomposition, with no overall trend. This difference between top-down and bottom-up effects of diversity is robust to different effect size metrics and could not be explained by differences in experimental systems or designs between detritivore and detrital manipulations. Our finding that resource diversity has no net effect on consumption in "brown" (detritus-consumer) food webs contrasts with previous findings from "green" (plant-herbivore) food webs and suggests that effects of plant diversity on consumption may fundamentally change after plant death.


Contraceptive Use Among Women with Prediabetes and Diabetes in a US National Sample.
Although elevated blood glucose is associated with adverse maternal and fetal health outcomes, evidence suggests that women with diabetes may not be receiving comprehensive reproductive health care, including family planning and preconception care. Using a population-based sample, we evaluated the relationship between contraceptive use and biomarker-identified diabetes. This cross-sectional study used data from 5548 women in the nationally representative National Longitudinal Study of Adolescent to Adult Health (Add Health) from 2007 to 2009. Women were aged 24 to 32 years, sexually active with men, and not pregnant. Hemoglobin A1C identified prediabetes and diabetes from blood specimens. The primary outcome was most effective contraception used in the past year: more effective (sterilization, intrauterine device, implant, combined hormonal methods, or injectable), less effective (condoms, diaphragms, spermicides, natural family planning, or withdrawal), or none. Multinomial regression models were adjusted for race and ethnicity, education, insurance, health care access, and body mass index. Of the women with diabetes, 37.6% used more effective contraception, 33.6% less effective contraception, and 28.8% none. Women with diabetes had higher odds of using no contraception, rather than more effective contraception, than women with normoglycemia (adjusted odds ratio [aOR], 1.90; 95% CI, 1.25-2.87). Women with diabetes who were undiagnosed had greater odds of using less effective contraception, rather than more effective contraception, compared with those who were diagnosed (aOR 3.39; 95% CI, 1.44-7.96). Contraceptive use did not differ between women with prediabetes and normoglycemia. Less effective contraceptive methods were commonly used by women with diabetes. Midwives and other women's health care providers can support women with diabetes to reach their pregnancy goals by providing preconception care and family planning.


A 20-year prospective study of cirrhosis.
A total of 512 people from a defined population in west Birmingham served by a district general hospital were found to have cirrhosis in the period 1959-76. The annual incidence rose from 5.6 per 100 000 to a peak of 15.3 per 100 000 in 1974. This was due to an increase in the incidence of alcoholic cirrhosis, which in the last six years accounted for two-thirds of cases. The proportion of patients with decompensated cirrhosis when first seen (65%) did not alter during the 18 years. This was reflected in a death rate of 78% among the 468 patients traced up to the end of 1978. Liver failure, hepatoma, and gastrointestinal haemorrhage accounted for almost three-quarters of the deaths. The proportion of patients who survived for five years was 36% for alcoholic cirrhosis, 14% for cryptogenic cirrhosis, and 60% for chronic active hepatitis, and these figures too remained constant throughout the 18 years. Modern methods of treatment for decompensated cirrhosis did not improve prognosis and only abstention in patients with alcoholic cirrhosis had a beneficial effect on survival. Since alcoholic cirrhosis is now the most common form of the disease it is important to recognise those at risk and to encourage abstinence; also, more efforts are needed to identify the causes of cryptogenic cirrhosis. Whatever the cause, cirrhosis needs to be diagnosed before decompensation occurs, if treatment is to have any effect.


The relationship between population structure and aluminum tolerance in cultivated sorghum.
Acid soils comprise up to 50% of the world's arable lands and in these areas aluminum (Al) toxicity impairs root growth, strongly limiting crop yield. Food security is thereby compromised in many developing countries located in tropical and subtropical regions worldwide. In sorghum, SbMATE, an Al-activated citrate transporter, underlies the Alt(SB) locus on chromosome 3 and confers Al tolerance via Al-activated root citrate release. Population structure was studied in 254 sorghum accessions representative of the diversity present in cultivated sorghums. Al tolerance was assessed as the degree of root growth inhibition in nutrient solution containing Al. A genetic analysis based on markers flanking Alt(SB) and SbMATE expression was undertaken to assess a possible role for Alt(SB) in Al tolerant accessions. In addition, the mode of gene action was estimated concerning the Al tolerance trait. Comparisons between models that include population structure were applied to assess the importance of each subpopulation to Al tolerance. Six subpopulations were revealed featuring specific racial and geographic origins. Al tolerance was found to be rather rare and present primarily in guinea and to lesser extent in caudatum subpopulations. Alt(SB) was found to play a role in Al tolerance in most of the Al tolerant accessions. A striking variation was observed in the mode of gene action for the Al tolerance trait, which ranged from almost complete recessivity to near complete dominance, with a higher frequency of partially recessive sources of Al tolerance. A possible interpretation of our results concerning the origin and evolution of Al tolerance in cultivated sorghum is discussed. This study demonstrates the importance of deeply exploring the crop diversity reservoir both for a comprehensive view of the dynamics underlying the distribution and function of Al tolerance genes and to design efficient molecular breeding strategies aimed at enhancing Al tolerance.


Development and Psychometric Evaluation of an Instrument to Assess Cross-Cultural Competence of Healthcare Professionals (CCCHP).
Cultural competence of healthcare professionals (HCPs) is recognized as a strategy to reduce cultural disparities in healthcare. However, standardised, valid and reliable instruments to assess HCPs' cultural competence are notably lacking. The present study aims to 1) identify the core components of cultural competence from a healthcare perspective, 2) to develop a self-report instrument to assess cultural competence of HCPs and 3) to evaluate the psychometric properties of the new instrument. The conceptual model and initial item pool, which were applied to the cross-cultural competence instrument for the healthcare profession (CCCHP), were derived from an expert survey (n = 23), interviews with HCPs (n = 12), and a broad narrative review on assessment instruments and conceptual models of cultural competence. The item pool was reduced systematically, which resulted in a 59-item instrument. A sample of 336 psychologists, in advanced psychotherapeutic training, and 409 medical students participated, in order to evaluate the construct validity and reliability of the CCCHP. Construct validity was supported by principal component analysis, which led to a 32-item six-component solution with 50% of the total variance explained. The different dimensions of HCPs' cultural competence are: Cross-Cultural Motivation/Curiosity, Cross-Cultural Attitudes, Cross-Cultural Skills, Cross-Cultural Knowledge/Awareness and Cross-Cultural Emotions/Empathy. For the total instrument, the internal consistency reliability was .87 and the dimension's Cronbach's α ranged from .54 to .84. The discriminating power of the CCCHP was indicated by statistically significant mean differences in CCCHP subscale scores between predefined groups. The 32-item CCCHP exhibits acceptable psychometric properties, particularly content and construct validity to examine HCPs' cultural competence. The CCCHP with its five dimensions offers a comprehensive assessment of HCPs' cultural competence, and has the ability to distinguish between groups that are expected to differ in cultural competence. This instrument can foster professional development through systematic self-assessment and thus contributes to improve the quality of patient care.


Synthesis of NaMoO3F and Na5W3O9F5 with Morphological Controllability in Non-Aqueous Solvents.
NaMoO3F and Na5W3O9F5 were synthesized by solvothermal reaction of MoO3 and WO3, respectively, with NaF in nonaqueous solvents. These reactions were realized at low temperatures (150-200 °C) without the use of HF. This synthesis method is much more facile and safe procedure compared with general synthesis methods for oxyfluorides which includes hydrothermal reaction under a presence of HF or solid-state reaction at high temperatures in vacuum sealed tube or under high pressure. In the case of the reaction of MoO3 with NaF, the kind of solvent largely affected the obtained morphologies of NaMoO3F. The morphology in the case of acetonitrile as a solvent was rodlike with a micrometer-scale size, while that in the case of ethanol was polyhedral with a size of several hundred nanometers. In addition, the solvothermal reaction of WO3 with NaF led to the formation of Na5W3O9F5. Also, the difference of solvents for the solvothermal reaction affected the obtained particle sizes. The effect of the solvents on the morphologies of the obtained oxyfluorides probably resulted from the difference of the solubility of NaF and the subsequent dissolution ratio of MoO3 or WO3 in the used solvents. Our synthesis method can expand the applicability of oxyfluorides by providing a new phase and/or unique morphology.


Consumers' Understanding of FDA Approval Requirements and Composite Scores in Direct-to-Consumer Prescription Drug Print Ads.
In 2 studies, we investigated how laypersons perceive the Food and Drug Administration (FDA) approval process, FDA authority, and the presentation of composite scores in direct-to-consumer (DTC) prescription drug print ads. The 1st study consisted of 4 focus groups (N = 38) in 2 cities. Using a semi-structured guide, a moderator led participants through the viewing of 3 existing DTC print ads that differed in the presence or absence of composite score information, and participants discussed their views of the ads and their understanding of composite scores. The 2nd study surveyed a nationally representative sample of 1,629 individuals from the general population who saw a fictitious DTC print ad and answered closed-ended questions about the same topics. Results showed that knowledge of FDA approval and authority was mixed, with several misconceptions apparent. Many consumers were not familiar with the use of composite scores in a medical context or in advertising and, in the 1st study, expressed distrust of the product and the ad after learning about how composite scores are used. In the 2nd study, receiving composite score information changed the perceived clarity of the ad but not the perceived risk or benefits. Implications for the presentation of complex medical information are discussed.


An investigation on optimum ridge width and exposed side strips width of terahertz quantum cascade lasers with metal-metal waveguides.
The impacts of side exposed side strips (for high order modes suppression) and ridge width on terahertz (THz) quantum cascade laser (QCL) performance are investigated through numerical modeling and verified experimentally. Our results show that shrinking ridge width of THz QCLs with metal-metal waveguides leads to a substantial degradation of device performance due to higher optical loss resulting from the side-exposed strips in the highly-doped top contact layer. Nevertheless, the side-exposed strips facilitate single mode operation by strongly suppressing higher-order modes. An optimal width of the side exposed strips is obtained for achieving adequate higher-order mode suppression and maintaining sufficiently low fundamental mode loss.


Realized niche analysis of phytoplankton communities involving HAB: Phaeocystis spp. as a case study.
The link between harmful algal blooms, phytoplankton community dynamics and global environmental change is not well understood. To tackle this challenging question, a new method was used to reveal how phytoplankton communities responded to environmental change with the occurrence of an harmful algae, using the coastal waters of the eastern English Channel as a case study. The great interannual variability in the magnitude and intensity of Phaeocystis spp. blooms, along with diatoms, compared to the ongoing gradual decrease in anthropogenic nutrient concentration and rebalancing of nutrient ratios; suggests that other factors, such as competition for resources, may also play an important role. A realized niche approach was used with the Outlying Mean Index analysis and the dynamics of the species' realized subniches were estimated using the Within Outlying Mean Indexes calculations under low (L) and high (H) contrasting Phaeocystis spp. abundance. The Within Outlying Mean Indexes allows the decomposition of the realized niche into realized subniches, found within the subset of habitat conditions and constrained by a subset of a biotic factor. The two contrasting scenarios were characterized by significantly different subsets of environmental conditions and diatom species (BV-step analysis), and different seasonality in salinity, turbidity, and nutrients. The subset L environmental conditions were potentially favorable for Phaeocystis spp. but it suffered from competitive exclusion by key diatom species such as Skeletonema spp., Thalassiosira gravida, Thalassionema nitzschioides and the Pseudo-nitzchia seriata complex. Accordingly, these diatoms species occupied 81% of Phaeocystis spp.'s existing fundamental subniche. In contrast, the greater number of diatoms, correlated with the community trend, within subset H exerted a weaker biological constraint and favored Phaeocystis spp. realized subniche expansion. In conclusion, the results strongly suggest that both abiotic and biotic interactions should be considered to understand Phaeocystis spp. blooms with greater consideration of the preceeding diatoms. HABs needs must therefore be studied as part of the total phytoplankton community.


Multi-trait genome-wide association study identifies a novel endometrial cancer risk locus that associates with testosterone levels.
To detect novel endometrial cancer risk variants, we leveraged information from endometrial cancer risk factors in a multi-trait GWAS analysis. We first assessed causal relationships between established and suspected endometrial cancer risk factors, and endometrial cancer using Mendelian randomization. Following multivariable analysis, five independent risk factors (waist circumference, testosterone levels, sex hormone binding globulin levels, age at menarche, and age at natural menopause) were included in a multi-trait Bayesian GWAS analysis. We identified three potentially novel loci that associate with endometrial cancer risk, one of which (7q22.1) replicated in an independent endometrial cancer GWAS dataset and was genome-wide significant in a meta-analysis. This locus may affect endometrial cancer risk through altered testosterone levels. Consistent with this, we observed colocalization between the signals for endometrial cancer risk and expression of CYP3A7, a gene involved in testosterone metabolism. Thus, our findings suggest opportunities for hormone therapy to prevent or treat endometrial cancer.


Cell cycle analysis of cultured mammalian cells after exposure to 4,5',8-trimethylpsoralen and long-wave ultraviolet light.
Cell cycle analysis was used to study the the effect of 4,5'8-trimethylpsoralen (TMP) and long-wave ultraviolet light (UV-A) on cultured mammalian cells. DNA distribution patterns were measured for murine melanoma cells (a cloned line of Cloudman S91) and a strain of diploid human skin fibroblasts (CRL 1295) using both a microfluorimetry procedure and flow cytometry. The untreated cells and those receiving TMP along and UV-A alone had identical DNA content as assessed at several posttreatment intervals (0-72 hr). The majority of cells in control groups contained a G1 DNA content, whereas exposure to TMP (2 x 10(-7) M) plus UV-A (1 Joule/cm2) led to the accumulation of cells in the G2 phase. These observations were similar for each cell type and both analytical techniques were in excellent agreement. The finding that psoralen plus UV-A induces a phase-specific G2 blockade in cultured cells has important implications for understanding the mechanisms which account for enhanced pigmentation and suppression of cellular proliferation following exposure to these agents in vivo.


[Epidemiology and care of myocardial infarct at the Fribourg Canton Hospital 1995].
This study evaluates epidemiological data in a population of patients admitted for acute myocardial infarction in a large Swiss community hospital. It focuses on the application of recent drug treatment and newer therapeutic techniques. Data acquisition was based on medical records of all patients who were admitted to the Cantonal Hospital of Fribourg in 1995. Their one-year follow-up was obtained through questionnaires sent to general practitioners. During the study period: 146 myocardial infarctions were diagnosed in 144 patients. Median age was 67.1 and 35% of patients were female. Nineteen percent were diabetics, 51% had hypertension and 28% had a positive family history for coronary artery disease. Active smokers made up 32%, 17% were past smokers. Myocardial infarction was anterior in 40%, inferior in 36% and non-Q wave myocardial infarction in 35%. Eighteen percent were subacute myocardial infarction. Killip class on admission were as follow: class I 65%, class II 21%, class III 1% and class IV 11%. Thrombolytic treatment was administered in 29% of patients. Vasoactive amines were used in 27% of patients and 8% were intubated some time during their hospital stay. At hospital discharge 81% were treated with Aspirin, 31% with anticoagulants, 47% with an ACE inhibitor, 38% with a beta-blocker, 34% with nitrates and 25% with a calcium antagonist. Among this population, 62% had an echocardiogram, 30% a stress test and 8% a Holter recording. Coronary angiography was performed in 52%, which revealed 33% one-vessel disease, 28% two-vessel disease, 25% three-vessel disease and 9% normal coronary arteries. Percutaneous coronary angioplasty was done in 53% of cases and a coronary stent implanted in 22%. Twelve percent had surgical revascularization. The mean hospital stay was 16.3 +/- 10.8 days, with in hospital mortality of up to 19.2% and a one-year mortality of 25.3%. Treatment modalities of patients admitted for acute myocardial infarction at the Hospital of Fribourg are comparable with literature data. Hypolipemic treatment has not been prescribed as often as recent guidelines recommend, but the use of ACE inhibitors was more common. As in other studies, older patients have the highest mortality. The absence of hospital coronarography facility did not seem to influence the prognosis of that population.


The balance of reproducibility, sensitivity, and specificity of lists of differentially expressed genes in microarray studies.
Reproducibility is a fundamental requirement in scientific experiments. Some recent publications have claimed that microarrays are unreliable because lists of differentially expressed genes (DEGs) are not reproducible in similar experiments. Meanwhile, new statistical methods for identifying DEGs continue to appear in the scientific literature. The resultant variety of existing and emerging methods exacerbates confusion and continuing debate in the microarray community on the appropriate choice of methods for identifying reliable DEG lists. Using the data sets generated by the MicroArray Quality Control (MAQC) project, we investigated the impact on the reproducibility of DEG lists of a few widely used gene selection procedures. We present comprehensive results from inter-site comparisons using the same microarray platform, cross-platform comparisons using multiple microarray platforms, and comparisons between microarray results and those from TaqMan - the widely regarded "standard" gene expression platform. Our results demonstrate that (1) previously reported discordance between DEG lists could simply result from ranking and selecting DEGs solely by statistical significance (P) derived from widely used simple t-tests; (2) when fold change (FC) is used as the ranking criterion with a non-stringent P-value cutoff filtering, the DEG lists become much more reproducible, especially when fewer genes are selected as differentially expressed, as is the case in most microarray studies; and (3) the instability of short DEG lists solely based on P-value ranking is an expected mathematical consequence of the high variability of the t-values; the more stringent the P-value threshold, the less reproducible the DEG list is. These observations are also consistent with results from extensive simulation calculations. We recommend the use of FC-ranking plus a non-stringent P cutoff as a straightforward and baseline practice in order to generate more reproducible DEG lists. Specifically, the P-value cutoff should not be stringent (too small) and FC should be as large as possible. Our results provide practical guidance to choose the appropriate FC and P-value cutoffs when selecting a given number of DEGs. The FC criterion enhances reproducibility, whereas the P criterion balances sensitivity and specificity.


Influence of chemotherapy on the Plasmodium gametocyte sex ratio of mice and humans.
Plasmodium species, the etiologic agents of malaria, are obligatory sexual organisms. Gametocytes, the precursors of gametes, are responsible for parasite transmission from human to mosquito. The sex ratio of gametocytes has been shown to have consequences for the success of this shift from vertebrate host to insect vector. We attempted to document the effect of chemotherapy on the sex ratio of two different Plasmodium species: Plasmodium falciparum in children from endemic area with uncomplicated malaria treated with chloroquine (CQ) or sulfadoxine-pyrimethamine (SP), and P. vinckei petteri in mice treated with CQ or untreated. The studies involved 53 patients without gametocytes at day 0 (13 CQ and 40 SP) followed for 14 days, and 15 mice (10 CQ and 5 controls) followed for five days. During the course of infection, a positive correlation was observed between the time of the length of infection and the proportion of male gametocytes in both Plasmodium species. No effects of treatment (CQ versus SP for P. falciparum or CQ versus controls for P. vinckei petteri) on the gametocyte sex ratio were found for either Plasmodium species. This indicates that parasites do not respond to chemotherapy by altering their sex allocation strategy, even though, in the case of P. falciparum, they apparently increase their overall investment in sexual stages. This suggests that malaria parasite species respond to different environmental cues for their sex differentiation and sex determination.


Parental nativity affects children's health and access to care.
To examine the effect of parental nativity on child health and access to health care. The 2002 National Survey of America's Families. Among US children, 14% have foreign-born parents; 5% have one foreign- and one native-born parent ("mixed-nativity"). In multivariate logistic regression analyses, children with foreign-born parents were less likely than children with US-born parents to be perceived in "very good" or "excellent health" [OR = 0.68; 95% CI (0.56-0.82)] and to have a usual health care site [OR = 0.52 (0.38-0.69)]; having mixed-nativity parents is associated with better perceived child health. These effects persisted for minority, but not white, children. Regardless of race and ethnicity, non-citizen children have worse access to care. Efforts to improve children of immigrants' health and access to care should focus on families in which both parents are immigrants, particularly those who are ethnic or racial minorities. Efforts to increase use of health services should focus on non-citizen children.


Profiling spermatogenic failure in adult testes bearing Sox9-deficient Sertoli cells identifies genes involved in feminization, inflammation and stress.
Sox9 (Sry box containing gene 9) is a DNA-binding transcription factor involved in chondrocyte development and sex determination. The protein's absence in testicular Sertoli nurse cells has been shown to disrupt testicular function in adults but little is known at the genome-wide level about molecular events concomitant with testicular break-down. To determine the genome-wide effect on mRNA concentrations triggered by the absence of Sox9 in Sertoli cells we analysed adult testicular tissue from wild-type versus mutant mice with high-density oligonucleotide microarrays and integrated the output of this experiment with regulatory motif predictions and protein-protein network data. We report the genome-wide mRNA signature of adult testes lacking Sox9 in Sertoli cells before and after the onset of late spermatogenic failure as compared to fertile controls. The GeneChip data integrated with evolutionarily conserved Sox9 DNA binding motifs and regulatory network data identified genes involved in feminization, stress response and inflammation. Our results extend previous observations that genes required for female gonadogenesis are up-regulated in the absence of Sox9 in fetal Sertoli cells to the adult stage. Importantly, we identify gene networks involved in immunological processes and stress response which is reminiscent of a phenomenon occurring in a sub-group of infertile men. This suggests mice lacking Sox9 in their Sertoli cells to be a potentially useful model for adult human testicular failure.


Particle-laden two-dimensional elastic turbulence.
The aggregation properties of heavy inertial particles in the elastic turbulence regime of an Oldroyd-B fluid with periodic Kolmogorov mean flow are investigated by means of extensive numerical simulations in two dimensions. Both the small- and large-scale features of the resulting inhomogeneous particle distribution are examined, focusing on their connection with the properties of the advecting viscoelastic flow. We find that particles preferentially accumulate on thin highly elastic propagating structures and that this effect is the largest for intermediate values of particle inertia. We provide a quantitative characterization of this phenomenon that allows to relate it to the accumulation of particles in filamentary highly strained flow regions producing clusters of correlation dimension close to 1. At larger scales, particles are found to undergo turbophoretic-like segregation. Indeed, our results indicate a close relationship between the profiles of particle density and fluid velocity fluctuations. The large-scale inhomogeneity of the particle distribution is interpreted in the framework of a model derived in the limit of small, but finite, particle inertia. The qualitative characteristics of different observables are, to a good extent, independent of the flow elasticity. When increased, the latter is found, however, to slightly reduce the globally averaged degree of turbophoretic unmixing.


Coding-sequence determinants of gene expression in Escherichia coli.
Synonymous mutations do not alter the encoded protein, but they can influence gene expression. To investigate how, we engineered a synthetic library of 154 genes that varied randomly at synonymous sites, but all encoded the same green fluorescent protein (GFP). When expressed in Escherichia coli, GFP protein levels varied 250-fold across the library. GFP messenger RNA (mRNA) levels, mRNA degradation patterns, and bacterial growth rates also varied, but codon bias did not correlate with gene expression. Rather, the stability of mRNA folding near the ribosomal binding site explained more than half the variation in protein levels. In our analysis, mRNA folding and associated rates of translation initiation play a predominant role in shaping expression levels of individual genes, whereas codon bias influences global translation efficiency and cellular fitness.


AAPM Report 373: The content, structure, and value of the Professional Doctorate in Medical Physics (DMP).
The Professional Doctorate in Medical Physics (DMP) was originally conceived as a solution to the shortage of medical physics residency training positions. While this shortage has now been largely satisfied through conventional residency training positions, the DMP has expanded to multiple institutions and grown into an educational pathway that provides specialized clinical training and extends well beyond the creation of additional training spots. As such, it is important to reevaluate the purpose and the value of the DMP. Additionally, it is important to outline the defining characteristics of the DMP to assure that all existing and future programs provide this anticipated value. Since the formation and subsequent accreditation of the first DMP program in 2009-2010, four additional programs have been created and accredited. However, no guidelines have yet been recommended by the American Association of Physicists in Medicine. CAMPEP accreditation of these programs has thus far been based only on the respective graduate and residency program standards. This allows the development and operation of DMP programs which contain only the requisite Master of Science (MS) coursework and a 2-year clinical training program. Since the MS plus 2-year residency pathway already exists, this form of DMP does not provide added value, and one may question why this existing pathway should be considered a doctorate. Not only do we, as a profession, need to outline the defining characteristics of the DMP, we need to carefully evaluate the potential advantages and disadvantages of this pathway within our education and training infrastructure. The aims of this report from the Working Group on the Professional Doctorate Degree for Medical Physicists (WGPDMP) are to (1) describe the current state of the DMP within the profession, (2) make recommendations on the structure and content of the DMP for existing and new DMP programs, and (3) evaluate the value of the DMP to the profession of medical physics.


Healthcare professional views and experiences of complementary and alternative therapies in obstetric practice in North East Scotland: a prospective questionnaire survey.
The aim of this study was to investigate the use of complementary and alternative medicines (CAMs) therapy by UK healthcare professionals involved in the care of pregnant women, and to identify key predictors of use. A prospective survey. Maternity services in Grampian, North East Scotland. All healthcare professionals (135) involved in the care of pregnant women (midwives, obstetricians, anaesthetists). Questionnaire development, piloting, and distribution. Descriptive and inferential statistical analysis. A response rate of 87% was achieved. A third of respondents (32.5%) had recommended (prescribed, referred, or advised) the use of CAMs to pregnant women. The most frequently recommended CAMs modalities were: vitamins and minerals (excluding folic acid) (55%); massage (53%); homeopathy (50%); acupuncture (32%); yoga (32%); reflexology (26%); aromatherapy (24%); and herbal medicine (21%). Although univariate analysis identified that those who recommended CAMs were significantly more likely to be midwives who had been in post for more than 5 years, had received training in CAMs, were interested in CAMs, and were themselves users of CAMs, the only variable retained in bivariate logistic regression was 'personal use of CAM', with an odds ratio of 8.26 (95% CI 3.09-22.05; P < 0.001). Despite the lack of safety or efficacy data, a wide variety of CAM therapies are recommended to pregnant women by approximately a third of healthcare professionals, with those recommending the use of CAMs being eight times more likely to be personal CAM users.


Medical licensing board characteristics and physician discipline: an empirical analysis.
This article investigates the relationship between the characteristics of medical licensing boards and the frequency with which boards discipline physicians. Specifically, we take advantage of variation in the structure of medical licensing boards between 1993 and 2003 to determine the effect of organizational and budgetary independence, public oversight, and resource constraints on rates of physician discipline. We find that larger licensing boards, boards with more staff, and boards that are organizationally independent from state government discipline doctors more frequently. Public oversight and political control over board budgets do not appear to influence the extent to which medical licensing boards discipline doctors. These findings are broadly consistent with theories of regulatory behavior that emphasize the importance of bureaucratic autonomy for effective regulatory enforcement.


Gamma Knife surgery for arteriovenous malformations in children.
The aim of this study was to evaluate the long-term imaging and clinical outcomes of intracranial arteriovenous malformations (AVMs) in children treated with Gamma Knife surgery (GKS). Between 1989 and 2007, 200 patients with AVMs who were 18 years of age or younger were treated at the University of Virginia Health System. Excluding 14 patients who had not reached 2-year follow-up, 186 patients comprised this study. Hemorrhage was the most common presenting symptom leading to the diagnosis of AVMs (71.5%). The mean nidus volume was 3.2 cm(3) at the time of GKS, and a mean prescription dose of 21.9 Gy was used. After initial GKS, 49.5% of patients achieved total angiographic obliteration. Forty-one patients whose AVM nidi remained patent underwent additional GKS. The obliteration rate increased to 58.6% after a second or multiple GKS. Subtotal obliteration was achieved in 9 patients (4.8%). Forty-nine patients (26.3%) still had a patent residual nidus. In 19 patients (10.2%), obliteration was confirmed on MR imaging only. Ten patients had 17 hemorrhages during the follow-up period. The hemorrhage rate was 5.4% within 2 years after GKS and 0.8% between 2 and 5 years. Six patients developed neurological deficits along with the radiation-induced changes. Two patients developed asymptomatic meningiomas 10 and 12 years after GKS. After a mean clinical follow-up of 98 months, less than 4% of patients had difficulty attending school or developing a career. Gamma Knife surgery offers a reasonable chance of obliteration of an AVM in pediatric patients. The incidence of symptomatic radiation-induced changes is relatively low; however, long-term clinical and imaging follow-up is required to identify delayed cyst formation and secondary tumors.


Early Identification of Potential SSDI Entrants in California: The Predictive Value of State Disability Insurance and Workers' Compensation Claims.
Purpose Examine the potential for using information in short-term disability claims to identify workers at high risk of leaving the workforce and entering Social Security Disability Insurance (SSDI). Methods We analyze state-wide California data on claimants of State Disability Insurance (SDI) and Workers' Compensation (WC) and present statistics on: (1) characteristics (primary diagnosis, sex, age, geography, wage level) by claim duration (0-3, 4-6, 7-12, 12 + months); and (2) the ability of initial claim characteristics to predict duration of at least 12 months. All data are for claims with disability lasting more than 1 week. Results 22.2% of SDI claims last longer than 6 months and 12.5% last 12 months. More WC claims reach these durations: 33.7 and 18.6%, respectively. Long-term SDI and WC claimants are similar to SSDI awardees, nationwide, but differ in age distribution; they are typically younger. Conclusions Characteristics of SDI and WC claims can help predict claims likely to last 12 months, but more information is needed to effectively target early intervention services. Waiting longer to intervene improves targeting but risks missing opportunities where early intervention could be more effective. Collecting additional information at SDI or WC entry or soon thereafter could improve both the efficiency and timing of interventions.


Affective theory of mind inferences contextually influence the recognition of emotional facial expressions.
The recognition of emotional facial expressions is often subject to contextual influence, particularly when the face and the context convey similar emotions. We investigated whether spontaneous, incidental affective theory of mind inferences made while reading vignettes describing social situations would produce context effects on the identification of same-valenced emotions (Experiment 1) as well as differently-valenced emotions (Experiment 2) conveyed by subsequently presented faces. Crucially, we found an effect of context on reaction times in both experiments while, in line with previous work, we found evidence for a context effect on accuracy only in Experiment 1. This demonstrates that affective theory of mind inferences made at the pragmatic level of a text can automatically, contextually influence the perceptual processing of emotional facial expressions in a separate task even when those emotions are of a distinctive valence. Thus, our novel findings suggest that language acts as a contextual influence to the recognition of emotional facial expressions for both same and different valences.


Kinetic folding and cis/trans prolyl isomerization of staphylococcal nuclease. A study by stopped-flow absorption, stopped-flow circular dichroism, and molecular dynamics simulations.
We studied the urea-induced unfolding transition of staphylococcal nuclease (SNase) and its five proline mutants (P47A, P47T, P117G, P47T/P117G, and P47A/P117G) [corrected] by peptide and aromatic circular dichroism and aromatic absorption spectroscopy at equilibrium and the refolding-unfolding kinetics of the proteins by stopped-flow circular dichroism and stopped-flow absorption techniques. Recent studies have revealed that the cis/trans isomerizations about the Pro47 and Pro117 peptide bonds of SNase occur not only in the unfolded state but also in the native state. The mutational effects on the stability and the refolding-unfolding kinetics of SNase were, however, remarkably different between the two sites. The substitution of Ala or Thr for Pro47 neither changed the stability nor affected the refolding-unfolding kinetics of SNase, whereas the substitution of Gly for Pro117 increased the protein stability by 1.2 kcal/mol (pH 7.0 and 20 degrees C) and affected the kinetics. These results have been attributed to the high flexibility of the loop around Pro47, which has been revealed by molecular dynamics simulations of native SNase. Under every condition studied, cooperative refolding-unfolding kinetics of SNase were observed. Refolding of wild-type SNase was represented by two urea concentration-dependent fast phases and a urea concentration-independent slow phase. The double mutant (P47T/P117G) [corrected] of SNase still showed multiphasic refolding kinetics that involved two urea concentration-independent slow phases, suggesting that isomerization of proline residues other than Pro47 and Pro117 may occur in the unfolded state of the mutant. Two phases were observed in the unfolding of the wild-type and mutant proteins that contained Pro117, a fast phase corresponding to the unfolding of the trans isomer and a slow phase corresponding to that of the cis isomer. On the basis of these results, the folding scheme of SNase is discussed.


Evaluation of a meridian-based intervention, Emotional Freedom Techniques (EFT), for reducing specific phobias of small animals.
This study explored whether a meridian-based procedure, Emotional Freedom Techniques (EFT), can reduce specific phobias of small animals under laboratory-controlled conditions. Randomly assigned participants were treated individually for 30 min with EFT (n = 18) or a comparison condition, diaphragmatic breathing (DB) (n = 17). ANOVAS revealed that EFT produced significantly greater improvement than did DB behaviorally and on three self-report measures, but not on pulse rate. The greater improvement for EFT was maintained, and possibly enhanced, at six- to nine-months follow-up on the behavioral measure. These findings suggest that a single treatment session using EFT to reduce specific phobias can produce valid behavioral and subjective effects. Some limitations of the study also are noted and clarifying research suggested.


Maternal bereavement and cryptorchidism in offspring.
Cryptorchidism (undescended testis) is a common anomaly with largely unexplained etiology. Animal studies have suggested maternal emotional stress as a potential risk factor, but this has not been studied in humans. We aimed to investigate whether maternal bereavement due to the death of a close relative in the antenatal period increases the occurrence of cryptorchidism in the offspring. In a population-based cohort, we studied death of a close relative as the exposure and cryptorchidism entries in nationwide medical registries as the outcome. Danish national registries included 898,961 (23,609 exposed) boys born from 1978 to 2008 with a maximum of 30 years of follow-up. A total of 20,947 boys had cryptorchidism, of whom 13,524 also underwent corrective surgery. We found no increased occurrence of cryptorchidism in the offspring (hazard ratio = 1.02 [95% confidence interval = 0.92-1.14]). Results were similar when the diagnosis was verified with surgery. We adjusted for maternal and paternal age, birth year, and family history of cryptorchidism. We observed no association between maternal bereavement before and during pregnancy and the occurrence of cryptorchidism in the offspring.


Increased plasma interleukin-7 level correlates with decreased CD127 and Increased CD132 extracellular expression on T cell subsets in patients with HIV-1 infection.
Interleukin (IL)-7 levels are increased in patients with human immunodeficiency virus type 1 (HIV-1)-associated lymphopenia; however, the effects of this on IL-7 receptor (IL-7R) expression, disease progression, and immune reconstitution remain unclear. Plasma IL-7 levels were measured, by enzyme-linked immunoassay, in patients with primary, chronic, or long-term nonprogressive HIV-1 infection (PHI, CHI, and LTNP, respectively) before and after 40-48 weeks of antiretroviral therapy (ART). Cell-surface expression and intracellular expression of the IL-7R components CD127 and CD132 were measured by flow cytometry. The effects of IL-7 and cycloheximide on IL-7R expression by peripheral blood mononuclear cells were examined in vitro. Plasma IL-7 levels were increased in both patients with PHI and those with CHI; administration of ART resulted in normalized plasma IL-7 levels in patients with PHI but not in those with CHI. Plasma IL-7 levels positively correlated with CD4(+) T cell immune reconstitution in patients with PHI. In vitro, exogenous IL-7 rapidly down-regulated cell-surface CD127 expression, but not CD132 expression, whereas subsequent reexpression required active protein synthesis. HIV-1 infection resulted in progressive decreases in the CD127(+)132(-) subset and increases in the CD127(-)132(+) subset of CD4(+) and CD8(+) T cells. Changes in CD4(+) T cell expression of IL-7R components were evident in patients with LTNP who lost viral control, and these changes preceded increases in plasma IL-7 levels. Perturbations in the IL-7/IL-7R system were clearly associated with disease progression but did not reliably predict immune reconstitution.


Constitutive overexpression of the OsNAS gene family reveals single-gene strategies for effective iron- and zinc-biofortification of rice endosperm.
Rice is the primary source of food for billions of people in developing countries, yet the commonly consumed polished grain contains insufficient levels of the key micronutrients iron (Fe), zinc (Zn) and Vitamin A to meet daily dietary requirements. Experts estimate that a rice-based diet should contain 14.5 µg g(-1) Fe in endosperm, the main constituent of polished grain, but breeding programs have failed to achieve even half of that value. Transgenic efforts to increase the Fe concentration of rice endosperm include expression of ferritin genes, nicotianamine synthase genes (NAS) or ferritin in conjunction with NAS genes, with results ranging from two-fold increases via single-gene approaches to six-fold increases via multi-gene approaches, yet no approach has reported 14.5 µg g(-1) Fe in endosperm. Three populations of rice were generated to constitutively overexpress OsNAS1, OsNAS2 or OsNAS3, respectively. Nicotianamine, Fe and Zn concentrations were significantly increased in unpolished grain of all three of the overexpression populations, relative to controls, with the highest concentrations in the OsNAS2 and OsNAS3 overexpression populations. Selected lines from each population had at least 10 µg g(-1) Fe in polished grain and two OsNAS2 overexpression lines had 14 and 19 µg g(-1) Fe in polished grain, representing up to four-fold increases in Fe concentration. Two-fold increases of Zn concentration were also observed in the OsNAS2 population. Synchrotron X-ray fluorescence spectroscopy demonstrated that OsNAS2 overexpression leads to significant enrichment of Fe and Zn in phosphorus-free regions of rice endosperm. The OsNAS genes, particularly OsNAS2, show enormous potential for Fe and Zn biofortification of rice endosperm. The results demonstrate that rice cultivars overexpressing single rice OsNAS genes could provide a sustainable and genetically simple solution to Fe and Zn deficiency disorders affecting billions of people throughout the world.


An augmented SMS intervention to improve access to antenatal CD4 testing and ART initiation in HIV-infected pregnant women: a cluster randomized trial.
Less than one-third of HIV-infected pregnant women eligible for combination antiretroviral therapy (ART) globally initiate treatment prior to delivery, with lack of access to timely CD4 results being a principal barrier. We evaluated the effectiveness of an SMS-based intervention to improve access to timely antenatal ART. We conducted a stepped-wedge cluster randomized trial of a low-cost programmatic intervention in 20 antenatal clinics in Gaborone, Botswana. From July 2011-April 2012, 2 clinics were randomly selected every 4 weeks to receive an ongoing clinic-based educational intervention to improve CD4 collection and to receive CD4 results via an automated SMS platform with active patient tracing. CD4 testing before 26 weeks gestation and ART initiation before 30 weeks gestation were assessed. Three-hundred-sixty-six ART-naïve women were included, 189 registering for antenatal care under Intervention and 177 under Usual Care periods. Of CD4-eligible women, 100 (59.2%) women under Intervention and 79 (50.6%) women under Usual Care completed CD4 phlebotomy before 26 weeks gestation, adjusted odds ratio (aOR, adjusted for time that a clinic initiated Intervention) 0.87 (95% confidence interval [CI]0.47-1.63, P = 0.67). The SMS-based platform reduced time to clinic receipt of CD4 test result from median of 16 to 6 days (P<0.001), was appreciated by clinic staff, and was associated with reduced operational cost. However, rates of ART initiation remained low, with 56 (36.4%) women registering under Intervention versus 37 (24.2%) women under Usual Care initiating ART prior to 30 weeks gestation, aOR 1.06 (95%CI 0.53-2.13, P = 0.87). The augmented SMS-based intervention delivered CD4 results more rapidly and efficiently, and this type of SMS-based results delivery platform may be useful for a variety of tests and settings. However, the intervention did not appear to improve access to timely antenatal CD4 testing or ART initiation, as obstacles other than CD4 impeded ART initiation during pregnancy.


An Efficient Approach for Driver Drowsiness Detection at Moderate Drowsiness Level Based on Electroencephalography Signal and Vehicle Dynamics Data.
Drowsy driving is one of the leading causes of severe accidents worldwide. In this study, an analyzing method based on drowsiness level proposed to detect drowsiness through electroencephalography (EEG) measurements and vehicle dynamics data. A driving simulator was used to collect brain data in the alert and drowsy states. The tests were conducted on 19 healthy men. Brain signals from the parietal, occipital, and central parts were recorded. Observer Ratings of Drowsiness (ORD) were used for the drowsiness stages assessment. This study used an innovative method, analyzing drowsiness EEG data were in respect to ORD instead of time. Thirteen features of EEG signal were extracted, then through Neighborhood Component Analysis, a feature selection method, 5 features including mean, standard deviation, kurtosis, energy, and entropy are selected. Six classification methods including K-nearest neighbors (KNN), Regression Tree, Classification Tree, Naive Bayes, Support vector machines Regression, and Ensemble Regression are employed. Besides, the lateral position and steering angle as a vehicle dynamic data were used to detect drowsiness, and the results were compared with classification result based on EEG data. According to the results of classifying EEG data, classification tree and ensemble regression classifiers detected over 87.55% and 87.48% of drowsiness at the moderate level, respectively. Furthermore, the classification results demonstrate that if only the single-channel P4 is used, higher performance can achieve than using data of all the channels (C3, C4, P3, P4, O1, O2). Classification tree classifier and regression classifiers showed 91.31% and 91.12% performance with data from single-channel P4. The best classification results based on vehicle dynamic data were 75.11 through KNN classifier. According to this study, driver drowsiness could be detected at the moderate drowsiness level based on features extracted from a single-channel P4 data.


Morphogenesis of the assembly and release of bovine enterovirus.
Fluorescent antibody (FA) studies of cells infected with bovine enterovirus showed cytoplasmic blebs with specific fluorescence to the virus. These structures were also found extracellularly in the debris of lysed cells and were RNA-positive by acridine orange (AO) staining. The morphology of virus-infected cells was further studied by scanning electron microscopy (SEM). Transmission electron microscopy (TEM) with immunoferritin tagging showed the development of long sacs with bilaminated and multilaminated membranes. These sacs had multiple twists at different intervals along their length forming a chain of vesicles. The development and maturation of the virus were observed in these vesicles. A number of virus-containing vesicles were also present extracellularly in the debris of lysed cells. In addition, virus was observed in layers of membranous cisternae closely associated with vacuoles and plasma membrane. Some of the cisternae opened to the extracellular space and appeared to allow the release of the virus. Virus particles were also found in patches and in crystals within the cytoplasmic matrix. Many lysed cells contained fibrils often associated with patches of ferritin-tagged virus. This study presents morphological evidence for the release of the virus in vesicles after cell lysis, via cisternae with openings to the extracellular space, and in cytoplasmic blebs.


Reconnecting cognition in the lab and cognition in real life: The role of compensatory social and motivational factors in explaining how cognition ages in the wild.
The papers in this Special Issue compellingly show that older adults' everyday cognitive life is governed not by the decline in elementary cognitive processes as measured in the lab, but by a multitude of compensatory mechanisms, most of which are of the social/motivational variety. Much of this compensatory behavior can be elicited with no or only little experimental prodding, underscoring the self-organizing or self-initiated nature of this type of behavior, even in advanced old age. We suggest that the study of compensation and the orchestration of cognitive, social, and motivational compensatory mechanisms in effective and healthy aging provides a meaningful challenge to traditional ways of examining developmental changes in cognitive performance.


Coding cerebral bypasses: a proposed nomenclature to better describe bypass constructs and revascularization techniques.
Bypass surgery has evolved into a complex surgical art with a variety of donor arteries, recipient arteries, interpositional grafts, anastomoses, and suturing techniques. Although innovation in contemporary bypasses has increased, the literal descriptions of these new bypasses have not kept pace. The existing nomenclature that joins donor and recipient arteries with a hyphen is simplistic, underinformative, and in need of improvement. This article proposes a nomenclature that systematically incorporates anatomical and technical details with alphanumeric abbreviations and is a clear, concise, and practical "code" for bypass surgery. Detailed descriptions and illustrations of the proposed nomenclature, which consists of abbreviations for donor and recipient arteries, arterial segments, arteriotomies, and sides (left or right), with hyphens and parentheses to denote the arteriotomies joined in the anastomosis and brackets and other symbols for combination bypasses, are presented. The literature was searched for articles describing bypasses, and descriptive nomenclature was categorized as donor and recipient arteries (donor-recipient), donor-recipient with additional details, less detail than donor-recipient, and complete, ambiguous, or descriptive text. In 483 publications, most bypass descriptions were categorized as donor-recipient (335, 69%), with superficial temporal artery-middle cerebral artery bypass described most frequently (299, 62%). Ninety-seven articles (20%) used donor-recipient descriptions with additional details, 45 (9%) were categorized as ambiguous, and none contained a complete bypass description. The authors found the proposed nomenclature to be easily applicable to the more complex bypasses reported in the literature. The authors propose a comprehensive nomenclature based on segmental anatomy and additional anastomotic details that allows bypasses to be coded simply, succinctly, and accurately. This alphanumeric shorthand allows greater precision in describing bypasses and clarifying technical details, which may improve reporting in the literature and thus help to advance the field of bypass surgery.


Transforming growth factor-beta inhibition of insulin-like growth factor-binding protein-5 synthesis in skeletal muscle cells involves a c-Jun N-terminal kinase-dependent pathway.
Transforming growth factor-beta (TGF-beta) and insulin-like growth factors (IGFs) play critical roles in the control of myogenesis. Insulin-like growth factor-binding protein-5 (IGFBP-5), by regulating the bioavailability of IGFs, is involved in controlling IGF-dependent differentiation. We investigated the effects of TGF-beta on the IGFBP-5 production induced by IGFs in mouse myoblasts. TGF-beta leads to a decrease in IGFBP-5 synthesis at both transcript and protein levels, and blocked muscle differentiation. The Smad proteins and the c-Jun N-terminal kinase (JNK) have been shown to be involved in TGF-beta signaling pathways. We provide evidence that the JNK pathway, rather than Smad proteins, is involved in the response of muscle cells to TGF-beta. This factor failed to stimulate the GAL4-Smad 2/3 transcriptional activities of the constructs used to transfect myoblasts. Moreover, stable expression of the antagonistic Smad7 did not abolish the inhibitory effect of TGF-beta on IGFBP-5 production whereas expression of a dominant-negative version of MKK4, an upstream activator of JNK, did. We also showed, using a specific inhibitor, that the p38 mitogen-activated protein kinase (p38 MAPK) was not involved in the inhibition of IGFBP-5 production. Thus, TGF-beta-mediated IGFBP-5 inhibition is independent of Smads and requires activation of the JNK signaling pathway.


Adaptive changes in automatic motor responses based on acquired visuomotor correspondence.
The present study tested whether remapping of visuomotor correspondence alters automatic motor responses induced by visual stimuli. We hypothesized that the congruency effect, an automatic modulation of motor responses based on stimulus-response congruency, changes in accordance with a new visuomotor correspondence acquired through an adaptation task. To induce visuomotor adaptation, participants performed a tracking task with 30° or 150° rotation of the visual feedback. The congruency effect was evaluated multiple times by a visual response task where participants moved their finger left or right. We predicted that the congruency effect, as a measure of automatic responses, would be almost reversed after adaptation to the 150° rotation, because a visual stimulus spatially opposite to the participant's own action would become a "congruent" stimulus in a 150°-rotated environment but not in a 30°-rotation environment. The results show that visuomotor adaptation to the 150° rotation did modulate the congruency effect in accordance with the acquired visuomotor correspondence, but did not completely reverse the effect. When the effect was assessed after the manipulation, which was assumed to switch an internal model back to its normal state, there was no change in automatic motor responses. Furthermore, we found that after effects developed as the training proceeded but decreased over time. These findings suggest that the visuomotor system subserving automatic modulation in motor responses is based on the currently active internal model and, therefore, highly adaptive. In addition, the mechanism underlying after effects in a visuomotor task is discussed in terms of a switching function of internal models.


Coupled-wave analysis of vector holograms. 2. Reflective gratings formed in photoanisotropic medium with uniaxial birefringence.
The diffraction properties of reflective anisotropic gratings, which can be recorded in photoanisotropic media with uniaxial birefringence by three-dimensional vector holography, were characterized through the use of coupled-wave analysis (CWA). By investigating the perturbation of the dielectric tensor, we demonstrated that the gratings with sinusoidal distribution of the azimuthal angle of the optic axis diffract polarized light in which the ordinary and extraordinary components are converted for incident light. The polarization conversion was consistent with that calculated by a numerical method. In addition, it was shown that CWA enables highly accurate calculation of the diffraction efficiency with wavelength dispersion when the amplitude of the azimuthal angle is small.


The Genetic Architecture of Shoot and Root Trait Divergence Between Mesic and Xeric Ecotypes of a Perennial Grass.
Environmental heterogeneity can drive patterns of functional trait variation and lead to the formation of locally adapted ecotypes. Plant ecotypes are often differentiated by suites of correlated root and shoot traits that share common genetic, developmental, and physiological relationships. For instance, although plant water loss is largely governed by shoot systems, root systems determine water access and constrain shoot water status. To evaluate the genetic basis of root and shoot trait divergence, we developed a recombinant inbred population derived from mesic and xeric ecotypes of the perennial grass Panicum hallii. Our study sheds light on the genetic architecture underlying the relationships between root and shoot traits. We identified several genomic "hotspots" which control suites of correlated root and shoot traits, thus indicating genetic coordination between plant organ systems in the process of ecotypic divergence. Genomic regions of colocalized quantitative trait locus (QTL) for the majority of shoot and root growth related traits were independent of colocalized QTL for shoot and root resource acquisition traits. The allelic effects of individual QTL underscore ecological specialization for drought adaptation between ecotypes and reveal possible hybrid breakdown through epistatic interactions. These results have implications for understanding the factors constraining or facilitating local adaptation in plants.


Development of subcutaneous sustained release nanoparticles encapsulating low molecular weight heparin.
The objective of the present research work was to prepare and evaluate sustained release subcutaneous (s.c.) nanoparticles of low molecular weight heparin (LMWH). The nanoparticles were prepared by water-in-oil in-water (w/o/w) emulsion and evaporation method using different grades of polylactide co-glycolide (50:50, 85:15), and different concentrations of polyvinyl alcohol (0.1%, 0.5%, 1%) aqueous solution as surfactant. The fabricated nanoparticles were evaluated for size, shape, zeta potential, encapsulation efficiency, in vitro drug release, and in vivo biological activity (anti-factor Xa activity) using the standard kit. The drug and excipient compatibility was analyzed by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and X-ray diffraction (XRD) studies. The formation of nanoparticles was confirmed by scanning electron microscopy; nanoparticles were spherical in shape. The size of prepared nanoparticles was found between 195 nm and 251 nm. The encapsulation efficiency of the nanoparticles was found between 46% and 70%. In vitro drug, release was about 16-38% for 10 days. In vivo drug, release shows the sustained release of drug for 10 days in rats. FTIR studies indicated that there was no loss in chemical integrity of the drug upon fabrication into nanoparticles. DSC and XRD results demonstrated that the drug was changed from the crystalline form to the amorphous form in the formulation during the fabrication process. The results of this study revealed that the s.c. nanoparticles were suitable candidates for sustained delivery of LMWH.


Efficacy of multimodal, systematic non-surgical treatment of knee osteoarthritis for patients not eligible for a total knee replacement: a study protocol of a randomised controlled trial.
It is recommended that non-operative treatment of knee osteoarthritis (KOA) should be individually tailored and include multiple treatment modalities. Despite these recommendations, no one has yet investigated the efficacy of combining several non-surgical treatment modalities in a randomised controlled study. The purpose of this randomised controlled study is to examine if an optimised, combined non-surgical treatment programme results in greater improvements in pain, function and quality of life in comparison with usual care in patients with KOA who are not eligible for total knee arthroplasty (TKA). This study will include 100 consecutive patients from the North Denmark Region not eligible for TKA with radiographic KOA (K-L grade ≥1) and mean pain during the previous week of ≤60 mm (0-100). The participants will be randomised to receive either a 12-week non-surgical treatment programme consisting of patient education, exercise, diet, insoles, paracetamol and/or NSAIDs or usual care (two information leaflets containing information on KOA and advice regarding the above non-surgical treatment). The primary outcome will be the change from baseline to 12 months on the self-report questionnaire Knee Injury and Osteoarthritis Outcome Score (KOOS)(4) defined as the average score for the subscale scores for pain, symptoms, activities of daily living and quality of life. Secondary outcomes include the five individual KOOS subscale scores, pain on a 100 mm Visual Analogue Scale, EQ-5D, self-efficacy, pain pressure thresholds, postural control and isometric knee flexion and knee extension strength. This study was approved by the local Ethics Committee of The North Denmark Region (N-20110085) and the protocol conforms to the principles of the Declaration of Helsinki. Data collection will be completed by April 2014. Publications will be ready for submission in the summer of 2014. This study is registered with http://clinicaltrials.gov (NCT01535001).


Differences in predictors of cervical and breast cancer screening by screening need in uninsured Latino women.
Latino women experience higher mortality for cervical cancer and lower 5-year survival for breast cancer than non-Latino White women. Adherence with screening recommendations can increase chances of survival, yet the factors that influence screening behaviors in uninsured women are not well documented. Uninsured Latino women (N = 467) recruited in four US cities participated in the study. Logistic regression was used to model adherence to recommendations by screening type (cervical or breast cancer) and screening need (needs to obtain initial screening, overdue for rescreening, up-to-date with rescreening). Predictors differed by type of screening and screening need. Women who reported exposure to cancer education were more likely to have had a mammogram and to be up-to-date with Pap smear screening than women without such exposure. Women who were younger, had more than a sixth grade education, and/or had children were more likely to have had a Pap smear. Older women who had been in the US the longest were more likely to be overdue for a Pap smear. Women with incomes 5000 to 7000 were more likely to have obtained a mammogram. Regional differences were found with respect to mammography screening and maintenance behaviors. Exposure to cancer education is an important predictor of screenings among uninsured urban Latino women. The potential of creating educational interventions that can increase screening rates among women who evidence health disparities is encouraging. Recruitment strategies to reach women in need of screenings are provided.


Genes encoding three new members of the leukocyte antigen 6 superfamily and a novel member of Ig superfamily, together with genes encoding the regulatory nuclear chloride ion channel protein (hRNCC) and an N omega-N omega-dimethylarginine dimethylaminohydrolase homologue, are found in a 30-kb segment of the MHC class III region.
Many of the genes in the class III region of the human MHC encode proteins involved in the immune and inflammatory responses. We have sequenced a 30-kb segment of the MHC class III region lying between the heat shock protein 70 and TNF genes as part of a program aimed at identifying genes that could be involved in autoimmune disease susceptibility. The sequence analysis has revealed the localization of seven genes, whose precise position and order is cen-G7-G6-G6A-G6B-G6C-G6D-G6E-tel, five of which are fully encoded in the sequence, allowing their genomic structures to be defined. Three of them (G6C, G6D, and G6E) encode putative proteins that belong to the Ly-6 superfamily, known to be GPI-anchored proteins attached to the cell surface. Members of the family are specifically expressed and are important in leukocyte maturation. A fourth gene, G6B, encodes a novel member of the Ig superfamily containing a single Ig V-like domain and a cytoplasmic tail with several signal transduction features. The G6 gene encodes a regulatory nuclear chloride ion channel protein, while the G6A gene encodes a putative homologue of the enzyme N omega,N omega-dimethylarginine dimethylaminohydrolase, which is thought to be involved in regulating nitric oxide synthesis. In addition, three microsatellite markers, 9N-1, 82-2, and D6S273 are contained within the sequence, the last two of which have been reported to be strongly associated with the autoimmune disease ankylosing spondylitis.


Comparative effectiveness of weight-loss interventions in clinical practice.
Obesity and its cardiovascular complications are extremely common medical problems, but evidence on how to accomplish weight loss in clinical practice is sparse. We conducted a randomized, controlled trial to examine the effects of two behavioral weight-loss interventions in 415 obese patients with at least one cardiovascular risk factor. Participants were recruited from six primary care practices; 63.6% were women, 41.0% were black, and the mean age was 54.0 years. One intervention provided patients with weight-loss support remotely--through the telephone, a study-specific Web site, and e-mail. The other intervention provided in-person support during group and individual sessions, along with the three remote means of support. There was also a control group in which weight loss was self-directed. Outcomes were compared between each intervention group and the control group and between the two intervention groups. For both interventions, primary care providers reinforced participation at routinely scheduled visits. The trial duration was 24 months. At baseline, the mean body-mass index (the weight in kilograms divided by the square of the height in meters) for all participants was 36.6, and the mean weight was 103.8 kg. At 24 months, the mean change in weight from baseline was -0.8 kg in the control group, -4.6 kg in the group receiving remote support only (P<0.001 for the comparison with the control group), and -5.1 kg in the group receiving in-person support (P<0.001 for the comparison with the control group). The percentage of participants who lost 5% or more of their initial weight was 18.8% in the control group, 38.2% in the group receiving remote support only, and 41.4% in the group receiving in-person support. The change in weight from baseline did not differ significantly between the two intervention groups. In two behavioral interventions, one delivered with in-person support and the other delivered remotely, without face-to-face contact between participants and weight-loss coaches, obese patients achieved and sustained clinically significant weight loss over a period of 24 months. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00783315.).


How to: accreditation of blood cultures' proceedings. A clinical microbiology approach for adding value to patient care.
Quality assurance and quality management are driving forces for controlling blood culture best practices but should not be disconnected from the end-point target, i.e. patient value. This article is intended to help microbiologists implement blood culture accreditation that is actually beneficial to patient management. Experience from a nationwide taskforce for promoting quality assurance and competence in clinical microbiology laboratories, guidelines on blood culture. Experience in blood culture accreditation according to International standard ISO 15189 standards is provided in this review, with a particular focus on critical points that are specific to blood culture (e.g. excluding strain identification or antimicrobial susceptibility testing). Blood culture test method verification is based on risk analysis, and evaluation of the test method's performance is based on the literature review and suppliers' data. In addition, blood culture performance relies largely on the quality of its pre-analytical phase, and the test method should be monitored based on key performance indicators such as the volume of blood cultured, the contamination rate and time to transportation. Other critical key indicators include the rate of false-positive signals, the rate of positive blood cultures, the ecology associated with positive results, and the timely communication of the results to the ward during the post-analytical phase. Finally, a critical analysis of quality controls and of the tools needed to improve blood culture monitoring in the future is provided. Appropriate quality assurance should focus on patient value rather than technical details to provide an appropriate clinical service.


Transmural sheet strains in the lateral wall of the ovine left ventricle.
In an attempt to provide a better understanding of our finding that regions with contracting left ventricular myofibers need not develop a significant transmural systolic wall thickening gradient, the analytic approach of Costa et al. was applied to the four-dimensional dynamic data obtained 1 and 8 wk after surgical implantation of transmural radiopaque beads in the lateral equatorial left ventricular wall in seven ovine hearts. Quantitative histology of tissue blocks demonstrated that fiber angles varied linearly across the wall in this region from -37 degrees in the subepicardium to +18 degrees in the subendocardium. Sheet angles exhibited a pleated-sheet behavior, alternating sign from subepicardium to subendocardium. From end diastole (reference configuration) to end systole (deformed configuration), fiber strain was uniformly negative, sheet extension and sheet thickening were uniformly positive, and sheet-normal shear contributed to wall thickening at all wall depths. Subepicardial radial wall thickening increased significantly from week 1 to week 8, with significant increases in the contributions from subepicardial sheet extension and sheet-normal shear. At 1 and 8 wk, the contribution of sheet-normal shear to wall thickening was substantial at all transmural depths; the contribution of sheet extension to wall thickening was greatest in the subepicardium and least in the subendocardium, and the contribution of sheet thickening to wall thickening was greatest in the subendocardium and least in the subepicardium. A mechanistic model is proposed that provides a working hypothesis that a selective decrease in subepicardial intercellular matrix stiffness is responsible for elimination of the transmural wall thickening gradient 1-8 wk after marker implantation surgery.


Recent Progress and Applications of Thermal Lens Spectrometry and Photothermal Beam Deflection Techniques in Environmental Sensing.
This paper presents recent development and applications of thermal lens microscopy (TLM) and beam deflection spectrometry (BDS) for the analysis of water samples and sea ice. Coupling of TLM detection to a microfluidic system for flow injection analysis (μFIA) enables the detection of microcystin-LR in waters with a four samples/min throughput (in triplicate injections) and provides an LOD of 0.08 µg/L which is 12-times lower than the MCL for microcystin-LR in water. μFIA-TLM was also applied for the determination of total Fe and Fe(II) in 3 µL samples of synthetic cloudwater. The LODs were found to be 100 nM for Fe(II) and 70 nM for total Fe. The application of µFIA-TLM for the determination of ammonium in water resulted in an LOD of 2.3 µM for injection of a 5 µL sample and TLM detection in a 100 µm deep microfluidic channel. For the determination of iron species in sea ice, the BDS was coupled to a diffusive gradient in the thin film technique (DGT). The 2D distribution of Fe(II) and total Fe on DGT gels provided by the BDS (LOD of 50 nM) reflected the distribution of Fe species in sea ice put in contact with DGT gels.


Determinants of genetic counseling uptake and its impact on breast cancer outcome: a population-based study.
Genetic counseling and BRCA1/BRCA2 genes testing are routinely offered in a clinical setting. However, no data are available on the proportion of breast cancer patients with a positive family history undergoing genetic counseling. By linking databases of the Oncogenetics and Cancer Prevention Unit at the Geneva University Hospitals and the population-based Geneva Cancer Registry, we evaluated the uptake of genetic counseling among 1709 breast cancer patients with familial risk of breast cancer and the determinants of such a consultation process. We also studied the impact of genetic counseling on contralateral breast cancer occurrence and survival. Overall, 191 (11.2 %) breast cancer patients had genetic counseling; this proportion was 25.1 % within the high familial risk group. Recent period of diagnosis, early-onset breast cancer, female offspring, high familial risk, tumor size, and chemotherapy treatment were statistically significantly associated with genetic counseling uptake in multivariate analysis. More than 2 % of patients had developed contralateral metachronous breast cancer. An increased risk of contralateral breast cancer of borderline significance was found for patients who had genetic counseling versus those who had not (Cox model adjusted hazard ratio 2.2, 95 % confidence intervals 1.0-5.2, P = 0.063). Stratification by BRCA1/BRCA2 mutation status showed that the occurrence of contralateral breast cancer was 8-fold higher among mutation carriers compared with non-carriers. Age-adjusted overall survival and breast cancer-specific survival were not significantly different between patients who underwent genetic counseling and those who did not. In conclusion, we observed a significant increase in the use of genetic counseling over time and found that breast cancer patients with high familial risk had more often genetic counseling than those with moderate familial risk. A more thorough evaluation of sociodemographic and clinical predictors to attend the cancer genetic unit may help improving the use of genetic counseling services for at-risk individuals at a population level.


Multidrug resistance and its association with Enterobacteriales and age among pregnant Peruvian women with- bacteremia.
This study aimed to assess the prevalence of multidrug resistance (MDR) and its associated factors among pregnant Peruvian women with bacteremia. In an 18-month cross-sectional study, all pregnant women were routinely tested with a presumptive diagnosis of sepsis admitted to the largest reference maternity hospital (Instituto Nacional Materno Perinatal) in Lima, Peru for bacteremia. Every isolate was tested for antimicrobial susceptibility as defined by the Institute of Clinical and Laboratory Standards (CLSI). Additionally, associated factors were assessed with MDR and the number of resistant antimicrobial categories using robust Poisson regression models with link log, especially focused on its association with age and bacterial families or species. A total of 236 blood cultures of pregnant women (33.4 ± 11.4 years old) was analyzed. The prevalence of MDR was 70% (95% confidence interval [CI]: 64%-76%). The main etiological agent was Escherichia coli (65%), showing an MDR rate of 74% (68%-81%). Overall, we observed that the MDR rate was associated with Enterobacteriales (adjusted prevalence rate, (aPR) = 1.29; 95% CI: 1.03-1.61) and age 35 or older (PR = 1.18; 95% CI: 1.01-1.39). However, the number of resistant antimicrobial categories was associated with Enterobacteriales (aPR = 1.44; 95% CI: 1.25-1.67) and hospital-acquired infections (PR = 0.81; 95% CI: 1.01-1.39). The prevalence of MDR among pregnant women with sepsis was alarmingly high, being even higher among women age 35 or older and among those with hospital-acquired infections.


EEG data compression to monitor DoA in telemedicine.
Data compression techniques have been widely used to process and transmit huge amount of EEG data in real-time and remote EEG signal processing systems. In this paper we propose a lossy compression technique, F-shift, to compress EEG signals for remote depth of Anaesthesia (DoA) monitoring. Compared with traditional wavelet compression techniques, our method not only preserves valuable clinical information with high compression ratios, but also reduces high frequency noises in EEG signals. Moreover, our method has negligible compression overheads (less than 0.1 seconds), which can greatly benefit real-time EEG signal monitoring systems. Our extensive experiments demonstrate the efficiency and effectiveness of the proposed compression method.


Formulation of dark chocolate as a carrier to deliver eicosapentaenoic and docosahexaenoic acids: Effects on product quality.
In this study, dark chocolate enriched with EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) was developed using various forms and origins. Quality characteristics such as physical, thermo-gravimetric, rheological, textural and sensory properties of chocolates were investigated. The highest EPA/DHA stability was determined in samples prepared by free-flowing powder and microencapsulated forms of omega-3 fatty acids (FA). The L∗ and C∗ values varied from 32.16-33.37 and 7.45-8.09, respectively for the all samples. Hardness values ranged between 6422 and 8367 N and the use of EPA/DHA in the triglyceride form caused softer chocolate whereas control sample was the hardest sample. Melting and rheological properties were not significantly affected by the studied EPA/DHA sources (P < 0.05). Microencapsulated EPA/DHA added chocolate was the most preferred source whereas sample with algae oil showed the lowest acceptability. According to the results, dark chocolate can be used for delivering omega-3 FA by considering their origin and physical form.


Glutamine Transporters Are Targets of Multiple Oncogenic Signaling Pathways in Prostate Cancer.
Despite the known importance of androgen receptor (AR) signaling in prostate cancer, the processes downstream of AR that drive disease development and progression remain poorly understood. This knowledge gap has thus limited the ability to treat cancer. Here, it is demonstrated that androgens increase the metabolism of glutamine in prostate cancer cells. This metabolism was required for maximal cell growth under conditions of serum starvation. Mechanistically, AR signaling promoted glutamine metabolism by increasing the expression of the glutamine transporters SLC1A4 and SLC1A5, genes commonly overexpressed in prostate cancer. Correspondingly, gene expression signatures of AR activity correlated with SLC1A4 and SLC1A5 mRNA levels in clinical cohorts. Interestingly, MYC, a canonical oncogene in prostate cancer and previously described master regulator of glutamine metabolism, was only a context-dependent regulator of SLC1A4 and SLC1A5 levels, being unable to regulate either transporter in PTEN wild-type cells. In contrast, rapamycin was able to decrease the androgen-mediated expression of SLC1A4 and SLC1A5 independent of PTEN status, indicating that mTOR complex 1 (mTORC1) was needed for maximal AR-mediated glutamine uptake and prostate cancer cell growth. Taken together, these data indicate that three well-established oncogenic drivers (AR, MYC, and mTOR) function by converging to collectively increase the expression of glutamine transporters, thereby promoting glutamine uptake and subsequent prostate cancer cell growth.Implications: AR, MYC, and mTOR converge to increase glutamine uptake and metabolism in prostate cancer through increasing the levels of glutamine transporters. Mol Cancer Res; 15(8); 1017-28. ©2017 AACR.


Electrostatics control actin filament nucleation and elongation kinetics.
The actin cytoskeleton is a central mediator of cellular morphogenesis, and rapid actin reorganization drives essential processes such as cell migration and cell division. Whereas several actin-binding proteins are known to be regulated by changes in intracellular pH, detailed information regarding the effect of pH on the actin dynamics itself is still lacking. Here, we combine bulk assays, total internal reflection fluorescence microscopy, fluorescence fluctuation spectroscopy techniques, and theory to comprehensively characterize the effect of pH on actin polymerization. We show that both nucleation and elongation are strongly enhanced at acidic pH, with a maximum close to the pI of actin. Monomer association rates are similarly affected by pH at both ends, although dissociation rates are differentially affected. This indicates that electrostatics control the diffusional encounter but not the dissociation rate, which is critical for the establishment of actin filament asymmetry. A generic model of protein-protein interaction, including electrostatics, explains the observed pH sensitivity as a consequence of charge repulsion. The observed pH effect on actin in vitro agrees with measurements of Listeria propulsion in pH-controlled cells. pH regulation should therefore be considered as a modulator of actin dynamics in a cellular environment.


Disposition of Phytocannabinoids, Their Acidic Precursors and Their Metabolites in Biological Matrices of Healthy Individuals Treated with Vaporized Medical Cannabis.
Inhalation by vaporization is a useful application mode for medical cannabis. In this study, we present the disposition of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), their acidic precursors, and their metabolites in serum, oral fluid, and urine together with the acute pharmacological effects in 14 healthy individuals treated with vaporized medical cannabis. THC and CBD peaked firstly in serum and then in oral fluid, with higher concentrations in the first biological matrices and consequent higher area under the curve AUCs. Acidic precursors Δ-9-tetrahydrocannabinolic acid A (THCA) and cannabidiolic acid (CBDA) showed a similar time course profile but lower concentrations due to the fact that vaporization partly decarboxylated these compounds. All THC and CBD metabolites showed a later onset with respect to the parent compounds in the absorption phase and a slower decrease to baseline. In agreement with serum kinetics, THC-COOH-GLUC and 7-COOH-CBD were the significantly most excreted THC and CBD metabolites. The administration of vaporized medical cannabis induced prototypical effects associated with the administration of cannabis or THC in humans, with a kinetic trend overlapping that of parent compounds and metabolites in serum. The pharmacokinetics of cannabinoids, their precursors, and their metabolites in biological fluids of individuals treated with vaporized medical cannabis preparations showed a high interindividual variability as in the case of oral medical cannabis decoction and oil. Inhaled medical cannabis was absorbed into the organism earlier than decoction and oil. Cannabinoids reached higher systemic concentrations, also due to the fact that the acid precursors decarboxylated to parent cannabinoids at high temperatures, and consequently, the physiological and subjective effects occurred earlier and resulted with higher intensity. No serious adverse effects were observed.


Fisetin is a senotherapeutic that extends health and lifespan.
Senescence is a tumor suppressor mechanism activated in stressed cells to prevent replication of damaged DNA. Senescent cells have been demonstrated to play a causal role in driving aging and age-related diseases using genetic and pharmacologic approaches. We previously demonstrated that the combination of dasatinib and the flavonoid quercetin is a potent senolytic improving numerous age-related conditions including frailty, osteoporosis and cardiovascular disease. The goal of this study was to identify flavonoids with more potent senolytic activity. A panel of flavonoid polyphenols was screened for senolytic activity using senescent murine and human fibroblasts, driven by oxidative and genotoxic stress, respectively. The top senotherapeutic flavonoid was tested in mice modeling a progeroid syndrome carrying a p16INK4a-luciferase reporter and aged wild-type mice to determine the effects of fisetin on senescence markers, age-related histopathology, disease markers, health span and lifespan. Human adipose tissue explants were used to determine if results translated. Of the 10 flavonoids tested, fisetin was the most potent senolytic. Acute or intermittent treatment of progeroid and old mice with fisetin reduced senescence markers in multiple tissues, consistent with a hit-and-run senolytic mechanism. Fisetin reduced senescence in a subset of cells in murine and human adipose tissue, demonstrating cell-type specificity. Administration of fisetin to wild-type mice late in life restored tissue homeostasis, reduced age-related pathology, and extended median and maximum lifespan. The natural product fisetin has senotherapeutic activity in mice and in human tissues. Late life intervention was sufficient to yield a potent health benefit. These characteristics suggest the feasibility to translation to human clinical studies. FUND: NIH grants P01 AG043376 (PDR, LJN), U19 AG056278 (PDR, LJN, WLL), R24 AG047115 (WLL), R37 AG013925 (JLK), R21 AG047984 (JLK), P30 DK050456 (Adipocyte Subcore, JLK), a Glenn Foundation/American Federation for Aging Research (AFAR) BIG Award (JLK), Glenn/AFAR (LJN, CEB), the Ted Nash Long Life and Noaber Foundations (JLK), the Connor Group (JLK), Robert J. and Theresa W. Ryan (JLK), and a Minnesota Partnership Grant (AMAY-UMN#99)-P004610401-1 (JLK, EAA).


Toward a quantitative understanding of the Wnt/β-catenin pathway through simulation and experiment.
Wnt signaling regulates cell survival, proliferation, and differentiation throughout development and is aberrantly regulated in cancer. The pathway is activated when Wnt ligands bind to specific receptors on the cell surface, resulting in the stabilization and nuclear accumulation of the transcriptional co-activator β-catenin. Mathematical and computational models have been used to study the spatial and temporal regulation of the Wnt/β-catenin pathway and to investigate the functional impact of mutations in key components. Such models range in complexity, from time-dependent, ordinary differential equations that describe the biochemical interactions between key pathway components within a single cell, to complex, multiscale models that incorporate the role of the Wnt/β-catenin pathway target genes in tissue homeostasis and carcinogenesis. This review aims to summarize recent progress in mathematical modeling of the Wnt pathway and to highlight new biological results that could form the basis for future theoretical investigations designed to increase the utility of theoretical models of Wnt signaling in the biomedical arena.


Fracture mechanisms in multilayer phosphorene assemblies: from brittle to ductile.
The outstanding mechanical performance of nacre has stimulated numerous studies on the design of artificial nacres. Phosphorene, a new two-dimensional (2D) material, has a crystalline in-plane structure and non-bonded interaction between adjacent flakes. Therefore, multi-layer phosphorene assemblies (MLPs), in which phosphorene flakes are piled up in a staggered manner, may exhibit outstanding mechanical performance, especially exceptional toughness. Therefore, molecular dynamics simulations are performed to study the dependence of the mechanical properties on the overlap distance between adjacent phosphorene layers and the number of phosphorene flakes per layer. The results indicate that when the flake number is equal to 1, a transition of fracture patterns is observed by increasing the overlap distance, from a ductile failure controlled by interfacial friction to a brittle failure dominated by the breakage of covalent bonds inside phosphorene flakes. Moreover, the failure pattern can be tuned by changing the number of flakes in each phosphorene layer. The results imply that the ultimate strength follows a power law with the exponent -0.5 in terms of the flake number, which is in good agreement with our analytical model. Furthermore, the flake number in each phosphorene layer is optimized as 2 when the temperature is 1 K in order to potentially achieve both high toughness and strength. Moreover, our results regarding the relations between mechanical performance and overlap distance can be explained well using a shear-lag model. However, it should be pointed out that increasing the temperature of MLPs could cause the transition of fracture patterns from ductile to brittle. Therefore, the optimal flake number depends heavily on temperature to achieve both its outstanding strength and toughness. Overall, our findings unveil the fundamental mechanism at the nanoscale for MLPs as well as provide a method to design phosphorene-based structures with targeted properties via tunable overlap distance and flake number in phosphorene layers.


Substantial and Sustained Improvements in Blood Pressure, Weight and Lipid Profiles from a Carbohydrate Restricted Diet: An Observational Study of Insulin Resistant Patients in Primary Care.
Hypertension is the second biggest known global risk factor for disease after poor diet; perhaps lifestyle interventions are underutilized? In a previous small pilot study, it was found that a low carbohydrate diet was associated with significant improvements in blood pressure, weight, 'deprescribing' of medications and lipid profiles. We were interested to investigate if these results would be replicated in a larger study based in 'real world' GP practice. 154 patients with type 2 diabetes or impaired glucose tolerance were recruited into an observational cohort study in primary care. The effects of a low carbohydrate diet sustained for an average of two years (interquartile range 10-32 months) on cardiovascular risk factors were examined. Results demonstrate significant and substantial reductions in blood pressure (mean reduction of systolic BP 10.9 mmHg (interquartile range 0-22 mmHg) (p < 0.0001), mean reduction in diastolic BP 6.3 mmHg (interquartile range 0-12.8 mmHg) (p < 0.0001) and mean weight reduction of 9.5 Kg (interquartile range 5-13 Kg) (p < 0.0001) together with marked improvement in lipid profiles. This occurred despite a 20% reduction in anti-hypertensive medications. This novel and potentially highly effective dietary modification, done very cheaply alongside routine care, offers hope that should be tested in a large prospective trial.