Examining Prevalence and Diversity of Tick-Borne Pathogens in Questing Ixodes pacificus Ticks in California.
Tick-borne diseases in California include Lyme disease (caused by Borrelia burgdorferi), infections with Borrelia miyamotoi, and human granulocytic anaplasmosis (caused by Anaplasma phagocytophilum). We surveyed multiple sites and habitats (woodland, grassland, and coastal chaparral) in California to describe spatial patterns of tick-borne pathogen prevalence in western black-legged ticks (Ixodes pacificus). We found that several species of Borrelia-B. burgdorferi, Borrelia americana, and Borrelia bissettiae-were observed in habitats, such as coastal chaparral, that do not harbor obvious reservoir host candidates. Describing tick-borne pathogen prevalence is strongly influenced by the scale of surveillance: aggregating data from individual sites to match jurisdictional boundaries (e.g., county or state) can lower the reported infection prevalence. Considering multiple pathogen species in the same habitat allows a more cohesive interpretation of local pathogen occurrence. IMPORTANCE Understanding the local host ecology and prevalence of zoonotic diseases is vital for public health. Using tick-borne diseases in California, we show that there is often a bias to our understanding and that studies tend to focus on particular habitats, e.g., Lyme disease in oak woodlands. Other habitats may harbor a surprising diversity of tick-borne pathogens but have been neglected, e.g., coastal chaparral. Explaining pathogen prevalence requires descriptions of data on a local scale; otherwise, aggregating the data can misrepresent the local dynamics of tick-borne diseases.


A beginning of the end: new insights into the functional organization of telomeres.
Ever since the first demonstration of their repetitive sequence and unique replication pathway, telomeres have beguiled researchers with how they function in protecting chromosome ends. Of course much has been learned over the years, and we now appreciate that telomeres are comprised of the multimeric protein/DNA shelterin complex and that the formation of t-loops provides protection from DNA damage machinery. Deriving their name from D-loops, t-loops are generated by the insertion of the 3' overhang into telomeric repeats facilitated by the binding of TRF2. Recent studies have uncovered novel forms of chromosome end-structure that may implicate telomere organization in cellular processes beyond its essential role in telomere protection and homeostasis. In particular, we have recently described that t-loops form in a TRF2-dependent manner at interstitial telomere repeat sequences, which we termed interstitial telomere loops (ITLs). These structures are also dependent on association of lamin A/C, a canonical component of the nucleoskeleton that is mutated in myriad human diseases, including human segmental progeroid syndromes. Since ITLs are associated with telomere stability and require functional lamin A/C, our study suggests a mechanistic link between cellular aging (replicative senescence induced by telomere shortening) and organismal aging (modeled by Hutchinson Gilford Progeria Syndrome). Here we speculate on other potential ramifications of ITL formation, from gene expression to genome stability to chromosome structure.


User testing and stakeholder feedback contributed to the development of understandable and useful Summary of Findings tables for Cochrane reviews.
To develop a Summary of Findings (SoF) table for use in Cochrane reviews that is understandable and useful for health professionals, acceptable to Cochrane Collaboration stakeholders, and feasible to implement. We gathered stakeholder feedback on the format and content of an SoF table from an advisory group of more than 50 participants and their constituencies through e-mail consultations. We conducted user tests using a think-aloud protocol method, collecting feedback from 21 health professionals and researchers in Norway and the UK. We analyzed the feedback, defined problem areas, and generated new solutions in brainstorming workshops. Stakeholders were concerned about precision in the data representation and about production feasibility. User testing revealed unexpected comprehension problems, mainly confusion about what the different numbers referred to (class reference). Resolving the tension between achieving table precision and table simplicity became the main focus of the working group. User testing led to a table more useful and understandable for clinical audiences. We arrived at an SoF table that was acceptable to the stakeholders and in principle feasible to implement technically. Some challenges remain, including presenting continuous outcomes and technical/editorial implementation.


Characteristics and in-hospital outcomes of patients undergoing balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension: a time-trend analysis from the Japanese nationwide registry.
Balloon pulmonary angioplasty (BPA), a novel technique initially introduced as a treatment for inoperable chronic thromboembolic pulmonary hypertension, is now increasingly being performed in a broader spectrum of patients. Here, we performed a time-trend analysis of the characteristics and in-hospital outcomes of patients who underwent BPA in Japan, using data extracted from nationwide procedure-based registration system. The Japanese Structural Heart Disease (J-SHD) registry was established and sponsored by the Japanese Association of Cardiovascular Intervention and Therapeutics and aims to provide basic statistics on the performance of structural interventions in Japan. J-SHD registers cases from approximately 200 institutions, representing more than 90% of SHD intervention-performing hospitals in the nation. We analysed the registered BPA data elements from January 2015 to December 2018. Successful BPA was defined as a session in which a physician successfully treated all targeted lesions. There were a total of 2512 BPA sessions; the number of institutions and registered sessions increased from 30 to 50 sites and from 479 to 852 sessions during the study period, respectively. The average age of the patients was 66±13 years, and 72.1% were women. In-hospital death was observed in 0.2%, and the total complications rate was 5.3%. The preoperative and postoperative mean pulmonary artery pressure were 32±11 mm Hg and 30±10 mm Hg, respectively. The number of BPA sessions increased during the study period, with an acceptable in-hospital complication rate.


A quick, reliable staining technique for human sperm morphology.
The evaluation of sperm morphology is still an important parameter in the diagnosis of the infertile male. Most techniques used for staining human sperm are very time-consuming. A routine stain used for determining differential count of leucocytes (Diff-Quik stain) was evaluated against the standard Papanicolaou stain. Morphology results from 20 duplicate semen smears using both staining methods were determined separately by 2 technicians using a blind protocol. No significant differences were observed when comparing the two staining methods (paired Student's t-test). The advantages of the Diff-Quik stain are: a) complete staining-to-reading time under 7 min, b) commercially prepared reagents, and c) case of staining procedure.


DNA methylation of BDNF as a biomarker of early-life adversity.
Early-life adversity increases the risk for psychopathology in later life. The underlying mechanism(s) is unknown, but epigenetic variation represents a plausible candidate. Early-life exposures can disrupt epigenetic programming in the brain, with lasting consequences for gene expression and behavior. This evidence is primarily derived from animal studies, with limited study in humans due to inaccessibility of the target brain tissue. In humans, although there is evidence for DNA methylation changes in the peripheral blood of psychiatric patients, a fundamental question remains as to whether epigenetic markers in the blood can predict epigenetic changes occurring in the brain. We used in utero bisphenol A (BPA) exposure as a model environmental exposure shown to disrupt neurodevelopment and exert long-term effects on behavior in animals and humans. We show that prenatal BPA induces lasting DNA methylation changes in the transcriptionally relevant region of the Bdnf gene in the hippocampus and blood of BALB/c mice and that these changes are consistent with BDNF changes in the cord blood of humans exposed to high maternal BPA levels in utero. Our data suggest that BDNF DNA methylation in the blood may be used as a predictor of brain BDNF DNA methylation and gene expression as well as behavioral vulnerability induced by early-life environmental exposure. Because BDNF expression and DNA methylation are altered in several psychiatric disorders that are associated with early-life adversity, including depression, schizophrenia, bipolar disorder, and autism, BDNF DNA methylation in the blood may represent a novel biomarker for the early detection of psychopathology.


Combined spin- and gradient-echo perfusion-weighted imaging.
In this study, a spin- and gradient-echo echo-planar imaging (SAGE EPI) MRI pulse sequence is presented that allows simultaneous measurements of gradient-echo and spin-echo dynamic susceptibility-contrast perfusion-weighted imaging data. Following signal excitation, five readout trains were acquired using spin- and gradient-echo echo-planar imaging, all of them with echo times of less than 100 ms. Contrast agent concentrations in brain tissue were determined based on absolute R2* and R(2) estimates rather than relative changes in the signals of individual echo trains, producing T(1)-independent dynamic susceptibility-contrast perfusion-weighted imaging data. Moreover, this acquisition technique enabled vessel size imaging through the simultaneous quantification of R2* and R(2), without an increase in acquisition time. In this work, the concepts of SAGE EPI pulse sequence and results in stroke and tumor imaging are presented. Overall, SAGE EPI combined the advantages of higher sensitivity to contrast agent passage of gradient-echo perfusion-weighted imaging with better microvascular selectivity of spin-echo perfusion-weighted imaging.


ARTSCENE: A neural system for natural scene classification.
How do humans rapidly recognize a scene? How can neural models capture this biological competence to achieve state-of-the-art scene classification? The ARTSCENE neural system classifies natural scene photographs by using multiple spatial scales to efficiently accumulate evidence for gist and texture. ARTSCENE embodies a coarse-to-fine Texture Size Ranking Principle whereby spatial attention processes multiple scales of scenic information, from global gist to local textures, to learn and recognize scenic properties. The model can incrementally learn and rapidly predict scene identity by gist information alone, and then accumulate learned evidence from scenic textures to refine this hypothesis. The model shows how texture-fitting allocations of spatial attention, called attentional shrouds, can facilitate scene recognition, particularly when they include a border of adjacent textures. Using grid gist plus three shroud textures on a benchmark photograph dataset, ARTSCENE discriminates 4 landscape scene categories (coast, forest, mountain, and countryside) with up to 91.85% correct on a test set, outperforms alternative models in the literature which use biologically implausible computations, and outperforms component systems that use either gist or texture information alone.


Pediatric Urinary System Neoplasms: An Overview and Update.
Pediatric urinary system neoplasms are a diverse group of tumors that frequently overlap in their clinical and radiologic features. By contrast, the histopathologic classification and treatment of these entities have become increasingly refined, resulting in improved outcomes, with the overall survival of Wilms tumors now exceeding 90%. Significantly, many contemporary protocols rely on radiologic diagnosis in the absence of tissue confirmation. This review article provides up-to-date clinical, epidemiologic, and imaging findings of pediatric urinary system neoplasms and their mimics frequently encountered in daily clinical practice.


Distribution of non-myelinating Schwann cells and their associations with leukocytes in mouse spleen revealed by immunofluorescence staining.
The nervous system and the immune system communicate extensively with each other in order to maintain homeostasis and to regulate the immune response. The peripheral nervous system (PNS) communicates specifically with the immune system according to local interactions, including the "hardwiring" of sympathetic/parasympathetic (efferent) and sensory nerves (afferent) to lymphoid tissue and organs. To reveal this type of bidirectional neuroimmune interaction at the microscopic level, we used immunofluorescent staining of glial fibrillary acidic protein (GFAP) coupled with confocal microscopy/3D reconstruction to reveal the distribution of non-myelinating Schwann cells (NMSCs) and their interactions with immune cells inside mouse spleen. Our results demonstrate i) the presence of an extensive network of NMSC processes in all splenic compartments including the splenic nodules, periarteriolar lymphoid sheath (PALS), marginal zone, trabecula, and red pulp; ii) the close association of NMSC processes with blood vessels (including central artries and their branches, marginal sinuses, penicillar arterioles and splenic sinuses); iii) the close "synapse-like" interaction/association of NMSC processes with various subsets of dendritic cells (DCs; e.g., CD4+CD11c+ DCs, B220+CD11c+ DCs, and F4/80+ CD11c+ DCs), macrophages (F4/80+), and lymphocytes (B cells, CD4+ T helper cells). Our novel findings concerning the distribution of NMSCs and NMSC-leukocytes interactions inside mouse spleen should improve our understanding of the mechanisms through which the PNS affects cellular- and humoral-mediated immune responses in a variety of health conditions and infectious/non-infectious diseases.


Human thromboxane A2 receptor genetic variants: in silico, in vitro and "in platelet" analysis.
Thromboxane and its receptor have emerged as key players in modulating vascular thrombotic events. Thus, a dysfunctional hTP genetic variant may protect against (hypoactivity) or promote (hyperactivity) vascular events, based upon its activity on platelets. After extensive in silico analysis, six hTP-α variants were selected (C(68)S, V(80)E, E(94)V, A(160)T, V(176)E, and V(217)I) for detailed biochemical studies based on structural proximity to key regions involved in receptor function and in silico predictions. Variant biochemical profiles ranged from severe instability (C(68)S) to normal (V(217)I), with most variants demonstrating functional alteration in binding, expression or activation (V(80)E, E(94)V, A(160)T, and V(176)E). In the absence of patient platelet samples, we developed and validated a novel megakaryocyte based system to evaluate human platelet function in the presence of detected dysfunctional genetic variants. Interestingly, variant V80E exhibited reduced platelet activation whereas A160T demonstrated platelet hyperactivity. This report provides the most comprehensive in silico, in vitro and "in platelet" evaluation of hTP variants to date and highlightscurrent inherent problems in evaluating genetic variants, with possible solutions. The study additionally provides clinical relevance to characterized dysfunctional hTP variants.


Comparison of two molecular methods used for subtyping of Legionella pneumophila 1 strains isolated from a hospital water supply.
The results of the pulsed-field gel electrophoresis and the sequence-based typing (using the loci flaA, pilE, asd, mip, mompS and proA) were compared for subtyping of Legionella pneumophila 1 strains isolated from a hospital water supply. Molecular typing was carried out on 61 isolates (38% of the positive samples) selected on space and temporal criteria in order to follow the evolution of the water-system colonization. For all the 61 isolates, the sequence of the amplified mip gene fragment identified Legionella pneumophila strain Wadsworth. Genotype testing by PFGE analysis showed three different patterns, correspondent to three SBT types according to the allelic profiles. Both PFGE and SBT indicated the circulation and the persistence in the hospital potable water-system of three types randomly distributed in space and time. The two molecular methods adopted showed a 100% concordance, although a low degree of genetic heterogeneity characterized the isolates. The electrophoretic patterns were sufficiently unambiguous to consider PFGE a highly discriminatory typing method, but the SBT technique besides accurately characterizing isolates, was able to identify Legionella strains through analysis of the mip gene. A typing method with this level of discriminatory power has great potential for assisting in epidemiological studies.


Type 2 Diabetes and Asthma: Systematic Review of the Bidirectional Relationship.
Obesity is an important contributor to the risk of both asthma and Type 2 Diabetes (T2DM). However, it has been suggested that T2DM and asthma are also independently associated. The aim of this systematic review was to synthesize the evidence for an independent relationship between T2DM and asthma. MEDLINE and EMBASE were searched for studies reporting the relationship between asthma and T2DM in adults. Given a potential bidirectional relationship, articles relating to T2DM as a risk factor for asthma, and asthma as a risk factor for T2DM were examined separately. Eight studies were identified for inclusion in the review (n=2,934,399 participants). Four studies examined incident diabetes in those with asthma. The pooled (random effects model) adjusted hazard ratio for incident T2DM in asthma was 1.37 (95%CI 1.12-1.69; p <0.001) after controlling for BMI. Four studies reported prevalence or incidence rates of asthma in people with T2DM; higher rates of asthma in those with T2DM were reported in all four studies. Meta-analysis of results was not possible due to methodological heterogeneity. The quality of included studies was good, but due to small numbers, publication bias cannot be excluded. The published literature suggests a bidirectional independent relationship between T2DM and asthma, although we cannot exclude publication bias.


In utero exposure to phthalates and fetal development.
The diesters of benzene-1,2-dicarboxylic (phthalic) acid, commonly known as phthalates, are a family of industrial compounds, primarily used as plasticizers in enormous quantities for a variety of industrial uses in the formulation of plastics. Di-(2-ethylhexyl) phthalate (DEHP) is the most commonly used plasticizer. These plasticizers are not covalently bound to the polymer and leach out into the environment, thus becoming ubiquitous environmental contaminants. Cumulating evidence points out on the adverse effects of phthalate exposure during intrauterine life. Recently, it has been documented that in utero phthalate exposure is associated with a shorter duration of pregnancy. Phthalates induce and activate a subset of peroxisome proliferator-activated receptors (PPARs) and have an intrinsic pro-inflammatory activity, while some natural PPAR agonists induce cyclooxygenase (COX)-2 expression. To this regard, COX-2 is thought to be overexpressed in chorioamnionitis (CA), a fetal systemic inflammatory response syndrome and a leading cause of preterm birth. An adequate maternal dietary intake of essential fatty acids, well known anti-inflammatory agents, is indispensable to fetal development. Recently, it has been shown that phthalates alter the placental essential fatty acids (EFAs) homeostasis so potentially leading to abnormal fetal development. Likewise, a possible down-regulation of COX-2 by omega-3 fatty acids has been suggested. As a consequence, maternal supplementation with omega 3 during pregnancy could counteract the adverse effects of phthalates exposure in the human fetus. Here, we analyze the existing evidence on the link between antenatal phthalate exposure and abnormal fetal development, as well as on possible therapeutic tools to fight the adverse effect of this exposure.


Non-psychoactive cannabinoids modulate the descending pathway of antinociception in anaesthetized rats through several mechanisms of action.
Two non-psychoactive cannabinoids, cannabidiol (CBD) and cannabichromene (CBC), are known to modulate in vitro the activity of proteins involved in nociceptive mechanisms, including transient receptor potential (TRP) channels of vanilloid type-1 (TRPV1) and of ankyrin type-1 (TRPA1), the equilibrative nucleoside transporter and proteins facilitating endocannabinoid inactivation. Here we have tested these two cannabinoids on the activity of the descending pathway of antinociception. Electrical activity of ON and OFF neurons of the rostral ventromedial medulla in anaesthetized rats was recorded extracellularly and tail flick latencies to thermal stimuli were measured. CBD or CBC along with various antagonists were injected into the ventrolateral periaqueductal grey. Cannabidiol and CBC dose-dependently reduced the ongoing activity of ON and OFF neurons in anaesthetized rats, whilst inducing antinociceptive responses in the tail flick-test. These effects were maximal with 3 nmol CBD and 6 nmol CBC, and were antagonized by selective antagonists of cannabinoid CB(1) adenosine A(1) and TRPA1, but not of TRPV1, receptors. Both CBC and CBD also significantly elevated endocannabinoid levels in the ventrolateral periaqueductal grey. A specific agonist at TRPA1 channels and a synthetic inhibitor of endocannabinoid cellular reuptake exerted effects similar to those of CBC and CBD. CBD and CBC stimulated descending pathways of antinociception and caused analgesia by interacting with several target proteins involved in nociceptive control. These compounds might represent useful therapeutic agents with multiple mechanisms of action.


Mutations in coronavirus nonstructural protein 10 decrease virus replication fidelity.
Coronaviruses (CoVs) are unique in encoding a 3'→5' exoribonuclease within nonstructural protein 14 (nsp14-ExoN) that is required for high-fidelity replication, likely via proofreading. nsp14 associates with the CoV RNA-dependent RNA polymerase (nsp12-RdRp), and nsp14-ExoN activity is enhanced by binding nsp10, a small nonenzymatic protein. However, it is not known whether nsp10 functions in the regulation of CoV replication fidelity. To test this, we engineered single and double alanine substitution mutations into the genome of murine hepatitis virus (MHV-A59) containing ExoN activity [ExoN(+)] at positions within nsp10 known to disrupt the nsp10-nsp14 interaction in vitro. We show that an nsp10 mutant, R80A/E82A-ExoN(+), was five to ten times more sensitive to treatment with the RNA mutagen 5-fluorouracil (5-FU) than wild-type (WT)-ExoN(+), suggestive of decreased replication fidelity. This decreased-fidelity phenotype was confirmed using two additional nucleoside analogs, 5-azacytidine and ribavirin. R80A/E82A-ExoN(+) reached a peak titer similar to and demonstrated RNA synthesis kinetics comparable to those seen with WT-ExoN(+). No change in 5-FU sensitivity was observed for R80A/E82A-ExoN(-) relative to MHV-ExoN(-), indicating that the decreased-fidelity phenotype of R80A/E82A-ExoN(-) is linked to the presence of ExoN activity. Our results demonstrate that nsp10 is important for CoV replication fidelity and support the hypothesis that nsp10 functions to regulate nsp14-ExoN activity during virus replication. The adaptive capacity of CoVs, as well as all other RNA viruses, is partially attributed to the presence of extensive population genetic diversity. However, decreased fidelity is detrimental to CoV replication and virulence; mutant CoVs with decreased replication fidelity are attenuated and more sensitive to inhibition by RNA mutagens. Thus, identifying the viral protein determinants of CoV fidelity is important for understanding CoV replication, pathogenesis, and virulence. In this report, we show that nsp10, a small, nonenzymatic viral protein, contributes to CoV replication fidelity. Our data support the hypothesis that CoVs have evolved multiple proteins, in addition to nsp14-ExoN, that are responsible for maintaining the integrity of the largest known RNA genomes.


Culture and Dehydration: A Comparative Study of Caída de la Mollera (Fallen Fontanel) in Three Latino Populations.
A sunken soft-spot or fontanel is a sign for dehydration in infants. Around the world, folk illnesses, such as caída de la mollera in some Latin American cultures, often incorporate this sign as a hallmark of illness, but may or may not incorporate re-hydration therapies in treatment strategies. This report describes a study of lay descriptions of causes, symptoms, and treatments for caída de la mollera in three diverse Latin American populations. A mixed-methods approach was used. Representative community-based samples were interviewed in rural Guatemala, Guadalajara, Mexico, and Edinburgh, Texas, with a 132 item questionnaire on the causes, susceptibility, symptoms, and therapies for caída de la mollera. Cultural consensus analysis was used to estimate community beliefs about caída. Interviews conducted in rural Guatemala (n = 60), urban Mexico (n = 62), and rural Texas on the Mexican border (n = 61) indicated consistency in thematic elements within and among these three diverse communities. The high degree of consistency in the illness explanatory models indicated shared beliefs about caída de la mollera in each of the communities and a core model shared across communities. However, an important aspect of the community beliefs was that rehydration therapies were not widely endorsed. The consistency in explanatory models in such diverse communities, as well as the high degree of recognition and experience with this illness, may facilitate communication between community members, and health care providers/public health intervention planners to increase use of rehydration therapies for caída de la mollera. Recommendations for culturally informed and respectful approaches to clinical communication are provided.


Platelets amplify inflammation in arthritis via collagen-dependent microparticle production.
In addition to their pivotal role in thrombosis and wound repair, platelets participate in inflammatory responses. We investigated the role of platelets in the autoimmune disease rheumatoid arthritis. We identified platelet microparticles--submicrometer vesicles elaborated by activated platelets--in joint fluid from patients with rheumatoid arthritis and other forms of inflammatory arthritis, but not in joint fluid from patients with osteoarthritis. Platelet microparticles were proinflammatory, eliciting cytokine responses from synovial fibroblasts via interleukin-1. Consistent with these findings, depletion of platelets attenuated murine inflammatory arthritis. Using both pharmacologic and genetic approaches, we identified the collagen receptor glycoprotein VI as a key trigger for platelet microparticle generation in arthritis pathophysiology. Thus, these findings demonstrate a previously unappreciated role for platelets and their activation-induced microparticles in inflammatory joint diseases.


Cryptic diversity, high host specificity and reproductive synchronization in army ant-associated Vatesus beetles.
Army ants and their arthropod symbionts represent one of the most species-rich animal associations on Earth, and constitute a fascinating example of diverse host-symbiont interaction networks. However, despite decades of research, our knowledge of army ant symbionts remains fragmentary due to taxonomic ambiguity and the inability to study army ants in the laboratory. Here, we present an integrative approach that allows us to reliably determine species boundaries, assess biodiversity, match different developmental stages and sexes, and to study the life cycles of army ant symbionts. This approach is based on a combination of community sampling, DNA barcoding, morphology and physiology. As a test case, we applied this approach to the staphylinid beetle genus Vatesus and its different Eciton army ant host species at La Selva Biological Station, Costa Rica. DNA barcoding led to the discovery of cryptic biodiversity and, in combination with extensive community sampling, revealed strict host partitioning with no overlap in host range. Using DNA barcoding, we were also able to match the larval stages of all focal Vatesus species. In combination with studies of female reproductive physiology, this allowed us to reconstruct almost the complete life cycles of the different beetle species. We show that Vatesus beetles are highly adapted to the symbiosis with army ants, in that their reproduction and larval development are synchronized with the stereotypical reproductive and behavioural cycles of their host colonies. Our approach can now be used to study army ant-symbiont communities more broadly, and to obtain novel insights into co-evolutionary and ecological dynamics in species-rich host-symbiont systems.


Lithography, metrology and nanomanufacturing.
Semiconductor chip manufacturing is by far the predominant nanomanufacturing technology in the world today. Top-down lithography techniques are used for fabrication of logic and memory chips since, in order to function, these chips must essentially be perfect. Assuring perfection requires expensive metrology. Top of the line logic sells for several hundred thousand dollars per square metre and, even though the required metrology is expensive, it is a small percentage of the overall manufacturing cost. The level of stability and control afforded by current lithography tools means that much of this metrology can be online and statistical. In contrast, many of the novel types of nanomanufacturing currently being developed will produce products worth only a few dollars per square metre. To be cost effective, the required metrology must cost proportionately less. Fortunately many of these nanofabrication techniques, such as block copolymer self-assembly, colloidal self-assembly, DNA origami, roll-2-roll nano-imprint, etc., will not require the same level of perfection to meet specification. Given the variability of these self-assembly processes, in order to maintain process control, these techniques will require some level of real time online metrology. Hence we are led to the conclusion that future nanomanufacturing may well necessitate "cheap" nanometre scale metrology which functions real time and on-line, e.g. at GHz rates, in the production stream. In this paper we review top-down and bottom-up nanofabrication techniques and compare and contrast the various metrology requirements.


Amphetamine: evaluation of d- and l-isomers as releasing agents and uptake inhibitors for 3H-dopamine and 3H-norepinephrine in slices of rat neostriatum and cerebral cortex.
Release of 3H-doapamine or of 3H-norepinephrine and inhibition of accumulation of 3H-dopamine or 3H-norepinephrine by d- and l-amphetamine were studied in slices of rat neostriatum and in slices of rat cerebral cortex. The two stereoisomers of amphetamine were equally potent as inhibitors of accumulation in the cortex, whereas d-amphetamine was approximately 3-fold more potent than l-amphetamine in the neostriatum. A similar relationship was observed between the two stereoisomers in release experiments. Some spontaneous efflux of 3H-dopamine from tissue slices was evident in absence of added drug in release experiments. When cocaine (2 X 10(-5) M), a known inhibitor of biogenic amine uptake, was added to the medium, there was very little increment in spontaneous efflux of 3H-dopamine in neostriatal slices, but cocaine blocked the release caused by d-amphetamine. This showed that the apparent releasing action of d-amphetamine in the neostriatum was not due to blockade of reuptake of spontaneously released material and that d-amphetamine itself must be taken up to evoke a releasing action. Experiments were designed to compare directly the releasing and uptake inhibiting actions of d-amphetamine. In the cortex, uptake inhibition of 3H-norepinephrine was greater than release over a wide concentration range, while in the neostriatum the two actions were essentially identical in magnitude for 3H-dopamine. We conclude that in the cortex, d-amphetamine can act both to release and to block uptake of 3H-norepinephrine. In the neostriatum, on the other hand, there is releasing action of 3H-dopamine by d-amphetamine (which is stronger than that in the cortex), but the apparent blockade of "uptake" is of questionable significance and appears to result from the release of previously accumulated 3H-dopamine


Polymorphic markers for identification of parasite population in Plasmodium malariae.
Molecular genotyping in Plasmodium serves many aims including providing tools for studying parasite population genetics and distinguishing recrudescence from reinfection. Microsatellite typing, insertion-deletion (INDEL) and single nucleotide polymorphisms is used for genotyping, but only limited information is available for Plasmodium malariae, an important human malaria species. This study aimed to provide a set of genetic markers to facilitate the study of P. malariae population genetics. Markers for microsatellite genotyping and pmmsp1 gene polymorphisms were developed and validated in symptomatic P. malariae field isolates from Myanmar (N = 37). Fragment analysis was used to determine allele sizes at each locus to calculate multiplicity of infections (MOI), linkage disequilibrium, heterozygosity and construct dendrograms. Nucleotide diversity (π), number of haplotypes, and genetic diversity (Hd) were assessed and a phylogenetic tree was constructed. Genome-wide microsatellite maps with annotated regions of newly identified markers were constructed. Six microsatellite markers were developed and tested in 37 P. malariae isolates which showed sufficient heterozygosity (0.530-0.922), and absence of linkage disequilibrium (IAS=0.03, p value > 0.05) (N = 37). In addition, a tandem repeat (VNTR)-based pmmsp1 INDEL polymorphisms marker was developed and assessed in 27 P. malariae isolates showing a nucleotide diversity of 0.0976, haplotype gene diversity of 0.698 and identified 14 unique variants. The size of VNTR consensus repeat unit adopted as allele was 27 base pairs. The markers Pm12_426 and pmmsp1 showed greatest diversity with heterozygosity scores of 0.920 and 0.835, respectively. Using six microsatellites markers, the likelihood that any two parasite strains would have the same microsatellite genotypes was 8.46 × 10-4 and was further reduced to 1.66 × 10-4 when pmmsp1 polymorphisms were included. Six novel microsatellites genotyping markers and a set of pmmsp1 VNTR-based INDEL polymorphisms markers for P. malariae were developed and validated. Each marker could be independently or in combination employed to access genotyping of the parasite. The newly developed markers may serve as a useful tool for investigating parasite diversity, population genetics, molecular epidemiology and for distinguishing recrudescence from reinfection in drug efficacy studies.


Rapid wavelength scans over one octave and application to laser-induced fluorescence.
Rapid excitation scans of laser-induced fluorescence (LIF) have been demonstrated. Broadband light was generated in a photonic crystal fiber and transmitted through a long fiber. Due to group-velocity dispersion in the long fiber, a wavelength scan emerged from the fiber in time. The wavelength was swept over approximately one octave in approximately 150 ns. The generated light was used to excite LD 700 Perchlorate diluted in methanol. The LIF excitation scan had a spectral resolution of approximately 15 nm, and the integrated fluorescence spectrum was found to be within 7% of the integrated absorption spectrum of the dye molecule. The method presented makes possible spatially and spectrally resolved LIF excitation scans with scanning speeds up to the limits set by the excited-state lifetime of the dye molecule.


Automated analysis of the Cinderella story.
AphasiaBank is a collaborative project whose goal is to develop an archival database of the discourse of individuals with aphasia. Along with databases on first language acquisition, classroom discourse, second language acquisition, and other topics, it forms a component of the general TalkBank database. It uses tools from the wider system that are further adapted to the particular goal of studying language use in aphasia. The goal of this paper is to illustrate how TalkBank analytic tools can be applied to AphasiaBank data. Both aphasic (n = 24) and non-aphasic (n = 25) participants completed a 1-hour standardised videotaped data elicitation protocol. These sessions were transcribed and tagged automatically for part of speech. One component of the larger protocol was the telling of the Cinderella story. For these narratives we compared lexical diversity across the groups and computed the top 10 nouns and verbs across both groups. We then examined the profiles for two participants in greater detail. Using these tools we showed that, in a story-retelling task, aphasic speakers had a marked reduction in lexical diversity and a greater use of light verbs. For example, aphasic speakers often substituted "girl" for "stepsister" and "go" for "disappear". These findings illustrate how it is possible to use TalkBank tools to analyse AphasiaBank data.


Lifetime of carbon capture and storage as a climate-change mitigation technology.
In carbon capture and storage (CCS), CO(2) is captured at power plants and then injected underground into reservoirs like deep saline aquifers for long-term storage. While CCS may be critical for the continued use of fossil fuels in a carbon-constrained world, the deployment of CCS has been hindered by uncertainty in geologic storage capacities and sustainable injection rates, which has contributed to the absence of concerted government policy. Here, we clarify the potential of CCS to mitigate emissions in the United States by developing a storage-capacity supply curve that, unlike current large-scale capacity estimates, is derived from the fluid mechanics of CO(2) injection and trapping and incorporates injection-rate constraints. We show that storage supply is a dynamic quantity that grows with the duration of CCS, and we interpret the lifetime of CCS as the time for which the storage supply curve exceeds the storage demand curve from CO(2) production. We show that in the United States, if CO(2) production from power generation continues to rise at recent rates, then CCS can store enough CO(2) to stabilize emissions at current levels for at least 100 y. This result suggests that the large-scale implementation of CCS is a geologically viable climate-change mitigation option in the United States over the next century.


Isolation and characterization of beta-glucan receptors on human mononuclear phagocytes.
beta-glucan receptors, with ligand specificity for yeast and fungal carbohydrate polymers, have been studied as phagocytic receptors of human monocytes. To characterize their structure, binding studies were carried out with human U937 cells and a rabbit IgG anti-Id that recognizes epitopes on monocyte beta-glucan receptors. Unstimulated U937 cells specifically bound large amounts of the anti-Id, but almost none of the control anti-isotype. At saturation, the number of anti-Id molecules bound per U937 cell was 2.6 x 10(6) with an apparent Ka of 1.9 x 10(7) M-1. Immunoprecipitates from detergent lysates of surface-radioiodinated U937 cells contained only two membrane proteins with antigenic specificity for the anti-Id, one having a mol wt of 180 kD and the other 160 kD. Both proteins were disulfide-linked and presented, after reduction, as five polypeptides of 95, 88, 60, 27, and 20 kD. Detergent lysates of unlabeled U937 cells, purified by affinity chromatography on anti-Id-Sepharose, yielded the same two nonreduced proteins and five reduction products in slab gels stained with Coomassie blue. In Western blots probed with the anti-Id, the most immunoreactive nonreduced and reduced affinity-purified products were the 160 and 20 kD molecules, respectively. Immunoblots of two-dimensional gels showed the 180 and 160 kD proteins to express a common epitope through disulfide linkage to the 20 kD polypeptide. By immunoblot analysis, U937 cell glucan-binding proteins from detergent lysates contained two cell proteins antigenic for the anti-Id that were indistinguishable from affinity-purified molecules in size and subunit composition. Studies of affinity-purified proteins from detergent lysed human monocytes were characterized by immunoblot analysis and found to be identical to U937 cell beta-glucan receptors. They consisted of two disulfide-linked proteins, with mol wt of 180 and 160 kD, and had in common a 20 kD polypeptide with the anti-Id epitope.


Sexual dimorphism of the enamel and dentine dimensions of the permanent canines of the Middle Pleistocene hominins from Sima de los Huesos (Burgos, Spain).
Sexual dimorphism is an important component of the total variation seen in populations and plays a key role in taxonomic debates. In this study, microtomographic (microcomputed tomography) techniques were applied to a sample of hominin teeth from the Sima de los Huesos site (Spain). Dental tissue proportions of the permanent canines were assessed to characterize the pattern and degree of sexual dimorphism within this population. In addition, the possible similarities and differences with the Homo neanderthalensis remains from Krapina (Croatia) and with a recent modern human sample were evaluated. A combination of classical statistical approaches with more novel techniques allowed us not only to ratify the sex allocation of the individuals previously assigned in the literature but also to estimate the sex of the youngest individuals, which were not assessed in previous studies. Likewise, the sexes of certain extensively worn canines and isolated pieces were estimated. As a result, the sex ratio observed in our dental sample from the Sima de los Huesos population is 5:9 (Nm:Nf). In general terms, both Sima de los Huesos and Krapina dental samples have a degree of sexual dimorphism in their permanent canine tissue proportions that does not surpass that of modern humans. The marked dimorphic root volume of Sima de los Huesos mandibular canines is the exception, which surpasses the modern human mean, although it falls within the 95% confidence interval. Therefore, our results do not support that dental tissue proportions of the European Middle Pleistocene populations were more dimorphic than in modern humans. However, the differences in canine tissue proportions are great enough to allow sex estimation with a high degree of confidence.


Whole-cell clamp study of Xenopus embryonic cholinergic neurons.
Whole-cell clamped myoballs are placed into direct visible contact with the growth cones of isolated neurons in embryonic Xenopus culture to serve as probe of acetylcholine (AcCHo) release in order to determine whether these neurons are cholinergic or not. Using a G omega -seal, whole-cell recording method, the electrophysiological properties of these identified cholinergic neurons are studied. It is found that these embryonic neurons, like adult frog motor neurons, exhibit repetitive firings in a certain embryonic developing stage. A development of repetitive firings is observed simultaneously. Tracing the development of one neuron, we find that the development of repetitive firing is completed at the 48th h after fertilization. Tetrodotoxin (TTX) which blocks Na+ channels can abolish all firings; and tetraethyl ammonium chloride (TEA), the blocker of K+ channels, reverses this development, i.e. it makes the repetitive firings disappear again. These data show that the nature of the development of repetitive firings is the development of K+ channels.


Correlation between preoperative endoscopic and intraoperative findings in localizing colorectal lesions.
Colonoscopy findings compared with findings at time of surgery have a discrepancy rate of 3-21%. The objective of our study was to investigate this discrepancy and provide potential resolutions. In this retrospective study, we identified 400 patients who underwent colonoscopy followed by colon resection at our community hospitals in 1999-2006. Discrepancies between colonoscopy and intraoperative findings were noted. Each discrepancy was classified as major if the surgical procedure had to be altered, the lesion was missed, an unnecessary segment was removed, or the incision was extended. A discrepancy was classified as minor if there was no alteration in planned surgery. Of the 400 cases, 160 (40%) were located in the right colon, 13 (3%) were in the transverse colon, 185 (46%) were in the left colon, and 42 (11%) were in the rectum. A total of 48 (12%) discrepancies between colonoscopy and intraoperative findings were identified: 26 (54%) were major and 22 (46%) were minor. Thirteen (27%) were in the proximal colon (3 major and 10 minor discrepancies), 3 (6.3%) were in the transverse colon (all major), 22 (46%) were in the distal colon (17 major and 5 minor), and 10 (21%) were in the rectum (3 major, 7 minor). Major discrepancies were significantly higher in the left colon (17 of the 185 left-sided lesions; 9.1%) than in the right colon (3/160; 1.9%; P = 0.045). In our study, colonoscopy has an error rate of 12% when used to localize tumors; more than half of these patients require significant unanticipated changes in their surgery. The discrepancies are significantly higher in left side of colon.


Novel method for l-methionine determination using l-methionine decarboxylase and application of the enzyme for l-homocysteine determination.
For many years, clinical studies have suggested that blood levels of l-methionine and L-homocysteine correlate with health status or homocystinuria/hypermethioninemia. l-Methionine in a solution containing 0%, 10%, or 20% human serum was detected in 10-200 µM using l-methionine decarboxylase (MetDC). Spike and recovery tests showed that the enzymatic assay could accurately and reproducibly determine the increases in l-methionine in serum samples. These results suggest that our enzymatic method using MetDC is useful for primary screening of hypermethioninemia or homocystinuria based on serum l-methionine concentration. Additionally, we confirmed that l-methionine (100 nmol) in solution was degraded to less than the detection limit by incubation at 37ºC for 10 min using 2 U of MetDC. Therefore, l-homocysteine in serum samples can be detected with equivalent sensitivity using l-methionine γ-lyase (MGL), in solutions that either did not contain l-methionine or contained l-methionine preincubated with MetDC.Abbreviations: DTT: dithiothreitol; IPTG: isopropyl-β-d-thiogalactopyranoside; KPB: potassium phosphate buffer; MBTH: 3-methyl-2-benzothiazolinonehydrazone; mdc: the gene coding l-methionine decarboxylase; MetDC: l-methionine decarboxylase; mgl: the gene coding l-methionine γ-lyase; MGL: l-methionine γ-lyase; PLP: pyridoxal 5'-phosphate.


The Genomic Architecture of Fowl Typhoid Resistance in Commercial Layers.
Salmonella enterica serovar Gallinarum causes devastating outbreaks of fowl typhoid across the globe, especially in developing countries. With the use of antimicrobial agents being reduced due to legislation and the absence of licensed vaccines in some parts of the world, an attractive complementary control strategy is to breed chickens for increased resistance to Salmonella. The potential for genetic control of salmonellosis has been demonstrated by experimental challenge of inbred populations. Quantitative trait loci (QTL) associated with resistance have been identified in many genomic regions. A major QTL associated with systemic salmonellosis has been identified in a region termed SAL1. In the present study, two outbreaks of fowl typhoid in 2007 and 2012 in the United Kingdom were used to investigate the genetic architecture of Salmonella resistance in commercial laying hens. In the first outbreak 100 resistant and 150 susceptible layers were genotyped using 11 single nucleotide polymorphism (SNP) and 3 microsatellite markers located in the previously identified SAL1 region on chromosome 5. From the second outbreak 100 resistant and 200 susceptible layers, belonging to a different line, were genotyped with a high-density (600 K) genome-wide SNP array. Substantial heritability estimates were obtained in both populations (h 2 = 0.22 and 0.26, for the layers in the first and second outbreak, respectively). Significant associations with three markers on chromosome 5 located close to AKT1 and SIVA1 genes, coding for RAC-alpha serine/threonine protein kinase, and the CD27-binding protein SIVA1, respectively, were identified in the first outbreak. From analysis of the second outbreak, eight genome-wide significant associations with Salmonella resistance were identified on chromosomes 1, 6, 7, 11, 23, 24, 26, 28 and several others with suggestive genome-wide significance were found. Pathway and network analysis revealed the presence of many innate immune pathways related to Salmonella resistance. Although, significant associations with SNPs located in the SAL1 locus were not identified by the genome-wide scan for layers from the second outbreak, pathway analysis revealed P13K/AKT signaling as the most significant pathway. In summary, resistance to fowl typhoid is a heritable polygenic trait that could possibly be enhanced through selective breeding.


Acute Chagas disease outbreak associated with oral transmission.
Seven individuals living in a town in the Southwest of Bahia developed sudden signs of cardiac and systemic impairment, with lethality of 28.6%. Serological tests were positive at least in one test in the five patients examined. Forty percent of the Triatoma sordida mynphs found inside or around Trypanosoma cruzi were found by blood culturig in there out five cases the homes of these cases were positive for Trypanosoma cruzi. Transmission probably occurred through consumption of water contaminated with triatomine feces. These findings emphasize the necessity to evaluation the importance of vectors like Triatoma sordida in maintaining the endemicity of this disease.


Citrullination in the periodontium--a possible link between periodontitis and rheumatoid arthritis.
The aim of the present study was to assess human and bacterial peptidylarginine deiminase (PAD) activity in the gingival crevicular fluid (GCF) in the context of serum levels of antibodies against citrullinated epitopes in rheumatoid arthritis and periodontitis. Human PAD and Porphyromonas gingivalis-derived enzyme (PPAD) activities were measured in the GCF of 52 rheumatoid arthritis (RA) patients (48 with periodontitis and 4 without) and 44 non-RA controls (28 with periodontitis and 16 without). Serum antibodies against citrullinated epitopes were measured by ELISA. Bacteria being associated with periodontitis were determined by nucleic-acid-based methods. Citrullination was present in 26 (50%) RA patients and 23 (48%) controls. PAD and PPAD activities were detected in 36 (69%) and 30 (58%) RA patients, respectively, and in 30 (68%) and 21 (50%) controls, respectively. PPAD activity was higher in RA and non-RA patients with periodontitis than in those without (p = 0.038; p = 0.004), and was detected in 35 of 59 P. gingivalis-positive samples, and in 16 of 37 P. gingivalis-negative samples in association with high antibody levels against that species. PAD and PPAD activities within the periodontium are elevated in RA and non-RA patients with periodontitis. PPAD secreted by P. gingivalis residing in epithelial cells may exert its citrullinating activity in distant regions of the periodontium or even distant tissues. In periodontitis, the citrullination of proteins/peptides by human and bacterial peptidylarginine deiminases may generate antibodies after breaching immunotolerance in susceptible individuals.


Concurrent inhibition of enzymatic activity and NF-Y-mediated transcription of Topoisomerase-IIα by bis-DemethoxyCurcumin in cancer cells.
Topoisomerases-IIα (TOP2A) enzyme is essential for cell viability due to its fundamental role in DNA metabolism and in chromatin organization during interphase and mitosis. TOP2A expression is finely regulated at the transcriptional level through the binding of the CCAAT-transcription factor NF-Y to its promoter. Overexpression and/or amplification of TOP2A have been observed in many types of cancers. For this reason, TOP2A is the target of the most widely successful drugs in cancer chemotherapy, such as TOP2A poisons, which stabilize TOP2A-DNA cleavage complexes and create DSBs, leading to chromosome damage and cell death. We previously reported that the Curcumin-derivative bis-DemethoxyCurcumin (bDMC) is an anti-proliferative agent that inhibits cell growth by concomitant G1/S and G2/M arrest. Here we showed that bDMC irreversibly induces DSBs in cancer cells, but not in normal cells, by targeting TOP2A activity and expression. TOP2A ablation by siRNA corroborates its contribution to apoptosis induced by bDMC. Short-term exposure to bDMC induces retention of TOP2A-DNA intermediates, while longer exposure inhibits TOP2A transcription by affecting expression and sub-cellular localization of NF-Y subunits. ChIP analysis highlighted reduced recruitment of NF-Y to TOP2A regulatory regions, concomitantly to histone deacetylation and decreased gene transcription. Our findings suggest that the dual activity of bDMC on TOP2A represents a novel therapeutic strategy to induce persistent apoptosis in cancer cells and identify NF-Y regulation as a promising approach in anti-cancer therapy.


A randomized, phase 2 trial of docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer.
The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory HNSCC. Patients with locally advanced, recurrent or metastatic HNSCC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to a combination of docetaxel (75mg/m(2) IV every 21days) with or without PX-866 (8mg PO daily; Arms A and B, respectively). The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (RR), overall survival (OS), toxicity, and correlation of biomarker analyses with efficacy outcomes. 85 patients were enrolled. There was a non-significant improvement in response rate in the combination arm (14% vs. 5%; P=0.13). Median PFS was 92days in Arm A and 82days in Arm B (P=0.42). There was no difference in OS between the two arms (263 vs. 195days; P=0.62). Grade 3 or higher adverse events were infrequent, but more common in the combination arm with respect to diarrhea (17% vs. 2%), nausea (7% vs. 0%), and febrile neutropenia (21% vs. 5%); grade 3 or higher anemia was more frequent in arm B (7% vs. 27%). PIK3CA mutations or PTEN loss were infrequently observed. The addition of PX-866 to docetaxel did not improve PFS, RR, or OS in patients with advanced, refractory HNSCC without molecular pre-selection.


Higher-Order Mentalising and Executive Functioning.
Higher-order mentalising is the ability to represent the beliefs and desires of other people at multiple, iterated levels - a capacity that sets humans apart from other species. However, there has not yet been a systematic attempt to determine what cognitive processes underlie this ability. Here we present three correlational studies assessing the extent to which performance on higher-order mentalising tasks relates to emotion recognition, self-reported empathy and self-inhibition. In Study 1a and 1b, examining emotion recognition and empathy, a relationship was identified between individual differences in the ability to mentalise and an emotion recognition task (the Reading the Mind in the Eyes task), but no correlation was found with the Empathy Quotient, a self-report scale of empathy. Study 2 investigated whether a relationship exists between individual mentalising abilities and four different forms of self-inhibition: motor inhibition, executive inhibition, automatic imitation and temporal discounting. Results demonstrate that only temporal discounting performance relates to mentalising ability; suggesting that cognitive skills relevant to representation of the minds of others' are not influenced by the ability to perform more basic inhibition. Higher-order mentalising appears to rely on the cognitive architecture that serves both low-level social cognition (emotion recognition), and complex forms of inhibition.


Comparison Between the Accuracy of NovApex Apex Locator and Radiographs in Determining Radiographic Apex.
Determination of the canal working length with radiographs has many drawbacks. Electronic apex locators have been developed to overcome some of these problems. Recently, a newly designed apex locator called NovApex has been introduced. All the studies conducted to determine the accuracy of NovApex have been carried out in-vitro on extracted teeth. The aim of this in vivo study was to evaluate the accuracy of NovApex compared with traditional radiographic method. Twenty-five patients whose lower molars that were candidates for extraction were selected. The teeth were accessed, and the radiographic working length was determined by measuring the length of the initial file 0.5mm short of the radiographic apex. Then, NovApex apex locator was used to measure the electronic working length. Subsequently, the tooth was extracted, and the actual working length was measured by introducing a size #15 K-file into each canal until the file tip was visible at the apex, then 1.5mm was subtracted to attain the working length. Cohen's Kappa was computed for each of the methods versus actual working length as a measure of reliability. The accuracies were compared using Chi-square test. The accuracy of NovApex apex locator and radiographic method in detecting the apical end point within ±0.5mm was 74.7% and 68%, respectively; this was not significantly different (P<0.001). The NovApex apex locator is useful in detecting the apical end point with the accuracy similar to radiographic method. However, neither technique is fully reliable in detecting the apical end point of the canal.


An EST resource for cassava and other species of Euphorbiaceae.
Cassava (Manihot esculenta) is a major food staple for nearly 600 million people in Africa, Asia, and Latin America. Major losses in yield result from biotic and abiotic stresses that include diseases such as Cassava Mosaic Disease (CMD) and Cassava Bacterial Blight (CBB), drought, and acid soils. Additional losses also occur from deterioration during the post-harvest storage of roots. To help cassava breeders overcome these obstacles, the scientific community has turned to modern genomics approaches to identify key genetic characteristics associated with resistance to these yield-limiting factors. One approach for developing a genomics program requires the development of ESTs (expressed sequence tags). To date, nearly 23,000 ESTs have been developed from various cassava tissues, and genotypes. Preliminary analysis indicates existing EST resources contain at least 6000-7000 unigenes. Data presented in this report indicate that the cassava ESTs will be a valuable resource for the study of genetic diversity, stress resistance, and growth and development, not only in cassava, but also other members of the Euphorbiaceae family.


Gene expression profiling of primary cutaneous melanoma and clinical outcome.
Gene expression profiling data for human primary cutaneous melanomas are scarce because of the lack of retrospective collections of frozen tumors. To identify differentially expressed genes that may be involved in melanoma progression and prognosis, we investigated the relationship between gene expression profiles and clinical outcome in a cohort of patients with primary melanoma. Labeled complementary RNA (cRNA) from each tissue sample was hybridized to a pangenomic 44K 60-mer oligonucleotide microarray. Class comparison and class prediction analyses were performed to identify genes whose expression in primary melanomas was associated with 4-year distant metastasis-free survival among 58 patients with at least 4 years of follow-up, distant metastasis, or death. Results were validated immunohistochemically at the protein level in 176 independent primary melanomas from patients with a median clinical follow-up of 8.5 years. Survival was analyzed with a Cox multivariable model and stratified log-rank test. All statistical tests were two-sided. We identified 254 genes that were associated with distant metastasis-free survival of patients with primary melanoma. These 254 genes include genes involved in activating DNA replication origins, such as minichromosome maintenance genes and geminin. Twenty-three of these genes were studied at the protein level; expression of five (MCM4, P = .002; MCM3, P = .030; MCM6, P = .004; KPNA2, P = .021; and geminin, P = .004) was statistically significantly associated with overall survival in the validation set. In a multivariable Cox model adjusted for tumor thickness, ulceration, age, and sex, expression of MCM4 (hazard ratio [HR] of death = 4.04, 95% confidence interval [CI] = 1.39 to 11.76; P = .010) and MCM6 (HR of death = 7.42, 95% CI = 1.99 to 27.64; P = .003) proteins was still statistically significantly associated with overall survival. We identified 254 genes whose expression was associated with metastatic dissemination of cutaneous melanomas. These genes may shed light on the molecular mechanisms underlying poor prognosis in melanoma patients.


Practices Caring For The Underserved Are Less Likely To Adopt Medicare's Annual Wellness Visit.
In 2011 Medicare introduced the annual wellness visit to help address the health risks of aging adults. The visit also offers primary care practices an opportunity to generate revenue, and may allow practices in accountable care organizations to attract healthier patients while stabilizing patient-practitioner assignments. However, uptake of the visit has been uneven. Using national Medicare data for the period 2008-15, we assessed practices' ability and motivation to adopt the visit. In 2015, 51.2 percent of practices provided no annual wellness visits (nonadopters), while 23.1 percent provided visits to at least a quarter of their eligible beneficiaries (adopters). Adopters replaced problem-based visits with annual wellness visits and saw increases in primary care revenue. Compared to nonadopters, adopters had more stable patient assignment and a slightly healthier patient mix. At the same time, visit rates were lower among practices caring for underserved populations (for example, racial minorities and those dually enrolled in Medicaid), potentially worsening disparities. Policy makers should consider ways to encourage uptake of the visit or other mechanisms to promote preventive care in underserved populations and the practices that serve them.


The influence of pregnancy on disability from multiple sclerosis: a population-based study in Middlesex County, Ontario.
We analyzed the effect of pregnancy on long-term disability resulting from multiple sclerosis in 185 women ascertained through a retrospective population-based survey of MS in Middlesex County, Ontario, Canada. There was no association between disability and total number of term pregnancies, timing of pregnancy relative to onset of MS, or either onset or worsening of MS in relation to a pregnancy. The mean number of pregnancies both before and after onset of MS was no different among groups stratified according to disability. This study addresses some of the difficulties inherent in studying the effect of pregnancy on disability resulting from MS.


Low-density liquid water is the mother of ice: on the relation between mesostructure, thermodynamics and ice crystallization in solutions.
Predicting the temperature and extent of ice freezing in aqueous solutions is crucial for areas as diverse as cryobiology and materials design. It has long been recognized that the thermodynamics of liquid water controls the temperature and kinetics of ice crystallization. Parameterizations of the freezing temperatures in terms of the water activity of the solution have been successfully established, but the fundamental origin of the thermodynamic control of the non-equilibrium crystallization of ice has remained elusive. Here we use large-scale molecular simulations to elucidate the relationship between the structure, thermodynamics, and ice crystallization temperatures for solutions of mW water and a strongly hydrophilic solute that mimics LiCI ions. Fast cooling of solutions with up to 20 mol% ions results in the formation of nanosegregated glasses with domains of low-density amorphous ice and an ion-rich vitrified solution. Slow cooling of the mixtures results in nucleation and growth of ice within the domains of four-coordinated liquid water. The temperature of crystallization Tx coincides with the temperature of appearance of nanoscopic domains of four-coordinated liquid water in the mixture, T(L). We use the insight provided by the simulations to derive a thermodynamic expression for the crystallization temperature as a function of the water activity, T(X)(a(W)), analogous to the dependence of the melting temperature, T(m)(a(W)). The simple expression derived in this work provides a good account of the experimental freezing temperatures of water and the well-known steepest dependence of Tx on solute concentration compared to that of T(m).


Housing and health in three contrasting neighbourhoods in Accra, Ghana.
Although the literature on housing and health is extensive, most research comes from developed countries. Relatively little work on the topic has been done in developing countries such as Ghana where socio-economic and cultural characteristics are generally different. This paper reports on primary research that investigates the relationship between housing and self reported general and mental health in Accra, Ghana. The study focused on how the social and economic dimensions of housing, specifically, demand, control and material attributes (affordability, dwelling type) influence individuals' attachment to their home as a refuge for daily living. A cross-sectional survey was administered to a randomly selected sample (n = 562) in three contrasting neighbourhoods. Overall, housing conditions, demand and control residents have to where they live, emerged as significant predictors of self reported general and mental health status. The influence of these variables superseded well known correlates of health status, income and educational attainment, attesting to their importance in a worsening housing environment. The findings point to the need for policy that recognizes that housing is not only a physical shelter but also an important health resource.


Calibrating a novel multi-sensor physical activity measurement system.
Advancing the field of physical activity (PA) monitoring requires the development of innovative multi-sensor measurement systems that are feasible in the free-living environment. The use of novel analytical techniques to combine and process these multiple sensor signals is equally important. This paper describes a novel multi-sensor 'integrated PA measurement system' (IMS), the lab-based methodology used to calibrate the IMS, techniques used to predict multiple variables from the sensor signals, and proposes design changes to improve the feasibility of deploying the IMS in the free-living environment. The IMS consists of hip and wrist acceleration sensors, two piezoelectric respiration sensors on the torso, and an ultraviolet radiation sensor to obtain contextual information (indoors versus outdoors) of PA. During lab-based calibration of the IMS, data were collected on participants performing a PA routine consisting of seven different ambulatory and free-living activities while wearing a portable metabolic unit (criterion measure) and the IMS. Data analyses on the first 50 adult participants are presented. These analyses were used to determine if the IMS can be used to predict the variables of interest. Finally, physical modifications for the IMS that could enhance the feasibility of free-living use are proposed and refinement of the prediction techniques is discussed.


Bidirectional associations between mothers' and fathers' parenting consistency and child BMI.
Research suggests that general parenting dimensions and styles are associated with children's BMI, but directionality in this relationship remains unknown. Moreover, there has been little attention to the influences of both mothers' and fathers' parenting. We aimed to examine reciprocal relationships between maternal and paternal parenting consistency and child BMI. Participants were 4002 children and their parents in the population-based Longitudinal Study of Australian Children. Mothers and fathers self-reported parenting consistency, and children's BMI was measured at 4 biennial waves starting at age 4 to 5 years in 2004. Bidirectionality between parenting and child BMI was examined by using regression analyses in cross-lagged models. The best-fitting models indicated a modest influence from parenting to child BMI, whereas no support was found for bidirectional influences. For mothers, higher levels of parenting consistency predicted lower BMI in children from Waves 1 to 2 and 3 to 4; for example, for every SD increase in mothers' parenting consistency at Wave 1, child BMIz fell by 0.025 in Wave 2 (95% confidence interval: -0.05 to -0.003). For fathers, higher levels of parenting consistency were associated with lower child BMI from Waves 1 to 2 and 2 to 3. Parenting inconsistency of mothers and fathers prospectively predicted small increases in offspring BMI over 2-year periods across middle childhood. However, child BMI did not appear to influence parenting behavior. These findings support recent calls for expanding childhood overweight interventions to address the broad parenting context while involving both mothers and fathers.


Latitude and longitude vertical disparities.
The literature on vertical disparity is complicated by the fact that several different definitions of the term "vertical disparity" are in common use, often without a clear statement about which is intended or a widespread appreciation of the properties of the different definitions. Here, we examine two definitions of retinal vertical disparity: elevation-latitude and elevation-longitude disparities. Near the fixation point, these definitions become equivalent, but in general, they have quite different dependences on object distance and binocular eye posture, which have not previously been spelt out. We present analytical approximations for each type of vertical disparity, valid for more general conditions than previous derivations in the literature: we do not restrict ourselves to objects near the fixation point or near the plane of regard, and we allow for non-zero torsion, cyclovergence, and vertical misalignments of the eyes. We use these expressions to derive estimates of the latitude and longitude vertical disparities expected at each point in the visual field, averaged over all natural viewing. Finally, we present analytical expressions showing how binocular eye position-gaze direction, convergence, torsion, cyclovergence, and vertical misalignment-can be derived from the vertical disparity field and its derivatives at the fovea.


Multiple locus linkage analysis of genomewide expression in yeast.
With the ability to measure thousands of related phenotypes from a single biological sample, it is now feasible to genetically dissect systems-level biological phenomena. The genetics of transcriptional regulation and protein abundance are likely to be complex, meaning that genetic variation at multiple loci will influence these phenotypes. Several recent studies have investigated the role of genetic variation in transcription by applying traditional linkage analysis methods to genomewide expression data, where each gene expression level was treated as a quantitative trait and analyzed separately from one another. Here, we develop a new, computationally efficient method for simultaneously mapping multiple gene expression quantitative trait loci that directly uses all of the available data. Information shared across gene expression traits is captured in a way that makes minimal assumptions about the statistical properties of the data. The method produces easy-to-interpret measures of statistical significance for both individual loci and the overall joint significance of multiple loci selected for a given expression trait. We apply the new method to a cross between two strains of the budding yeast Saccharomyces cerevisiae, and estimate that at least 37% of all gene expression traits show two simultaneous linkages, where we have allowed for epistatic interactions. Pairs of jointly linking quantitative trait loci are identified with high confidence for 170 gene expression traits, where it is expected that both loci are true positives for at least 153 traits. In addition, we are able to show that epistatic interactions contribute to gene expression variation for at least 14% of all traits. We compare the proposed approach to an exhaustive two-dimensional scan over all pairs of loci. Surprisingly, we demonstrate that an exhaustive two-dimensional scan is less powerful than the sequential search used here. In addition, we show that a two-dimensional scan does not truly allow one to test for simultaneous linkage, and the statistical significance measured from this existing method cannot be interpreted among many traits.


Interactive exploration of surveillance video through action shot summarization and trajectory visualization.
We propose a novel video visual analytics system for interactive exploration of surveillance video data. Our approach consists of providing analysts with various views of information related to moving objects in a video. To do this we first extract each object's movement path. We visualize each movement by (a) creating a single action shot image (a still image that coalesces multiple frames), (b) plotting its trajectory in a space-time cube and (c) displaying an overall timeline view of all the movements. The action shots provide a still view of the moving object while the path view presents movement properties such as speed and location. We also provide tools for spatial and temporal filtering based on regions of interest. This allows analysts to filter out large amounts of movement activities while the action shot representation summarizes the content of each movement. We incorporated this multi-part visual representation of moving objects in sViSIT, a tool to facilitate browsing through the video content by interactive querying and retrieval of data. Based on our interaction with security personnel who routinely interact with surveillance video data, we identified some of the most common tasks performed. This resulted in designing a user study to measure time-to-completion of the various tasks. These generally required searching for specific events of interest (targets) in videos. Fourteen different tasks were designed and a total of 120 min of surveillance video were recorded (indoor and outdoor locations recording movements of people and vehicles). The time-to-completion of these tasks were compared against a manual fast forward video browsing guided with movement detection. We demonstrate how our system can facilitate lengthy video exploration and significantly reduce browsing time to find events of interest. Reports from expert users identify positive aspects of our approach which we summarize in our recommendations for future video visual analytics systems.


NF2 Loss Promotes Oncogenic RAS-Induced Thyroid Cancers via YAP-Dependent Transactivation of RAS Proteins and Sensitizes Them to MEK Inhibition.
Ch22q LOH is preferentially associated with RAS mutations in papillary and in poorly differentiated thyroid cancer (PDTC). The 22q tumor suppressor NF2, encoding merlin, is implicated in this interaction because of its frequent loss of function in human thyroid cancer cell lines. Nf2 deletion or Hras mutation is insufficient for transformation, whereas their combined disruption leads to murine PDTC with increased MAPK signaling. Merlin loss induces RAS signaling in part through inactivation of Hippo, which activates a YAP-TEAD transcriptional program. We find that the three RAS genes are themselves YAP-TEAD1 transcriptional targets, providing a novel mechanism of promotion of RAS-induced tumorigenesis. Moreover, pharmacologic disruption of YAP-TEAD with verteporfin blocks RAS transcription and signaling and inhibits cell growth. The increased MAPK output generated by NF2 loss in RAS-mutant cancers may inform therapeutic strategies, as it generates greater dependency on the MAPK pathway for viability. Intensification of mutant RAS signaling through copy-number imbalances is commonly associated with transformation. We show that NF2/merlin inactivation augments mutant RAS signaling by promoting YAP/TEAD-driven transcription of oncogenic and wild-type RAS, resulting in greater MAPK output and increased sensitivity to MEK inhibitors.


Confronting surface hopping molecular dynamics with Marcus theory for a molecular donor-acceptor system.
We investigate the performance of fewest switches surface hopping (SH) in describing electron transfer (ET) for a molecular donor-acceptor system. Computer simulations are carried out for a wide range of reorganisation energy (λ), electronic coupling strength (Hab) and driving force using our recently developed fragment orbital-based SH approach augmented with a simple decoherence correction. This methodology allows us to compute SH ET rates over more than four orders of magnitude, from the sub-picosecond to the nanosecond time regime. We find good agreement with semi-classical ET theory in the non-adiabatic ET regime. The correct scaling of the SH ET rate with electronic coupling strength is obtained and the Marcus inverted regime is reproduced, in line with previously reported results for a spin-boson model. Yet, we find that the SH ET rate falls below the semi-classical ET rate in the adiabatic regime, where the free energy barrier is in the order of kBT in our simulations. We explain this by first signatures of non-exponential population decay of the initial charge state. For even larger electronic couplings (Hab = λ/2), the free energy barrier vanishes and ET rates are no longer defined. At this point we observe a crossover from ET on the vibronic time scale to charge relaxation on the femtosecond time scale that is well described by thermally averaged Rabi oscillations. The extension of the analysis from the non-adiabatic limit to large electronic couplings and small or even vanishing activation barriers is relevant for our understanding of charge transport in organic semiconductors.


No association observed between schizophrenia and non-HLA coeliac disease genes: integration with the initial MYO9B association with coeliac disease.
Schizophrenia is a severe psychotic illness with a heterogeneous presentation and a devastating impact on social and occupational function. Worldwide variations in schizophrenia incidence rates suggest that local conditions may modify disease risk. The human leukocyte antigen (HLA) region has been confirmed to be associated with schizophrenia by genome-wide association studies in populations across the world. While the presence of autoimmune processes in a subgroup of schizophrenia cases is contentious, the immune system could allow environmental exposures to lead to schizophrenia by generating improper immune response. To investigate this topic, we reviewed the current evidence of the relationship between schizophrenia and coeliac disease. Based on this review, we performed genetic analysis of the MYO9B gene and the IL-2/IL-21 locus by genotyping SNPs that have been previously associated with coeliac disease or schizophrenia in 223 families, 108 unrelated individuals with schizophrenia and 120 controls. Finding no evidence for association with these two loci in our study samples, we applied meta-analytic techniques to combine our findings with previous reports. This synthesis, in light of our review of previous reports, suggests a differing developmental trajectory for schizophrenia and coeliac disease. It is possible that these two conditions do not share any functional overlap.


Resource utilization of pediatric patients exposed to venom.
Treating envenomation with antivenom is costly. Many patients being treated with antivenom are in observation status, a billing designation for patients considered to need care that is less resource-intensive, and less expensive, than inpatient care. Observation status is also associated with lower hospital reimbursements and higher patient cost-sharing. The goal of this study was to examine resource utilization for treatment of envenomation under observation and inpatient status, and to compare patients in observation status receiving antivenom with all other patients in observation status. This was a retrospective study of patients with a primary diagnosis of toxic effect of venom seen during 2009 at 33 freestanding children's hospitals in the Pediatric Health Information System. Data on age, length of stay, adjusted costs (ratio cost to charges), ICU flags, and antivenom utilization were collected. Comparisons were conducted according to admission status (emergency department only, observation status, and inpatient status), and between patients in observation status receiving antivenom and patients in observation status with other diagnoses. A total of 2755 patients had a primary diagnosis of toxic effect of venom. Of the 335 hospitalized, either under observation (n = 124) or inpatient (n = 211) status, 107 (31.9%) received antivenom. Of those hospitalized patients receiving antivenom, 24 (22.4%) were designated as observation status. Costs were substantially higher for patients who received antivenom and were driven by pharmacy costs (mean cost: $17 665 for observation status, $20 503 for inpatient status). Mean costs for the 47 162 patients in observation status with other diagnoses were $3001 compared with $17 665 for observation-status patients who received antivenom. Treatment of envenomation with antivenom represents a high-cost outlier within observation-status hospitalizations. Observation status can have financial consequences for hospitals and patients.


High-Speed Efficient Terahertz Modulation Based on Tunable Collective-Individual State Conversion within an Active 3 nm Two-Dimensional Electron Gas Metasurface.
Terahertz (THz) modulators are always realized by dynamically manipulating the conversion between different resonant modes within a single unit cell of an active metasurface. In this Letter, to achieve real high-speed THz modulation, we present a staggered netlike two-dimensional electron gas (2DEG) nanostructure composite metasurface that has two states: a collective state with massive surface resonant characteristics and an individual state with meta-atom resonant characteristics. By controlling the electron transport of the nanoscale 2DEG with an electrical grid, collective-individual state conversion can be realized in this composite metasurface. Unlike traditional resonant mode conversion confined in meta-units, this state conversion enables the resonant modes to be flexibly distributed throughout the metasurface, leading to a frequency shift of nearly 99% in both the simulated and experimental transmission spectra. Moreover, such a mechanism can effectively suppress parasitic modes and significantly reduce the capacitance of the metasurface. Thereby, this composite metasurface can efficiently control the transmission characteristics of THz waves with high-speed modulations. As a result, 93% modulation depth is observed in the static experiment and modulated sinusoidal signals up to 3 GHz are achieved in the dynamic experiment, while the -3 dB bandwidth can reach up to 1 GHz. This tunable collective-individual state conversion may have great application potential in wireless communication and coded imaging.


Reproductive health surveillance in the US-Mexico border region, 2003-2006: the Brownsville-Matamoros Sister City Project for Women's Health.
High birth and immigration rates in the US-Mexico border region have led to large population increases in recent decades. Two national, 10 state, and more than 100 local government entities deliver reproductive health services to the region's 14 million residents. Limited standardized information about health risks in this population hampers capacity to address local needs and assess effectiveness of public health programs. We worked with binational partners to develop a system for reproductive health surveillance in the sister communities of Matamoros, Tamaulipas, Mexico, and Cameron County, Texas, as a model for a broader regional approach. We used a stratified, systematic cluster-sampling design to sample women giving birth in hospitals in each community during an 81-day period (August 21-November 9) in 2005. We conducted in-hospital computer-assisted personal interviews that addressed prenatal, behavioral, and lifestyle factors. We evaluated survey response rates, data quality, and other attributes of effective surveillance systems. We estimated population coverage using vital records data. Among the 999 women sampled, 947 (95%) completed interviews, and the item nonresponse rate was low. The study sample included 92.7% of live births in Matamoros and 98.3% in Cameron County. Differences between percentage distributions of birth certificate characteristics in the study and target populations did not exceed 2.0. Study population coverage among hospitals ranged from 92.9% to 100.0%, averaging 97.3% in Matamoros and 97.4% in Cameron County. Results indicate that hospital-based sampling and postpartum interviewing constitute an effective approach to reproductive health surveillance. Such a system can yield valuable information for public health programs serving the growing US-Mexico border population.


High titers and low fucosylation of early human anti-SARS-CoV-2 IgG promote inflammation by alveolar macrophages.
Patients diagnosed with coronavirus disease 2019 (COVID-19) become critically ill primarily around the time of activation of the adaptive immune response. Here, we provide evidence that antibodies play a role in the worsening of disease at the time of seroconversion. We show that early-phase severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific immunoglobulin G (IgG) in serum of critically ill COVID-19 patients induces excessive inflammatory responses by human alveolar macrophages. We identified that this excessive inflammatory response is dependent on two antibody features that are specific for patients with severe COVID-19. First, inflammation is driven by high titers of anti-spike IgG, a hallmark of severe disease. Second, we found that anti-spike IgG from patients with severe COVID-19 is intrinsically more proinflammatory because of different glycosylation, particularly low fucosylation, of the antibody Fc tail. Low fucosylation of anti-spike IgG was normalized in a few weeks after initial infection with SARS-CoV-2, indicating that the increased antibody-dependent inflammation mainly occurs at the time of seroconversion. We identified Fcγ receptor (FcγR) IIa and FcγRIII as the two primary IgG receptors that are responsible for the induction of key COVID-19-associated cytokines such as interleukin-6 and tumor necrosis factor. In addition, we show that anti-spike IgG-activated human macrophages can subsequently break pulmonary endothelial barrier integrity and induce microvascular thrombosis in vitro. Last, we demonstrate that the inflammatory response induced by anti-spike IgG can be specifically counteracted by fostamatinib, an FDA- and EMA-approved therapeutic small-molecule inhibitor of Syk kinase.


Expression and purification of histidine-tagged bacteriophage T7 DNA polymerase.
The formation of inclusion bodies is a frequent consequence of high-level production of foreign protein in the cytoplasm of Escherichia coli. This phenomenon is also observed with bacteriophage T7 gene 5 protein, the phage-encoded subunit of T7 DNA polymerase, if expression is based on the T5 promoter/lac operator transcription-translation system present in a vector with ColE1 origin of replication. To avoid tedious procedures for recovering protein from insoluble aggregates, we studied the expression of T7 gene 5 protein using a series of E. coli strains, and optimized the yield of soluble, histidine-tagged (His-tagged) protein by varying the respective growth conditions (temperature, amount of inducer isopropyl-beta-d-thiogalactopyranoside, and presence of organic osmolytes). Although the expression levels in three different strains (BL21, SG13009, and XL1-Blue) were almost comparable with a given set of growth conditions, the yields of soluble protein differed markedly. The largest quantities of soluble, His-tagged T7 gene 5 protein were achieved using "cloning strain" XL1-Blue which benefitted significantly from the presence of sorbitol and glycine betaine-in contrast to the expression strains BL21 and SG13009. Purification of His-tagged T7 gene 5 protein was achieved using single-step metal-affinity chromatography that yielded large amounts of highly active polymerase (97% homogeneity). The application of this expression/purification approach represents not only a useful method to purify large quantities of T7 DNA polymerase for structural investigations but also, provides a fast and efficient protocol for the parallel purification of T7 DNA polymerase variants, e.g., for automated screenings or directed evolution experiments.


Ostrich eggshell bead diameter in the Holocene: Regional variation with the spread of herding in eastern and southern Africa.
Despite their ubiquity in Holocene African archaeological assemblages, ostrich eggshell (OES) beads are rarely studied in detail. An exception is in southern Africa, where there is a proposed relationship between OES bead diameter and the arrival of herding ~2000 years before present. In 1987, Leon Jacobson first observed that beads from forager sites in Namibia tended to be smaller than those associated with herder sites. Studies examining bead size around the Western Cape have generally confirmed Jacobson's findings, though the driving forces of the diameter change remain unknown. Since this time, diameter has become an informal way of distinguishing forager and herder assemblages in southern Africa, but no large-scale studies of OES bead variation have been undertaken. Here we present an expanded analysis of Holocene OES bead diameters from southern, and for the first time, eastern Africa. Results reveal distinct patterns in OES bead size over time, reflecting different local dynamics associated with the spread of herding. In southern Africa, OES diameters display low variability and smaller absolute size through time. While larger beads begin to appear <2000 years ago, most beads in our study remained smaller. In contrast, eastern African OES bead diameters are consistently larger over the last 10,000 years and show no appreciable size change with the introduction of herding. Notably, larger beads thought to be associated with herders in southern Africa fall within the range of eastern African beads, indicating a potential connection between these regions in the Late Holocene consistent with genetic findings. Regional differences in bead size are subtle, on the order of millimeters, yet offer a potentially important line of evidence for investigating the spread of herding in sub-Saharan Africa. In order to understand the meaning of these changes, we encourage additional studies of OES bead assemblages and urge researchers to report individual bead diameters, rather than averages by level.


Synchronous high-resolution phenotyping of leaf and root growth in Nicotiana tabacum over 24-h periods with GROWMAP-plant.
Root growth is highly responsive to temporal changes in the environment. On the contrary, diel (24 h) leaf expansion in dicot plants is governed by endogenous control and therefore its temporal pattern does not strictly follow diel changes in the environment. Nevertheless, root and shoot are connected with each other through resource partitioning and changing environments for one organ could affect growth of the other organ, and hence overall plant growth. We developed a new technique, GROWMAP-plant, to monitor growth processes synchronously in leaf and root of the same plant with a high resolution over the diel period. This allowed us to quantify treatment effects on the growth rates of the treated and non-treated organ and the possible interaction between them. We subjected the root system of Nicotiana tabacum seedlings to three different conditions: constant darkness at 22°C (control), constant darkness at 10°C (root cooling), and 12 h/12 h light-dark cycles at 22°C (root illumination). In all treatments the shoot was kept under the same 12 h/12 h light-dark cycles at 22°C. Root growth rates were found to be constant when the root-zone environment was kept constant, although the root cooling treatment significantly reduced root growth. Root velocity was decreased after light-on and light-off events of the root illumination treatment, resulting in diel root growth rhythmicity. Despite these changes in root growth, leaf growth was not affected substantially by the root-zone treatments, persistently showing up to three times higher nocturnal growth than diurnal growth. GROWMAP-plant allows detailed synchronous growth phenotyping of leaf and root in the same plant. Root growth was very responsive to the root cooling and root illumination, while these treatments altered neither relative growth rate nor diel growth pattern in the seedling leaf. Our results that were obtained simultaneously in growing leaves and roots of the same plants corroborate the high sensitivity of root growth to the environment and the contrasting robustness of diel growth patterns in dicot leaves. Further, they also underpin the importance to carefully control the experimental conditions for root growth analysis to avoid or/and minimize artificial complications.


Dental care for patients with heart failure: an update.
Heart failure (HF) is a common clinical syndrome that affects an estimated 5.7 million Americans. It is a growing health problem, particularly in people 65 years or older. Therefore, the probability that dental practitioners will have patients who have HF is increasing. The authors reviewed medical literature from 2000 through 2009 to determine the incidence, classifications, pathophysiology and advances in the medical diagnosis and treatment of HF. They also reviewed available dental literature during the same period to formulate treatment recommendations for dental care of people who have HF. Medicine has made advances in understanding and treating HF. These advances have resulted in the development of revised classification systems, a more structured approach to patient assessment and improved therapeutic options. Dentists need to be aware of advances in the diagnosis and treatment of HF. Keeping in mind the potential for morbidity in patients who have HF, identifying and accurately assessing these patients is imperative for clinical management. Often it is necessary for dentists to consult with patients' physicians to coordinate care and determine whether treatment can be rendered appropriately in a routine dental setting or whether advanced support, monitoring or both are necessary.


Systemic injections of alpha-1 adrenergic agonists produce antinociception in the formalin test.
The role of alpha 1 receptors in antinociception was investigated in the formalin test, a well established test of tonic pain. The effect of systemic injections of selective alpha 1-adrenergic agonists (phenylephrine and methoxamine), a mixed alpha agonist selective for alpha 2 receptors (ST-91), and 2 adrenergic antagonists (prazosin and idazoxan) was measured in groups of Long-Evans rats. All agonists tested produced significant antinociception in this test. Dose-response curves for each agonist were statistically parallel and equally efficacious (100% antinociception). Prior injection of 0.15 mg/kg prazosin (an alpha 1 antagonist) completely antagonized the antinociception produced by either an ED50 or a maximally effective dose of each agonist tested. Idazoxan (0.5 mg/kg), an alpha 2 antagonist, was without effect on the antinociception produced by phenylephrine or methoxamine. ST-91 produced significant antinociception in the presence of idazoxan although the response was different from that obtained with ST-91 alone. The observed antinociception in the formalin test was not due to drug-induced changes in peripheral inflammation as measured using plethysmometry. Moreover, none of the drugs tested produced significant changes in coordinated motor behavior (accelerated rotarod test) at doses that produced significant analgesia (ED50). We conclude that alpha 1 receptors contribute significantly to adrenergic analgesia in the formalin test by an undefined action on sensory processing mechanisms.