Automated dispersion and orientation analysis for carbon nanotube reinforced polymer composites.
The properties of carbon nanotube (CNT)/polymer composites are strongly dependent on the dispersion and orientation of CNTs in the host matrix. Quantification of the dispersion and orientation of CNTs by means of microstructure observation and image analysis has been demonstrated as a useful way to understand the structure-property relationship of CNT/polymer composites. However, due to the various morphologies and large amount of CNTs in one image, automatic and accurate identification of CNTs has become the bottleneck for dispersion/orientation analysis. To solve this problem, shape identification is performed for each pixel in the filler identification step, so that individual CNTs can be extracted from images automatically. The improved filler identification enables more accurate analysis of CNT dispersion and orientation. The dispersion index and orientation index obtained for both synthetic and real images from model compounds correspond well with the observations. Moreover, these indices help to explain the electrical properties of CNT/silicone composite, which is used as a model compound. This method can also be extended to other polymer composites with high-aspect-ratio fillers.


First Report of Tatsoi Downy Mildew Caused by Hyaloperonospora brassicae in Korea.
Tatsoi (Brassica narinosa L.H. Bailey), also called spinach mustard or spoon mustard, is cultivated for edible greens in Asia. In Korea, this plant has recently become popular as a sprout vegetable that is grown to harvestable size in 5 to 6 days. During April 2012, tatsoi seedlings showing typical symptoms of downy mildew were found in plastic greenhouses in Pyeongtaek City of Korea. Infection resulted in chlorotic areas on the leaves with a white mildew developing on the abaxial surface, and finally led to necrosis of the lesions. Affected sprouts were unmarketable and abandoned without harvesting. A sample was deposited in the Korea University herbarium (Accession No. KUS-F26445). Microscopic examination of fresh material was performed under a light microscope. Conidiophores emerging from stomata were hyaline, 270 to 550 × 10 to 25 μm, straight, and monopodially branched in six to eight orders. Ultimate branchlets were mostly in pairs, flexuous, and 15 to 25 μm long. Conidia were hyaline, subglobose, and 20.5 to 26.5 × 19.5 to 24.5 μm with a length/width ratio of 1.05 to 1.20. These characteristics unequivocally indicate the genus Hyaloperonospora (1). Previously H. parasitica (formerly under Peronospora) has been considered a causal agent of downy mildew on tatsoi (2,4), but the present Korean accession is morphologically distinct from the former species by possessing subglobose conidia with a low length/width ratio. To confirm this morphological difference, amplification and sequencing of the internal transcribed spacer (ITS) region of rDNA of the Korean specimen were performed using procedures outlined by Göker et al. (3). The resulting 874-bp sequence of the region was deposited in GenBank (Accession No. JX401551). A comparison with the ITS sequences available in the GenBank database revealed that it was identical to Hyaloperonospora brassicae found on Brassica oleracea var. italica (EU137726), and showed only one base pair substitution compared to pathogens from B. rapa ssp. pekinensis (JF975613) and B. napus spp. napus (EU049248), but is significantly different from H. parasitica on Capsella bursa-pastoris (AY210988) with a base-pair dissimilarity of about 13%. Therefore, the pathogen found in Korea was confirmed to be H. brassicae. Pathogenicity was demonstrated by shaking diseased leaves onto the leaves of healthy tatsoi seedlings, incubating the plants in a dew chamber at 20°C for 24 h, and then maintaining them in a greenhouse (22 to 26°C). After 3 days, inoculated plants developed downy mildew symptoms from which identical fungi were observed, thus fulfilling Koch's postulates. Control plants treated with sterile water did not develop any symptoms or signs of downy mildew. This is the first report of a downy mildew on tatsoi in Korea, although it has been found in China (2) and Japan (4). To our knowledge, there is no record of tatsoi downy mildew outside East Asia (2,4). References: (1) O. Constantinescu and J. Fatehi. Nova Hedwigia 74:291, 2002. (2) D. F. Farr and A. Y. Rossman. Fungal Databases, Systematic Mycology and Microbiology Laboratory, ARS, USDA. Retrieved from http://nt.ars-grin.gov/fungaldatabases/ July 18, 2012. (3) M. Göker et al. Mycol. Res. 113:308, 2009. (4) M. Satou et al. Annu. Rep. Soc. Plant Protect. N. Jpn. 50:62, 1999.


Control of adult neurogenesis by programmed cell death in the mammalian brain.
The presence of neural stem cells (NSCs) and the production of new neurons in the adult brain have received great attention from scientists and the public because of implications to brain plasticity and their potential use for treating currently incurable brain diseases. Adult neurogenesis is controlled at multiple levels, including proliferation, differentiation, migration, and programmed cell death (PCD). Among these, PCD is the last and most prominent process for regulating the final number of mature neurons integrated into neural circuits. PCD can be classified into apoptosis, necrosis, and autophagic cell death and emerging evidence suggests that all three may be important modes of cell death in neural stem/progenitor cells. However, the molecular mechanisms that regulate PCD and thereby impact the intricate balance between self-renewal, proliferation, and differentiation during adult neurogenesis are not well understood. In this comprehensive review, we focus on the extent, mechanism, and biological significance of PCD for the control of adult neurogenesis in the mammalian brain. The role of intrinsic and extrinsic factors in the regulation of PCD at the molecular and systems levels is also discussed. Adult neurogenesis is a dynamic process, and the signals for differentiation, proliferation, and death of neural progenitor/stem cells are closely interrelated. A better understanding of how adult neurogenesis is influenced by PCD will help lead to important insights relevant to brain health and diseases.


Inverse sparse tracker with a locally weighted distance metric.
Sparse representation has been recently extensively studied for visual tracking and generally facilitates more accurate tracking results than classic methods. In this paper, we propose a sparsity-based tracking algorithm that is featured with two components: 1) an inverse sparse representation formulation and 2) a locally weighted distance metric. In the inverse sparse representation formulation, the target template is reconstructed with particles, which enables the tracker to compute the weights of all particles by solving only one l1 optimization problem and thereby provides a quite efficient model. This is in direct contrast to most previous sparse trackers that entail solving one optimization problem for each particle. However, we notice that this formulation with normal Euclidean distance metric is sensitive to partial noise like occlusion and illumination changes. To this end, we design a locally weighted distance metric to replace the Euclidean one. Similar ideas of using local features appear in other works, but only being supported by popular assumptions like local models could handle partial noise better than holistic models, without any solid theoretical analysis. In this paper, we attempt to explicitly explain it from a mathematical view. On that basis, we further propose a method to assign local weights by exploiting the temporal and spatial continuity. In the proposed method, appearance changes caused by partial occlusion and shape deformation are carefully considered, thereby facilitating accurate similarity measurement and model update. The experimental validation is conducted from two aspects: 1) self validation on key components and 2) comparison with other state-of-the-art algorithms. Results over 15 challenging sequences show that the proposed tracking algorithm performs favorably against the existing sparsity-based trackers and the other state-of-the-art methods.


Distinct responses to reduplicated chromosomes require distinct Mad2 responses.
Duplicating chromosomes once each cell cycle produces sister chromatid pairs, which separate accurately at anaphase. In contrast, reduplicating chromosomes without separation frequently produces polytene chromosomes, a barrier to accurate mitosis. Chromosome reduplication occurs in many contexts, including: polytene tissue development, polytene tumors, and following treatment with mitosis-blocking chemotherapeutics. However, mechanisms responding to or resolving polyteny during mitosis are poorly understood. Here, using Drosophila, we uncover two distinct reduplicated chromosome responses. First, when reduplicated polytene chromosomes persist into metaphase, an anaphase delay prevents tissue malformation and apoptosis. Second, reduplicated polytene chromosomes can also separate prior to metaphase through a spindle-independent mechanism termed Separation-Into-Recent-Sisters (SIRS). Both reduplication responses require the spindle assembly checkpoint protein Mad2. While Mad2 delays anaphase separation of metaphase polytene chromosomes, Mad2's control of overall mitotic timing ensures efficient SIRS. Our results pinpoint mechanisms enabling continued proliferation after genome reduplication, a finding with implications for cancer progression and prevention.


Evanescent wave coupling in terahertz waveguide arrays.
We study energy transfer among an array of identical finite-width parallel-plate waveguides in close proximity, via evanescent wave coupling of broadband terahertz waves. We observe stronger coupling with larger plate separations and longer propagation paths. This work establishes a platform to investigate new opportunities for THz components and devices based on evanescent wave coupling.


A clonal analysis of the IgE response and its implications with regard to isotope commitment.
In a clonal analysis of the IgE response, it was found that a small proportion of primary or nonimmune B cells in spleen and mesenteric lymph nodes can be stimulated by antigen to produce IgE-secreting clones. In addition, there appears to be no substantial difference in the frequency of such cells between the classical low and high IgE responder strains. An analysis of immune, or memory, B cells revealed substantial increases in the frequency of B cells secreting IgE as compared with primary B cells, although the actual proportion of B cells secreting IgE remained relatively low. When the IgE-secreting clones derived from either primary or secondary B cells were reanalyzed for the presence of other isotypes, it was found that all clones secreting IgE were secreting at least one other isotype, with the majority secreting two or three other isotypes in addition to IgE. This demonstrates that there is no distinct subpopulation of B cells committed to IgE expression per se.


Self-protection and diversity in self-replicating cellular automata.
The concept of self-protection, a capability of an organism to protect itself from exogenous attacks, is introduced into the design of artificial evolutionary systems as a possible method to create and maintain diversity in the population. Three different mechanisms of self-protection are considered and implemented on a cellular-automaton-based evolutionary system, the evoloop. Simulation results imply a positive effect of those mechanisms on diversity maintenance, especially when the self-protection is moderate so that it conserves both the attacker and the attacked. This letter briefly reports the models and the simulation results obtained using those models.


Correlation of proton release and electrochromic shifts of the optical spectrum due to oxidation of tyrosine in reaction centers from Rhodobacter sphaeroides.
Reaction centers from the Y(L167) mutant of Rhodobacter sphaeroides, containing a highly oxidizing bacteriochlorophyll dimer and a tyrosine residue substituted at Phe L167, were compared to reaction centers from the Y(M) mutant, with a tyrosine at M164, and a quadruple mutant containing a highly oxidizing dimer but no nearby tyrosine residue. Distinctive features in the light-induced optical and EPR spectra showed that the oxidized bacteriochlorophyll dimer was reduced by Tyr L167 in the Y(L167) mutant, resulting in a tyrosyl radical, as has been found for Tyr M164 in the Y(M) mutant. In the Y(L167) mutant, the net proton uptake after formation of the tyrosyl radical and the reduced primary quinone ranged from +0.1 to +0.3 H(+)/reaction center between pH 6 and pH 10, with a dependence that is similar to the quadruple mutant but different than the large proton release observed in the Y(M) mutant. In the light-induced absorption spectrum in the 700-1000 nm region, the Y(L167) mutant exhibited unique changes that can be assigned as arising primarily from an approximately 30 nm blue shift of the dimer absorption band. The optical signals in the Y(L167) mutant were pH dependent, with a pK(a) value of approximately 8.7, indicating that the tyrosyl radical is stabilized at high pH. The results are modeled by assuming that the phenolic proton of Tyr L167 is trapped in the protein after oxidation of the tyrosine, resulting in electrostatic interactions with the tetrapyrroles and nearby residues.


Proactive telephone support provided to breastfeeding mothers of preterm infants after discharge: a randomised controlled trial.
The aim was to evaluate the effectiveness of proactive telephone support provided to breastfeeding mothers of preterm infants after discharge from neonatal intensive care units (NICU). Between March 2013 and December 2015, a randomised controlled trial was conducted at six NICUs across Sweden. At each NICU, a breastfeeding support team recruited, randomised and delivered the support to participating mothers. The intervention group received a daily proactive telephone call up to 14 days after discharge from the support team. The control group could initiate telephone contact themselves. Primary outcome was exclusive breastfeeding eight weeks after discharge. Secondary outcomes were maternal satisfaction with breastfeeding, attachment, quality of life and parental stress. In total, 493 mothers were randomised, 231 to intervention group and 262 to control group. There were no differences between the groups for exclusive breastfeeding, odds ratio 0.96, 95% CI 0.66-1.38, nor for maternal satisfaction with breastfeeding, attachment or quality of life. The intervention group reported significantly less parental stress than the controls, t = 2.44, 95% CI 0.03-0.23, effect size d = 0.26. In this trial, proactive telephone support was not associated with increased exclusive breastfeeding prevalence eight weeks following discharge. However, intervention group mothers showed significantly lower parental stress.


Punctuated Evolution of Myxoma Virus: Rapid and Disjunct Evolution of a Recent Viral Lineage in Australia.
Myxoma virus (MYXV) has been evolving in a novel host species-European rabbits-in Australia since 1950. Previous studies of viruses sampled from 1950 to 1999 revealed a remarkably clock-like evolutionary process across all Australian lineages of MYXV. Through an analysis of 49 newly generated MYXV genome sequences isolated in Australia between 2008 and 2017, we show that MYXV evolution in Australia can be characterized by three lineages, one of which exhibited a greatly elevated rate of evolutionary change and a dramatic breakdown of temporal structure. Phylogenetic analysis revealed that this apparently punctuated evolutionary event occurred between 1996 and 2012. The branch leading to the rapidly evolving lineage contained a relatively high number of nonsynonymous substitutions, and viruses in this lineage reversed a mutation found in the progenitor standard laboratory strain (SLS) and all previous sequences that disrupts the reading frame of the M005L/R gene. Analysis of genes encoding proteins involved in DNA synthesis or RNA transcription did not reveal any mutations likely to cause rapid evolution. Although there was some evidence for recombination across the MYXV phylogeny, this was not associated with the increase in the evolutionary rate. The period from 1996 to 2012 saw significant declines in wild rabbit numbers, due to the introduction of rabbit hemorrhagic disease and prolonged drought in southeastern Australia, followed by the partial recovery of populations. It is therefore possible that a rapidly changing environment for virus transmission changed the selection pressures faced by MYXV, altering the course and pace of virus evolution.IMPORTANCE The coevolution of myxoma virus (MYXV) and European rabbits in Australia is one of the most important natural experiments in evolutionary biology, providing insights into virus adaptation to new hosts and the evolution of virulence. Previous studies of MYXV evolution have also shown that the virus evolves both relatively rapidly and in a strongly clock-like manner. Using newly acquired MYXV genome sequences from Australia, we show that the virus has experienced a dramatic change in evolutionary behavior over the last 20 years, with a breakdown in clock-like structure, the appearance of a rapidly evolving virus lineage, and the accumulation of multiple nonsynonymous and indel mutations. We suggest that this punctuated evolutionary event may reflect a change in selection pressures as rabbit numbers declined following the introduction of rabbit hemorrhagic disease virus and drought in the geographic regions inhabited by rabbits.


Ferroxidase and ascorbate oxidase activities of caeruloplasmin in synovial fluid from rheumatoid patients.
1. The protein caeruloplasmin inhibits certain free radical reactions, in part probably due to its ability to oxidize Fe2+ into Fe3+ (ferroxidase activity). Since caeruloplasmin is present in synovial fluid from rheumatoid patients, we investigated its properties in relation to protection of the joint from damage by oxygen radicals produced by activated phagocytes. 2. The ferroxidase and ascorbate oxidase activities of serum from both normal and rheumatoid patients could be accounted for by the caeruloplasmin present, as determined immunologically. More caeruloplasmin is present in the serum of rheumatoid patients than in normal serum. 3. Synovial fluid from rheumatoid patients contains caeruloplasmin protein but its ferroxidase and ascorbate oxidase activities are abnormally low. It is suggested that ferroxidase deficiency contributes to radical damage in the rheumatoid joint.


A Cognitive Autopsy Approach Towards Explaining Diagnostic Failure.
Diagnostic failure has emerged as one of the most significant threats to patient safety. It is important to understand the antecedents of such failures both for clinicians in practice as well is those in training. A consensus has developed in the literature that the majority of failures are due to individual or system factors or some combination of the two. A major source of variance in individual clinical performance is cognitive and affective biases; however, their role in clinical decision making has been difficult to assess partly because they are difficult to investigate experimentally. A significant drawback has been that experimental manipulations appear to confound the assessment of the context surrounding the diagnostic process itself. We conducted an exercise on selected actual cases of diagnostic errors to explore the effect of biases in the 'real world' emergency medicine (EM) context. Thirty anonymized EM cases were analysed in depth through a process of root cause analysis that included an assessment of error-producing conditions (EPCs), knowledge-based errors, and how clinicians were thinking and deciding during each case. A prominent feature of the exercise was the identification of the occurrence of and interaction between specific cognitive and affective biases, through a process called cognitive autopsy. The cases covered a broad range of diagnoses across a wide variety of disciplines. A total of 24 discrete cognitive and affective biases that contributed to misdiagnosis were identified and their incidence recorded. Five to six biases were detected per case, and observed on 168 occasions across the 30 cases. Thirteen EPCs were identified. Knowledge-based errors were rare, occurring in only five definite instances. The ordinal position in which biases appeared in the diagnostic process was recorded. This experiment provides a baseline for investigating and understanding the critical role that biases play in clinical decision making as well as providing a credible explanation for why diagnoses fail.


Predictors of falls among elderly people. Results of two population-based studies.
A study was performed to identify and rank risk factors for falling among populations of institutionalized (fallers, N = 79, nonfallers, N = 70) and noninstitutionalized (fallers, N = 34, nonfallers, N = 34) elderly persons. Fallers were matched by age, sex, and living location to nonfaller control subjects. A nurse practitioner performed a comprehensive physical assessment in all subjects using a standardized protocol and physician consultation. Fallers in both populations were significantly more physically and functionally impaired than control subjects. Logistic regression identified hip weakness, poor balance, and number of prescribed medications as factors most strongly associated with falling among institutionalized subjects. A fall prediction model was developed from these findings yielding 76% overall predictive accuracy (89% sensitivity, 60% specificity). Using the model, the predicted 1-year risk of falling ranged from 12% for persons with none of the three risk factors to 100% for persons with all three risk factors. Findings among noninstitutionalized subjects were similar. These data support the concept of performing focused fall risk assessments to identify elderly patients at high risk for falling.


Adolescents with prenatal cocaine exposure show subtle alterations in striatal surface morphology and frontal cortical volumes.
Published structural neuroimaging studies of prenatal cocaine exposure (PCE) in humans have yielded somewhat inconsistent results, with several studies reporting no significant differences in brain structure between exposed subjects and controls. Here, we sought to clarify some of these discrepancies by applying methodologies that allow for the detection of subtle alterations in brain structure. We applied surface-based anatomical modeling methods to magnetic resonance imaging (MRI) data to examine regional changes in the shape and volume of the caudate and putamen in adolescents with prenatal cocaine exposure (n = 40, including 28 exposed participants and 12 unexposed controls, age range 14 to 16 years). We also sought to determine whether changes in regional brain volumes in frontal and subcortical regions occurred in adolescents with PCE compared to control participants. The overall volumes of the caudate and putamen did not significantly differ between PCE participants and controls. However, we found significant (P <0.05, uncorrected) effects of levels of prenatal exposure to cocaine on regional patterns of striatal morphology. Higher levels of prenatal cocaine exposure were associated with expansion of certain striatal subregions and with contraction in others. Volumetric analyses revealed no significant changes in the volume of any subcortical region of interest, but there were subtle group differences in the volumes of some frontal cortical regions, in particular reduced volumes of caudal middle frontal cortices and left lateral orbitofrontal cortex in exposed participants compared to controls. Prenatal cocaine exposure may lead to subtle and regionally specific patterns of regional dysmorphology in the striatum and volumetric changes in the frontal lobes. The localized and bidirectional nature of effects may explain in part the contradictions in the existing literature.


Maitake Pro4X has anti-cancer activity and prevents oncogenesis in BALBc mice.
The understanding of the molecular mechanisms of the immune tolerance induced by the tumoral microenvironment is fundamental to prevent cancer development or to treat cancer patients using immunotherapy. Actually, there are investigations about "addressed-drugs" against cancer cells without affecting normal cells. It could be ideal to find selective and specific compounds that only recognize and destroy tumor cells without damaging the host normal cells. For thousands of years, mushrooms have been used for medicinal purposes because of their curative properties. D-Fraction, an extract of Maitake (from the edible Grifola frondosa mushroom), rich in β-glucans, exert notable effects in the immune system. Until now, some published articles suggest that Maitake D-Fraction could have anti-tumoral activity, prevent oncogenesis and metastasis in some tumor types. However, there are no clear data about Maitake D-Fraction action on breast cancer prevention and its exact molecular mechanisms are not yet elucidated. The experiments were performed employing 25 female BALBc mice that were treated with and without Maitake D-Fraction Pro4X or Maitake Standard for 15 days by daily intraperitoneal injection. After treatment period, all mice were implanted with murine tumor cells LM3 to induce mammary tumorigenesis. Animals were checked weekly and killed after 46 days of LM3 transplant; percentage of cancer prevention, rate of tumor growing, and overall survival were determined. Under dissection, the internal organs were evaluated histologically and genetically by RT-PCR. We found that 5 mg/kg per day of Maitake D-Fraction Pro4X, administered dairy during 15 days to BALBc mice was able to block more than 60% breast cancer development. However, Maitake Standard prevents oncogenesis in 26% to respect control. In this work, we found that Maitake D-Fraction Pro4X, administered to BALBc mice, prevents breast carcinogenesis, block tumor invasiveness, reduce angiogenesis, and increase overall survival.


Use of focus groups in multi-site, multi-ethnic research projects for women's health: a Study of Women Across the Nation (swan) example.
To outline the lessons learned about the use of focus groups for the multisite, multi-ethnic longitudinal Study of Women Across the Nation (SWAN). Focus groups were designed to identify potential cultural differences in the incidence of symptoms and the meaning of transmenopause among women of diverse cultures, and to identify effective recruitment and retention strategies. Inductive and deductive focus groups for a multi-ethnic study. Seven community research sites across the United States conducted focus groups with six ethnic populations: African American, Chinese American, Japanese American, Mexican American, non-Hispanic white, and Puerto Rican. Community women from each ethnic group of color. A set of four/five focus groups in each ethnic group as the formative stage of the deductive, quantitative SWAN survey. Identification of methodological advantages and challenges to the successful implementation of formative focus groups in a multi-ethnic, multi-site population-based epidemiologic study. We provide recommendations from our lessons learned to improve the use of focus groups in future studies with multi-ethnic populations. Mixed methods using inductive and deductive approaches require the scientific integrity of both research paradigms. Adequate resources and time must be budgeted as essential parts of the overall strategy from the outset of study. Inductive cross-cultural researchers should be key team members, beginning with inception through each subsequent design phase to increase the scientific validity, generalizability, and comparability of the results across diverse ethnic groups, to assure the relevance, validity and applicability of the findings to the multicultural population of focus.


Clinical photography in wound management.
The IMI National Guidelines have been prepared as baseline guides on specific aspects of medical illustration practice, and provide auditable standards for the future. They can be implemented in full, or may be amended according to individual requirements. The following is an abridged version of guidelines prepared by Carol Fleming. The full version, including references and appendices, can be downloaded at www.imi.org.uk.


Anatomical network analysis shows decoupling of modular lability and complexity in the evolution of the primate skull.
Modularity and complexity go hand in hand in the evolution of the skull of primates. Because analyses of these two parameters often use different approaches, we do not know yet how modularity evolves within, or as a consequence of, an also-evolving complex organization. Here we use a novel network theory-based approach (Anatomical Network Analysis) to assess how the organization of skull bones constrains the co-evolution of modularity and complexity among primates. We used the pattern of bone contacts modeled as networks to identify connectivity modules and quantify morphological complexity. We analyzed whether modularity and complexity evolved coordinately in the skull of primates. Specifically, we tested Herbert Simon's general theory of near-decomposability, which states that modularity promotes the evolution of complexity. We found that the skulls of extant primates divide into one conserved cranial module and up to three labile facial modules, whose composition varies among primates. Despite changes in modularity, statistical analyses reject a positive feedback between modularity and complexity. Our results suggest a decoupling of complexity and modularity that translates to varying levels of constraint on the morphological evolvability of the primate skull. This study has methodological and conceptual implications for grasping the constraints that underlie the developmental and functional integration of the skull of humans and other primates.


The association between health literacy and cancer-related attitudes, behaviors, and knowledge.
Using a multidimensional assessment of health literacy (the Cancer Message Literacy Test-Listening, the Cancer Message Literacy Test-Reading, and the Lipkus Numeracy Scale), the authors assessed a stratified random sample of 1013 insured adults (40-70 years of age). The authors explored whether low health literacy across all 3 domains (n =111) was associated with sets of variables likely to affect engagement in cancer prevention and screening activities: (a) attitudes and behaviors relating to health care encounters and providers, (b) attitudes toward cancer and health, (c) knowledge of cancer screening tests, and (d) attitudes toward health related media and actual media use. Adults with low health literacy were more likely to report avoiding doctor's visits, to have more fatalistic attitudes toward cancer, to be less accurate in identifying the purpose of cancer screening tests, and more likely to avoid information about diseases they did not have. Compared with other participants, those with lower health literacy were more likely to say that they would seek information about cancer prevention or screening from a health care professional and less likely to turn to the Internet first for such information. Those with lower health literacy reported reading on fewer days and using the computer on fewer days than did other participants. The authors assessed the association of low health literacy with colorectal cancer screening in an age-appropriate subgroup for which colorectal cancer screening is recommended. In these insured subjects receiving care in integrated health care delivery systems, those with low health literacy were less likely to be up to date on screening for colorectal cancer, but the difference was not statistically significant.


Culturally-tailored smoking cessation for American Indians: study protocol for a randomized controlled trial.
Cigarette smoking is the number one cause of preventable death among American Indian and Alaska Natives, AI/ANs. Two out of every five AI/AN will die from tobacco-related diseases if the current smoking rates of AI/ANs (40.8%) persist. Currently, there is no proven, effective culturally-tailored smoking cessation program designed specifically for a heterogeneous population of AI.The primary aim of this group randomized clinical trial is to test the efficacy of "All Nations Breath of Life" (ANBL) program compared to a non-tailored "Current Best Practices" smoking cessation program among AI smokers. We will randomize 56 groups (8 smokers per group) to the tailored program or non-tailored program for a total sample size of 448 American Indian smokers. All participants in the proposed study will be offered pharmacotherapy, regardless of group assignment. This study is the first controlled trial to examine the efficacy of a culturally-tailored smoking cessation program for American Indians. If the intervention is successful, the potential health impact is significant because the prevalence of smoking is the highest in this population. ClinicalTrials.gov: NCT01106456.


Pubertal stage and deliberate self-harm in adolescents.
To ascertain the association between pubertal stage and deliberate self-harm. Cross-sectional survey of 12- to 15-year-olds in 300 secondary schools in the U.S. state of Washington in February-April 2002 and the Australian state of Victoria in June-August 2002. A total of 3,332 students in grades 7 and 9 provided complete data on episodes of deliberate self-harm in the previous 12 months and pubertal stage. Pubertal stage was assessed with the Pubertal Development Scale. The prevalence of deliberate self-harm was 3.7% with a more than twofold higher rate in females. Late puberty was associated with a more than fourfold higher rate of self-harm (odds ratio 4.6, 95% confidence interval 1.5-14) after adjustment for age and school grade level. In contrast age had a protective association (odds ratio 0.7, confidence interval 0.4-1.0). The sharpest rises in prevalence across puberty were for self-laceration and self-poisoning in females. Higher rates of depressive symptoms, frequent alcohol use, and initiation of sexual activity largely accounted for the association between self-harm and pubertal stage in multivariate models. Puberty is associated with changes in the form and frequency of self-harm. For adolescents with a gap between puberty and brain development, risk factors such as early sexual activity and substance abuse may be particularly potent.


MRI structural connectivity, disruption of primary sensorimotor pathways, and hand function in cerebral palsy.
Brain injury and subsequent plasticity of sensory and corticospinal pathways play an integral role in determining paretic hand function in congenital hemiplegia. There is limited knowledge regarding the relationship between the disruption of sensorimotor thalamic pathways projecting into the primary motor cortex and motor control. This study sought to investigate the relationship between the structural connectivity of motor networks that anatomically link the brain stem with the precentral and postcentral gyri with paretic motor sensory function by using an automated analysis strategy. Magnetic resonance imaging structural connectivity was measured by using high-angular-resolution diffusion imaging, probabilistic tractography, and the anatomic parcellation of high-resolution structural images in 16 children with congenital unilateral periventricular white-matter damage. Connectivity of the corticospinal and corticothalamic pathways was determined by using an asymmetry index based on the number of streamlines contained within these projections and compared with measures of paretic hand function and bimanual coordination. For cortical development, the volume of the ipsilesional precentral gyrus was significantly reduced. For connectivity measures, the numbers of streamlines in corticospinal tracts and corticothalamic pathways within the ipsilesional hemisphere were decreased compared with the contralesional side. The sensorimotor thalamic projections were more significantly correlated with paretic hand functions than were the corticospinal tracts. These data support the concept that preservation of sensorimotor thalamic pathways that directly project into the primary motor cortex has more influence on motor function control of the paretic hand than does preservation of corticospinal tracts.


Intrinsic and extrinsic factors in protein antigenic structure.
Recent advances in the preparation of synthetic peptide vaccines and the use of synthetic peptides as probes of antigenic structure and function have led to renewed interest in the prediction of antigenic sites recognized by antibodies and T cells. This review focuses on antibodies. Features intrinsic to the antigen, such as hydrophilicity and mobility, may be useful in the selection of amino acid sequences of the native protein that will elicit antibodies cross-reacting with peptides, or sequences which, as peptides, will be more likely to elicit antibodies cross-reactive with the native protein. Structural mobility may also contribute to protein-protein interactions in general. However, the entire accessible surface of a protein is likely to be detectable by a large enough panel of antibodies. Which of these antibodies are made in any individual depends on factors extrinsic to the antigen molecule, host factors such as self-tolerance, immune response genes, idiotype networks, and the immunoglobulin structural gene repertoire.


Role of Bacteriological Agents in Idiopathic Granulomatous Mastitis: Real or Not?
Granulomatous mastitis is a rare, benign, chronic inflammatory disease of the breast of unknown etiology. This study evaluated bacteriologic agents that might play a role in the etiology of granulomatous mastitis using a molecular method with a universal primer after isolating deoxyribonucleic acid (DNA) from pathology specimens from patients diagnosed with granulomatous mastitis. Breast biopsy material in the pathology department obtained between July 2008 and June 2013 was analyzed. The history of the granulomatous mastitis patients was examined in detail and paraffin block sections of the biopsy material were used to determine the presence of bacteria with a universal DNA primer. This study examined 45 granulomatous mastitis patients who had been diagnosed using excisional, incisional, or core biopsies. We evaluated multiple bacterial taxa, but obtained no positive result using a nucleic-acid-based assay with a universal primer. The etiology of idiopathic granulomatous mastitis remains unclear. Further studies with a large number of patients should aim to identify the causative agent.


Non-word repetition assesses phonological memory and is related to vocabulary development in 20- to 24-month-olds.
Two studies test the hypotheses that individual differences in phonological memory among children younger than two years can be assessed using a non-word repetition task (NWR) and that these differences are related to the children's rates of vocabulary development. NWR accuracy, real word repetition accuracy and productive vocabulary were assessed in 15 children between 1 ; 9 and 2 ; 0 in Study 1 and in 21 children between 1 ; 8 and 2 ; 0 in Study 2. In both studies, NWR accuracy was significantly related to vocabulary percentile and, furthermore, uniquely accounted for a substantial portion of the variance in vocabulary when real word repetition accuracy was held constant. The findings establish NWR as a valid measure of phonological memory in very young children, and they open the door for further studies of the role of phonological memory in early word learning.


Genome-wide search for breast cancer linkage in large Icelandic non-BRCA1/2 families.
A significant proportion of high-risk breast cancer families are not explained by mutations in known genes. Recent genome-wide searches (GWS) have not revealed any single major locus reminiscent of BRCA1 and BRCA2, indicating that still unidentified genes may explain relatively few families each or interact in a way obscure to linkage analyses. This has drawn attention to possible benefits of studying populations where genetic heterogeneity might be reduced. We thus performed a GWS for linkage on nine Icelandic multiple-case non-BRCA1/2 families of desirable size for mapping highly penetrant loci. To follow up suggestive loci, an additional 13 families from other Nordic countries were genotyped for selected markers. GWS was performed using 811 microsatellite markers providing about five centiMorgan (cM) resolution. Multipoint logarithm of odds (LOD) scores were calculated using parametric and nonparametric methods. For selected markers and cases, tumour tissue was compared to normal tissue to look for allelic loss indicative of a tumour suppressor gene. The three highest signals were located at chromosomes 6q, 2p and 14q. One family contributed suggestive LOD scores (LOD 2.63 to 3.03, dominant model) at all these regions, without consistent evidence of a tumour suppressor gene. Haplotypes in nine affected family members mapped the loci to 2p23.2 to p21, 6q14.2 to q23.2 and 14q21.3 to q24.3. No evidence of a highly penetrant locus was found among the remaining families. The heterogeneity LOD (HLOD) at the 6q, 2p and 14q loci in all families was 3.27, 1.66 and 1.24, respectively. The subset of 13 Nordic families showed supportive HLODs at chromosome 6q (ranging from 0.34 to 1.37 by country subset). The 2p and 14q loci overlap with regions indicated by large families in previous GWS studies of breast cancer. Chromosomes 2p, 6q and 14q are candidate sites for genes contributing together to high breast cancer risk. A polygenic model is supported, suggesting the joint effect of genes in contributing to breast cancer risk to be rather common in non-BRCA1/2 families. For genetic counselling it would seem important to resolve the mode of genetic interaction.


Plain-radiographic image labeling: a process to improve clinical outcomes.
To determine the rate of film-labeling errors and to describe a process for improved plain-film image labeling and the clinical outcomes from this process improvement. Image-labeling errors (absent or incorrectly assigned left or right lateral identifier marker, absent or incorrect patient-identifying number, absent or incorrect examination date, incorrect marker placement, absent technologist initial marker, or incorrect body-part order) were measured among 2,536 consecutive plain-film radiographs over a 2-week period. Following a process improvement initiative based on failure mode effectiveness analysis, left-side and right-side indicator markers, patient demographics, and date labels were identified as the most common sources of error. An improvement initiative using larger and colored left and right lateral indicator markers, an automated process to label patient demographics, and direct patient verification of identification was begun. The numbers of labeling errors were again assessed in 2,421 consecutive plain radiographs over a 2-week period. The error rates before and after the improvement initiatives were compared. Plain-radiographic labeling errors occurred in 62 of 2,536 (2.4%) images before the improvement initiative. Labeling errors were reduced to 17 of 2,421 (0.70%; 95% exact binomial confidence interval, 0.4% to 1.1%; P < .001, chi-square test) by using the improvement tools. Plain radiographic image labeling can be improved using bar-code reading of patient demographic information, linked to patient Digital Imaging and Communications in Medicine modality work lists and image printing. Patient verification of demographic information is key and can be electronically managed. Lateral marker identification can be improved with larger (more easily read) and color-coded indicators.


Psoriatic arthritis.
Psoriatic arthritis (PsA) is a complex inflammatory disease with heterogeneous clinical features, which complicates psoriasis in 30% of patients. There are no diagnostic criteria or tests available. Diagnosis is most commonly made by identifying inflammatory musculoskeletal features in joints, entheses or the spine in the presence of skin and/or nail psoriasis and in the usual absence of rheumatoid factor and anti-cyclic citrullinated peptide. The evolution of psoriasis to PsA may occur in stages, although the mechanisms are unclear. In many patients, there may be little or no relationship between severity of musculoskeletal inflammation and severity of skin or nail psoriasis. The reason for this disease heterogeneity may be explained by differences in genotype, especially in the HLA region. New targeted therapies for PsA have been approved with additional therapies in development. These developments have substantially improved both short-term and long-term outcomes including a reduction in musculoskeletal and skin manifestations and in radiographic damage. With efforts underway aimed at improving our understanding of the molecular basis for the heterogeneity of PsA, a personalized approach to treating PsA may become possible.


Blood fuel metabolites in asthma during and after progressive submaximal exercise.
Ten male stable asthmatic subjects and 10 matched control subjects performed a progressive exercise test on a treadmill to 85% of their predicted maximum heart rate. Blood lactate, pyruvate, hydrogen ion, glucose, alanine, glycerol and total ketone body concentrations were measured at frequent intervals during and up to 60 min after exercise. Carbon dioxide production, oxygen consumption, ventilation, respiratory exchange ratio and oxygen saturation were also measured during and up to 10 min after exercise. There were no significant differences between the asthmatic and control subjects in levels of carbon dioxide production, oxygen consumption and ventilation. The respiratory exchange ratio was greater in the asthmatic subjects during recovery from exercise (P less than 0.05). No changes in oxygen saturation were observed during exercise in either group. In both asthmatic and control subjects, lactate, pyruvate, hydrogen ion, alanine and glycerol concentrations showed an increase from baseline levels, reaching maximum levels up to 10 min after exercise and returning to baseline within 1 h after exercise. Total ketone body concentrations decreased during exercise. There were no significant differences between the asthmatic and control subjects in the concentration of any metabolite over the study period. These data indicate that fuel metabolism during and after short-term progressive exercise is similar in stable asthmatic and normal subjects.


Novel inhibitors of bacterial cytokinesis identified by a cell-based antibiotic screening assay.
The continuous emergence of antibiotic resistance demands that novel classes of antibiotics continue to be developed. The division machinery of bacteria is an attractive target because it comprises seven or more essential proteins that are conserved almost throughout the bacteria but are absent from humans. We describe the development of a cell-based assay for inhibitors of cell division and its use to isolate a new inhibitor of FtsZ protein, a key player in the division machinery. Biochemical, cytological, and genetic data are presented that demonstrate that FtsZ is the specific target for the compound. We also describe the effects of more potent analogues of the original hit compound that act on important pathogens, again at the level of cell division. The assay and the compounds have the potential to provide novel antibiotics with no pool of pre-existing resistance. They have provided new insight into cytokinesis in bacteria and offer important reagents for further studies of the cell division machinery.


Changes in northeast African hydrology and vegetation associated with Pliocene-Pleistocene sapropel cycles.
East African climate change since the Late Miocene consisted of persistent shorter-term, orbital-scale wet-dry cycles superimposed upon a long-term trend towards more open, grassy landscapes. Either or both of these modes of palaeoclimate variability may have influenced East African mammalian evolution, yet the interrelationship between these secular and orbital palaeoclimate signals remains poorly understood. Here, we explore whether the long-term secular climate change was also accompanied by significant changes at the orbital-scale. We develop northeast African hydroclimate and vegetation proxy data for two 100 kyr-duration windows near 3.05 and 1.75 Ma at ODP Site 967 in the eastern Mediterranean basin, where sedimentation is dominated by eastern Sahara dust input and Nile River run-off. These two windows were selected because they have comparable orbital configurations and bracket an important increase in East African C4 grasslands. We conducted high-resolution (2.5 kyr sampling) multiproxy biomarker, H- and C-isotopic analyses of plant waxes and lignin phenols to document orbital-scale changes in hydrology, vegetation and woody cover for these two intervals. Both intervals are dominated by large-amplitude, precession-scale (approx. 20 kyr) changes in northeast African vegetation and rainfall/run-off. The δ(13)Cwax values and lignin phenol composition record a variable but consistently C4 grass-dominated ecosystem for both intervals (50-80% C4). Precessional δDwax cycles were approximately 20-30‰ in peak-to-peak amplitude, comparable with other δDwax records of the Early Holocene African Humid Period. There were no significant differences in the means or variances of the δDwax or δ(13)Cwax data for the 3.05 and 1.75 Ma intervals studied, suggesting that the palaeohydrology and palaeovegetation responses to precessional forcing were similar for these two periods. Data for these two windows suggest that the eastern Sahara did not experience the significant increase in C4 vegetation that has been observed in East Africa over this time period. This observation would be consistent with a proposed mechanism whereby East African precipitation is reduced, and drier conditions established, in response to the emergence of modern zonal sea surface temperature gradients in the tropical oceans between 3 and 2 Ma.This article is part of the themed issue 'Major transitions in human evolution'.


The T-win® technology: immune-modulating vaccines.
The T-win® technology is an innovative investigational approach designed to activate the body's endogenous anti-regulatory T cells (anti-Tregs) to target regulatory as well as malignant cells. Anti-Tregs are naturally occurring T cells that can directly react against regulatory immune cells because they recognize proteins that these targets express, including indoleamine 2,3-dioxygenase (IDO), tryptophan 2,6-dioxygenase, arginase, and programmed death ligand 1 (PD-L1). The T-win® technology is characterized by therapeutic vaccination with long peptide epitopes derived from these antigens and therefore offers a novel way to target genetically stable cells with regular human leukocyte antigen expression in the tumor microenvironment. The T-win® technology thus also represents a novel way to attract pro-inflammatory cells to the tumor microenvironment where they can directly affect immune inhibitory pathways, potentially altering tolerance to tumor antigens. The modification of an immune regulatory environment into a pro-inflammatory milieu potentiates effective anti-tumor T cell responses. Many regulatory immune cells may be reverted into effector cells given the right stimulus. Because T-win® technology is based on the immune-modulatory function of the vaccines, the vaccines activate both CD4 and CD8 anti-Tregs. Of importance, in clinical trials, vaccinations against IDO or PD-L1 to potentiate anti-Tregs have so far proved to be safe, with minimal toxicity.


Ring chromosome 20 and nonconvulsive status epilepticus. A new epileptic syndrome.
Six cases of epilepsy associated with ring chromosome 20 are presented. The study of these cases and 20 cases reported in the literature revealed that they constitute a distinct epileptic syndrome: frequent seizures consisting of a prolonged confusional state, with or without additional motor seizures, and an ictal EEG pattern of long-lasting bilateral paroxysmal high-voltage slow waves with occasional spikes. Neurological examination results were normal, and neuroimaging studies often failed to disclose a brain lesion. The seizures were resistant to antiepileptic drug therapy. Comparison of the electroclinical features of nonconvulsive status epilepticus in six patients with and four patients without ring chromosome 20 revealed that the group with the chromosomal anomaly had more frequent, comparatively brief episodes of confusion associated with a less prominent spike component on the EEG. We propose that epilepsy associated with ring chromosome 20 constitutes a new syndrome that may provide an opportunity to scrutinize a genetic mechanism of epilepsy.


The risk of cesarean delivery after labor induction among women with prior pregnancy complications: a subgroup analysis of the AFFIRM study.
To determine the risk of cesarean delivery after labor induction among patients with prior placenta-mediated pregnancy complications (pre-eclampsia, late pregnancy loss, placental abruption or intrauterine growth restriction). The AFFIRM database includes patient level data from 9 randomized controlled trials that evaluated the role of LMWH versus no LMWH during pregnancy to prevent recurrent placenta-mediated pregnancy complications. The primary outcome of this sub-study was the proportion of women who had an unplanned cesarean delivery after induction of labor compared to after spontaneous labor. There were 512 patients from 7 randomized trials included in our sub-study. There was no difference in the risk of cesarean delivery between women with labor induction (21/148, 14.2%) and spontaneous labor (79/364, 21.7%) (odds ratio (OR) 0.60, 95% CI, 0.35-1.01; p = 0.052). Among 274 women who used LMWH prophylaxis during pregnancy, the risk of cesarean delivery was lower among those that underwent labor induction (9.8%) compared to spontaneous labor (22.4%) (OR 0.38, 95% CI, 0.17-0.84; p = 0.01). The risk of cesarean delivery is not increased after labor induction among a higher risk patient population with prior pregnancy complications. Our results suggest that women who receive LMWH during pregnancy might benefit from labor induction.


Rapid distributed fronto-parieto-occipital processing stages during working memory in humans.
Cortical potentials were recorded from implanted electrodes during a difficult working memory task requiring rapid storage, modification and retrieval of multiple memoranda. Synchronous event-related potentials were generated in distributed occipital, parietal, Rolandic and prefrontal sites beginning approximately 130 ms after stimulus onset and continuing for >500 ms. Coherent phase-locked, event-related oscillations supported interaction between these dorsal stream structures throughout the task period. The Rolandic structures generated early as well as sustained potentials to sensory stimuli in the absence of movement. Activation peaks and phase lags between synaptic populations suggested that perceptual processing occurred exclusively in the visual association cortex from approximately 90 to 130 ms, with its results projected to fronto-parietal areas for interpretation from approximately 130 to 280 ms. The direction of interaction then appeared to reverse from approximately 300 to 400 ms, consistent with mental arithmetic being performed by fronto-parietal areas operating upon a visual scratch pad in the dorsolateral occipital cortex. A second reversal, from approximately 420 to 600 ms, may have represented an updating of memoranda stored in fronto-parietal sites. Lateralized perisylvian oscillations suggested an articulatory loop. Anterior cingulate activity was evoked by feedback signals indicating errors. These results indicate how a fronto-centro-parietal 'central executive' might interact with an occipital visual scratch pad, perisylvian articulatory loop and limbic monitor to implement the sequential stages of a complex mental operation.


Sub-Atomic Resolution Crystal Structures Reveal Conserved Geometric Outliers at Functional Sites.
Myelin protein 2 (P2) is a peripheral membrane protein of the vertebrate nervous system myelin sheath, having possible roles in both lipid transport and 3D molecular organization of the multilayered myelin membrane. We extended our earlier crystallographic studies on human P2 and refined its crystal structure at an ultrahigh resolution of 0.72 Å in perdeuterated form and 0.86 Å in hydrogenated form. Characteristic differences in C-H…O hydrogen bond patterns were observed between extended β strands, kinked or ending strands, and helices. Often, side-chain C-H groups engage in hydrogen bonding with backbone carbonyl moieties. The data highlight several amino acid residues with unconventional conformations, including both bent aromatic rings and twisted guanidinium groups on arginine side chains, as well as non-planar peptide bonds. In two locations, such non-ideal conformations cluster, providing proof of local functional strain. Other ultrahigh-resolution protein structures similarly contain chemical groups, which break planarity rules. For example, in Src homology 3 (SH3) domains, a conserved bent aromatic residue is observed near the ligand binding site. Fatty acid binding protein (FABP) 3, belonging to the same family as P2, has several side chains and peptide bonds bent exactly as those in P2. We provide a high-resolution snapshot on non-ideal conformations of amino acid residues under local strain, possibly relevant to biological function. Geometric outliers observed in ultrahigh-resolution protein structures are real and likely relevant for ligand binding and conformational changes. Furthermore, the deuteration of protein and/or solvent are promising variables in protein crystal optimization.


Insulin receptor and cancer.
The widespread epidemic of obesity and type 2 diabetes has raised concern for the impact of these disorders as risk factors for cancer and has renewed the interest for studies regarding the involvement of hyperinsulinemia and insulin receptor (IR) in cancer progression. Overexpression of IR in cancer cells may explain their increased sensitivity to hyperinsulinemia. Moreover, IR isoform A (IR-A) together with autocrine production of its ligand IGF2 is emerging as an important mechanism of normal and cancer stem cell expansion and is a feature of several malignancies. De novo activation of the IR-A/IGF2 autocrine loop also represents a mechanism of resistance to anticancer therapies. Increasing knowledge of the IR role in cancer has important implications for cancer prevention, which should include control of insulin resistance and hyperinsulinemia in the population and meticulous evaluation of new antidiabetic drugs for their metabolic:mitogenic ratio. We are now aware that several anticancer treatments may induce or worsen insulin resistance that may limit therapy efficacy. Future anticancer therapies need to target the IR-A pathway in order to inhibit the tumor promoting effect of IR without impairing the metabolic effect of insulin.


Eight Cycles of ABVD Versus Four Cycles of BEACOPPescalated Plus Four Cycles of BEACOPPbaseline in Stage III to IV, International Prognostic Score ≥ 3, High-Risk Hodgkin Lymphoma: First Results of the Phase III EORTC 20012 Intergroup Trial.
To compare patients with high-risk stage III to IV Hodgkin lymphoma (HL) in the phase III European Organisation for Research and Treatment of Cancer 20012 Intergroup trial (Comparison of Two Combination Chemotherapy Regimens in Treating Patients With Stage III or Stage IV Hodgkin's Lymphoma) who were randomly assigned to either doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or to bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP). Patients with clinical stage III or IV HL, International Prognostic Score of 3 or higher, and age 60 years or younger received ABVD for eight cycles (ABVD8) or escalated-dose BEACOPP (BEACOPPescalated) for four cycles followed by baseline BEACOPP (BEACOPPbaseline) for four cycles (BEACOPP4+4) without radiotherapy. Primary end points were event-free survival (EFS), treatment discontinuation, no complete response (CR) or unconfirmed complete response (CRu) after eight cycles, progression, relapse, or death. Secondary end points were CR rate, overall survival (OS), quality of life, secondary malignancies, and disease-free survival in CR/CRu patients. Between 2002 and 2010, 549 patients were randomly assigned to ABVD8 (n = 275) or BEACOPP4+4 (n = 274). Other characteristics included median age, 35 years; male, 75%; stage IV, 74%; "B" symptoms, 81%; and International Prognostic Score ≥ 4, 59%. WHO performance status was 0 (34%), 1 (48%), or 2 (17%). Median follow-up was 3.6 years. CR/CRu was 82.5% in both arms. At 4 years, EFS was 63.7% for ABVD8 versus 69.3% for BEACOPP4+4 (hazard ratio [HR], 0.86; 95% CI, 0.64 to 1.15; P = .312); disease-free survival was 85.8% versus 91.0% (HR, 0.59; 95% CI, 0.33 to 1.06; P = .076), and OS was 86.7% versus 90.3% (HR, 0.71; 95% CI, 0.42 to 1.21; P = .208). Death as a result of toxicity occurred in six and five patients, early discontinuation (before cycle 5) in 12 and 26 patients, treatment crossovers in five and 10 patients, and secondary malignancies in eight and 10 patients in the ABVD8 and BEACOPP4+4 arms, respectively. ABVD8 and BEACOPP4+4 resulted in similar EFS and OS in patients with high-risk advanced-stage HL. Because BEACOPP4+4 did not demonstrate a favorable effectiveness or toxicity ratio compared with ABVD8, treatment burden, immediate and late toxicities, and associated costs must be considered before selecting one of these regimens on which to build future treatment strategies.


Modelling Cyclic Behaviour of Martensitic Steel with J2 Plasticity and Crystal Plasticity.
In order to capture the stress-strain response of metallic materials under cyclic loading, it is necessary to consider the cyclic hardening behaviour in the constitutive model. Among different cyclic hardening approaches available in the literature, the Chaboche model proves to be very efficient and convenient to model the kinematic hardening and ratcheting behaviour of materials observed during cyclic loading. The purpose of this study is to determine the material parameters of the Chaboche kinematic hardening material model by using isotropic J2 plasticity and micromechanical crystal plasticity (CP) models as constitutive rules in finite element modelling. As model material, we chose a martensitic steel with a very fine microstructure. Thus, it is possible to compare the quality of description between the simpler J2 plasticity and more complex micromechanical material models. The quality of the results is rated based on the quantitative comparison between experimental and numerical stress-strain hysteresis curves for a rather wide range of loading amplitudes. It is seen that the ratcheting effect is captured well by both approaches. Furthermore, the results show that concerning macroscopic properties, J2 plasticity and CP are equally suited to describe cyclic plasticity. However, J2 plasticity is computationally less expensive whereas CP finite element analysis provides insight into local stresses and plastic strains on the microstructural length scale. With this study, we show that a consistent material description on the microstructural and the macroscopic scale is possible, which will enable future scale-bridging applications, by combining both constitutive rules within one single finite element model.


The association−dissociation behavior of the ApoE proteins: kinetic and equilibrium studies.
The apolipoprotein E family consists of three major protein isoforms: apolipoprotein E4 (ApoE4), ApoE3, and ApoE2. The isoforms, which contain 299 residues, differ only by single-amino acid changes, but of the three, only ApoE4 is a risk factor for Alzheimer's disease. At micromolar concentrations, lipid-free ApoE exists predominantly as tetramers. In more dilute solutions, lower-molecular mass species predominate. Using fluorescence correlation spectroscopy (FCS), intermolecular fluorescence resonance energy transfer (FRET), and sedimentation methods, we found that the association−dissociation reaction of ApoE can be modeled with a monomer−dimer−tetramer process. Equilibrium constants have been determined from the sedimentation data, while the individual rate constants for association and dissociation were determined by measurement of the kinetics of dissociation of ApoE and are in agreement with the equilibrium constants. Dissociation kinetics as measured by intermolecular FRET show two phases reflecting the dissociation of tetramer to dimer and of dimer to monomer, with dissociation from tetramer to dimer being more rapid than the dissociation from dimer to monomer. The rate constants differ for the different ApoE isoforms, showing that the association−dissociation process is isoform specific. Strikingly, the association rate constants are almost 2 orders of magnitude slower than expected for a diffusion-controlled process. Dissociation kinetics were also monitored by tryptophan fluorescence in the presence of acrylamide and the data found to be consistent with the monomer−dimer−tetramer model. The approach combining multiple methods establishes the reaction scheme of ApoE self-association.


Morphological evidence for early dog domestication in the European Pleistocene: New evidence from a randomization approach to group differences.
The antiquity of the wolf/dog domestication has been recently pushed back in time from the Late Upper Paleolithic (~14,000 years ago) to the Early Upper Paleolithic (EUP; ~36,000 years ago). Some authors questioned this early dog domestication claiming that the putative (EUP) Paleolithic dogs fall within the morphological range of recent wolves. In this study, we reanalyzed a data set of large canid skulls using unbalanced- and balanced-randomized discriminant analyses to assess whether the putative Paleolithic dogs are morphologically unique or whether they represent a subsample of the wolf morpho-population. We evaluated morphological differences between 96 specimens of the 4 a priori reference groups (8 putative Paleolithic dogs, 41 recent northern dogs, 7 Pleistocene wolves, and 40 recent northern wolves) using discriminant analysis based on 5 ln-transformed raw and allometrically size-adjusted cranial measurements. Putative Paleolithic dogs are classified with high accuracies (87.5 and 100.0%, cross-validated) and randomization experiment suggests that these classification rates cannot be exclusively explained by the small and uneven sample sizes of reference groups. It indicates that putative Upper Paleolithic dogs may represent a discrete canid group with morphological signs of domestication (a relatively shorter skull and wider palate and braincase) that distinguish them from sympatric Pleistocene wolves. The present results add evidence to the view that these specimens could represent incipient Paleolithic dogs that were involved in daily activities of European Upper Paleolithic forager groups.


Monitoring the serological proteome: the latest modality in prostate cancer detection.
Various strategies have recently emerged to improve the diagnostic prediction of prostate cancer (CaP). One such strategy includes the mass profiling of serum protein fractions selectively adsorbed onto chemically modified probes. In the current study we further validated this approach, while offering a more versatile, less expensive and yet equally predictive alternative to existing technologies. A solid core lipophilic C-18 resin was used to extract and enrich the low molecular weight protein fraction from patient serum for further analysis by mass spectrometry. Mass spectra generated from a 48 patient training set were data mined using multivariate analysis to identify diagnostically significant protein peaks. These peaks were then used to test a blinded study set comprising 168 patients with common statistical algorithms and commercially available software packages. A total of 36 peaks generated from the training set were used to test the combined set of 168 serum samples obtained from 98 healthy individuals and 70 patients with CaP. We report a sensitivity of 94.1% and a specificity of 99.0% with 1 false-positive, 4 false-negative and 5 nondiagnosed cases. Our results further indicate that mass profiling of serological proteins provides a means for the accurate detection of CaP. In addition, our approach was found to be superior to chip based protocols, generating rich, sharp, highly reproducible spectra attainable in a high throughput manner and at minimal cost. This technique is also scaleable for subsequent protein characterization using multidimensional protein identification technologies. Finally, analyses of mass spectra with commercially available statistical applications was found to be highly effective in generating highly discriminatory m/z values for CaP diagnosis.


Nanocapillary Adhesion between Parallel Plates.
Molecular dynamics simulations are used to study capillary adhesion from a nanometer scale liquid bridge between two parallel flat solid surfaces. The capillary force, Fcap, and the meniscus shape of the bridge are computed as the separation between the solid surfaces, h, is varied. Macroscopic theory predicts the meniscus shape and the contribution of liquid/vapor interfacial tension to Fcap quite accurately for separations as small as two or three molecular diameters (1-2 nm). However, the total capillary force differs in sign and magnitude from macroscopic theory for h ≲ 5 nm (8-10 diameters) because of molecular layering that is not included in macroscopic theory. For these small separations, the pressure tensor in the fluid becomes anisotropic. The components in the plane of the surface vary smoothly and are consistent with theory based on the macroscopic surface tension. Capillary adhesion is affected by only the perpendicular component, which has strong oscillations as the molecular layering changes.


Predictive values of serum estradiol, calcium, and 25-hydroxyvitamin D levels for recurrence of benign paroxysmal positional vertigo in postmenopausal women.
This study aims to explore the predictive values of serum estradiol, calcium and 25-hydroxyvitamin D [25(OH)D] levels for benign paroxysmal positional vertigo (BPPV) recurrence in postmenopausal women. A total of 156 postmenopausal women (mean age: 59.5±7.4 years; range, 46 to 75 years) diagnosed with primary BPPV between January 2015 and August 2018 were included. After follow-up for one year, they were divided into non-recurrence (n=126) and recurrence groups (n=30). Fifty healthy females (mean age: 60.3±7.4 years; range, 48 to 75 years) with natural menopause for over one year were enrolled as the control group. Serum estradiol, calcium and 25(OH)D levels were compared, and their correlations in the recurrence group were analyzed by Pearson method. The predictive values of these levels for recurrence were evaluated using the receiver operating characteristic curve. Predisposing factors were determined by univariate and multivariate logistic regression analyses. Serum estradiol, calcium, and 25(OH)D levels of the control group were significantly higher than the non-recurrence and recurrence groups (p<0.05). The levels of recurrence group exceeded those of non-recurrence group (p<0.05). In recurrence group, estradiol level was positively correlated with those of calcium and 25(OH)D (r=0.7501, 0.7871, p<0.001), and calcium level was positively correlated with that of 25(OH)D (r=0.7904, p<0.001). The three levels had diagnostic values for recurrence. The maximum Youden's index of their combination was 0.476, and the corresponding prognostic index was 13.04, suggesting a higher recurrence probability. Number of repositioning, Self-Rating Depression Scale score, levels of estradiol, calcium and 25(OH)D were predisposing factors for recurrence. Serum estradiol, calcium, and 25(OH)D levels are significantly positively correlated in postmenopausal women with BPPV recurrence and their combination can be used to predict recurrence.


Embryo aneuploidy and the role of morphological and genetic screening.
Chromosome abnormalities are common among human oocytes and are usually lethal to any embryos they produce. It therefore seems logical that a reliable technique for distinguishing between normal and aneuploid embryos would be a useful tool for physicians and embryologists, assisting the choice of which embryo(s) to prioritize for uterine transfer. This concept has led to the development of a variety of methods for the detection of chromosome abnormalities in oocytes and embryos, most often referred to as preimplantation genetic screening (PGS). However, several well-controlled studies have been unable to show an advantage of chromosome screening in terms of pregnancy and birth rates. Some investigators have suggested that damage to embryos, sustained during cleavage-stage biopsy, might explain why PGS has not always provided the anticipated benefits. This paper asks whether there is evidence that a non-invasive, morphological analysis could allow chromosomally normal embryos to be accurately identified and reviews data from the most recent publication concerning IVF outcome following PGS.


A retrospective audit of insulin infusion management involving a locally developed dynamic insulin infusion guideline in a tertiary ICU.
The ideal target blood glucose range for intensive care patients on insulin infusions is controversial. Avoidance of hyperglycaemia and hypoglycaemia are well supported goals. An audit of insulin infusion management was conducted following the institution of an insulin infusion guideline in a tertiary adult intensive care unit (ICU). The primary aim was to evaluate this guideline for safety and efficacy. Secondary aims were to compare outcomes such as ICU and hospital mortality, rate of severe hypoglycaemia, length of time within target zones, length of stay in ICU and hospital, ventilator hours and use of renal replacement therapy. Data analysis involved descriptive statistical techniques to allow comparison with other reported outcomes. Thirty-eight (38) patients were included, representing 137 days of insulin infusions and 2537 blood glucose readings. The mean insulin infusion treatment time was 86.4h (sd ± 86.4), median 48 h (IQR 14.4-141.6). The mean insulin dose per day was 97.6 units (sd ± 115.7), with a median of 68.7 (IQR 38.9-108.3). Blood glucose level (BGL) readings were within the desired target (6-9 mmols/L) and/or the buffer zones (4-6 and 9-12 mmols/L), 92.3% of the time. There were no episodes of severe hypoglycaemia (BGL ≤ 2.2 mmols/L). The median length of ICU stay was 5.9 days. Eighty-four (84) % of the cohort received mechanical ventilation and 26% received renal replacement therapy. The mean ventilation and renal replacement duration were days 6.9 and 9.4 days, respectively. The ICU and hospital mortality was 13.2% and 18.4%, respectively. The use of this locally developed insulin infusion guideline for hyperglycaemia within this ICU appears safe and effective. When compared to related published randomised controlled trials, the outcomes of this small scale single centre retrospective audit appear congruent. It achieved a severe hypoglycaemic rate of zero, with BGLs within target and buffer zones greater than 90%. It may be worthwhile for intensive care units to consider evaluating their own locally developed insulin infusion guidelines to ensure safety and efficacy.


Digital multiplexed mRNA analysis of functionally important genes in single human oocytes and correlation of changes in transcript levels with oocyte protein expression.
To investigate functionally important transcripts in single human oocytes with the use of NanoString technology and determine whether observed differences are biologically meaningful. Analysis of human oocytes with the use of NanoString and immunoblotting. University-affiliated reproductive medicine unit. Women undergoing in vitro fertilization. Human oocytes were analyzed with the use of NanoString or immunoblotting. The abundance of transcripts for ten functionally important genes-AURKA, AURKC, BUB1, BUB1B (encoding BubR1), CDK1, CHEK1, FYN, MOS, MAP2K1, and WEE2-and six functionally dispensable genes were analyzed with the use of NanoString. BubR1 protein levels in oocytes from younger and older women were compared with the use of immunoblotting. All ten functional genes but none of the six dispensable genes were detectable with the use of NanoString in single oocytes. There was 3- to 5-fold variation in BUB1, BUB1B, and CDK1 transcript abundance among individual oocytes from a single patient. Transcripts for these three genes-all players within the spindle assembly checkpoint surveillance mechanism for preventing aneuploidy-were reduced in the same oocyte from an older patient. Mean BUB1B transcripts were reduced by 1.5-fold with aging and associated with marked reductions in BubR1 protein levels. The abundance of functionally important transcripts exhibit marked oocyte-to-oocyte heterogeneity to a degree that is sufficient to affect protein expression. Observed variations in transcript abundance are therefore likely to be biologically meaningful, especially if multiple genes within the same pathway are simultaneously affected.


Saccharomyces cerevisiae Rrm3p DNA helicase promotes genome integrity by preventing replication fork stalling: viability of rrm3 cells requires the intra-S-phase checkpoint and fork restart activities.
Rrm3p is a 5'-to-3' DNA helicase that helps replication forks traverse protein-DNA complexes. Its absence leads to increased fork stalling and breakage at over 1,000 specific sites located throughout the Saccharomyces cerevisiae genome. To understand the mechanisms that respond to and repair rrm3-dependent lesions, we carried out a candidate gene deletion analysis to identify genes whose mutation conferred slow growth or lethality on rrm3 cells. Based on synthetic phenotypes, the intra-S-phase checkpoint, the SRS2 inhibitor of recombination, the SGS1/TOP3 replication fork restart pathway, and the MRE11/RAD50/XRS2 (MRX) complex were critical for viability of rrm3 cells. DNA damage checkpoint and homologous recombination genes were important for normal growth of rrm3 cells. However, the MUS81/MMS4 replication fork restart pathway did not affect growth of rrm3 cells. These data suggest a model in which the stalled and broken forks generated in rrm3 cells activate a checkpoint response that provides time for fork repair and restart. Stalled forks are converted by a Rad51p-mediated process to intermediates that are resolved by Sgs1p/Top3p. The rrm3 system provides a unique opportunity to learn the fate of forks whose progress is impaired by natural impediments rather than by exogenous DNA damage.


Genetic diversity and relationships among Streptococcus pyogenes strains expressing serotype M1 protein: recent intercontinental spread of a subclone causing episodes of invasive disease.
Chromosomal diversity and relationships among 126 Streptococcus pyogenes strains expressing M1 protein from 13 countries on five continents were analyzed by multilocus enzyme electrophoresis and restriction fragment profiling by pulsed-field gel electrophoresis. All isolates were studied for the presence of the gene encoding streptococcal pyrogenic exotoxin A by PCR. Strain subsets were also examined by automated DNA sequencing for allelic polymorphism in genes encoding M protein (emm), streptococcal pyrogenic exotoxin A (speA), streptokinase (ska), pyrogenic exotoxin B (interleukin-1 beta convertase) (speB), and C5a peptidase (scp). Seven distinct emm1 alleles that encode M proteins differing at one or more amino acids in the N-terminal variable region were identified. Although substantial levels of genetic diversity exist among M1-expressing organisms, most invasive disease episodes are caused by two subclones marked by distinctive multilocus enzyme electrophoretic profiles and pulsed-field gel electrophoresis restriction fragment length polymorphism (RFLP) types. One of these subclones (ET 1/RFLP pattern 1a) has the speA gene and was recovered worldwide. Identity of speA, emm1, speB, and ska alleles in virtually all isolates of ET 1/RFLP type 1a means that these organisms share a common ancestor and that global dispersion of this M1-expressing subclone has occurred very recently. The occurrence of the same emm and ska alleles in strains that are well differentiated in overall chromosomal character demonstrates that horizontal transfer and recombination play a fundamental role in diversifying natural populations of S. pyogenes.


The Ontogeny of Gap Crossing Behaviour in Bornean Orangutans (Pongo pygmaeus wurmbii).
For orangutans, the largest predominantly arboreal primates, discontinuous canopy presents a particular challenge. The shortest gaps between trees lie between thin peripheral branches, which offer the least stability to large animals. The affordances of the forest canopy experienced by orangutans of different ages however, must vary substantially as adult males are an order of magnitude larger in size than infants during the early stages of locomotor independence. Orangutans have developed a diverse range of locomotor behaviour to cross gaps between trees, which vary in their physical and cognitive demands. The aims of this study were to examine the ontogeny of orangutan gap crossing behaviours and to determine which factors influence the distance orangutans crossed. A non-invasive photographic technique was used to quantify forearm length as a measure of body size. We also recorded locomotor behaviour, support use and the distance crossed between trees. Our results suggest that gap crossing varies with both physical and cognitive development. More complex locomotor behaviours, which utilized compliant trunks and lianas, were used to cross the largest gaps, but these peaked in frequency much earlier than expected, between the ages of 4 and 5 years old, which probably reflects play behaviour to perfect locomotor techniques. Smaller individuals also crossed disproportionately large gaps relative to their size, by using support deformation. Our results suggest that orangutans acquire the full repertoire of gap crossing techniques, including the more cognitively demanding ones, before weaning, but adjust the frequency of the use of these techniques to their increasing body size.


Meaningful and Accurate Disclosure of Conflict of Interest at the ASTRO National Meeting: A Need for Reassessment of Current Policies.
Conflict of interest (COI) disclosure is essential to research integrity. The average reading comprehension in English is 3.8 words per second (wps). This study examines presenters at the American Society for Radiation Oncology (ASTRO) national meeting over a recent 3-year period to determine whether disclosure is presented accurately and in a manner that allows the audience to comprehend the content. We examined videos of presentations as well as slides from 2014 to 2016 from the ASTRO virtual meeting, noting whether a COI slide was presented, the duration the slide was visible, and the number of disclosures. Disclosures were cross-referenced for discrepancies with the publicly reported Centers for Medicare and Medicaid Services Open Payments database. Using a cutoff of 4 wps, we noted how many presentations were presented at speeds of ≤ 4 wps and > 4 wps. The final data set consisted of 401 presentations delivered by 364 presenters. Using a threshold of 4 wps, 34.0% of presenters had COI slides shown too fast for the average audience to comprehend. Moreover, 16.3% of US physicians incorrectly underreported industry funding received. Of these presentations with discrepancies, 32.6% did not have a COI slide, 39.5% failed to disclose any COI, 27.9% partially disclosed COIs, and 11.6% contained multiple discrepancies. The number of wps were correlated with having a discrepancy on multivariable regression ( P = .046; odds ratio, 1.08; 95% CI, 1.01 to 1.19). A substantial minority of presentations at ASTRO lack meaningful disclosure, and a surprising number incorrectly reported COIs. Additional guidance may be needed to promote more meaningful and accurate disclosure of COIs at major national meetings in oncology.


Positive nitrogen balance using isotonic crystalline amino acid solution.
A study of 50 patients was undertaken to determine the effects of an isotonic 5 percent crystalline amino acid solution on nitrogen balance. Patients were divided randomly into two groups: 24 receiving amino acids and 25 receiving dextrose in water. (One patient in the treatment group dropped out after one day of intravenous therapy.) Administration of amino acids postoperatively maintained nitrogen balance, as compared with controls. No untoward metabolic changes or other complications occurred. Amino acid peripherally administered is an alternate source of calories and nitrogen. It is of value in treating short-term under-nutrition.


Renal damage progresses despite improvement of renal function after relief of unilateral ureteral obstruction in adult rats.
Progression of renal damage after relief of unilateral ureteral obstruction (UUO) has been demonstrated, especially in neonatal rats. We evaluated renal function and renal damage after relief of 3-day UUO in five groups of adult rats: group 1, no treatment; group 2, 3-day UUO; groups 3-5, 3-day UUO followed by relief; group 3, 7-day relief; group 4, 14-day relief; and group 5, 28-day relief. Glomerular filtration rate (GFR), renal blood flow (RBF), tissue transforming growth factor-beta (TGF-beta), interstitial fibrosis and fibroblast expression, tubular apoptosis, macrophage infiltration, expression of nitric oxide synthases (NOS), and urinary nitrate/nitrite (NO(2)/NO(3)) were evaluated. RBF and GFR were decreased to <10% of baseline by 3 days of UUO. GFR and RBF in a previously obstructed kidney (POK) returned to baseline by 14 days after relief. Both tissue TGF-beta(1) and interstitial fibrosis were significantly higher in POK of groups 3-5 compared with groups 1 and 2 . In group 5, the numbers of infiltrating macrophages, fibroblasts, and apoptotic tubular cells were higher in POK compared with group 1. Urinary NO(2)/NO(3) was significantly higher than baseline from 3 to 27 days after relief of UUO. Expression of NOS isoforms was increased in tubules. As interstitial fibrosis contributes to decreased renal function, these results suggest that the acute recovery in function may be compromised in the long term by the progressive renal fibrosis which was found. Furthermore, pharmacological intervention at the time of relief of UUO, targeted to fibrotic processes, may contribute to long-term recovery of renal function.


Comparison of toxicity of benzene metabolite hydroquinone in hematopoietic stem cells derived from murine embryonic yolk sac and adult bone marrow.
Benzene is an occupational toxicant and an environmental pollutant that potentially causes hematotoxicity and leukemia in exposed populations. Epidemiological studies suggest an association between an increased incidence of childhood leukemia and benzene exposure during the early stages of pregnancy. However, experimental evidence supporting the association is lacking at the present time. It is believed that benzene and its metabolites target hematopoietic stem cells (HSCs) to cause toxicity and cancer in the hematopoietic system. In the current study, we compared the effects of hydroquinone (HQ), a major metabolite of benzene in humans and animals, on mouse embryonic yolk sac hematopoietic stem cells (YS-HSCs) and adult bone marrow hematopoietic stem cells (BM-HSCs). YS-HSCs and BM-HSCs were isolated and enriched, and were exposed to HQ at increasing concentrations. HQ reduced the proliferation and the differentiation and colony formation, but increased the apoptosis of both YS-HSCs and BM-HSCs. However, the cytotoxic and apoptotic effects of HQ were more apparent and reduction of colony formation by HQ was more severe in YS-HSCs than in BM-HSCs. Differences in gene expression profiles were observed in HQ-treated YS-HSCs and BM-HSCs. Cyp4f18 was induced by HQ both in YS-HSCs and BM-HSCs, whereas DNA-PKcs was induced in BM-HSCs only. The results revealed differential effects of benzene metabolites on embryonic and adult HSCs. The study established an experimental system for comparison of the hematopoietic toxicity and leukemogenicity of benzene and metabolites during mouse embryonic development and adulthood.


Clinical and mycological benefits of topical application of honey, olive oil and beeswax in diaper dermatitis.
Twelve infants suffering from diaper dermatitis were treated four times daily for 7 days with a mixture containing honey, olive oil and beeswax. The severity of erythema was evaluated on a five-point scale. Three infants had severe erythema and ulceration, four had moderate erythema, and five had moderate erythema with maceration. The initial mean lesion score of 2.91 +/- 0.79 declined significantly (p < 0.05) to 2.0 +/- 0.98 (day 3), 1.25 +/- 0.96 (day 5) and 0.66 +/- 0.98 (day 7). Candida albicans was isolated initially from four patients, but from only two patients after treatment. This topical treatment was safe and well-tolerated, and demonstrated clinical and mycological benefits in the treatment of diaper dermatitis.


Sex-biased dispersal in sperm whales: contrasting mitochondrial and nuclear genetic structure of global populations.
The social organization of most mammals is characterized by female philopatry and male dispersal. Such sex-biased dispersal can cause the genetic structure of populations to differ between the maternally inherited mitochondrial DNA (mtDNA) and the bi-parental nuclear genome. Here we report on the global genetic structure of oceanic populations of the sperm whale, one of the most widely distributed mammalian species. Groups of females and juveniles are mainly found at low latitudes, while males reach polar waters, returning to tropical and subtropical waters to breed. In comparisons between oceans, we did not find significant heterogeneity in allele frequencies of microsatellite loci (exact test; p = 0.23). Estimates of GST = 0.001 and RST = 0.005 also indicated negligible if any nuclear DNA differentiation. We have previously reported significant differentiation between oceans in mtDNA sequences. These contrasting patterns suggest that interoceanic movements have been more prevalent among males than among females, consistent with observations of females being the philopatric sex and having a more limited latitudinal distribution than males. Consequently, the typical mammalian dispersal pattern may have operated on a global scale in sperm whales.


The effects of sleep deprivation on pain inhibition and spontaneous pain in women.
Impaired central pain modulation is implicated in the pathophysiology of chronic pain. In this controlled experiment, we evaluated whether partial sleep loss altered endogenous pain inhibition and reports of spontaneous pain. Thirty-two healthy females were studied polysomnographically for 7 nights. On Nights 1-2 (Baseline), subjects slept undisturbed for 8 hours. After Night 2, subjects were randomized to Control (N = 12), Forced Awakening (FA, N = 10), or Restricted Sleep Opportunity (RSO, N = 10) conditions. Controls continued to sleep undisturbed. FA underwent 8 forced awakenings (one per hour) on Nights 3-5. RSO subjects were yoked to FA on total sleep time (TST), receiving partial sleep deprivation by delayed bedtime. On Night 6, both FA & RSO underwent 36 hours total sleep deprivation (TSD), followed by 11-hour recovery sleep (Night 7). Subjects completed twice-daily psychophysical assessments of mechanical pain thresholds and pain inhibition (Diffuse Noxious Inhibitory Controls), via use of a conditioning stimulus (i.e., cold pressor) paradigm. FA and RSO demonstrated 50% reductions in total sleep time and increases in nonpainful somatic symptoms during partial sleep deprivation. While sleep deprivation had no effect on pain thresholds, during partial sleep deprivation the FA group demonstrated a significant loss of pain inhibition and an increase in spontaneous pain; neither of the other 2 groups showed changes in pain inhibition or spontaneous pain during partial sleep deprivation. These data suggest that sleep continuity disturbance, but not simple sleep restriction, impairs endogenous pain-inhibitory function and increases spontaneous pain, supporting a possible pathophysiologic role of sleep disturbance in chronic pain.


Correlation of peak aortic and carotid flow acceleration during coronary occlusion in conscious baboons.
1. Peak blood flow acceleration measured in the common carotid artery was compared with peak flow acceleration measured in the ascending aorta of three baboons. 2. The response to occlusion for 60s of the circumflex branch or the anterior descending branch of the left coronary artery was investigated. 3. Both accelerations decreased approximately to the same extent. Peak aortic flow velocity, stroke volume and cardiac output also decreased but to a smaller extent. 4. It is concluded that peak aortic flow acceleration is a sensitive index of myocardial function during acute coronary occlusion in conscious primates and that peak carotid flow acceleration is an indirect measure of myocardial performance under the same conditions.


Discoveries of Exoribonuclease-Resistant Structures of Insect-Specific Flaviviruses Isolated in Zambia.
To monitor the arthropod-borne virus transmission in mosquitoes, we have attempted both to detect and isolate viruses from 3304 wild-caught female mosquitoes in the Livingstone (Southern Province) and Mongu (Western Province) regions in Zambia in 2017. A pan-flavivirus RT-PCR assay was performed to identify flavivirus genomes in total RNA extracted from mosquito lysates, followed by virus isolation and full genome sequence analysis using next-generation sequencing and rapid amplification of cDNA ends. We isolated a newly identified Barkedji virus (BJV Zambia) (10,899 nt) and a novel flavivirus, tentatively termed Barkedji-like virus (BJLV) (10,885 nt) from Culex spp. mosquitoes which shared 96% and 75% nucleotide identity with BJV which has been isolated in Israel, respectively. These viruses could replicate in C6/36 cells but not in mammalian and avian cell lines. In parallel, a comparative genomics screening was conducted to study evolutionary traits of the 5'- and 3'-untranslated regions (UTRs) of isolated viruses. Bioinformatic analyses of the secondary structures in the UTRs of both viruses revealed that the 5'-UTRs exhibit canonical stem-loop structures, while the 3'-UTRs contain structural homologs to exoribonuclease-resistant RNAs (xrRNAs), SL-III, dumbbell, and terminal stem-loop (3'SL) structures. The function of predicted xrRNA structures to stop RNA degradation by Xrn1 exoribonuclease was further proved by the in vitro Xrn1 resistance assay.


Light harvesting improvement of organic solar cells with self-enhanced active layer designs.
We present designs of organic solar cells (OSCs) incorporating periodically arranged gradient type active layer. The designs can enhance light harvesting with patterned organic materials themselves (i.e. self-enhanced active layer design) to avoid degrading electrical performances of OSCs in contrast to introducing inorganic concentrators into OSC active layers such as silicon and metallic nanostructures. Geometry of the OSC is fully optimized by rigorously solving Maxwell's equations with fast and efficient scattering matrix method. Optical absorption is accessed by a volume integral of the active layer excluding the metallic absorption. Our numerical results show that the OSC with a self-enhanced active layer, compared with the conventional planar active layer configuration, has broadband and wide-angle range absorption enhancement due to better geometric impedance matching and prolonged optical path. This work provides a theoretical foundation and engineering reference for high performance OSC designs.


A novel, dual cytokine-secretion assay for the purification of human Th22 cells that do not co-produce IL-17A.
Interleukin-22 is produced by certain T helper cells subsets (Th17, Th22) and at lower levels by γ-δ T cells, NKT and innate lymphoid cells. Th22 cells are unique immune cells that regulate tissue responses by IL-22 production. The exact discrimination between Th17 cells that co-produce IL-22 and single IL-22-producing Th22 cells has not been possible until the present study. Isolation of pure Th22 cells without co-expression of cytokines of other T-cell subsets is essential to better understand their function in humans. The aim of this study is the isolation and characterization of viable, human IL-22-producing CD4+ T cells that do not produce IL-17A. Isolation of viable Th22 cells was performed with the combination of two cytokine secretion assays detecting IL-17A- and IL-22-producing cells in a single purification step. The newly developed cytokine secretion assay consists of anti-IL-22 and anti-IL-17A catch antibodies, which via biotin-streptavidin interaction are bound to the biotinylated surface of the target cell, and anti-IL-22 and IL-17A detection antibody labelled with a fluorescent dye, which detects cytokines bound to these catch antibodies. A unique population of human Th22 cells, which do not produce IL-17A, was sorted, and cytokine expression pattern was confirmed by quantitative PCR analysis and ELISA. The presented technique allows the detection and isolation of pure human Th22 cells. This technique may allow the purification of any single cytokine-producing cell subset, and the combination of several different cytokine secretion assays can be used to purify and characterize novel and unique cell subsets.