Deep Rationality: The Evolutionary Economics of Decision Making.
What is a "rational" decision? Economists traditionally viewed rationality as maximizing expected satisfaction. This view has been useful in modeling basic microeconomic concepts, but falls short in accounting for many everyday human decisions. It leaves unanswered why some things reliably make people more satisfied than others, and why people frequently act to make others happy at a cost to themselves. Drawing on an evolutionary perspective, we propose that people make decisions according to a set of principles that may not appear to make sense at the superficial level, but that demonstrate rationality at a deeper evolutionary level. By this, we mean that people use adaptive domain-specific decision-rules that, on average, would have resulted in fitness benefits. Using this framework, we re-examine several economic principles. We suggest that traditional psychological functions governing risk aversion, discounting of future benefits, and budget allocations to multiple goods, for example, vary in predictable ways as a function of the underlying motive of the decision-maker and individual differences linked to evolved life-history strategies. A deep rationality framework not only helps explain why people make the decisions they do, but also inspires multiple directions for future research.


Mode conversion and coupling in a slanted grating.
We have proposed a novel transmission slanted grating at the central wavelength of 1550 nm, which can be used in optical communication. We have presented an approximate analytical expression that provides an insightful physical description of the simplified modal method for the slanted grating. The odd grating mode, which only exists in the asymmetric structure under normal incidence, plays the positive role of enhancing the -1st order diffraction efficiency. The analytic expressions of mode conversion and coupling can be obtained to explain the asymmetric field distribution, which cannot occur in the rectangular grating region. Numerical results achieved by the rigorous wave analysis verify the validity of the simplified modal method. We expect that the theoretical modal method set forth in this work will be helpful for the tremendous potential application of the slanted grating.


The Emerging Role of Nutritional Vitamin D in Secondary Hyperparathyroidism in CKD.
In chronic kidney disease (CKD), hyperphosphatemia induces fibroblast growth factor-23 (FGF-23) expression that disturbs renal 1,25-dihydroxy vitamin D (1,25D) synthesis; thereby increasing parathyroid hormone (PTH) production. FGF-23 acts on the parathyroid gland (PTG) to increase 1α-hydroxylase activity and results in increase intra-gland 1,25D production that attenuates PTH secretion efficiently if sufficient 25D are available. Interesting, calcimimetics can further increase PTG 1α-hydroxylase activity that emphasizes the demand for nutritional vitamin D (NVD) under high PTH status. In addition, the changes in hydroxylase enzyme activity highlight the greater parathyroid 25-hydroxyvitmain D (25D) requirement in secondary hyperparathyroidism (SHPT); the higher proportion of oxyphil cells as hyperplastic parathyroid progression; lower cytosolic vitamin D binding protein (DBP) content in the oxyphil cell; and calcitriol promote vitamin D degradation are all possible reasons supports nutritional vitamin D (NVD; e.g., Cholecalciferol) supplement is crucial in SHPT. Clinically, NVD can effectively restore serum 25D concentration and prevent the further increase in PTH level. Therefore, NVD might have the benefit of alleviating the development of SHPT in early CKD and further lowering PTH in moderate to severe SHPT in dialysis patients.


Comparative genomics of Salmonella enterica serovar Montevideo reveals lineage-specific gene differences that may influence ecological niche association.
Salmonella enterica serovar Montevideo has been linked to recent foodborne illness outbreaks resulting from contamination of products such as fruits, vegetables, seeds and spices. Studies have shown that Montevideo also is frequently associated with healthy cattle and can be isolated from ground beef, yet human salmonellosis outbreaks of Montevideo associated with ground beef contamination are rare. This disparity fuelled our interest in characterizing the genomic differences between Montevideo strains isolated from healthy cattle and beef products, and those isolated from human patients and outbreak sources. To that end, we sequenced 13 Montevideo strains to completion, producing high-quality genome assemblies of isolates from human patients (n=8) or from healthy cattle at slaughter (n=5). Comparative analysis of sequence data from this study and publicly available sequences (n=72) shows that Montevideo falls into four previously established clades, differentially occupied by cattle and human strains. The results of these analyses reveal differences in metabolic islands, environmental adhesion determinants and virulence factors within each clade, and suggest explanations for the infrequent association between bovine isolates and human illnesses.


Livedoid vasculopathy and high levels of lipoprotein (a): response to danazol.
Livedoid vasculopathy (LV) is a thrombo occlusive disorder presenting with recurrent painful ulcers of lower extremities. Association of LV with increased level of lipoprotein (a) (LP(a)), a risk factor for cardiovascular disease, has been reported. Danazol has been used with success in the management of LV, but none of the previous studies looked at the correlation between response to the treatment and level of LP(a). The aim of this study was to demonstrate the efficacy of low-dose danazol in the treatment of LV and its effects on LP(a). We present four cases with LV who were successfully treated with low-dose danazol, assessing the clinical characteristics and laboratory tests including the level of LP(a). The average age of the patients was 45 years and the mean duration of the disease was 19 years. The treatment regime of danazol 200 mg daily led to complete healing of ulcers and reduction in pain and a 70% (ranging from 52 to 87%) reduction in the level of LP(a). The limitation of this study is "small sample size." In our patients with LV, low-dose danazol led to clinical improvement along with significant reduction in the level of LP(a).


Effects of Active and Passive Hearing Protection Devices on Sound Source Localization, Speech Recognition, and Tone Detection.
Hearing protection devices (HPDs) such as earplugs offer to mitigate noise exposure and reduce the incidence of hearing loss among persons frequently exposed to intense sound. However, distortions of spatial acoustic information and reduced audibility of low-intensity sounds caused by many existing HPDs can make their use untenable in high-risk (e.g., military or law enforcement) environments where auditory situational awareness is imperative. Here we assessed (1) sound source localization accuracy using a head-turning paradigm, (2) speech-in-noise recognition using a modified version of the QuickSIN test, and (3) tone detection thresholds using a two-alternative forced-choice task. Subjects were 10 young normal-hearing males. Four different HPDs were tested (two active, two passive), including two new and previously untested devices. Relative to unoccluded (control) performance, all tested HPDs significantly degraded performance across tasks, although one active HPD slightly improved high-frequency tone detection thresholds and did not degrade speech recognition. Behavioral data were examined with respect to head-related transfer functions measured using a binaural manikin with and without tested HPDs in place. Data reinforce previous reports that HPDs significantly compromise a variety of auditory perceptual facilities, particularly sound localization due to distortions of high-frequency spectral cues that are important for the avoidance of front-back confusions.


Disruption of LDL but not VLDL clearance in autosomal recessive hypercholesterolemia.
Genetic defects in LDL clearance result in severe hypercholesterolemia and premature atherosclerosis. Mutations in the LDL receptor (LDLR) cause familial hypercholesterolemia (FH), the most severe form of genetic hypercholesterolemia. A phenocopy of FH, autosomal recessive hypercholesterolemia (ARH), is due to mutations in an adaptor protein involved in LDLR internalization. Despite comparable reductions in LDL clearance rates, plasma LDL levels are substantially lower in ARH than in FH. To determine the metabolic basis for this difference, we examined the synthesis and catabolism of VLDL in murine models of FH (Ldlr(-/-)) and ARH (Arh(-/-)). The hyperlipidemic response to a high-sucrose diet was greatly attenuated in Arh(-/-) mice compared with Ldlr(-/-) mice despite similar rates of VLDL secretion. The rate of VLDL clearance was significantly higher in Arh(-/-) mice than in Ldlr(-/-) mice, suggesting that LDLR-dependent uptake of VLDL is maintained in the absence of ARH. Consistent with these findings, hepatocytes from Arh(-/-) mice (but not Ldlr(-/-) mice) internalized beta-migrating VLDL (beta-VLDL). These results demonstrate that ARH is not required for LDLR-dependent uptake of VLDL by the liver. The preservation of VLDL remnant clearance attenuates the phenotype of ARH and likely contributes to greater responsiveness to statins in ARH compared with FH.


A Novel Malaria Pf/Pv Ab Rapid Diagnostic Test Using a Differential Diagnostic Marker Identified by Network Biology.
Rapid diagnostic tests (RDTs) can detect anti-malaria antibodies in human blood. As they can detect parasite infection at the low parasite density, they are useful in endemic areas where light infection and/or re-infection of parasites are common. Thus, malaria antibody tests can be used for screening bloods in blood banks to prevent transfusion-transmitted malaria (TTM), an emerging problem in malaria endemic areas. However, only a few malaria antibody tests are available in the microwell-based assay format and these are not suitable for field application. A novel malaria antibody (Ab)-based RDT using a differential diagnostic marker for falciparum and vivax malaria was developed as a suitable high-throughput assay that is sensitive and practical for blood screening. The marker, merozoite surface protein 1 (MSP1) was discovered by generation of a Plasmodium-specific network and the hierarchical organization of modularity in the network. Clinical evaluation revealed that the novel Malaria Pf/Pv Ab RDT shows improved sensitivity (98%) and specificity (99.7%) compared with the performance of a commercial kit, SD BioLine Malaria P.f/P.v (95.1% sensitivity and 99.1% specificity). The novel Malaria Pf/Pv Ab RDT has potential for use as a cost-effective blood-screening tool for malaria and in turn, reduces TTM risk in endemic areas.


Barrett's esophagus: recent insights into pathogenesis and cellular ontogeny.
Esophageal adenocarcinoma (EAC) has increased 6-fold in its incidence in the last 2 decades. Evidence supports the hypothesis of stepwise progression from normal squamous epithelium → reflux esophagitis → metaplasia (Barrett's esophagus, BE) → dysplasia → adenocarcinoma. The precursor, BE, stands as the bridge connecting the widespread but naive reflux disease and the rare but fatal EAC. The step of metaplasia from squamous to intestine-like columnar phenotype is perhaps pivotal in promoting dysplastic vulnerability. It is widely accepted that chronic inflammation because of gastroesophageal reflux disease leads to the development of metaplasia, however the precise molecular mechanism is yet to be discovered. Additionally, how this seemingly adaptive change in the cellular phenotype promotes dysplasia remains a mystery. This conceptual void is deterring further translational research and clouding clinical decision making. This article critically reviews theories on the pathogenesis of Barrett's esophagus and the various controversies surrounding its diagnosis. We further discuss unanswered questions and future directions, which are vital in formulating effective preventive and therapeutic guidelines for Barrett's esophagus.


Mapping of a candidate region for susceptibility to inclusion body myositis in the human major histocompatibility complex.
Inclusion body myositis (IBM) is a form of idiopathic inflammatory myopathy of unknown aetiology. A strong association with HLA class II (HLA-DR3) suggested a role for genes in the human major histocompatibility complex (MHC) in the predisposition to this disease. In this study, we have taken advantage of the ancestral haplotype (AH) concept and historical recombinations to map for a possible susceptibility gene(s) in the MHC. We performed detailed typing of three MHC-related HSP70 genes and defined allelic combinations in the context of MHC AH. We also modified existing methods to give a simple and accurate method for typing two TNF microsatellites. Using the HSP70 and TNF markers and HLA-DR, -B, and C4 typing of our patients with IBM, we defined a potential site for the MHC-associated susceptibility gene(s) in the region between HLA-DR and C4.


Non-strategic ignorance: Considering the potential for a paradigm shift in evidence-based mental health.
Randomised controlled trials form a central building block within the prevailing evidence-based mental health paradigm. Both methodology and paradigm have been widely problematised since their emergence in the mid-late twentieth century. We draw on the concept of 'strategic ignorance' to understand why the paradigm still prevails. We present focus group data gathered from 37 participants (service users, public, carers, general practitioners, commissioners) concerning the way they made sense of a randomised controlled trial of psychotherapy for treatment-resistant depression. Thematic analysis of the findings revealed an overall critique of randomised controlled trial methods which we refer to as 'non-strategic ignorance'. Specifically, participants problematised the construct of depression, unseating the premise of the randomised controlled trial; they were sceptical about the purpose and highlighted its failure to show how therapy works or who might benefit; the randomised controlled trial was seen as inadequate for informing decisions about how to select a therapy. Participants assumed the treatment would be cost-effective given the client group and nature of the therapy, irrespective of any randomised controlled trial findings. Each area of lay ('non-strategic') critique has an analogous form within the methodological expert domain. We argue that 'expert' critiques have generally failed to have paradigmatic impact because they represent strategic ignorance. Yet parallel non-strategic critiques have common sense appeal, highlighting the potential power of lay voices. The discussion considers whether the evidence-based mental health paradigm is faced with epistemological problems of such complexity that the conditions exist for a new paradigm in which service user views are central and randomised controlled trials peripheral.


Cerebrospinal Fluid Total Prion Protein in the Spectrum of Prion Diseases.
Cerebrospinal fluid (CSF) total prion protein (t-PrP) is decreased in sporadic Creutzfeldt-Jakob disease (sCJD). However, data on the comparative signatures of t-PrP across the spectrum of prion diseases, longitudinal changes during disease progression, and levels in pre-clinical cases are scarce. T-PrP was quantified in neurological diseases (ND, n = 147) and in prion diseases from different aetiologies including sporadic (sCJD, n = 193), iatrogenic (iCJD, n = 12) and genetic (n = 209) forms. T-PrP was also measured in serial lumbar punctures obtained from sCJD cases at different symptomatic disease stages, and in asymptomatic prion protein gene (PRNP) mutation carriers. Compared to ND, t-PrP concentrations were significantly decreased in sCJD, iCJD and in genetic prion diseases associated with the three most common mutations E200K, V210I (associated with genetic CJD) and D178N-129M (associated with fatal familial insomnia). In contrast, t-PrP concentrations in P102L mutants (associated with the Gerstmann-Sträussler-Scheinker syndrome) remained unaltered. In serial lumbar punctures obtained at different disease stages of sCJD patients, t-PrP concentrations inversely correlated with disease progression. Decreased mean t-PrP values were detected in asymptomatic D178-129M mutant carriers, but not in E200K and P102L carriers. The presence of low CSF t-PrP is common to all types of prion diseases regardless of their aetiology albeit with mutation-specific exceptions in a minority of genetic cases. In some genetic prion disease, decreased levels are already detected at pre-clinical stages and diminish in parallel with disease progression. Our data indicate that CSF t-PrP concentrations may have a role as a pre-clinical or early symptomatic diagnostic biomarker in prion diseases as well as in the evaluation of therapeutic interventions.


Active fluids at circular boundaries: swim pressure and anomalous droplet ripening.
We investigate the swim pressure exerted by non-chiral and chiral active particles on convex or concave circular boundaries. Active particles are modeled as non-interacting and non-aligning self-propelled Brownian particles. The convex and concave circular boundaries are used to model a fixed inclusion immersed in an active bath and a cavity (or container) enclosing the active particles, respectively. We first present a detailed analysis of the role of convex versus concave boundary curvature and of the chirality of active particles in their spatial distribution, chirality-induced currents, and the swim pressure they exert on the bounding surfaces. The results will then be used to predict the mechanical equilibria of suspended fluid enclosures (generically referred to as 'droplets') in a bulk with active particles being present either inside the bulk fluid or within the suspended droplets. We show that, while droplets containing active particles behave in accordance with standard capillary paradigms when suspended in a normal bulk, those containing a normal fluid exhibit anomalous behaviors when suspended in an active bulk. In the latter case, the excess swim pressure results in non-monotonic dependence of the inside droplet pressure on the droplet radius; hence, revealing an anomalous regime of behavior beyond a threshold radius, in which the inside droplet pressure increases upon increasing the droplet size. Furthermore, for two interconnected droplets, mechanical equilibrium can occur also when the droplets have different sizes. We thus identify a regime of anomalous droplet ripening, where two unequal-sized droplets can reach a final state of equal size upon interconnection, in stark contrast with the standard Ostwald ripening phenomenon, implying shrinkage of the smaller droplet in favor of the larger one.


Life under COVID-19 for LGBT+ people in the UK: systematic review of UK research on the impact of COVID-19 on sexual and gender minority populations.
To systematically review all published and unpublished evidence on the impact of the COVID-19 pandemic on the health and well-being of UK sexual and gender minority (LGBT+; lesbian, gay, bisexual, transgender, non-binary, intersex and queer) people. Any relevant studies with or without comparator were included, with outcomes of: COVID-19 incidence, hospitalisation rates, illness severity, death rates, other health and well-being. Six databases (platforms) were searched-CINAHL Plus (Ovid), Cochrane Central (Cochrane Library), Medline (Ovid), Embase (Ovid), Science Citation Index (Web of Science) and Scopus between 2019 and 2020 in December 2020, using synonyms for sexual and gender minorities and COVID-19 search terms. Data extraction and quality assessment (using the relevant Joanna Briggs checklist) were in duplicate with differences resolved through discussion. Results were tabulated and synthesis was through narrative description. No published research was found on any outcomes. Eleven grey literature reports found to be of low quality were included, mostly conducted by small LGBT+ charities. Only four had heterosexual/cisgender comparators. Mental health and well-being, health behaviours, safety, social connectedness and access to routine healthcare all showed poorer or worse outcomes than comparators. Lack of research gives significant concern, given pre-existing health inequities. Social and structural factors may have contributed to poorer outcomes (mental health, well-being and access to healthcare). Paucity of evidence is driven by lack of routinely collected sexual orientation and gender identity data, possibly resulting from institutional homophobia/transphobia which needs to be addressed. Men are more at risk of serious illness from COVID-19 than women, so using data from trans women and men might have started to answer questions around whether higher rates were due to sex hormone or chromosomal effects. Routine data collection on sexual orientation and gender identity is required to examine the extent to which COVID-19 is widening pre-existing health inequalities. CRD42020224304.


Posttraumatic stress among hospitalized and nonhospitalized survivors of serious car crashes: a population-based study.
This study investigated the prevalence of posttraumatic stress among survivors of serious injury-producing car crashes. This population-based prospective cohort study, conducted in New Zealand, recruited hospitalized car occupants (passengers and drivers) as well as nonhospitalized drivers after a crash in which at least one occupant was hospitalized. Fifty-nine hospitalized passengers (62%) and 209 drivers (72%) completed five- and 18-month interviews. The Impact of Event Scale assessed symptoms of posttraumatic stress. At five months 28% of hospitalized passengers, 24% of hospitalized drivers, and 24% of nonhospitalized drivers reported symptoms consistent with posttraumatic stress disorder. At 18 months, 23% of hospitalized passengers, 11% of hospitalized drivers, and 7% of nonhospitalized drivers reported significant levels of stress. Strategies to prevent disabling sequelae of crashes must address the needs of hospitalized and nonhospitalized survivors.


Time scales for sorption-desorption and surface precipitation of uranyl on goethite.
The sorption of uranium on mineral surfaces can significantly influence the fate and transport of uranium contamination in soils and groundwater. The rates of uranium adsorption and desorption on a synthetic goethite have been evaluated in batch experiments conducted at constant pH of 6 and ionic strength of 0.1 M. Adsorption and desorption reactions following the perturbation of initial states were complete within minutes to hours. Surface-solution exchange rates as measured by an isotope exchange method occur on an even shorter time scale. Although the uranium desorption rate was unaffected by the aging of uranium-goethite suspensions, the aging process appears to remove a portion of adsorbed uranium from a readily exchangeable pool. The distinction between sorption control and precipitation control of the dissolved uranium concentration was also investigated. In heterogeneous nucleation experiments, the dissolved uranium concentration was ultimately controlled by the solubility of a precipitated uranyl oxide hydrate. The X-ray diffraction pattern of the precipitate is characteristic of the mineral schoepite. Precipitation is kinetically hindered at low degrees of supersaturation. In one experiment, metastable sorption controlled dissolved uranium concentrations in excess of the solubility limit for more than 30 d.


Peer Adoption and Development of Health Innovations by Patients: National Representative Study of 6204 Citizens.
There is growing evidence that many patients and caregivers innovate by developing new solutions to cope with their health disorders. Given the easy access to vast internet resources and peers globally, it is increasingly important to understand what may influence user innovation and its adoption in health for improving individual well-being and ensuring their safety, in particular, how interactions with peers and physicians or search behavior, along with sociodemographics, may influence the decision to develop a solution or adopt one developed by a peer. The aim of this paper was to study the development and peer-to-peer adoption of user innovations in health care and identify individual-level factors associated with these processes. Data were collected via computer-assisted phone survey from a large, random, and representative sample of adult residents in Portugal (N=6204). User innovation questions were added to 1 wave of an ongoing observational, longitudinal, population-based epidemiological study. By asking about individual innovation activity, the sample was split into 3 groups: (1) the developers of health-related solutions for own use (developers), (2) the adopters of solutions developed by other patients or caregivers (peer-to-peer adopters), and (3) the rest of the population. Within the last group, intention to adopt was measured and used as a proxy of future behavior. Regression analysis is used to test the associations. In the population considered in this paper, an estimated 1.3% (75/6008) reported having developed a solution for own use and 3.3% reported to have adopted a solution developed by peers. The 3 groups (developers, adopters, and remaining population) have distinctive characteristics. Gender plays an important role in the solution development, as women are less likely to develop one (odds ratio [OR] 0.4, 95% CI 0.20-0.81; P<.05). Education is positively associated with the development activity (OR 1.13, 95% CI 1.03-1.24; P<.05) but also with the intentions to adopt a peer-developed solution. Search for health-related information is positively associated with the development, adoption, and the intentions to adopt a solution. Interactions with peers over the internet are rare, but in-person interactions are frequent and have a positive association with the dependent variables in all 3 groups. The results also suggest that trust in doctors represents an important dimension that shapes the attitudes of the population toward peer-developed solutions. This paper demonstrates the importance of the peer community, doctor-patient relationship, citizen's search for information on innovation, and individual attitudes toward peer-to-peer adoption in health care. It stresses the need for a reliable Web-based health-related information and the necessity to deeper understand complex relationships between the need to improve health and fulfill the need and the perception of the health care system.


A novel double-image encryption scheme based on cross-image pixel scrambling in gyrator domains.
Recently, a number of double-image cryptosystems have been developed. However, there are notable security performance differences between the two encryption channels in these algorithms. This weakness downgrades the security level and practicability of these cryptosystems, as the cryptosystems cannot guarantee all the input images be transmitted in the channel with higher security level. In this paper, we propose a novel double-image encryption scheme based on cross-image pixel scrambling in gyrator domains. The two input images are firstly shuffled by the proposed cross-image pixel scrambling approach, which can well balance the pixel distribution across the input images. The two scrambled images will be encoded into the real and imaginary parts of a complex function, and then converted into gyrator domains. An iterative architecture is designed to enhance the security level of the cryptosystem, and the cross-image pixel scrambling operation is performed to the real and imaginary parts of the generated complex encrypted data in each round. Numerical simulation results prove that a satisfactory and balanced security performance can be achieved in both channels.


Compressed scaling of abstract numerosity representations in adult humans and monkeys.
There is general agreement that nonverbal animals and humans endowed with language possess an evolutionary precursor system for representing and comparing numerical values. However, whether nonverbal numerical representations in human and nonhuman primates are quantitatively similar and whether linear or logarithmic coding underlies such magnitude judgments in both species remain elusive. To resolve these issues, we tested the numerical discrimination performance of human subjects and two rhesus monkeys (Macaca mulatta) in an identical delayed match-to-numerosity task for a broad range of numerosities from 1 to 30. The results demonstrate a noisy nonverbal estimation system obeying Weber's Law in both species. With average Weber fractions in the range of 0.51 and 0.60, nonverbal numerosity discriminations in humans and monkeys showed similar precision. Moreover, the detailed analysis of the performance distributions exhibited nonlinearly compressed numerosity representations in both primate species. However, the difference between linear and logarithmic scaling was less pronounced in humans. This may indicate a gradual transformation of a logarithmic to linear magnitude scale in human adults as the result of a cultural transformation process during the course of mathematical education.


Human-specific gene ARHGAP11B promotes basal progenitor amplification and neocortex expansion.
Evolutionary expansion of the human neocortex reflects increased amplification of basal progenitors in the subventricular zone, producing more neurons during fetal corticogenesis. In this work, we analyze the transcriptomes of distinct progenitor subpopulations isolated by a cell polarity-based approach from developing mouse and human neocortex. We identify 56 genes preferentially expressed in human apical and basal radial glia that lack mouse orthologs. Among these, ARHGAP11B has the highest degree of radial glia-specific expression. ARHGAP11B arose from partial duplication of ARHGAP11A (which encodes a Rho guanosine triphosphatase-activating protein) on the human lineage after separation from the chimpanzee lineage. Expression of ARHGAP11B in embryonic mouse neocortex promotes basal progenitor generation and self-renewal and can increase cortical plate area and induce gyrification. Hence, ARHGAP11B may have contributed to evolutionary expansion of human neocortex.


[The role of contrast-enhanced ultrasonography for the detection of hepatocellular carcinoma].
The incidence of the hepatocellular carcinoma (HCC) is increasing in Occident, as well as in France. Primary prevention is the only solution for early detection. The combination of ultrasound (US) and alphaFP each 4 to 6 Months dosage has many limitations. The sensitivity of US examination is rather poor (less than 70% for lesions below 2 cm in diameter) and serum alphaFP values remain normal in almost 50% of HCC. US contrast agents (USCAs) with perfluorocarbon gases increase the backscattered signals during all phases of the liver transit, including arterial, portal and delayed phases. Hepatocellular lesions exhibit a specific kinetics with strong enhancement during arterial phase, and rapid wash-out during portal and delayed phases. USCAs increase the detection of HCCs and allow characterization of additional focal lesions found in cirrhotic livers (regenerative and dysplastic nodules, haemangiomas.). Indeed, regenerative nodules contrast uptake is synchronous to the surrounding parenchyma, and usually disappear during portal and delayed phases. However, US in cirrhosis remains a difficult examination, with limitations due to limited access to sub-diaphragmatic localization, attenuation of the ultrasound beam and shortness of the arterial phase.


No raw data, no science: another possible source of the reproducibility crisis.
A reproducibility crisis is a situation where many scientific studies cannot be reproduced. Inappropriate practices of science, such as HARKing, p-hacking, and selective reporting of positive results, have been suggested as causes of irreproducibility. In this editorial, I propose that a lack of raw data or data fabrication is another possible cause of irreproducibility.As an Editor-in-Chief of Molecular Brain, I have handled 180 manuscripts since early 2017 and have made 41 editorial decisions categorized as "Revise before review," requesting that the authors provide raw data. Surprisingly, among those 41 manuscripts, 21 were withdrawn without providing raw data, indicating that requiring raw data drove away more than half of the manuscripts. I rejected 19 out of the remaining 20 manuscripts because of insufficient raw data. Thus, more than 97% of the 41 manuscripts did not present the raw data supporting their results when requested by an editor, suggesting a possibility that the raw data did not exist from the beginning, at least in some portions of these cases.Considering that any scientific study should be based on raw data, and that data storage space should no longer be a challenge, journals, in principle, should try to have their authors publicize raw data in a public database or journal site upon the publication of the paper to increase reproducibility of the published results and to increase public trust in science.


Effects of historical climate change, habitat connectivity, and vicariance on genetic structure and diversity across the range of the red tree vole (Phenacomys longicaudus) in the Pacific Northwestern United States.
Phylogeographical analyses conducted in the Pacific Northwestern United States have often revealed concordant patterns of genetic diversity among taxa. These studies demonstrate distinct North/South genetic discontinuities that have been attributed to Pleistocene glaciation. We examined phylogeographical patterns of red tree voles (Phenacomys longicaudus) in western Oregon by analysing mitochondrial control region sequences for 169 individuals from 18 areas across the species' range. Cytochrome b sequences were also analysed from a subset of our samples to confirm the presence of major haplotype groups. Phylogenetic network analyses suggested the presence of two haplotype groups corresponding to northern and southern regions of P. longicaudus' range. Spatial genetic analyses (samova and Genetic Landscape Shapes) of control region sequences demonstrated a primary genetic discontinuity separating northern and southern sampling areas, while a secondary discontinuity separated northern sampling areas into eastern and western groups divided by the Willamette Valley. The North/South discontinuity likely corresponds to a region of secondary contact between lineages rather than an overt barrier. Although the Cordilleran ice sheet (maximum approximately 12,000 years ago) did not move southward to directly affect the region occupied by P. longicaudus, climate change during glaciation fragmented the forest landscape that it inhabits. Signatures of historical fragmentation were reflected by positive associations between latitude and variables such as Tajima's D and patterns associated with location-specific alleles. Genetic distances between southern sampling areas were smaller, suggesting that forest fragmentation was reduced in southern vs. northern regions.


Grain size dependence of surface plasmon enhanced photoluminescence.
Photoluminescence (PL) in the InGaN quantum well based light-emitting diodes (LED) is greatly mediated through the coupling with the Surface Plasmons (SPs) at the interface of the sputtered Ag film. SPs coupled PL is independently tuned through controlling the grain size of the sputtered Ag films. The grain size of ~50 nm exhibits the maximum light extraction efficiency (LEE) at the wavelength of 460 nm. This grain size agrees with the periodic lattice constant of the grating structure in the calculation, where the momentum mismatch between the SPs and the radiative light can be compensated.


Life history evolution in cichlids 1: revisiting the evolution of life histories in relation to parental care.
Empirical links between egg size and duration of parental care in fishes have generated a considerable amount of theory concerning life history evolution. However, to date, this link has not been investigated in relation to other important life-history traits such as clutch size and body size, or while controlling for shared ancestry between species. We provide the first phylogenetically based tests using a database with information on egg size, clutch size, body size and care duration in cichlid fishes (Cichlidae). Multiple regression analyses, based on independent contrasts on both the species and the genus level, showed that clutch size is the variable most closely related to duration of care. This pattern appeared to be driven by post-hatch care relationships. Our results show that, contrary to expectation, there is no positive link between egg size and care duration in Cichlidae. Instead, greater reproductive output through increased clutch size investment appears to have coevolved with greater care of offspring. We suggest that re-evaluation of the generality of current models of the evolution of egg size under parental care in fishes is needed.


A model-based approach to assess the exposure-response relationship of Lorenzo's oil in adrenoleukodystrophy.
X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder, most commonly affecting boys, associated with increased very long chain fatty acids (C26:0) in all tissues, causing cerebral demyelination and adrenocortical insufficiency. Certain monounsaturated long chain fatty acids including oleic and erucic acids, known as Lorenzo's oil (LO), lower plasma C26:0 levels. The aims of this study were to characterize the effect of LO administration on plasma C26:0 concentrations and to determine whether there is an association between plasma concentrations of erucic acid or C26:0 and the likelihood of developing brain MRI abnormalities in asymptomatic boys. Non-linear mixed effects modelling was performed on 2384 samples collected during an open label single arm trial. The subjects (n = 104) were administered LO daily at ~2-3 mg kg(-1) with a mean follow-up of 4.88 ± 2.76 years. The effect of erucic acid exposure on plasma C26:0 concentrations was characterized by an inhibitory fractional Emax model. A Weibull model was used to characterize the time-to-developing MRI abnormality. The population estimate for the fractional maximum reduction of C26:0 plasma concentrations was 0.76 (bootstrap 95% CI 0.73, 0.793). Our time-to-event analyses showed that every mg l(-1) increase in time-weighted average of erucic acid and C26:0 plasma concentrations was, respectively, associated with a 3.7% reduction and a 753% increase in the hazard of developing MRI abnormality. However, the results were not significant (P = 0.5344, 0.1509, respectively). LO administration significantly reduces the abnormally high plasma C26:0 concentrations in X-ALD patients. Further studies to evaluate the effect of LO on the likelihood of developing brain MRI abnormality are warranted.


Geriatric Assessment-Guided Care Processes for Older Adults: A Delphi Consensus of Geriatric Oncology Experts.
Structured care processes that provide a framework for how oncologists can incorporate geriatric assessment (GA) into clinical practice could improve outcomes for vulnerable older adults with cancer, a growing population at high risk of toxicity from cancer treatment. We sought to obtain consensus from an expert panel on the use of GA in clinical practice and to develop algorithms of GA-guided care processes. The Delphi technique, a well-recognized structured and reiterative process to reach consensus, was used. Participants were geriatric oncology experts who attended NIH-funded U13 or Cancer and Aging Research Group conferences. Consensus was defined as an interquartile range of 2 or more units, or 66.7% or greater, selecting a utility/helpfulness rating of 7 or greater on a 10-point Likert scale. For nominal data, consensus was defined as agreement among 66.7% or more of the group. From 33 invited, 30 participants completed all 3 rounds. Most experts (75%) used GA in clinical care, and the remainder were involved in geriatric oncology research. The panel met consensus that "all patients aged 75 years or older and those who are younger with age-related health concerns" should undergo GA and that all domains (function, physical performance, comorbidity/polypharmacy, cognition, nutrition, psychological status, and social support) should be included. Consensus was met for how GA could guide nononcologic interventions and cancer treatment decisions. Algorithms for GA-guided care processes were developed. This Delphi investigation of geriatric oncology experts demonstrated that GA should be performed for older patients with cancer to guide care processes.


Craniometric similarities within and between human populations in comparison with neutral genetic data.
The statement that pairs of individuals from different populations are often more genetically similar than pairs from the same population is a widespread idea inside and outside the scientific community. Witherspoon et al. ["Genetic similarities within and between human populations," Genetics 176:351-359 (2007)] proposed an index called the dissimilarity fraction (omega) to access in a quantitative way the validity of this statement for genetic systems. Witherspoon demonstrated that, as the number of loci increases, omega decreases to a point where, when enough sampling is available, the statement is false. In this study, we applied the dissimilarity fraction to Howells's craniometric database to establish whether or not similar results are obtained for cranial morphological traits. Although in genetic studies thousands of loci are available, Howells's database provides no more than 55 metric traits, making the contribution of each variable important. To cope with this limitation, we developed a routine that takes this effect into consideration when calculating omega. Contrary to what was observed for the genetic data, our results show that cranial morphology asymptotically approaches a mean omega of 0.3 and therefore supports the initial statement--that is, that individuals from the same geographic region do not form clear and discrete clusters--further questioning the idea of the existence of discrete biological clusters in the human species. Finally, by assuming that cranial morphology is under an additive polygenetic model, we can say that the population history signal of human craniometric traits presents the same resolution as a neutral genetic system dependent on no more than 20 loci.


The Fascinating Effects of Baicalein on Cancer: A Review.
Cancer is one of the leading causes of death worldwide and a major global health problem. In recent decades, the rates of both mortality and morbidity of cancer have rapidly increased for a variety of reasons. Despite treatment options, there are serious side effects associated with chemotherapy drugs and multiple forms of drug resistance that significantly reduce their effects. There is an accumulating amount of evidence on the pharmacological activities of baicalein (e.g., anti-inflammatory, antioxidant, antiviral, and antitumor effects). Furthermore, there has been great progress in elucidating the target mechanisms and signaling pathways of baicalein's anti-cancer potential. The anti-tumor functions of baicalein are mainly due to its capacities to inhibit complexes of cyclins to regulate the cell cycle, to scavenge oxidative radicals, to attenuate mitogen activated protein kinase (MAPK), protein kinase B (Akt) or mammalian target of rapamycin (mTOR) activities, to induce apoptosis by activating caspase-9/-3 and to inhibit tumorinvasion and metastasis by reducing the expression of matrix metalloproteinase-2/-9 (MMP-2/-9). In this review, we focused on the relevant biological mechanisms of baicalein involved in inhibiting various cancers, such as bladder cancer, breast cancer, and ovarian cancer. Moreover, we also summarized the specific mechanisms by which baicalein inhibited the growth of various tumors in vivo. Taken together, baicalein may be developed as a potential, novel anticancer drug to treat tumors.


Augmented vascular smooth muscle cell stiffness and adhesion when hypertension is superimposed on aging.
Hypertension and aging are both recognized to increase aortic stiffness, but their interactions are not completely understood. Most previous studies have attributed increased aortic stiffness to changes in extracellular matrix proteins that alter the mechanical properties of the vascular wall. Alternatively, we hypothesized that a significant component of increased vascular stiffness in hypertension is due to changes in the mechanical and adhesive properties of vascular smooth muscle cells, and that aging would augment the contribution from vascular smooth muscle cells when compared with the extracellular matrix. Accordingly, we studied aortic stiffness in young (16-week-old) and old (64-week-old) spontaneously hypertensive rats and Wistar-Kyoto wild-type controls. Systolic and pulse pressures were significantly increased in young spontaneously hypertensive rats when compared with young Wistar-Kyoto rats, and these continued to rise in old spontaneously hypertensive rats when compared with age-matched controls. Excised aortic ring segments exhibited significantly greater elastic moduli in both young and old spontaneously hypertensive rats versus Wistar-Kyoto rats. were isolated from the thoracic aorta, and stiffness and adhesion to fibronectin were measured by atomic force microscopy. Hypertension increased both vascular smooth muscle cell stiffness and vascular smooth muscle cell adhesion, and these increases were both augmented with aging. By contrast, hypertension did not affect histological measures of aortic collagen and elastin, which were predominantly changed by aging. These findings support the concept that stiffness and adhesive properties of vascular smooth muscle cells are novel mechanisms contributing to the increased aortic stiffness occurring with hypertension superimposed on aging.


Beneficial Effect of Ubiquinol on Hematological and Inflammatory Signaling during Exercise.
Strenuous exercise (any activity that expends six metabolic equivalents per minute or more causing sensations of fatigue and exhaustion to occur, inducing deleterious effects, affecting negatively different cells), induces muscle damage and hematological changes associated with high production of pro-inflammatory mediators related to muscle damage and sports anemia. The objective of this study was to determine whether short-term oral ubiquinol supplementation can prevent accumulation of inflammatory mediators and hematological impairment associated to strenuous exercise. For this purpose, 100 healthy and well-trained firemen were classified in two groups: Ubiquinol (experimental group), and placebo group (control). The protocol was two identical strenuous exercise tests with rest period between tests of 24 h. Blood samples were collected before supplementation (basal value) (T1), after supplementation (T2), after first physical exercise test (T3), after 24 h of rest (T4), and after second physical exercise test (T5). Hematological parameters, pro- and anti-inflammatory cytokines and growth factors were measured. Red blood cells (RBC), hematocrit, hemoglobin, VEGF, NO, EGF, IL-1ra, and IL-10 increased in the ubiquinol group while IL-1, IL-8, and MCP-1 decreased. Ubiquinol supplementation during high intensity exercise could modulate inflammatory signaling, expression of pro-inflammatory, and increasing some anti-inflammatory cytokines. During exercise, RBC, hemoglobin, hematocrit, VEGF, and EGF increased in ubiquinol group, revealing a possible pro-angiogenic effect, improving oxygen supply and exerting a possible protective effect on other physiological alterations.


WWOX and p53 Dysregulation Synergize to Drive the Development of Osteosarcoma.
Osteosarcoma is a highly metastatic form of bone cancer in adolescents and young adults that is resistant to existing treatments. Development of an effective therapy has been hindered by very limited understanding of the mechanisms of osteosarcomagenesis. Here, we used genetically engineered mice to investigate the effects of deleting the tumor suppressor Wwox selectively in either osteoblast progenitors or mature osteoblasts. Mice with conditional deletion of Wwox in preosteoblasts (WwoxΔosx1) displayed a severe inhibition of osteogenesis accompanied by p53 upregulation, effects that were not observed in mice lacking Wwox in mature osteoblasts. Deletion of p53 in WwoxΔosx1 mice rescued the osteogenic defect. In addition, the Wwox;p53Δosx1 double knockout mice developed poorly differentiated osteosarcomas that resemble human osteosarcoma in histology, location, metastatic behavior, and gene expression. Strikingly, the development of osteosarcomas in these mice was greatly accelerated compared with mice lacking p53 only. In contrast, combined WWOX and p53 inactivation in mature osteoblasts did not accelerate osteosarcomagenesis compared with p53 inactivation alone. These findings provide evidence that a WWOX-p53 network regulates normal bone formation and that disruption of this network in osteoprogenitors results in accelerated osteosarcoma. The Wwox;p53Δosx1 double knockout establishes a new osteosarcoma model with significant advancement over existing models. Cancer Res; 76(20); 6107-17. ©2016 AACR.


Ontogeny of B-lymphocyte function. III. In vivo and in vitro studies on the ease of tolerance induction in B lymphocytes from fetal, neonatal, and adult mice.
The ease of tolerance induction in B lymphocytes from fetal, neonatal, and adult mice was studied in vivo, in a cell transfer system, and in vitro. Three different tolerogens were used: ultracentrifuged BGG, DNP(6)-D-GL, and ultracentrifuged DNP(22)-BGG. Irradiated thymectomized mice were reconstituted with B cells from fetal or neonatal liver or adult spleen or bone marrow. The mice were injected with tolerogen 1 day later. They were given normal thymus cells and challenged with either BGG or DNP(44)-BGG between 4 and 14 days after tolerance induction. With BGG no difference in ease of B-cell tolerance induction was observed in mice reconstituted with B cells from 17-day fetal liver, neonatal liver, 8- day-old spleen, adult spleen, or adult bone marrow. B cells from 14-day fetal donors are relatively resistant to tolerance induction. In contrast, with DNP(6)-D-GL and DNP(22)-BGG B cells from neonatal donors were clearly more susceptible to tolerance induction than were B cells from adult donors. Comparable results were obtained in studies on tolerance induction in vitro. Neonatal B cells were more susceptible than adult B cells to tolerance induction upon culture with DNP(6)-D-GL or DNP(22)-BGG. However, neonatal and adult B cells were identical with respect to ease of tolerance induction in vitro with deaggregated BGG. The results suggest that there are multiple mechanisms for B-cell tolerance induction. Immature B cells appear to be more susceptible to tolerance induction by some mechanisms but not by others. It is suggested that immature B cells are more susceptible to tolerance induction with moderately polyvalent antigens such as hapten-carrier conjugates. With antigens like BGG which do not haverepeated epitopes no difference between mature and fetal B cells in regard to ease of tolerance induction is observed. These observations raise questions about the importance of relative ease of tolerance induction in immature B cells as a mechanism controlling the normal induction of self tolerance.


Joint pressure influences synovial tissue blood flow as determined by colored microspheres.
We measured regional blood flow in synovial tissue of the antebrachiocarpal, midcarpal, and metacarpophalangeal joints of six normal adult anesthetized horses by using 15-microns-diameter polystyrene colored microspheres. The midcarpal fibrous capsule and synovial membrane blood flows (SMBF) were compared, and the effect of increased intra-articular pressure (30 and 60 mmHg) on midcarpal SMBF was investigated. Dorsal, medial palmar, and lateral palmar midcarpal SMBF measured 108 +/- 36, 61 +/- 12, and 50 +/- 11 microliters.min-1.g-1, respectively. Antebrachiocarpal, dorsal, and palmar metacarpophalangeal SMBF measured 103 +/- 8, 17 +/- 3, and 26 +/- 5 microliters.min-1.g-1, respectively. Midcarpal fibrous joint capsule blood flow was significantly lower than that of the synovial membrane. An increase in midcarpal intra-articular pressure to 30 or 60 mmHg resulted in an 84% decrease in SMBF. Colored microspheres provided a useful technique to determine sequential SMBF. Increased intra-articular pressure significantly altered SMBF, suggesting a role of the regional circulation in the pathogenesis of joint disease.


Is the gap between guidelines and clinical practice in heart failure treatment being filled? Insights from the IMPACT RECO survey.
Recent registries have shown that recommended drugs for the treatment of chronic heart failure (CHF) are under-prescribed in daily practice. To determine prescription rates of CHF drugs, and to assess predictive factors for drug prescription using data from a large panel of French cardiologists. We included 1919 outpatients, with NYHA class II-IV heart failure and a left ventricular ejection fraction <40%. The most frequently prescribed drugs were diuretics (83%), angiotensin converting enzyme inhibitors (ACE-I) (71%), beta-blockers (65%), spironolactone (35%) and angiotensin receptor blockers (ARB) (21%); 61% of patients received a combination of a beta-blocker and an ACE-I or ARB. Target doses were reached in 49% of the patients for ACE-I, but in only 18% for beta-blockers and in 9% for ARBs. Multivariate analyses showed that age >75 years was an independent factor associated with under-prescription of ACE-I-ARBs, beta-blockers or spironolactone. Renal failure was associated with a lower prescription of ACE-I-ARB and spironolactone, and asthma was a predictor of under-prescription of beta-blockers. In this contemporary survey, prescription rates of CHF drugs were higher than previously reported. However, dosages were lower than those recommended in guidelines. Age remained an independent predictor of under-prescription of CHF drugs.


Achieving optimal essential fatty acid status in vegetarians: current knowledge and practical implications.
Although vegetarian diets are generally lower in total fat, saturated fat, and cholesterol than are nonvegetarian diets, they provide comparable levels of essential fatty acids. Vegetarian, especially vegan, diets are relatively low in alpha-linolenic acid (ALA) compared with linoleic acid (LA) and provide little, if any, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Clinical studies suggest that tissue levels of long-chain n-3 fatty acids are depressed in vegetarians, particularly in vegans. n-3 Fatty acids have numerous physiologic benefits, including potent cardioprotective effects. These effects have been demonstrated for ALA as well as EPA and DHA, although the response is generally less for ALA than for EPA and DHA. Conversion of ALA by the body to the more active longer-chain metabolites is inefficient: < 5-10% for EPA and 2-5% for DHA. Thus, total n-3 requirements may be higher for vegetarians than for nonvegetarians, as vegetarians must rely on conversion of ALA to EPA and DHA. Because of the beneficial effects of n-3 fatty acids, it is recommended that vegetarians make dietary changes to optimize n-3 fatty acid status.


Gender-specific differences in birthweight and the odds of puberty: NHANES III, 1988-94.
The association between birthweight and the odds ratio (OR) of pubertal status in girls aged between 8 and 11 and in boys aged between 8 and 12 was examined using the 1988-94 Third National Health and Nutrition Examination Survey (NHANES III). Girls (n = 956), and boys (n = 1199), who had data on birthweight and Tanner staging were included. Maternal-reported birthweight, smoking in pregnancy and other information were provided in a home interview, while Tanner staging to assess pubertal status was part of a medical examination. Multiple logistic regression models were computed for the endpoints of the OR [95% confidence interval (CI)] of being Tanner Stage 2+ vs. 1 or being 2+ vs. 1 in an asynchronous pubertal pathway after adjustment for the complex sampling design of NHANES, age, race, height and body mass index (BMI). Birthweight was not associated with the OR of Tanner stage 2+ among girls; however, boys who were low birthweight (<2500 g) and boys born higher than average birthweight (3500-3999 g) were more likely to be Tanner stage 2+ than 1. Childhood BMI was associated with the OR of having entered puberty among girls, but not boys. In an analysis of asynchronous maturation, girls born at high birthweight (>4000 g) were more likely to have breast development 3+ than girls of normal birthweight, OR = 3.18 [95% CI 1.39, 8.25]. Thus, the birthweight-puberty association varies by gender and by pubertal pathway. Our findings need replication in prospective longitudinal studies, and research to understand the mechanisms underlying the relation of early life exposures to cancer risk.


A study of 9-nitrocamptothecin (RFS-2000) in patients with advanced pancreatic cancer.
This ongoing study evaluates the efficacy of oral 9-nitrocamptothecin (9NC), or RFS-2000, in the treatment of advanced pancreatic cancer. Patients received 9NC orally for 5 days/week; 8 weeks of therapy is required to achieve minimum effective dose. Starting dose was 1.5 mg/m2/day, with adjustments made as necessary. Patients were analyzed for changes in tumor size by CT scan, changes in serum CA 19-9 tumor marker levels, quality of life, and survival. 107 consecutive patients with advanced adenocarcinoma of the pancreas were enrolled before November 3, 1997. Of this group, 47 patients did not receive the minimum 2 courses of treatment necessary to induce response, leaving 60 evaluable patients. Primary dose-limiting toxicities were myelosuppression and interstitial cystitis. No deaths were attributed to 9NC. Median survival was 6.5 months for the 107 total patients and 8.7 months for the 60 evaluable patients, with one patient surviving at 44+ months. Of the 60 evaluable patients, 31.7% were responders (median survival 18.6 months; range 6.5-44.7+ months), 31.7% were stable (median survival 9.7 months), and 36.6% were non-responders (median survival 6.8 months). Fifty-seven previously untreated patients had a median survival of 7.3 months compared to 4.7 months for the 50 previously treated patients. Thirty-three patients who failed gemcitabine therapy prior to 9NC treatment had a median survival of 4.7 months. 9NC is safe and efficacious as first-line therapy for the treatment of advanced pancreatic cancer. It also shows some modest success as second-line therapy in treating gemcitabine failures.


Genetic, morphological, geographical and ecological approaches reveal phylogenetic relationships in complex groups, an example of recently diverged pinyon pine species (Subsection Cembroides).
Elucidating phylogenetic relationships and species boundaries within complex taxonomic groups is challenging for intrinsic and extrinsic (i.e., technical) reasons. Mexican pinyon pines are a complex group whose phylogenetic relationships and species boundaries have been widely studied but poorly resolved, partly due to intrinsic ecological and evolutionary features such as low morphological and genetic differentiation caused by recent divergence, hybridization and introgression. Extrinsic factors such as limited sampling and difficulty in selecting informative molecular markers have also impeded progress. Some of the Mexican pinyon pines are of conservation concern but others may remain unprotected because the species boundaries have not been established. In this study we combined approaches to resolve the phylogenetic relationships in this complex group and to establish species boundaries in four recently diverged taxa: P. discolor, P. johannis, P. culminicola and P. cembroides. We performed phylogenetic analyses using the chloroplast markers matK and psbA-trnH as well as complete and partial chloroplast genomes of species of Subsection Cembroides. Additionally, we performed a phylogeographic analysis combining genetic data (18 chloroplast markers), morphological data and geographical data to define species boundaries in four recently diverged taxa. Ecological divergence was supported by differences in climate among localities for distinct genetic lineages. Whereas the phylogenetic analysis inferred with matK and psbA-trnH was unable to resolve the relationships in this complex group, we obtained a resolved phylogeny with the use of the chloroplast genomes. The resolved phylogeny was concordant with a haplotype network obtained using chloroplast markers. In species with potential for recent divergence, hybridization or introgression, nonhierarchical network-based approaches are probably more appropriate to protect against misclassification due to incomplete lineage sorting. The boundaries among genetic lineages were delimited by the inclusion of morphological, geographical and ecological data in the haplotype network. These multiple lines of evidence help to assign species boundaries in this complex group. P. johannis, P. discolor, P. culminicola and P. cembroides are different species based on their genetic, morphological and ecological niche differences. We suggest a reevaluation of the conservation status of these species considering the information generated in this study.


MRI and withdrawal of life support from newborn infants with hypoxic-ischemic encephalopathy.
The majority of deaths in infants with hypoxic-ischemic encephalopathy (HIE) follow decisions to withdraw life-sustaining treatment. Clinicians use prognostic tests including MRI to help determine prognosis and decide whether to consider treatment withdrawal. A recently published meta-analysis provided valuable information on the prognostic utility of magnetic resonance (MR) biomarkers in HIE and suggested, in particular, that proton MR spectroscopy is the most accurate predictor of neurodevelopmental outcome. How should this evidence influence treatment-limitation decisions? In this article I outline serious limitations in existing prognostic studies of HIE, including small sample size, selection bias, vague and overly inclusive outcome assessment, and potential self-fulfilling prophecies. Such limitations make it difficult to answer the most important prognostic question. Reanalysis of published data reveals that severe abnormalities on conventional MRI in the first week have a sensitivity of 71% (95% confidence interval: 59%-91%) and specificity of 84% (95% confidence interval: 68%-93%) for very adverse outcome in infants with moderate encephalopathy. On current evidence, MR biomarkers alone are not sufficiently accurate to direct treatment-limitation decisions. Although there may be a role for using MRI or MR spectroscopy in combination with other prognostic markers to identify infants with very adverse outcome, it is not possible from meta-analysis to define this group clearly. There is an urgent need for improved prognostic research into HIE.


L-triiodothyronine stimulates growth by means of an autocrine factor in a cultured growth-hormone-producing cell line.
L-Triiodothyronine (T3) stimulates DNA synthesis and replication of cultured GC cells, a T3-responsive growth hormone (GH)-secreting cell line. To determine whether T3 stimulates secretion of an autocrine growth factor, we compared the growth-promoting activity of medium conditioned by T3-stimulated and T3-depleted cells to that of unconditioned medium. Addition of polyclonal rabbit anti-T3 serum to T3-containing media decreased cellular T3 content by 50-70%. In unconditioned medium, anti-T3 serum decreased T3-induced cell growth and GH production by 40-70%. In conditioned medium, anti-T3 serum also effected a 45-70% decrease in induction of GH secretion but did not attenuate the growth-promoting activity. Growth-promoting activity was not detected in medium conditioned by T3-depleted cells. Thus, conditioned medium from T3-containing GC cell cultures contains growth-promoting activity that is independent of T3. Further, the induction of GC cel growth by T3 may occur, at least in part, by induction of an autocrine growth factor.


Revascularisation surgery for paediatric moyamoya: a review of the literature.
The role of and optimal surgical revascularisation technique for paediatric moyamoya syndrome (MMS) are controversial. In this literature review our primary aim was to evaluate the evidence base for the efficacy of surgical revascularisation for the treatment of paediatric MMS. Secondary aims were to estimate the rate of peri-operative complications and to ascertain whether direct or indirect revascularisation techniques resulted in differences in clinical or radiological outcomes. Papers describing surgical revascularisation and its outcome in the treatment of children with MMS were identified from the OVID Medline database (1966-2004). Only papers in English were reviewed. Data were abstracted using a standardised form. Fifty-seven studies, including data on 1,448 patients, were reviewed. Most were Japanese; 10% were from Western institutions. Indications for revascularisation were described in <15% of studies and varied between centres. Indirect procedures were most commonly performed (alone in 73% of cases, combined with direct procedures in 23%). The rates of peri-operative stroke and reversible ischaemic events were 4.4 and 6.1% respectively. Out of 1,156 (87%) patients, 1,003 derived symptomatic benefit from surgical revascularisation (complete disappearance or reduction in symptomatic cerebral ischaemia), with no significant difference between the indirect and direct/combined groups. Data on developmental and functional outcomes were limited and of uncertain significance as they were not related to pre-operative status. Good collateral formation was significantly more frequent in the direct/combined group than in the indirect group (chi(2), p<0.001). Data from the medical literature suggest that surgical revascularisation is a safe intervention for paediatric MMS and most treated patients derive some symptomatic benefit. However, paucity of data on selection criteria and more global outcome measures means that the impact of surgical revascularisation on natural history remains uncertain. Direct and/or combined procedures provide better revascularisation, but this is not associated with differences in symptomatic outcome. International standardisation of the clinical approach to the treatment of paediatric MMS is urgently needed to critically evaluate the optimal indications for and timing of surgical revascularisation.


Protocol for a randomised controlled trial of standard wound management versus negative pressure wound therapy in the treatment of adult patients with an open fracture of the lower limb: UK Wound management of Lower Limb Fractures (UK WOLLF).
Patients who sustain open lower limb fractures have reported infection risks as high as 27%. The type of dressing applied after initial debridement could potentially affect this risk. In this trial, standard dressings will be compared with a new emerging treatment, negative pressure wound therapy, for patients with open lower limb fractures. All adult patients presenting with an open lower limb fracture, with a Gustilo and Anderson (G&A) grade 2/3, will be considered for inclusion. 460 consented patients will provide 90% power to detect a difference of eight points in the Disability Rating Index (DRI) score at 12 months, at the 5% level. A randomisation sequence, stratified by trial centre and G&A grade, will be produced and administered by a secure web-based service. A qualitative substudy will assess patients' experience of giving consent for the trial, and acceptability of trial procedures to patients and staff. Patients will have clinical follow-up in a fracture clinic up to a minimum of 12 months as per standard National Health Service (NHS) practice. Functional and quality of life outcome data will be collected using the DRI, SF12 and EQ-5D questionnaires at 3, 6, 9 and 12 months postoperatively. In addition, information will be requested with regards to resource use and any late complications or surgical interventions related to their injury. The main analysis will investigate differences in the DRI score at 1 year after injury, between the two treatment groups on an intention-to-treat basis. Tests will be two sided and considered to provide evidence for a significant difference if p values are less than 0.05. Ethical approval was given by NRES Committee West Midlands-Coventry & Warwickshire on 6/2/2012 (ref: 12/WM/0001). The results of the trial will be disseminated via peer-reviewed publications and presentations at relevant conferences. ISRCTN33756652.


Ecosystem functional response across precipitation extremes in a sagebrush steppe.
Precipitation is predicted to become more variable in the western United States, meaning years of above and below average precipitation will become more common. Periods of extreme precipitation are major drivers of interannual variability in ecosystem functioning in water limited communities, but how ecosystems respond to these extremes over the long-term may shift with precipitation means and variances. Long-term changes in ecosystem functional response could reflect compensatory changes in species composition or species reaching physiological thresholds at extreme precipitation levels. We conducted a five year precipitation manipulation experiment in a sagebrush steppe ecosystem in Idaho, United States. We used drought and irrigation treatments (approximately 50% decrease/increase) to investigate whether ecosystem functional response remains consistent under sustained high or low precipitation. We recorded data on aboveground net primary productivity (ANPP), species abundance, and soil moisture. We fit a generalized linear mixed effects model to determine if the relationship between ANPP and soil moisture differed among treatments. We used nonmetric multidimensional scaling to quantify community composition over the five years. Ecosystem functional response, defined as the relationship between soil moisture and ANPP, was similar among irrigation and control treatments, but the drought treatment had a greater slope than the control treatment. However, all estimates for the effect of soil moisture on ANPP overlapped zero, indicating the relationship is weak and uncertain regardless of treatment. There was also large spatial variation in ANPP within-years, which contributes to the uncertainty of the soil moisture effect. Plant community composition was remarkably stable over the course of the experiment and did not differ among treatments. Despite some evidence that ecosystem functional response became more sensitive under sustained drought conditions, the response of ANPP to soil moisture was consistently weak and community composition was stable. The similarity of ecosystem functional responses across treatments was not related to compensatory shifts at the plant community level, but instead may reflect the insensitivity of the dominant species to soil moisture. These species may be successful precisely because they have evolved life history strategies that buffer them against precipitation variability.


Presence of antiseptic resistance genes in porcine methicillin-resistant Staphylococcus aureus.
Numerous studies have documented the presence of methicillin-resistant Staphylococcus aureus (MRSA) in meat-producing animals, which has led to concern about its spread into the community. Disinfectants play an important role in reduction of contamination in both animal husbandry and food-preparation, helping control spread of organisms from foodstuffs, including raw meat. Plasmid-borne antiseptic resistance (AR) genes increasing tolerance to several disinfectants have been reported in S. aureus of human origin (qacA/B and smr) and from bovine, equine, and caprine staphylococcal isolates (qacG, qacH, and qacJ). This study investigated the presence of AR genes in porcine MRSA isolates. Plasmid DNA from 100 MRSA ST9 strains isolated from pig carcasses was amplified for the presence of AR genes. Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) to benzalkonium chloride (BC) and chlorhexidine gluconate (CHX) were determined in AR gene-positive isolates. qacG was present in 45 strains, eight of which also harbored smr. No strains carried qacA/B, qacH or qacJ. Presence of smr increased MICs to both BC and CHX and MBCs of CHX, but qacG presence only resulted in elevated MBC for CHX. This is the first report of AR genes from a porcine source. AR gene positivity has previously been associated with methicillin resistance and AR gene presence in these strains may increase their ability to persist in the environment. Improved implementation of hygiene measures during transportation and pre- and post-slaughter should be considered to prevent spread in the community.


Trihalomethane formation by chlorination of ammonium- and bromide-containing groundwater in water supplies of Hanoi, Vietnam.
The occurrence and the fate of trihalomethanes (THMs) in the water supply system of Hanoi City, Vietnam was investigated from 1998 to 2001. The chlorination efficiency, THM speciation, and, THM formation potential (THMFP) was determined in the water works and in tap water. With regard to THM formation, three types of groundwater resources were identified: (I) high bromide, (II) low bromide, and (III) high bromide combined with high ammonia and high dissolved organic carbon (DOC) concentrations. Under typical treatment conditions (total chlorine residual 0.5-0.8 mg/L), the total THM formation was always below WHO, EU, and USEPA drinking water standards and decreased in the order type I > type II > type III, although the THMFP was > 400 micrograms/L for type III water. The speciation showed > 80% of bromo-THMs in type I water due to the noticeable high bromide level (< or = 140 micrograms/L). In type II water, the bromo-THMs still accounted for some 40% although the bromide concentration is significantly lower (< or = 30 micrograms/L). In contrast, only traces of bromo-THMs were formed (approximately 5%) in type III water, despite bromide levels were high (< or = 240 micrograms/L). This observation could be explained by competition kinetics of chlorine reacting with ammonia and bromide. Based on chlorine exposure (CT) estimations, it was concluded that the current chlorination practice for type I and II waters is sufficient for > or = 2-log inactivation of Giardia lamblia cysts. However, in type III water the applied chlorine is masked as chloramine with a much lower disinfection efficiency. In addition to high levels of ammonia, type III groundwater is also contaminated by arsenic that is not satisfactory removed during treatment. N-nitrosodimethylamine, a potential carcinogen suspected to be formed during chloramination processes, was below the detection limit of 0.02 microgram/L in type III water.


Pyrazolo[3,4-d]pyrimidines as sigma-1 receptor ligands for the treatment of pain. Part 2: Introduction of cyclic substituents in position 4.
The replacement of acylamino by cyclic substituents in the position 4 of the pyrazolo[3,4-d]pyrimidine scaffold, led to highly active sigma-1 receptor (σ1R) ligands. Phenyl or pyrazolyl groups were the best in terms of affinity for the σ1R and the 4-(1-methylpyrazol-5-yl) derivative, 12f, was the most selective. Compound 12f is also one of the best σ1R ligands ever described in terms of lipophilic ligand efficiency, which translates into a good physicochemical and ADMET profile. In addition, 12f was identified as an antagonist of the σ1R in view of its potent antinociceptive profile in several pain models in mice.


Processes governing primary biofilm formation.
Biofilm accumulation under turbulent flow condition on the surface of a circular tube is the net result of several process including the following: (1) transport and firm adhesion of soluble components and microbial cell to the surface; (2) metabolic conversions within the biofilm in cluding growth and maintenance decay process; (3) detachment of portions of the biofilm and reentrainment in the bulk fluid. Experiments in tabular reactor were designed to measure the rates of these process during the early stages of biofilm accumulation as a function of the Reynolds number and suspended biomass concentration. Results indicate deposition (i.e., combined transport and adsorption) is only important in the very early stages of biofilm accumulation and is significantly influenced by negligible for the thin biofilms encountered in these experiments. Net biofilm production rates in all experiments decrease to same level and this level is not affected by changes in Reynolds number or suspended biomass concentration. Biofilm detachment rate increases continuously with biofilm accumulation and with increasing Reynolds number.


Chimpanzees (Pan troglodytes) are predominantly right-handed: replication in three populations of apes.
Population-level right-handedness has historically been considered a hallmark of human evolution. Even though recent studies in chimpanzees (Pan troglodytes) have demonstrated population-level right-handedness for certain behaviors, some have questioned the validity and consistency of these findings by arguing that reported laterality effects are specific to certain colonies of apes and to those chimpanzees reared by humans. The authors report evidence of population-level right-handedness in 3 separate colonies of chimpanzees. Moreover, handedness in the 3 colonies was unrelated to the proportion of subjects that were raised by humans. This is the strongest evidence to date that population-level handedness is evident in chimpanzees and is not an artifact of human rearing.


Lymphomas affecting the submandibular glands.
Lymphomas affecting the submandibular glands are very uncommon and few reports are currently available in the literature. Therefore, the aim of the current study is to describe the clinical and microscopic features of an original series of lymphomas affecting the submandibular glands. The pathology files of two institutions were searched for lymphoma cases affecting the submandibular glands. The original hematoxylin and eosin, and immunohistochemical slides were revised by a pathologist for diagnosis confirmation following the revised 4th edition of the World Health Organization classification of tumours of haematopoietic and lymphoid tissues. Clinical data regarding age, sex, clinical manifestation, treatment, follow-up and status at last appointment were retrieved from the patients' medical charts. During the period investigated, 16 cases were included in the study. Females predominated (10:6) with a mean age of 57.8 years-old. Tumors usually presented as asymptomatic swellings. MALT lymphoma represented the most common subtype, followed by diffuse large B cell lymphoma and follicular lymphoma. Three patients died, one of them affected by plasmablastic lymphoma, one by DLBCL and one by MALT lymphoma. Low-grade B cell lymphomas predominate in the submandibular glands, but DLBCL and other subtypes may also be rarely diagnosed in this salivary gland.


Nucleotides modulate the low affinity binding sites for [3H]glibenclamide in the rat brain.
Receptors for hypoglycemic sulfonylureas, such as glibenclamide, are commonly linked to the activity of ATP-sensitive K+ channels (K-ATP). High and low affinity binding sites for glibenclamide were described previously in numerous tissues. High affinity binding sites have been thought to be responsible of the modulation of K-ATP, but new evidences suggest that low affinity ones could also regulate these channels. In order to clarify the properties of the two binding sites, with respect to their interaction with K-ATP, we characterized biochemically and pharmacologically [3H]glibenclamide binding in the rat brain cortex. Competitive inhibition plots with [3H]glibenclamide performed on membranes of adult and neonatal rat brain cortex exhibited a biphasic pattern with similar binding parameters, indicating the presence of two similar binding sites in adult as well as in neonatal animals. Membranes of adult rat cortex treated with thiol groups modifying agents, N-ethylmaleimide or 1,4-dithiothreitol, increased the inhibition constant of glibenclamide for the low affinity binding sites (K(i)L) by about 4-fold. The divalent cations Mg++ and Ca++ also increased K(i)L by 3- to 6-fold and enhanced the low affinity binding capacity (BmaxL) by 55 and 103%, respectively, both cations increasing BmaxL by 144%. Among the numerous nucleotides studied, adenine and guanidine triphosphate nucleotides were the most potent to affect the low affinity binding sites. ATP, ADP, GTP and respective nonhydrolysable nucleotides increased K(i)L by 7- to 12-fold and decreased BmaxL by 10 to 30%. The effects of nucleotides were not Mg++ dependent.(ABSTRACT TRUNCATED AT 250 WORDS)


Tailored catalysts for plant cell-wall degradation: redesigning the exo/endo preference of Cellvibrio japonicus arabinanase 43A.
Enzymes acting on polymeric substrates are frequently classified as exo or endo, reflecting their preference for, or ignorance of, polymer chain ends. Most biotechnological applications, especially in the field of polysaccharide degradation, require either endo- or exo-acting hydrolases, or they harness the essential synergy between these two modes of action. Here, we have used genomic data in tandem with structure to modify, radically, the chain-end specificity of the Cellvibrio japonicus exo-arabinanase CjArb43A. The structure of Bacillus subtilis endo-arabinanase 43A (BsArb43A) in harness with chain-end recognition kinetics of CjArb43A directed a rational design approach that led to the conversion of the Cellvibrio enzyme from an exo to an endo mode of action. One of the exo-acting mutants, D35L/Q316A, displays similar activity to WT CjArb43A and the removal of the steric block mediated by the side chains of Gln-316 and Asp-53 at the -3 subsite confers its capacity to attack internal glycoside bonds. This study provides a template for the production of tailored industrial catalysts. The introduction of subtle changes informed by comparative 3D structural and genomic data can lead to fundamental changes in the mode of action of these enzymes.


Influence of respiratory drive on upper airway resistance in normal men.
The variations in nasal and pharyngeal resistance induced by changes in the central inspiratory drive were studied in 10 normal men. To calculate resistances we measured upper airway pressures with two low-bias flow catheters; one was placed at the tip of the epiglottis and the other in the posterior nasopharynx, and we measured flow with a Fleisch no. 3 pneumotachograph connected to a tightly fitting mask. Both resistances were obtained continuously during CO2 rebreathing (Read's method) and during the 2 min after a 1-min voluntary maximal hyperventilation. The inspiratory drive was estimated by measurements of inspiratory pressure generated at 0.1 s after the onset of inspiration (P0.1) and by the mean inspiratory flow (VT/TI). In each subject both resistances decreased during CO2 rebreathing; these decreases were correlated with the increase in P0.1. During the posthyperventilation period, ventilation fell below base line in seven subjects; this was accompanied by an increase in both nasal and pharyngeal resistances. These resistances increased exponentially as VT/TI decreased. Parallel changes in nasal and pharyngeal resistances were seen during CO2 stimulus and during the period after the hyperventilation. We conclude that 1) the indexes quantifying the inspiratory drive reflect the activation of nasopharyngeal dilator muscles (as assessed by the changes in upper airway resistance) and 2) both nasal and pharyngeal resistances are similarly influenced by changes in the respiratory drive.


[Nutritional anemia in nursing women in Costa Rica].
It is reported the prevalence, magnitude and determinant factors of nutritional anaemia in a sample of nursing women (NW), collected during the National Nutrition Survey, of Costa Rica done in 1996. Nutritional anaemia was determinate through measurements of haemoglobin, and plasma ferritin, folates, cianocobalamin and retinol. Methodologies used were cianometahaemoglobin, solid phase immunoradiometric assay, solid phase radioimmunoassay and high-pressure liquid chromatography. WHO cut-off points were used. Anaemia was present in 22.1% of the women. Iron and folate deficiency were found in 48.7 and 84.2% NW, respectively. The magnitude of anaemia was mild and iron and folate deficiencies were severe. Vitamin B12 and A deficiencies were 5.3 and 4.9%, respectively and did not represent a public health problem in this group. Prevalent deficiency was mixed (iron and folates, 46.6%) followed by exclusive folates deficiency (32%). Anaemia was caused by a combined deficiency of iron and folates (61.1%) and most iron deficiencies were accompanied by folates (92%). The logistic regression analysis demonstrated that low socio-economic level of NW and their families was the principal factor determining the appearance of nutritional anaemia, and educative interventions to the mother are possibly recommended. In conclusion anaemia in NW is a moderate health problem of nutritional type, that is more important when severe folates and iron deficiencies are present in Costa Rica. These problems have remained constant throughout the last three decades; although recently, possibly an improvement has occurred because the prevalence of neural tube defects in the infant population has reduced, maybe due to food iron and folates fortification public health policies implementation.


Lambda clone B22 contains a 7676 bp genomic fragment of Saccharomyces cerevisiae chromosome VII spanning the VAM7-SPM2 intergenic region and containing three novel transcribed open reading frames.
A genomic clone of 7676 bp designated B22 from Saccharomyces cerevisiae has been sequenced. The 5' end matches the previously described gene, VAM7, and the 3' end matches the previously described gene, SPM2, both of which have been assigned to the left arm of chromosome VII. The intergenic region contains three transcribed open reading frames (ORFs). The first is related to an uncharacterized ORF of Bacillus subtilis and more weakly to MesJ in Escherichia coli; this is found as a single transcript of 1.1 kb by Northern blotting. The second ORF encodes a small ras-like GTPase of 222 residues with strong homology to yeast Ypt8p and to mammalian Rab11; this is found as a single transcript of 1.1 kb by Northern blotting. The third ORF generates a transcript of 1.6 kb and encodes a protein of 382 residues including a perfect match to the consensus sequence of a C2H2 zinc finger domain; it shares a strong homology with yeast Mig1p and Cre-A from Aspergillus, Emericella and E. coli. This ORF also has a striking similarity to a putative 43 kDa zinc finger protein encoded by an ORF (YEL8) immediately downstream of YPT8, raising the possibility that a region between VAM7 and SPM2 on chromosome VII arose as a duplication of the YPT8-YEL8 region of chromosome V, followed by a translocation.


The influence of donor brain death on short and long-term outcome of solid organ allografts.
Long-term survival rates of solid organ allografts have improved relatively little during the transplant experience despite more effective immunosuppression, better organ preservation techniques and advances in perioperative management. Because grafts of potentially diminished quality are increasingly accepted to reduce the severe shortage of organs, it has become apparent that a variety of donor-associated risk factors may influence adversely their short and long-term outcome. Recent interest has focused particularly on systemic changes occurring after donor brain death (BD). Numbers of experimental and clinical studies have elucidated the complexities of the hemodynamic, metabolic, neurohormonal, and other physiological alterations following this devastating central injury. This article will address the potential derangements in peripheral organs which may influence their behavior after transplantation.


Induction of the ChREBPβ Isoform Is Essential for Glucose-Stimulated β-Cell Proliferation.
Carbohydrate-responsive element-binding protein (ChREBP) is a glucose-sensing transcription factor required for glucose-stimulated proliferation of pancreatic β-cells in rodents and humans. The full-length isoform (ChREBPα) has a low glucose inhibitory domain (LID) that restrains the transactivation domain when glucose catabolism is minimal. A novel isoform of ChREBP (ChREBPβ) was recently described that lacks the LID domain and is therefore constitutively and more potently active. ChREBPβ has not been described in β-cells nor has its role in glucose-stimulated proliferation been determined. We found that ChREBPβ is highly expressed in response to glucose, particularly with prolonged culture in hyperglycemic conditions. In addition, small interfering RNAs that knocked down ChREBPβ transcripts without affecting ChREBPα expression or activity decreased glucose-stimulated expression of carbohydrate response element-containing genes and glucose-stimulated proliferation in INS-1 cells and in isolated rat islets. Quantitative chromatin immunoprecipitation, electrophoretic mobility shift assays, and luciferase reporter assays were used to demonstrate that ChREBP binds to a newly identified powerful carbohydrate response element in β-cells and hepatocytes, distinct from that in differentiated 3T3-L1 adipocytes. We conclude that ChREBPβ contributes to glucose-stimulated gene expression and proliferation in β-cells, with recruitment of ChREBPα to tissue-specific elements of the ChREBPβ isoform promoter.


Comparison between Normalised and Unnormalised 454-Sequencing Libraries for Small-Scale RNA-Seq Studies.
Next-generation sequencing of transcriptomes (RNA-Seq) is being used increasingly in studies of nonmodel organisms. Here, we evaluate the effectiveness of normalising cDNA libraries prior to sequencing in a small-scale study of the zebra finch. We find that assemblies produced from normalised libraries had a larger number of contigs but used fewer reads compared to unnormalised libraries. Considerably more genes were also detected using the contigs produced from normalised cDNA, and microsatellite discovery was up to 73% more efficient in these. There was a positive correlation between the detected expression level of genes in normalised and unnormalised cDNA, and there was no difference in the number of genes identified as being differentially expressed between blood and spleen for the normalised and unnormalised libraries. We conclude that normalised cDNA libraries are preferable for many applications of RNA-Seq and that these can also be used in quantitative gene expression studies.


Essential Oils from Ugandan Aromatic Medicinal Plants: Chemical Composition and Growth Inhibitory Effects on Oral Pathogens.
The study assessed the growth inhibitory effects of essential oils extracted from ten Ugandan medicinal plants (Bidens pilosa, Helichrysum odoratissimum, Vernonia amygdalina, Hoslundia opposita, Ocimum gratissimum, Cymbopogon citratus, Cymbopogon nardus, Teclea nobilis, Zanthoxylum chalybeum, and Lantana trifolia) used traditionally in the management of oral diseases against oral pathogens. Chemical compositions of the oils were explored by GC-MS. Inhibitory effects of the oils were assessed on periodontopathic Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans and cariogenic Streptococcus mutans and Lactobacillus acidophilus using broth dilution methods at concentrations of 1%, 0.1%, and 0.01%. The most sensitive organism was A. actinomycetemcomitans. Its growth was markedly inhibited by six of the oils at all the concentrations tested. Essential oil from C. nardus exhibited the highest activity with complete growth inhibition of A. actinomycetemcomitans and P. gingivalis at all the three concentrations tested, the major constituents in the oil being mainly oxygenated sesquiterpenes. Most of the oils exhibited limited effects on L. acidophilus. We conclude that essential oils from the studied plants show marked growth inhibitory effects on periodontopathic A. actinomycetemcomitans and P. gingivalis, moderate effects on cariogenic S. mutans, and the least effect on L. acidophilus. The present study constitutes a basis for further investigations and development of certain oils into alternative antiplaque agents.


Histone deacetylation promotes transcriptional silencing at facultative heterochromatin.
It is important to accurately regulate the expression of genes involved in development and environmental response. In the fission yeast Schizosaccharomyces pombe, meiotic genes are tightly repressed during vegetative growth. Despite being embedded in heterochromatin these genes are transcribed and believed to be repressed primarily at the level of RNA. However, the mechanism of facultative heterochromatin formation and the interplay with transcription regulation is not understood. We show genome-wide that HDAC-dependent histone deacetylation is a major determinant in transcriptional silencing of facultative heterochromatin domains. Indeed, mutation of class I/II HDACs leads to increased transcription of meiotic genes and accumulation of their mRNAs. Mechanistic dissection of the pho1 gene where, in response to phosphate, transient facultative heterochromatin is established by overlapping lncRNA transcription shows that the Clr3 HDAC contributes to silencing independently of SHREC, but in an lncRNA-dependent manner. We propose that HDACs promote facultative heterochromatin by establishing alternative transcriptional silencing.


Second primary cancers after an index head and neck cancer: subsite-specific trends in the era of human papillomavirus-associated oropharyngeal cancer.
Patients with head and neck squamous cell carcinoma (HNSCC) are at elevated risk of second primary malignancies (SPM), most commonly of the head and neck (HN), lung, and esophagus. Our objectives were to identify HNSCC subsite-specific differences in SPM risk and distribution and to describe trends in risk over 3 decades, before and during the era of human papillomavirus (HPV) -associated oropharyngeal SCC. Population-based cohort study of 75,087 patients with HNSCC in the Surveillance, Epidemiology, and End Results (SEER) program. SPM risk was quantified by using standardized incidence ratios (SIRs), excess absolute risk (EAR) per 10,000 person-years at risk (PYR), and number needed to observe. Trends in SPM risk were analyzed by using joinpoint log-linear regression. In patients with HNSCC, the SIR of second primary solid tumor was 2.2 (95% CI, 2.1 to 2.2), and the EAR was 167.7 cancers per 10,000 PYR. The risk of SPM was highest for hypopharyngeal SCC (SIR, 3.5; EAR, 307.1 per 10,000 PYR) and lowest for laryngeal SCC (SIR, 1.9; EAR, 147.8 per 10,000 PYR). The most common SPM site for patients with oral cavity and oropharynx SCC was HN; for patients with laryngeal and hypopharyngeal cancer, it was the lung. Since 1991, SPM risk has decreased significantly among patients with oropharyngeal SCC (annual percentage change in EAR, -4.6%; P = .03). In patients with HNSCC, the risk and distribution of SPM differ significantly according to subsite of the index cancer. Before the 1990s, hypopharynx and oropharynx cancers carried the highest excess risk of SPM. Since then, during the HPV era, SPM risk associated with oropharyngeal SCC has declined to the lowest risk level of any subsite.


Novel pharmacotherapy for fibromyalgia.
Fibromyalgia is a common disorder that is characterized by chronic widespread pain, tenderness to light palpation, fatigue and sleep disturbances. The present lack of a well-accepted model of the disorder has hampered progress towards adequate treatment. A review of potential models to explain the pathophysiology underlying its primary symptom (i.e., chronic widespread pain) lends insight on the therapeutic potential of novel therapies. Following this, a mechanistic evaluation of those medications that are under consideration for the treatment of the disorder is offered. Adequate treatment will be likely to involve the identification of biologic subgroups within the greater fibromyalgia construct. Key insights from basic research are the basis for increased optimism for effective relief among patients and clinicians.


A role for Leu118 of loop E in agonist binding to the alpha 7 nicotinic acetylcholine receptor.
Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels mediating fast cholinergic synaptic transmission in the brain and at neuromuscular junctions. We used the structure of the acetylcholine binding protein from Lymnaea stagnalis to model the chicken alpha7 agonist-binding domain. The initial models and a preliminary docking study suggested that position Leu118 may play an important role in determining agonist actions on alpha7. A prediction from these in silico studies, that L118E and L118D would retain binding to acetylcholine but L118K and L118R would not, was confirmed in electrophysiological studies on functional recombinant mutant receptors expressed in Xenopus laevis oocytes. The functional studies also demonstrated that residues at position 118 have a dramatic effect on the actions of imidacloprid (a partial agonist of wild-type alpha7 receptors) and its des-nitro derivative. Molecular dynamics simulations confirmed that Leu118 can strongly influence agonist binding and that the model was robust in terms of its prediction for acetylcholine binding. Together, the results indicate a role for Leu118 in influencing agonist actions on alpha7 nAChRs.