Management for quality: continuous quality improvement to increase access to outpatient mental health services.
A health maintenance organization (HMO) examined whether continuous quality improvement could be used to address the problem of long waiting times for outpatient mental health services from a closed panel of providers during peak periods of demand. A task force at a staff model HMO in Burlington, Vermont, used continuous quality improvement methods to identify and solve specific service access problems in five categories: quality, protocol, and standards; systems and processes; management and administration; clinical practice management; and public relations and marketing. Over a two-year period, the task force identified 13 specific problems, for which solutions were implemented. For example, two new support positions were created to meet clinicians' needs. Triage categories were defined, and acceptable waiting times for appointments, along with goals for percent compliance, were established. A weekly training program in brief psychotherapy and an extensive group psychotherapy program were implemented. A network of community providers was formed to complement the HMO's fixed provider panel during periods of high demand. The average waiting time was reduced from 22 days to six days, and patients' satisfaction increased markedly. Use of continuous quality improvement can guide clinical leaders in their central role of reinstating clinical quality as the goal of management. The author suggests that continuous quality improvement with balanced clinical and administrative leadership is the means to forge the needed synthesis of quality and cost capable of improving mental health.


Reactivity to bacterial, fungal, and parasite antigens in patients with lymphedema and elephantiasis.
Both secondary infections and antifilarial immunity are thought to play roles in the development and progression of lymphedema. To investigate this issue, immune responses to a panel of bacterial, fungal, and parasite antigens were examined for women with lymphedema and elephantiasis (n = 28) and for women with no clinical evidence of lymphatic dysfunction who were either microfilaremic (Mf+, n = 23) or microfilaria- and filarial antigen-negative (Ag-, n = 24). The prevalence and intensity of delayed-type hypersensitivity (DTH) responses was similar for most recall antigens; for individual antigens, lymphedema patients were significantly more likely to be reactive only to Proteus. Lymphedema patients with a history of three or more attacks of adenolymphangitis in the last 18 months showed increased DTH reactivity to Trichophyton. Proliferative responses to fungal and bacterial antigens were similar for all three groups; however, antigen-negative women, independent of disease status, mounted greater responses to filarial antigen. In contrast, lymphedema patients had higher levels of antifilarial specific IgG1, IgG2, and IgG3 and higher IgG responses to streptolysin O than either Ag- or Mf+ women. In persons with lymphatic filariasis, immune reactivity is influenced by disease status as well as infection status.


Incertitude, Hepatitis B, and Infant Vaccination in West and Central Africa.
This comparative study explores incertitude about hepatitis B (HBV) and its implications for childhood vaccination in Bangui, Central African Republic, and the Cascades region, Burkina Faso. Anthropological approaches to vaccination, which counter stereotypes of "ignorant" publics needing education to accept vaccination, excavate alternative ways of knowing about illness and vaccination. We build on these approaches, evaluating different kinds of incertitude (ambiguity, uncertainty, ignorance) about infancy, HBV, health protection, and vaccination. Using interviews and participant observation, we find that Bangui and Cascades publics framed their incertitude differently through stories of infancy, illness, and protection. We locate different forms of incertitude within their historical contexts to illuminate why vaccination practices differ in the Cascades region and Bangui. A more nuanced approach to incomplete knowledge, situated in political, economic, and social histories of the state and vaccination, can contribute to more appropriate global health strategies to improve HBV prevention.


Organic and inorganic selenium: I. Oral bioavailability in ewes.
Although the essentiality of dietary Se for sheep has been known for decades, the chemical source and Se dosage for optimal health remain unclear. In the United States, the Food and Drug Administration (FDA) regulates Se supplementation, regardless of the source of Se, at 0.3 mg of Se/kg of diet (as fed), which is equivalent to 0.7 mg of Se/d or 4.9 mg of Se/wk per sheep. The objectives of this study were to evaluate the effects of Se source (inorganic vs. organic) and supplementation rate (FDA vs. supranutritional rates of 14.7 and 24.5 mg of Se/wk) on whole-blood (WB) and serum-Se concentrations. Mature ewes (n = 240) were randomly assigned to 8 treatment groups (n = 30 each) based on Se supplementation rate (4.9, 14.7, and 24.5 mg of Se•wk(-1)•sheep(-1)) and source [Na-selenite, Na-selenate (4.9 mg/wk only), and organic Se-yeast] with a no-Se control group (0 mg of Se/wk). Treatment groups were balanced for healthy and footrot-affected ewes. For 1 yr, ewes were individually dosed once weekly with 0, 4.9, 14.7, or 24.5 mg of Se, quantities equivalent to their summed daily supplementation rates. Serum- and WB-Se concentrations were measured every 3 mo in all ewes; additionally, WB-Se concentrations were measured once monthly in one-half of the ewes receiving 0 or 4.9 mg of Se/wk. Ewes receiving no Se showed a 78.8 and 58.8% decrease (P < 0.001) in WB- (250 to 53 ng/mL) and serum- (97 to 40 ng/mL) Se concentrations, respectively, over the duration of the study. Whole-blood Se decreased primarily during pregnancy (-57%; 258 to 111 ng/mL) and again during peak lactation (-44%; 109 to 61 ng/mL; P < 0.001). At 4.9 mg of Se/wk, Se-yeast (364 ng/mL, final Se concentration) was more effective than Na-selenite (269 ng/mL) at increasing WB-Se concentrations (P < 0.001). Supranutritional Se-yeast dosages increased WB-Se concentrations in a dose-dependent manner (563 ng/mL, 14.7 mg of Se/wk; 748 ng/mL, 24.5 mg of Se/wk; P < 0.001), whereas WB-Se concentrations were not different for the Na-selenite groups (350 ng/mL, 14.7 mg of Se/wk; 363 ng/mL, 24.5 mg of Se/wk) or the 4.9 mg of Se/wk Se-yeast group (364 ng/mL). In summary, the dose range whereby Se supplementation increased blood Se concentrations was more limited for inorganic Na-selenite than for organic Se-yeast. The smallest rate (FDA-recommended quantity) of organic Se supplementation was equally effective as supranutritional rates of Na-selenite supplementation in increasing WB-Se concentrations, demonstrating the greater oral bioavailability of organic Se.


Is Gulf War Syndrome actually chronic Lyme disease?
Symptoms of Gulf War Syndrome and chronic Lyme disease are very similar. Lyme disease is a condition which can be difficult to diagnose since one of the main features of the condition, the erythema migrans rash, may be absent or overlooked and serological testing for Lyme disease may be falsely negative. Symptoms of Lyme disease may not became apparent until years after exposure to the causative organism. Military personnel during training in the field are at risk of tick bites and it may be that those who developed Gulf War Syndrome entered the conflict with latent Lyme disease. There has been no systematic examination of Gulf War Syndrome sufferers for chronic Lyme disease and it is hypothesized that chronic Lyme disease has been overlooked as a cause of Gulf War Syndrome. To address this it is suggested that sufferers of Gulf War Syndrome or similar illnesses should be examined by physicians who have experience diagnosing and treating large numbers of patients with Lyme disease.


Steroid sulfatase: a pivotal player in estrogen synthesis and metabolism.
Steroid sulfatase plays a pivotal role in regulating the formation of biologically active steroids from inactive steroid sulfates. It is responsible for the hydrolysis of estrone sulfate and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone, respectively, both of which can be subsequently reduced to steroids with estrogenic properties (i.e. estradiol and androstenediol) that can stimulate the growth of tumors in hormone-responsive tissues of the breast, endometrium and prostate. Hence, the action of steroid sulfatase is implicated in physiological processes and pathological conditions. It has been five years since our group last reviewed the important role of this enzyme in steroid synthesis and the progress made in the development of potent inhibitors of this important enzyme target. This timely review therefore concentrates on recent advances in steroid sulfatase research, and summarises the findings of clinical trials with Irosustat (BN83495), the only steroid sulfatase inhibitor that is being trialed in postmenopausal women with breast or endometrial cancer.


Proteins encoded by open reading frames 3 and 4 of the genome of Lelystad virus (Arteriviridae) are structural proteins of the virion.
Four structural proteins of Lelystad virus (Arteriviridae) were recognized by monoclonal antibodies in a Western immunoblotting experiment with purified virus. In addition to the 18-kDa integral membrane protein M and the 15-kDa nucleocapsid protein N, two new structural proteins with molecular masses of 45 to 50 kDa and 31 to 35 kDa, respectively, were detected. Monoclonal antibodies that recognized proteins of 45 to 50 kDa and 31 to 35 kDa immunoprecipitated similar proteins expressed from open reading frames (ORFs) 3 and 4 in baculovirus recombinants, respectively. Therefore, the 45- to 50-kDa protein is encoded by ORF3 and the 31- to 35-kDa protein is encoded by ORF4. Peptide-N-glycosidase F digestion of purified virus reduced the 45- to 50-kDa and 31- to 35-kDa proteins to core proteins of 29 and 16 kDa, respectively, which indicates N glycosylation of these proteins in the virion. Monoclonal antibodies specific for the 31- to 35-kDa protein neutralized Lelystad virus, which indicates that at least part of this protein is exposed at the virion surface. We propose that the 45- to 50-kDa and 31- to 35-kDa structural proteins of Lelystad virus be named GP3 and GP4, to reflect their glycosylation and the ORFs from which they are expressed. Antibodies specific for GP3 and GP4 were detected by a Western immunoblotting assay in swine serum after an infection with Lelystad virus.


Structural and dynamic studies of substrate binding in porous metal-organic frameworks.
Porous metal-organic frameworks (MOFs) are the subject of considerable research interest because of their high porosity and capability of specific binding to small molecules, thus underpinning a wide range of materials functions such as gas adsorption, separation, drug delivery, catalysis, and sensing. MOFs, constructed by the designed assembly of metal ions and functional organic linkers, are an emerging class of porous materials with extended porous structures containing periodic binding sites. MOFs thus provide a new platform for the study of the chemistry and reactivity of small molecules in confined pores using advanced diffraction and spectroscopic techniques. In this review, we focus on recent progress in experimental investigations on the crystallographic, dynamic and kinetic aspects of substrate binding within porous MOFs. In particular, we focus on studies on host-guest interactions involving open metal sites or pendant functional groups in the pore as the primary binding sites for guest molecules.


Developing a national mentorship scheme to enhance the contribution of clinical academics to health care.
To provide a template for developing a national mentoring scheme to enhance the contribution practitioner researchers can make to the quality of health care in England. The authors describe the background to and organisation of a mentorship scheme to support those awarded National Institute for Health Research (NIHR) fellowships as part of the Clinical Academic Training (CAT) scheme for nurses, midwives and the allied health professionals in England. The paper draws on relevant policy documents to explain the development of the NIHR mentorship scheme. It also reviews the literature regarding mentoring in nursing and the health professions. The review was conducted systematically using keywords: mentorship, clinical academic careers, research, nursing research, clinical academic careers, evidence, health care. Databases included PubMed, CINAHL and Google Scholar. An integrated approach was adopted. Kirkpatrick's ( 2006 ) four-level evaluation model provided a framework to evaluate the scheme and explore the role of mentorship in supporting NIHR fellows. Preliminary findings from baseline and end-of-year evaluations revealed mentees' expectations of mentorship and its effects on their professional development. Developing a career as a clinical academic can be a challenging journey for novice researchers. In addition, there is a vital need to integrate research with clinical practice. Mentoring appears valuable in enabling NIHR fellows to navigate the challenges of demanding clinical roles in England's National Health Service while making a high-level contribution to research. The importance of preparing mentors for their role is well documented in the literature but mentees also need preparation and guidance to manage this important relationship. The evaluation has implications for embedding similar schemes across nursing, midwifery and the allied health professions to promote capacity and leadership in clinical academic careers. This study has uniquely identified the need to support mentees as well as mentors in such programmes to ensure the optimal benefit of the programme reaches all participants.


ZAK is required for doxorubicin, a novel ribotoxic stressor, to induce SAPK activation and apoptosis in HaCaT cells.
Doxorubicin is an anthracycline drug that is one of the most effective and widely used anticancer agents for the treatment of both hematologic and solid tumors. The stress-activated protein kinases (SAPKs) are frequently activated by a number of cancer chemotherapeutics. When phosphorylated, the SAPKs initiate a cascade that leads to the production of proinflammatory cytokines. Some inhibitors of protein synthesis, known as ribotoxic stressors, coordinately activate SAPKs and lead to apoptotic cell death. We demonstrate that doxorubicin effectively inhibits protein synthesis, activates SAPKs, and causes apoptosis. Ribotoxic stressors share a common mechanism in that they require ZAK, an upstream MAP3K, to activate the pro-apoptotic and proinflammatory signaling pathways that lie downstream of SAPKs. By employing siRNA mediated knockdown of ZAK or administration of sorafenib and nilotinib, kinase inhibitors that have a high affinity for ZAK, we provide evidence that ZAK is required for doxorubicin-induced proinflammatory and apoptotic responses in HaCaT cells, a pseudo-normal keratinocyte cell line, but not in HeLa cells, a cancerous cell line. ZAK has two different isoforms, ZAK-α (91 kDa) and ZAK-β (51 kDa). HaCaT or HeLa cells treated with doxorubicin and immunoblotted for ZAK displayed a progressive decrease in the ZAK-α band and the appearance of ZAK-β bands of larger size. Abrogation of these changes after exposure of cells to sorafenib and nilotinib suggests that these alterations occur following stimulation of ZAK. We suggest that ZAK inhibitors such as sorafenib or nilotinib may be effective when combined with doxorubicin to treat cancer patients.


BldC Delays Entry into Development To Produce a Sustained Period of Vegetative Growth in Streptomyces venezuelae.
Streptomycetes are filamentous bacteria that differentiate by producing spore-bearing reproductive structures called aerial hyphae. The transition from vegetative to reproductive growth is controlled by the bld (bald) loci, and mutations in bld genes prevent the formation of aerial hyphae, either by blocking entry into development (typically mutations in activators) or by inducing precocious sporulation in the vegetative mycelium (typically mutations in repressors). One of the bld genes, bldC, encodes a 68-residue DNA-binding protein related to the DNA-binding domain of MerR-family transcription factors. Recent work has shown that BldC binds DNA by a novel mechanism, but there is less insight into its impact on Streptomyces development. Here we used ChIP-seq coupled with RNA-seq to define the BldC regulon in the model species Streptomyces venezuelae, showing that BldC can function both as a repressor and as an activator of transcription. Using electron microscopy and time-lapse imaging, we show that bldC mutants are bald because they initiate development prematurely, bypassing the formation of aerial hyphae. This is consistent with the premature expression of BldC target genes encoding proteins with key roles in development (e.g., whiD, whiI, sigF), chromosome condensation and segregation (e.g., smeA-sffA, hupS), and sporulation-specific cell division (e.g., dynAB), suggesting that BldC-mediated repression is critical to maintain a sustained period of vegetative growth prior to sporulation. We discuss the possible significance of BldC as an evolutionary link between MerR family transcription factors and DNA architectural proteins.IMPORTANCE Understanding the mechanisms that drive bacterial morphogenesis depends on the dissection of the regulatory networks that underpin the cell biological processes involved. Recently, Streptomyces venezuelae has emerged as an attractive model system for the study of morphological differentiation in Streptomyces This has led to significant progress in identifying the genes controlled by the transcription factors that regulate aerial mycelium formation (Bld regulators) and sporulation (Whi regulators). Taking advantage of S. venezuelae, we used ChIP-seq coupled with RNA-seq to identify the genes directly under the control of BldC. Because S. venezuelae sporulates in liquid culture, the complete spore-to-spore life cycle can be examined using time-lapse microscopy, and we applied this technique to the bldC mutant. These combined approaches reveal BldC to be a member of an emerging class of Bld regulators that function principally to repress key sporulation genes, thereby extending vegetative growth and blocking the onset of morphological differentiation.


Adult schizophrenia following prenatal exposure to an influenza epidemic.
In the context of a Finnish birth cohort, we tested the hypothesis that viral infection during the latter two thirds of fetal development would increase the risk of adult schizophrenic outcome. Psychiatric hospital diagnoses were recorded for all individuals in greater Helsinki who were fetuses during the 1957 type A2 influenza epidemic. Those exposed to the viral epidemic during their second trimester of fetal development were at elevated risk of being admitted to a psychiatric hospital with a diagnosis of schizophrenia. This was true for both males and females and independently in several psychiatric hospitals. The second-trimester effect was seen in the elevated proportion of schizophrenics among those admitted to a psychiatric hospital and also in higher rates of schizophrenia per 1000 live births in the city of Helsinki. The study has several limitations: (1) We have no direct evidence that the subjects actually suffered a viral infection. (2) The psychiatric data were obtained only for subjects up to the age of 26 years, 56 days. (3) The findings are based on hospital diagnoses. (4) The determination of stage of gestation at time of exposure to the epidemic is based on date of birth. The viral infection might have occurred outside the official epidemic window; the infant may have had a preterm or postterm delivery. These sources of error, however, should not serve to enhance the findings. The observed viral effect is interpreted as being one of many potential perturbations of gestation. We suggest that it is less the type than the timing of the disturbance during fetal neural development that is critical in determining risk for schizophrenia.


The prognostic significance of postoperative neutrophil-to-lymphocyte ratio after radical prostatectomy for localized prostate cancer.
The pretreatment neutrophil-to-lymphocyte ratio has prognostic value after radical prostatectomy for treating localized prostate cancer. However, the use of postoperative neutrophil-to-lymphocyte ratio has not been evaluated in this population. We investigated the prognostic significance of early postoperative neutrophil-to-lymphocyte ratio after radical prostatectomy for prostate cancer. We retrospectively reviewed clinical data from 2,302 patients with localized prostate cancer who underwent radical prostatectomy at our institution between years 2000 and 2010. Only patients with pre- and postoperative complete blood counts with differential results were included. Patients who received neoadjuvant or postoperative adjuvant treatment and those without adequate medical records were excluded. Kaplan-Meier analyses were performed to analyze biochemical recurrence-free survival and overall survival rates. Univariate and multivariate Cox regression models were used for each endpoint. Kaplan-Meier curves showed that high postoperative neutrophil-to-lymphocyte ratio (>3.5) was significantly associated with decreased biochemical recurrence-free survival (p = 0.009) and overall survival (p = 0.010). In the univariate and multivariate Cox regression analyses, high postoperative neutrophil-to-lymphocyte ratio was a significant predictor of biochemical recurrence (hazard ratio 1.270, p = 0.008) and overall survival (hazard ratio 1.437, p = 0.033). Our results demonstrate that postoperative neutrophil-to-lymphocyte ratio is an independent factor for biochemical recurrence and overall survival in patients who underwent radical prostatectomy for prostate cancer. These findings suggest that neutrophil-to-lymphocyte ratio can be a potentially valuable tool for stratifying high-risk patients and facilitating choices of postoperative therapy in patients with prostate cancer.


Preventive echocardiographic examination in athletes and workers - Quadricuspid aortic valve and atrial septal aneurysm in a young basketball player.
Ensuring safety of young athletes and employees who perform hard physical work within the scope of their professional duties, with a special focus on prevention of a sudden cardiac death at sports fields or during hard physical work is one of the most important tasks, which demands joint effort of cardiologists and sport physicians or occupational physicians, who qualify patients for a job or a sport discipline. Apart from hypertrophic and arhythmogenic right ventricular cardiomyopathy, coronary anomalies and aortic dissection belong to the most frequent causes of dramatic complications during competitive exercise or work with an increased energy expenditure. Although a detailed medical history and a physical examination combined with 12-lead ECG assessment may significantly improve the safety in competitive sports, adding echocardiography examination gives a detailed and noninvasive insight into the heart morphology and function. Therefore, in our opinion, it should constitute a standard part of the evaluation of candidates for competitive sports. The practice indicates that beyond subjects with severe heart diseases and those classified as normal, there is a group of individuals with abnormalities which should be more closely monitored, but are not contraindications against professional sports or work with an increased energy expenditure. We describe the case of a young female with a diagnosis of rare congenital aortic valve disease, quadricuspid valve, with mild regurgitation and atrial septal aneurysm which was established during transthoracic echocardiography and confirmed and expanded during TEE examination.


A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.
Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.


A telephone-delivered lifestyle intervention for colorectal cancer survivors 'CanChange': a pilot study.
To investigate the feasibility and short-term effectiveness of a lifestyle intervention for colorectal cancer (CRC) survivors. CanChange was telephone-delivered to 20 CRC survivors by health coaches over 6 weeks supported by an interactive participant handbook. We assessed program feasibility (program retention and satisfaction) and health outcomes [CRC-specific symptoms (fatigue, nausea, diarrhoea), quality of life (QOL), and lifestyle variables (physical activity, dietary intake, alcohol intake, smoking, body mass index (BMI))] at baseline and post-intervention. Post-intervention, 76% of participants rated the program as excellent, 100% rated the health coach as excellent, and 75% rated the handbook as excellent. In addition, 80% said that CanChange addressed their issues, 72% said that CanChange helped them deal more effectively with their problems, and 100% said that CanChange made them more motivated to make positive life changes. Finally, all participants said that they would recommend CanChange to other CRC survivors. From baseline to post-intervention we observed: non-significant improvements in all CRC-specific symptoms and QOL; a significant decrease in processed meat intake [median (interquartile range): 1.0 (3.0) vs 0.0 (1.0), p=0.01]; as well as non-significant improvements in sedentary behaviour, and the proportion of participants meeting the national guidelines for fruit and vegetable intake. We observed no change in smoking status, while the results for alcohol intake, physical activity, and BMI were variable. CanChange was a feasible and potentially effective lifestyle intervention to improve health outcomes for CRC survivors. A large randomised controlled trial will follow to test the longer-term effects of this approach.


Measurement of lattice displacements at planar defects in 2H and 18R martensites.
A review of transmission electron microscopy studies of planar defects in 18R and 2H martensites in Cu-Zn-Al alloys is presented. The non-basal plane faults observed in the 2H structure, the F1 faults, show two kinds of dislocations at their ends. In contrast, two types of non-basal plane faults are observed in the 18R structure, Fo and Fx faults. The non-basal plane faults can be composed of segments of Fo and Fx faults. Six types of imperfect dislocations appear, depending on the type of basal plane fault ending at the non-basal plane fault. The Burgers vectors of all these dislocations have been determined from the contrast analysis of the images and HREM observations.


Whole Body Vibration Therapy after Ischemia Reduces Brain Damage in Reproductively Senescent Female Rats.
A risk of ischemic stroke increases exponentially after menopause. Even a mild-ischemic stroke can result in increased frailty. Frailty is a state of increased vulnerability to adverse outcomes, which subsequently increases risk of cerebrovascular events and severe cognitive decline, particularly after menopause. Several interventions to reduce frailty and subsequent risk of stroke and cognitive decline have been proposed in laboratory animals and patients. One of them is whole body vibration (WBV). WBV improves cerebral function and cognitive ability that deteriorates with increased frailty. The goal of the current study is to test the efficacy of WBV in reducing post-ischemic stroke frailty and brain damage in reproductively senescent female rats. Reproductively senescent Sprague-Dawley female rats were exposed to transient middle cerebral artery occlusion (tMCAO) and were randomly assigned to either WBV or no-WBV groups. Animals placed in the WBV group underwent 30 days of WBV (40 Hz) treatment performed twice daily for 15 min each session, 5 days each week. The motor functions of animals belonging to both groups were tested intermittently and at the end of the treatment period. Brains were then harvested for inflammatory markers and histopathological analysis. The results demonstrate a significant reduction in inflammatory markers and infarct volume with significant increases in brain-derived neurotrophic factor and improvement in functional activity after tMCAO in middle-aged female rats that were treated with WBV as compared to the no-WBV group. Our results may facilitate a faster translation of the WBV intervention for improved outcome after stroke, particularly among frail women.


2-Deoxyglucose selectively inhibits Fc and complement receptor-mediated phagocytosis in mouse peritoneal macrophages. I. Description of the inhibitory effect.
Incubation of normal or thioglycollate-elicited mouse peritoneal macrophages with 2-deoxy-D-glucose (2-dG) inhibits the capacity of these macrophages to phagocytize IgG- or complement-coated particles via their Fc and C3 receptors. 2-dG has no inhibitory effect on the capacity of these macrophages to phagocytize latex or zymosan particles, which are ingested in the absence of specific opsonins, and it does not inhibit binding of IgG- or C3-coated particles to their respective receptors on the macrophage's plasma membrane. 2-dG exerts its inhibitory effect on the macrophage and not on the opsonized particle. The inhibition is independent of particle size, occurs within 15-30 min of addition of this glucose analogue to the medium at 37 degrees C, cannot be overcome by supra-agglutinating amounts of opsonizing antibody, and is completely reversible by substitution of 5.5 mM glucose for 50 mM 2-dG in the medium. Addition of equimolar amounts of glucose or mannose, but not of fructose, galactose, fucose, or glucosamine, to medium containing 50 mM 2-dG results in substantial reversal of the inhibitory effect of 2-dG on Fc and C3 receptor mediated phagocytosis.


A green chemistry approach for synthesizing biocompatible gold nanoparticles.
Gold nanoparticles (AuNPs) are a fascinating class of nanomaterial that can be used for a wide range of biomedical applications, including bio-imaging, lateral flow assays, environmental detection and purification, data storage, drug delivery, biomarkers, catalysis, chemical sensors, and DNA detection. Biological synthesis of nanoparticles appears to be simple, cost-effective, non-toxic, and easy to use for controlling size, shape, and stability, which is unlike the chemically synthesized nanoparticles. The aim of this study was to synthesize homogeneous AuNPs using pharmaceutically important Ganoderma spp. We developed a simple, non-toxic, and green method for water-soluble AuNP synthesis by treating gold (III) chloride trihydrate (HAuCl4) with a hot aqueous extract of the Ganoderma spp. mycelia. The formation of biologically synthesized AuNPs (bio-AuNPs) was characterized by ultraviolet (UV)-visible absorption spectroscopy, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), energy dispersive X-ray (EDX), dynamic light scattering (DLS), and transmission electron microscopy (TEM). Furthermore, the biocompatibility of as-prepared AuNPs was evaluated using a series of assays, such as cell viability, lactate dehydrogenase leakage, and reactive oxygen species generation (ROS) in human breast cancer cells (MDA-MB-231). The color change of the solution from yellow to reddish pink and strong surface plasmon resonance were observed at 520 nm using UV-visible spectroscopy, and that indicated the formation of AuNPs. DLS analysis revealed the size distribution of AuNPs in liquid solution, and the average size of AuNPs was 20 nm. The size and morphology of AuNPs were investigated using TEM. The biocompatibility effect of as-prepared AuNPs was investigated in MDA-MB-231 breast cancer cells by using various concentrations of AuNPs (10 to 100 μM) for 24 h. Our findings suggest that AuNPs are non-cytotoxic and biocompatible. To the best of our knowledge, this is the first report to describe the synthesis of monodispersed, biocompatible, and soluble AuNPs with an average size of 20 nm using Ganoderma spp. This study opens up new possibilities of using an inexpensive and non-toxic mushroom extract as a reducing and stabilizing agent for the synthesis of size-controlled, large-scale, biocompatible, and monodispersed AuNPs, which may have future diagnostic and therapeutic applications.


Change in Reciprocal Inhibition of the Forearm with Motor Imagery among Patients with Chronic Stroke.
We investigated cortically mediated changes in reciprocal inhibition (RI) following motor imagery (MI) in short- and long(er)-term periods. The goals of this study were (1) to describe RI during MI in patients with chronic stroke and (2) to examine the change in RI after MI-based brain-machine interface (BMI) training. Twenty-four chronic stroke patients participated in study 1. All patients imagined wrist extension on the affected side. RI from the extensor carpi radialis to the flexor carpi radialis (FCR) was assessed using a FCR H reflex conditioning-test paradigm. We calculated the "MI effect score on RI" (RI value during MI divided by that at rest) and compared that score according to lesion location. RI during MI showed a significant enhancement compared with RI at rest. The MI effect score on RI in the subcortical lesion group was significantly greater than that in the cortical lesion group. Eleven stroke patients participated in study 2. All patients performed BMI training for 10 days. The MI effect score on RI at a 20 ms interstimulus interval was significantly increased after BMI compared with baseline. In conclusion, mental practice with MI may induce plastic change in spinal reciprocal inhibitory circuits in patients with stroke.


Decoding intention: a neuroergonomic perspective.
Decoding the intentions of other people based on non-linguistic cues such as their body movement is a major requirement of many jobs. Whether it is maintaining security at an airport or negotiating with locals in a foreign country, there is a need to maximize the effectiveness of training or real-time performance in this decoding process. This review considers the potential utility of neuroergonomic solutions, and in particular, of electroencephalographic (EEG) methods for augmenting action understanding. Focus is given to body movements and hand-object interactions, where there is a rapid growth in relevant science. The interpretation of EEG-based signals is reinforced by a consideration of functional magnetic resonance imaging experiments demonstrating underlying brain mechanisms that support goal oriented action. While no EEG method is currently implemented as a practical application for enhancing the understanding of unspoken intentions, there are a number of promising approaches that merit further development.


Patterns of adolescent smoking initiation rates by ethnicity and sex.
To define US national sex specific rates of smoking initiation among Hispanic, non-Hispanic white, and African American adolescents aged 12-17 years for each calendar year from 1940 through 1992. Adult survey data from the tobacco use supplement of the Current Population Survey in 1992-93 and 1995-96 were used to reconstruct the age at which individuals began to smoke and the calendar year in which they were that age. From these data, the number of individuals who began a calendar year as never smokers and who were aged 12-17 years during that year could be estimated and formed the denominator of the initiation rate. The number of these individuals who reported taking up smoking during that year formed the numerator of the initiation rate. Initiation rates among male adolescents in each of the three racial/ethnic groups have declined since 1945. However, since 1983, initiation rates among male adolescents overall have increased. Non-Hispanic white male adolescents generally initiated cigarette smoking at higher rates than Hispanic or African American male adolescents. Initiation rates among Hispanic male adolescents have not been statistically different from initiation rates among African American male adolescents. From 1978 to 1982, initiation rates among Hispanic and African American male adolescents experienced a sharp decline, and the rate of decline was steeper than that experienced by non-Hispanic white male adolescents. Initiation rates among female adolescents have increased since 1940, catching up to male adolescent initiation rates by the mid 1970s. Initiation rates among female adolescents appeared to level off or increased slightly again from the mid 1980s to 1990. Non-Hispanic white female adolescents generally initiate cigarette smoking at higher rates than Hispanic or African American female adolescents. Initiation rates among non-Hispanic white and African American female adolescents equalled the initiation rates of their male counterparts by the mid 1970s, but initiation rates among Hispanic female adolescents did not overlap with initiation rates of Hispanic male adolescents until 1990. From 1975 to 1980, initiation rates among African American female adolescents decreased sharply, but, unlike initiation rates among the two other ethnic groups, rates continued to decline from 1984 to 1990. Different patterns of increasing and decreasing smoking initiation among sex and ethnic adolescent groups suggest the effect of varying social and cultural influences. These findings support the importance of including ethnic factors in studies of smoking behaviour.


The role of the therapeutic alliance on pain relief in musculoskeletal rehabilitation: A systematic review.
The aim of this systematic review was to investigate the role of therapeutic alliance in pain relief in patients with musculoskeletal disorders treated by physiotherapy. Manual and database searches (Medline, Embase, ISI Web of Knowledge, CINAHL, PEDro, Lilacs, Cochrane Library, and PsycINFO) were performed with no restrictions of language and publication date. We included prospective studies with samples of patients undergoing physiotherapy for musculoskeletal conditions, with one measure of therapeutic alliance and the outcome pain. Methodological quality was assessed by the Methodological Index for Nonrandomized Studies and the Cochrane tool for risk of bias. Six articles from four studies were included out of the 936 manuscripts identified. All studies used samples composed of patients with chronic low back pain. Two studies applied therapeutic alliance incentive measures during treatment and reported significant improvement in pain. The remaining studies, without alliance incentives, showed divergence regarding the relationship between the therapeutic alliance and pain. Methodological quality analysis determined low risk of bias of the studies. A lack of studies on the therapeutic alliance regarding musculoskeletal physiotherapy was verified. Existing studies fail to provide evidence of a strong relationship between the therapeutic alliance and pain relief.


Specific grasp characteristics of children with trisomy 21.
Children with trisomy 21 display atypical manual skills that change to some extent during development. We examined grasp characteristics and their development in 35 children with trisomy 21, aged 4-18 years, who performed simple manual tasks (two manual tasks of the Movement Assessment Battery for Children, and grasping of five wooden blocks whose size was determined by their hand size). The age-matched comparison group included 35 typically developing children. Children with trisomy 21 were found to use fewer fingers than children in the comparison group in each task. They also used specific grasps and tended to extend fingers that were not involved in the grip. While some specific grasp characteristics of children with trisomy 21 decreased with age, other did not, and remained present throughout development. The perceptual-motor development of children with trisomy 21 should be analyzed in terms of atypical development rather than developmental delay.


A Morphological Test of the Monophyly of the Cardueline Finches (Aves: Fringillidae, Carduelinae).
Monophyly of the cardueline finches (Aves: Fringillidae, Carduelinae), an assemblage of 119 species of seed-eating songbirds, has not yet been rigorously tested. To test the hypothesis of cardueline monophyly I examined 37 taxa, among them 1 or 2 representatives from 16 of the 19 cardueline-finch genera as well as 4 Hawaiian honeycreepers. Each taxon was scored for 225 morphological characters, 148 from the skeleton and 77 from the integument. Cladistic analysis of these data found the carduelines to be monophyletic, so long as the honeycreeper Telespiza cantans is considered to be cardueline; as for the other honeycreepers, they form a clade but do not group with either Telespiza or the carduelines. Both cardueline monophyly and the nonmonophyly of honeycreepers have comparatively strong support, with support for cardueline monophyly coming primarily from evolutionary modifications to the head skeleton.


Disordered FGF23 and mineral metabolism in children with CKD.
In children with CKD, information is limited regarding the prevalence and determinants of fibroblast growth factor 23 excess and 1,25-dihyroxyvitamin D deficiency across the spectrum of predialysis CKD. This study characterized circulating concentrations of fibroblast growth factor 23 and 1,25-dihyroxyvitamin D, and investigated their interrelationships and associations with GFR and secondary hyperparathyroidism in children with CKD who were enrolled in the Chronic Kidney Disease in Children observational cohort study. Plasma fibroblast growth factor 23 concentrations and determinants of mineral metabolism were measured in 464 children ages 1-16 years with predialysis CKD. GFR was measured by plasma disappearance of iohexol in 70% of participants and estimated by the Chronic Kidney Disease in Children estimating equation using serum creatinine and cystatin C concentrations in the remainder of the participants. Participants were grouped according to CKD stage and by 10-ml/min categories of GFR. Median GFR for the cohort was 45 ml/min per 1.73 m(2) (interquartile range=33-57; range=15-109). Plasma fibroblast growth factor 23 concentration was above the normal range in 67% of participants (with higher levels observed among participants with lower GFR) before higher levels of serum parathyroid hormone and phosphorus were observed. Plasma fibroblast growth factor 23 levels were 34% higher in participants with glomerular disease than in participants with nonglomerular disease, despite similar GFR. Serum phosphorus levels, adjusted for age, were significantly lower at GFR of 60-69 ml/min per 1.73 m(2) than higher GFR, but thereafter they became higher in parallel with fibroblast growth factor 23 as GFR declined. Serum 1,25-dihyroxyvitamin D concentrations were lower in those participants with low GFR values, high fibroblast growth factor 23 levels, 25-hydroxyvitamin D deficiency, and proteinuria. Secondary hyperparathyroidism was present in 55% of participants with GFR<50 ml/min per 1.73 m(2). In children with predialysis CKD, high plasma fibroblast growth factor 23 is the earliest detectable abnormality in mineral metabolism, and levels are highest in glomerular diseases.


Color vision in ADHD: part 2--does attention influence color perception?
To investigate the impact of exogenous covert attention on chromatic (blue and red) and achromatic visual perception in adults with and without Attention Deficit Hyperactivity Disorder (ADHD). Exogenous covert attention, which is a transient, automatic, stimulus-driven form of attention, is a key mechanism for selecting relevant information in visual arrays. 30 adults diagnosed with ADHD and 30 healthy adults, matched on age and gender, performed a psychophysical task designed to measure the effects of exogenous covert attention on perceived color saturation (blue, red) and contrast sensitivity. The effects of exogenous covert attention on perceived blue and red saturation levels and contrast sensitivity were similar in both groups, with no differences between males and females. Specifically, exogenous covert attention enhanced the perception of blue saturation and contrast sensitivity, but it had no effect on the perception of red saturation. The findings suggest that exogenous covert attention is intact in adults with ADHD and does not account for the observed impairments in the perception of chromatic (blue and red) saturation.


Identification of conserved potentially regulatory sequences of the SRY gene from 10 different species of mammals.
We have sequenced the 5' region of the SRY gene from human, chimpanzee, sheep, and mouse and from four additional mammalian species, not previously characterized (gorilla, gazelle, rat, and guinea pig). In order to identify conserved DNA elements potentially involved in the regulation of the SRY gene, the newly determined sequences were analyzed and compared to all mammalian SRY promoter sequences available at present. Ten highly conserved potential regulatory elements have been identified in all 10 species (AP1, Barbie, GATA, Gfi1, cMyb, vMyb, NF1, Oct1, Sp1, and SRY). The known function of several of these regulatory elements fits well with the known expression of the SRY gene. However, except for the highly conserved coding HMG motif, only a short region close to the initiation of transcription in the human SRY is conserved in the exact position along the gene in all the species analyzed. This lack of sequence identity at the orthologous positions is consistent with the suggested rapid evolution of the SRY gene. This relative lack of homology contrasts with a high sequence identity of the putative regulatory sequences found within each taxonomic group of species (primates, bovids, and rodents), which supports a common mechanism of SRY expression and possibly also a similar function.


D-dimer, oral anticoagulation, and venous thromboembolism recurrence.
Venous thromboembolism (VTE) requires prolonged treatment to prevent late recurrences. However, the optimal duration of vitamin K antagonist (VKA) therapy is still controversial. More recently, D-dimer (D-d) has emerged as a predictive factor for recurrences. D-d has been evaluated both during and after VKA treatment. Some patients with DVT of the lower limbs have persistently high D-d during anticoagulation and this could reflect insufficient anticoagulation despite apparently adequate antithrombotic treatment. Altered D-d during anticoagulation is more frequent in patients with idiopathic or cancer-associated VTE than in those with secondary VTE. In subjects with an unprovoked VTE event, the time spent at near normal international normalization ratio (INR) values (< 1.5) during the first 3 months of treatment is associated with higher D-d during and after VKA treatment and with a higher risk for late recurrences. Moreover, the combination of altered D-d and inherited thrombophilia, and not residual venous obstruction, is associated with a significantly higher hazard ratio for recurrence. Preliminary results of a management study, the PROLONG study, indicate that subjects with normal D-d at 1 month after VKA withdrawal have a low risk of recurrence, and those with altered D-d have a significantly higher risk and deserve prolonged treatment.


Psychiatric phenotype of the fragile X-associated tremor/ataxia syndrome (FXTAS) in males: newly described fronto-subcortical dementia.
The authors describe and quantify the neuropsychiatric symptoms present in a cohort of males with the fragile X mental retardation 1 (FMR1) premutation allele who have developed fragile X-associated tremor/ataxia syndrome (FXTAS). Fourteen male carriers of the FMR1 premutation who had clinical manifestations of the FXTAS syndrome and 14 age- and education-matched controls were assessed with the Neuropsychiatric Inventory (NPI), formal cognitive testing, and genetic analysis. Males with FXTAS had significantly higher total NPI scores (p < .004) and significantly higher scores on the agitation/aggression (p < .004), depression (p < .004), apathy (p < .004), disinhibition (p < .004), and irritability (p < .004) scales, compared with controls. Cognitive performances on the Mini-Mental State Examination did not correlate with severity of symptoms on the NPI. The neuropsychiatric manifestations of FXTAS, based on this preliminary report, appear to cluster as a fronto-subcortical dementia. Clinicians encountering patients with clinical dementia with motor symptoms suggesting FXTAS should consider genetic testing to determine whether the patient's dementia syndrome is secondary to a fragile X premutation carrier status.


Early senescence in heterozygous ABCA1 mutation skin fibroblasts: a gene dosage effect beyond HDL deficiency?
Homozygous ABCA1 gene mutation causes Tangier disease (TD). The effects reported in heterozygous state regard plasma HDL, cell cholesterol efflux and coronary artery disease. We investigated whether in vitro replicative skin fibroblast senescence shown in TD proband (Hom), his father (Het), and in a healthy control might be induced in a "gene-dosage way". Senescence was evaluated by staining test for β-Galactosidase and telomere length (TL) on fibroblast DNA at different replicative stages. ABCG1 and LDLR (low density lipoprotein receptor) gene expression was also evaluated. Hom cells showed early senescent morphology and reduced growth at all passages in vitro. The cell positive percentage for β-Galactosidase test was highly increased in Hom compared to Het cells at late replicative status (66.1% vs 41.3% respectively). TL was significantly shorter at high stage either in Hom (p<0.0001) or in Het (p<0.005). At early replication cycles ABCG1 gene expression was about 3-fold higher in Hom compared to Het cells (0.44 vs 0.14 arbitrary unit). ABCA1 gene mutation may have "gene-dosage way" effect on in vitro fibroblast senescence. Furthermore, increased ABCG1 and LDLR gene expression could highlight a role of ABCA1 on cytoskeleton regulation associated to cell cholesterol metabolism.


Strength of German accent under altered auditory feedback.
Borden's (1979, 1980) hypothesis that speakers with vulnerable speech systems rely more heavily on feedback monitoring than do speakers with less vulnerable systems was investigated. The second language (L2) of a speaker is vulnerable, in comparison with the native language, so alteration to feedback should have a detrimental effect on it, according to this hypothesis. Here, we specifically examined whether altered auditory feedback has an effect on accent strength when speakers speak L2. There were three stages in the experiment. First, 6 German speakers who were fluent in English (their L2) were recorded under six conditions--normal listening, amplified voice level, voice shifted in frequency, delayed auditory feedback, and slowed and accelerated speech rate conditions. Second, judges were trained to rate accent strength. Training was assessed by whether it was successful in separating German speakers speaking English from native English speakers, also speaking English. In the final stage, the judges ranked recordings of each speaker from the first stage as to increasing strength of German accent. The results show that accents were more pronounced under frequency-shifted and delayed auditory feedback conditions than under normal or amplified feedback conditions. Control tests were done to ensure that listeners were judging accent, rather than fluency changes caused by altered auditory feedback. The findings are discussed in terms of Borden's hypothesis and other accounts about why altered auditory feedback disrupts speech control.


Spring warming in Yukon mountains is not amplified by the snow albedo feedback.
Decreasing spring snow cover may amplify Arctic warming through the snow albedo feedback. To examine the impact of snowmelt on increasing temperature we used a 5,000 m elevation gradient in Yukon, Canada, extending from valley-bottom conifer forests, through middle elevation tundra, to high elevation icefields, to compare validated downscaled reanalysis air temperature patterns across elevational bands characterized by different patterns of spring snowmelt. From 2000 to 2014 we observed surface warming of 0.01 °C/a·1,000 m in May (0.14 °C/a at 1,000 m to 0.19 °C/a at 5,000 m), and uniform cooling of 0.09 °C/a in June at all elevations. May temperature trends across elevationally dependent land cover types were highly correlated with each other despite large variations in albedo and snow cover trends. Furthermore, a clear dependency of infrared skin temperature on snow cover mediated albedo decline was observed in tundra, but this was insufficient to influence average diurnal air temperature. We observed negative June temperature trends which we attribute to increasing daytime cloud cover because albedo and snow cover trends were unchanging. We conclude that 8-day and monthly averaged Spring air temperature trends are responding to a synoptic external forcing that is much stronger than the snow albedo feedback in sub-Arctic mountains.


Doing statistics, enacting the nation: The performative powers of categories.
It has been widely acknowledged in debates about nationalism and ethnicity that identity categories used for classifying people along the lines of culture, race, and ethnicity help to enact, that is, bring into being, the collective identities they name. However, we know little about how categories acquire their performative powers. The contribution of this paper is twofold: first, it proposes a conceptual framework based on concepts and insights from science and technology studies for investigating the performative powers of statistical identity categories and possibly also other domains. Second, it demonstrates, through an empirical study of two examples from Estonian and Dutch official population statistics, that statistical identity categories enact more than the groups to which they refer. We argue that they also enact national identities and notions of national belonging of majoritarian groups in the host countries. Therefore, statistical identity categories can be used as analytical lenses to study nationalism and processes of nation-building.


Glycogen synthase kinase-3 inhibition induces glioma cell death through c-MYC, nuclear factor-kappaB, and glucose regulation.
Glycogen synthase kinase 3 (GSK3), a serine/threonine kinase, is involved in diverse cellular processes ranging from nutrient and energy homeostasis to proliferation and apoptosis. Its role in glioblastoma multiforme has yet to be elucidated. We identified GSK3 as a regulator of glioblastoma multiforme cell survival using microarray analysis and small-molecule and genetic inhibitors of GSK3 activity. Various molecular and genetic approaches were then used to dissect out the molecular mechanisms responsible for GSK3 inhibition-induced cytotoxicity. We show that multiple small molecular inhibitors of GSK3 activity and genetic down-regulation of GSK3alpha/beta significantly inhibit glioma cell survival and clonogenicity. The potency of the cytotoxic effects is directly correlated with decreased enzyme activity-activating phosphorylation of GSK3alpha/beta Y276/Y216 and with increased enzyme activity inhibitory phosphorylation of GSK3alpha S21. Inhibition of GSK3 activity results in c-MYC activation, leading to the induction of Bax, Bim, DR4/DR5, and tumor necrosis factor-related apoptosis-inducing ligand expression and subsequent cytotoxicity. Additionally, down-regulation of GSK3 activity results in alteration of intracellular glucose metabolism resulting in dissociation of hexokinase II from the outer mitochondrial membrane with subsequent mitochondrial destabilization. Finally, inhibition of GSK3 activity causes a dramatic decrease in intracellular nuclear factor-kappaB activity. Inhibition of GSK3 activity results in c-MYC-dependent glioma cell death through multiple mechanisms, all of which converge on the apoptotic pathways. GSK3 may therefore be an important therapeutic target for gliomas. Future studies will further define the optimal combinations of GSK3 inhibitors and cytotoxic agents for use in gliomas and other cancers.


Biomechanics of two-thumb versus two-finger chest compression for cardiopulmonary resuscitation in an infant manikin model.
The loading force applied in infant external chest compression (ECC) has not been determined. The objective of this crossover study was to quantify the actual force involved in two-thumb (TT)-encircling hands and two-finger (TF) methods during infant cardiopulmonary resuscitation. A total of 42 emergency medical professionals performed lone rescuer infant external chest compression (ECC) with TF and TT methods. The order of two methods was arranged randomly, with an interval of 30 min in between. The force was collected by MatScan as primary outcomes. The secondary outcomes, quality of chest compressions, and fatigue level were also recorded by SkillReporter and perceived exertion scale. Using the TT method, the rescuers performed cardiopulmonary resuscitation (CPR) with higher ECC quality, but more incomplete recoil than they did using the TF method. The mean compression forces delivered in the first and second minutes were 3.53 ± 1.27 kg and 3.22 ± 1.11 kg (P = 0.012) for TF and 4.11 ± 1.80 kg and 4.04 ± 1.83 kg (P = 0.568) for TT, respectively. Pairwise comparison indicates that the compression force delivered through the TF method during the first and second minute of ECC were inferior to that delivered through the TT method. The TF method involved greater perceived exertion than the TT method (5.27 ± 4.69 vs. 4.02 ± 2.31; P = 0.007). The median perceived exertions for the TF and TT methods were 5 and 4, respectively. For infant CPR, the TT method involved greater loading force, lower fatigue, and higher overall ECC quality than the TF method. The optimal compression force is about 3.8-4.3 kg.


Noncoding sequences near duplicated genes evolve rapidly.
Gene expression divergence and chromosomal rearrangements have been put forward as major contributors to phenotypic differences between closely related species. It has also been established that duplicated genes show enhanced rates of positive selection in their amino acid sequences. If functional divergence is largely due to changes in gene expression, it follows that regulatory sequences in duplicated loci should also evolve rapidly. To investigate this hypothesis, we performed likelihood ratio tests (LRTs) on all noncoding loci within 5 kb of every transcript in the human genome and identified sequences with increased substitution rates in the human lineage since divergence from Old World Monkeys. The fraction of rapidly evolving loci is significantly higher nearby genes that duplicated in the common ancestor of humans and chimps compared with nonduplicated genes. We also conducted a genome-wide scan for nucleotide substitutions predicted to affect transcription factor binding. Rates of binding site divergence are elevated in noncoding sequences of duplicated loci with accelerated substitution rates. Many of the genes associated with these fast-evolving genomic elements belong to functional categories identified in previous studies of positive selection on amino acid sequences. In addition, we find enrichment for accelerated evolution nearby genes involved in establishment and maintenance of pregnancy, processes that differ significantly between humans and monkeys. Our findings support the hypothesis that adaptive evolution of the regulation of duplicated genes has played a significant role in human evolution.


[Synovial lipoma arborescens].
The synovial lipoma are uncommon articular tumors of unknown origin. We report two cases of synovial lipoma arborescens arisen in a man and a woman respectively 41 and 27 years old. Both had already consulted for a tumefaction progressively increasing in volume. It was accompanied in the first case by a laxity in the knee joint. Radiography and arthroscopy showed an important hyperplasia of the articular synovia. A total synovectomy was performed in both cases. The synovia had a hairy aspect and was extremely thickened. It weighted 1.5 kg in the first case and its section had a fatty aspect. The histological examination confirmed the diagnosis of synovial lipoma arborescens. The observed aspect of the two tumors and particularly their volume, which was very important in the first case are arguments in favor of their tumoral nature.


Impact of the current economy on facial aesthetic surgery.
American Society for Aesthetic Plastic Surgery (ASAPS) survey data showed a 16.7% decrease in the total number of aesthetic surgical procedures from 2008 to 2009, whereas plastic surgeons have seen an increase of 0.6% in their nonsurgical cosmetic procedures. The authors describe the results of two surveys-one administered to potential patients, one to physicians-assessing the impact of the economy on patient choices in aesthetic facial surgery. Two surveys were conducted for this study-one from the American Academy of Facial Plastic and Reconstructive Surgeons (AAFPRS) and one from the Aesthetic Surgery Education and Research Foundation (ASERF). Both surveys utilized the unique maximum difference (MaxDiff) scaling format, which assesses respondent opinions through attribute/question grouping and multiple exposures to the same parameter, rather than traditional one-time questioning. In this way, MaxDiff analysis helped identify the varied drivers of patients' medical antiaging treatment (MAT) selection. The AAFPRS survey was conducted online through Synovate's Global Opinion Panel to identify an appropriate audience of potential patients. The ASERF survey contained both MaxDiff and traditional questions and was e-mailed to 2267 ASAPS members. Data from the AAFPRS patient survey showed that 53% of respondents had been affected by the economy in their decisions regarding MAT procedures, with many seeking out less-costly options such as microdermabrasion. An overwhelming majority (95%) also reported that they would prefer a longer-lasting treatment over an immediate effect with shorter duration; furthermore, 60% felt that duration of treatment was more important than cost in selecting a facial aesthetic procedure. In the ASERF surgeon-based portion of the study, 61% of plastic surgeons felt that patients preferred long-lasting results over immediate ones, but 63% also reported that cost was a more important factor for their patients than duration. Extrapolating from the patient-reported survey preferences, the authors conclude that nonsurgical facial aesthetic treatment plans should currently be focused more on longevity rather than on immediate impact. There is currently a disconnect between patient preferences and surgeon perception of those preferences, which may be remedied with increased education for both groups. It is worth noting that many patients would be willing to accept a higher cost if it was correlated with a longer-lasting result.


Mating system variation drives rapid evolution of the female transcriptome in Drosophila pseudoobscura.
Interactions between the sexes are believed to be a potent source of selection on sex-specific evolution. The way in which sexual interactions influence male investment is much studied, but effects on females are more poorly understood. To address this deficiency, we examined gene expression in virgin female Drosophila pseudoobscura following 100 generations of mating system manipulations in which we either elevated polyandry or enforced monandry. Gene expression evolution following mating system manipulation resulted in 14% of the transcriptome of virgin females being altered. Polyandrous females elevated expression of a greater number of genes normally enriched in ovaries and associated with mitosis and meiosis, which might reflect female investment into reproductive functions. Monandrous females showed a greater number of genes normally enriched for expression in somatic tissues, including the head and gut and associated with visual perception and metabolism, respectively. By comparing our data with a previous study of sex differences in gene expression in this species, we found that the majority of the genes that are differentially expressed between females of the selection treatments show female-biased expression in the wild-type population. A striking exception is genes associated with male-specific reproductive tissues (in D. melanogaster), which are upregulated in polyandrous females. Our results provide experimental evidence for a role of sex-specific selection arising from differing sexual interactions with males in promoting rapid evolution of the female transcriptome.


Genome-wide patterns of population structure and admixture in West Africans and African Americans.
Quantifying patterns of population structure in Africans and African Americans illuminates the history of human populations and is critical for undertaking medical genomic studies on a global scale. To obtain a fine-scale genome-wide perspective of ancestry, we analyze Affymetrix GeneChip 500K genotype data from African Americans (n = 365) and individuals with ancestry from West Africa (n = 203 from 12 populations) and Europe (n = 400 from 42 countries). We find that population structure within the West African sample reflects primarily language and secondarily geographical distance, echoing the Bantu expansion. Among African Americans, analysis of genomic admixture by a principal component-based approach indicates that the median proportion of European ancestry is 18.5% (25th-75th percentiles: 11.6-27.7%), with very large variation among individuals. In the African-American sample as a whole, few autosomal regions showed exceptionally high or low mean African ancestry, but the X chromosome showed elevated levels of African ancestry, consistent with a sex-biased pattern of gene flow with an excess of European male and African female ancestry. We also find that genomic profiles of individual African Americans afford personalized ancestry reconstructions differentiating ancient vs. recent European and African ancestry. Finally, patterns of genetic similarity among inferred African segments of African-American genomes and genomes of contemporary African populations included in this study suggest African ancestry is most similar to non-Bantu Niger-Kordofanian-speaking populations, consistent with historical documents of the African Diaspora and trans-Atlantic slave trade.


The systemic imprint of growth and its uses in ecological (meta)genomics.
Microbial minimal generation times range from a few minutes to several weeks. They are evolutionarily determined by variables such as environment stability, nutrient availability, and community diversity. Selection for fast growth adaptively imprints genomes, resulting in gene amplification, adapted chromosomal organization, and biased codon usage. We found that these growth-related traits in 214 species of bacteria and archaea are highly correlated, suggesting they all result from growth optimization. While modeling their association with maximal growth rates in view of synthetic biology applications, we observed that codon usage biases are better correlates of growth rates than any other trait, including rRNA copy number. Systematic deviations to our model reveal two distinct evolutionary processes. First, genome organization shows more evolutionary inertia than growth rates. This results in over-representation of growth-related traits in fast degrading genomes. Second, selection for these traits depends on optimal growth temperature: for similar generation times purifying selection is stronger in psychrophiles, intermediate in mesophiles, and lower in thermophiles. Using this information, we created a predictor of maximal growth rate adapted to small genome fragments. We applied it to three metagenomic environmental samples to show that a transiently rich environment, as the human gut, selects for fast-growers, that a toxic environment, as the acid mine biofilm, selects for low growth rates, whereas a diverse environment, like the soil, shows all ranges of growth rates. We also demonstrate that microbial colonizers of babies gut grow faster than stabilized human adults gut communities. In conclusion, we show that one can predict maximal growth rates from sequence data alone, and we propose that such information can be used to facilitate the manipulation of generation times. Our predictor allows inferring growth rates in the vast majority of uncultivable prokaryotes and paves the way to the understanding of community dynamics from metagenomic data.


Predictors of Health-Related Quality of Life in Patients with Co-Morbid Diabetes and Chronic Kidney Disease.
People living with diabetes and chronic kidney disease (CKD) experience compromised quality of life. Consequently, it is critical to identify and understand factors influencing their health-related quality of life (HRQoL). This study examined factors associated with HRQoL among patients with diabetes and CKD. A cross sectional study among adults with comorbid diabetes and CKD (eGFR <60 mL/min/1.73m2) recruited from renal and diabetes clinics of four large tertiary referral hospitals in Australia was performed. Each participant completed the Kidney Disease Quality of Life (KDQoL ™ -36) questionnaire, which is comprised of two composite measures of physical and mental health and 3 kidney disease specific subscales with possible scores ranging from 0 to 100 with higher values indicating better HRQoL. Demographic and clinical data were also collected. Regression analyses were performed to determine the relationship between HRQoL and potential predictor factors. A total of 308 patients were studied with a mean age of 66.9 (SD = 11.0) years and 70% were males. Mean scores for the physical composite summary, mental composite summary, symptom/problem list, effects of kidney disease and burden of kidney disease scales were 35.2, 47.0, 73.8, 72.5 and 59.8 respectively. Younger age was associated with lower scores in all subscales except for the physical composite summary. Female gender, obese or normal weight rather than overweight, and smoking were all associated with lower scores in one or more subscales. Scores were progressively lower with more advanced stage of CKD (p<0.05) in all subscales except for the mental composite summary. In patients with diabetes and CKD, younger age was associated with lower scores in all HRQoL subscales except the physical composite summary and female gender, obese or normal weight and more advanced stages of CKD were associated with lower scores in one or more subscales. Identifying these factors will inform the timely implementation of interventions to improve the quality of life of these patients.


Low molecular weight heparin administered once versus twice daily in patients with venous thromboembolism: a meta-analysis.
Low molecular weight heparin is as effective and safe as unfractionated heparin for treatment of acute venous thromboembolism. It is uncertain whether low molecular weight heparin should be administered once-daily or twice-daily in this setting. A meta-analysis of randomized studies which directly compared once- and twice-daily administration of low molecular weight heparin for the treatment of acute venous thromboembolism was performed. A literature search was performed using Advanced Pub Med and the Cochrane library database, and abstracts from recent meetings were reviewed. Two investigators extracted data independently. Five studies, involving 1522 patients, were eligible. There were no statistically significant differences in the frequencies of symptomatic (odds ratio, 0.85 in favor of once-daily therapy at three months, p = 0.6), and asymptomatic, recurrent venous thromboembolism, total and major bleeds (odds ratio, 1.16 in favor of twice-daily therapy at 10 days, p = 0.8); and death, at 10 days, as well as at three months of follow-up. Once-daily low molecular weight heparin appears to be as effective and safe as twice-daily administration for the acute treatment of venous thromboembolism. However, there is inadequate data from studies that directly compared once-daily and twice-daily administration to be able to exclude the possibility of a higher frequency of fatal bleeding with once-daily therapy.


Comprehensive genomic characterization of squamous cell lung cancers.
Lung squamous cell carcinoma is a common type of lung cancer, causing approximately 400,000 deaths per year worldwide. Genomic alterations in squamous cell lung cancers have not been comprehensively characterized, and no molecularly targeted agents have been specifically developed for its treatment. As part of The Cancer Genome Atlas, here we profile 178 lung squamous cell carcinomas to provide a comprehensive landscape of genomic and epigenomic alterations. We show that the tumour type is characterized by complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumour. We find statistically recurrent mutations in 11 genes, including mutation of TP53 in nearly all specimens. Previously unreported loss-of-function mutations are seen in the HLA-A class I major histocompatibility gene. Significantly altered pathways included NFE2L2 and KEAP1 in 34%, squamous differentiation genes in 44%, phosphatidylinositol-3-OH kinase pathway genes in 47%, and CDKN2A and RB1 in 72% of tumours. We identified a potential therapeutic target in most tumours, offering new avenues of investigation for the treatment of squamous cell lung cancers.


Minimally important change, measurement error, and responsiveness for the Self-Reported Foot and Ankle Score.
Background and purpose - Patient-reported outcome measures (PROMs) are increasingly used to evaluate results in orthopedic surgery. To enhance good responsiveness with a PROM, the minimally important change (MIC) should be established. MIC reflects the smallest measured change in score that is perceived as being relevant by the patients. We assessed MIC for the Self-reported Foot and Ankle Score (SEFAS) used in Swedish national registries. Patients and methods - Patients with forefoot disorders (n = 83) or hindfoot/ankle disorders (n = 80) completed the SEFAS before surgery and 6 months after surgery. At 6 months also, a patient global assessment (PGA) scale-as external criterion-was completed. Measurement error was expressed as the standard error of a single determination. MIC was calculated by (1) median change scores in improved patients on the PGA scale, and (2) the best cutoff point (BCP) and area under the curve (AUC) using analysis of receiver operating characteristic curves (ROCs). Results - The change in mean summary score was the same, 9 (SD 9), in patients with forefoot disorders and in patients with hindfoot/ankle disorders. MIC for SEFAS in the total sample was 5 score points (IQR: 2-8) and the measurement error was 2.4. BCP was 5 and AUC was 0.8 (95% CI: 0.7-0.9). Interpretation - As previously shown, SEFAS has good responsiveness. The score change in SEFAS 6 months after surgery should exceed 5 score points in both forefoot patients and hindfoot/ankle patients to be considered as being clinically relevant.


Lactoferrin expression in the mouse reproductive tract during the natural estrous cycle: correlation with circulating estradiol and progesterone.
Lactoferrin (LTF), an iron-binding glycoprotein present in most exocrine secretions and in the secondary granules of polymorphonuclear leucocytes (PMN), is regulated by estrogen in the mouse reproductive tract. We investigated the expression of LTF mRNA and protein during the natural estrous cycle to increase our understanding of how this uterine secretory protein is regulated under physiological conditions. There was a positive correlation between LTF mRNA expression in the genital tract and serum estradiol (E2) concentrations. When E2 peaked in proestrus, LTF mRNA and protein were expressed in the uterus; however, during metestrus, when both E2 and progesterone levels were high, LTF mRNA was expressed, while LTF protein was decreasing. LTF protein expression may be hindered by progesterone or some other local factor in the endometrial epithelium after ovulation. Immunohistochemistry demonstrated two distinct staining patterns for LTF in the vaginal and endometrial epithelium. In one staining pattern, the colorimetric reaction was noted over the cytoplasm, and in the other, the nuclear region stained more intensely. This suggests the possibility that in addition to its known role as a secretory protein, LTF may be transported to the nucleus, serving an autocrine role. Our results also indicated that LTF protein is a useful marker for tracking PMN. Nonproliferating epithelial cells in the vagina and endometrium may synthesize chemotactic and/or adhesion molecules for PMN.


Pre-experimental familiarization increases hippocampal activity for both targets and lures in recognition memory: an fMRI study.
In the present study, items pre-exposed in a familiarization series were included in a list discrimination task to manipulate memory strength. At test, participants were required to discriminate strong targets and strong lures from weak targets and new lures. This resulted in a concordant pattern of increased "old" responses to strong targets and lures. Model estimates attributed this pattern to either equivalent increases in memory strength across the two types of items (unequal variance signal detection model) or equivalent increases in both familiarity and recollection (dual process signal detection [DPSD] model). Hippocampal activity associated with strong targets and lures showed equivalent increases compared with missed items. This remained the case when analyses were restricted to high-confidence responses considered by the DPSD model to reflect predominantly recollection. A similar pattern of activity was observed in parahippocampal cortex for high-confidence responses. The present results are incompatible with "noncriterial" or "false" recollection being reflected solely in inflated DPSD familiarity estimates and support a positive correlation between hippocampal activity and memory strength irrespective of the accuracy of list discrimination, consistent with the unequal variance signal detection model account.


Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies.
Antibody-based drugs and vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being expedited through preclinical and clinical development. Data from the study of SARS-CoV and other respiratory viruses suggest that anti-SARS-CoV-2 antibodies could exacerbate COVID-19 through antibody-dependent enhancement (ADE). Previous respiratory syncytial virus and dengue virus vaccine studies revealed human clinical safety risks related to ADE, resulting in failed vaccine trials. Here, we describe key ADE mechanisms and discuss mitigation strategies for SARS-CoV-2 vaccines and therapies in development. We also outline recently published data to evaluate the risks and opportunities for antibody-based protection against SARS-CoV-2.


First and Second Language at Hand: A Chronometric Transcranial-Magnetic Stimulation Study on Semantic and Motor Resonance.
According to embodied theories, motor and language processing bidirectionally interact: Motor activation modulates behavior in lexico-semantic tasks (semantic resonance), and understanding motor-related words entails activation of the corresponding motor brain areas (motor resonance). Whereas many studies investigated such interaction in the first language (L1), only few did so in a second language (L2), focusing on motor resonance. Here, we directly compared L1 and a late L2, for the first time both in terms of semantic and motor resonance and both in terms of magnitude and timing, by taking advantage of single-pulse TMS. Twenty-five bilinguals judged, in each language, whether hand motor-related ("grasp") and non-motor-related verbs ("believe"), were physical or mental. Meanwhile, we applied TMS on the hand motor cortex at 125, 275, 350, and 500 msec post verb onset, and recorded behavioral responses and TMS-induced motor evoked potentials. TMS induced faster responses for L1 versus L2 motor and nonmotor verbs at 125 msec (three-way interaction β = -0.0442, 95% CI [0.0814, -0.0070]), showing a semantic resonance effect at an early stage of word processing in L1 but not in L2. Concerning motor resonance, TMS-induced motor evoked potentials at 275 msec revealed higher motor cortex excitability for L2 versus L1 processing (two-way interaction β = 0.095, 95% CI [0.017, 0.173]). These findings confirm action-language interaction at early stages of word recognition, provide further evidence that L1 and L2 are differently embodied, and call for an update of existing models of bilingualism and embodiment, concerning both language representations and processing.


First Report of Melampsora larici-populina on Populus spp. in Eastern North America.
In September 2002, yellow spots were observed on the leaf surface of a hybrid poplar (Populus maximowiczii Henry × P. balsamifera L.) grown at the Berthier forest nursery (46°2'N, 73°11'W) in the St. Lawrence Valley (Lanaudière Region, Québec, Canada). Disease severity was low, but the pathogen was present on a hybrid that was previously thought to be resistant to Melampsora medusae Thuem, the only reported poplar rust in eastern North America. Uredinia typical of a Melampsora sp. were observed on the abaxial leaf surface. The observed urediniospores were longer (32 to 48 μm) than the expected range for M. medusae (23 to 35 μm) and possessed an apical bald spot; thick paraphyses were also observed. These characteristics are diagnostic of M. larici-populina Kleb (2). Samples were deposited in the National Mycological Herbarium of Canada (DAOM 232107 and 232108) and in the Quebec Forest Biology Herbarium (QFB14703 and 14704). DNA was extracted from uredinia, and the internal transcribed spacer (ITS) of the ribosomal RNA gene was amplified and sequenced (GenBank Accession Nos. AY429656 and AY429657). There was a 100% match between the two sequences obtained and that of M. larici-populina (GenBank Accession No. AY375267), but there was approximately 12% divergence with the ITS sequence of M. medusae (GenBank Accession No. AY375273-5). This is the first report of M. larici-populina in eastern North America. This fungus was reported on P. trichocarpa × P. deltoides hybrids in the western United States in the early 1990s (1). It appears that M. larici-populina can overwinter in Québec because it was observed again at the nursery in September 2003. The occurrence of M. larici-populina in eastern North America has direct implications for the poplar industry since the host specificities of M. medusae and M. larici-populina differ; P. balsamifera and P. maximowiczii are sensitive to M. larici-populina (3). Hybrids with P. balsamifera or P. trichocarpa components may be particularly at risk. References: (1) G. Newcombe and G. A. Chastagner. Plant Dis. 77:532, 1993. (2) J. Pinon. Eur. J. For. Pathol. 3:221, 1973. (3) J. Pinon. Silvae Genet. 41:25, 1992.


Estimating the Timing of Multiple Admixture Pulses During Local Ancestry Inference.
Admixture, the mixing of genetically distinct populations, is increasingly recognized as a fundamental biological process. One major goal of admixture analyses is to estimate the timing of admixture events. Whereas most methods today can only detect the most recent admixture event, here, we present coalescent theory and associated software that can be used to estimate the timing of multiple admixture events in an admixed population. We extensively validate this approach and evaluate the conditions under which it can successfully distinguish one- from two-pulse admixture models. We apply our approach to real and simulated data of Drosophila melanogaster We find evidence of a single very recent pulse of cosmopolitan ancestry contributing to African populations, as well as evidence for more ancient admixture among genetically differentiated populations in sub-Saharan Africa. These results suggest our method can quantify complex admixture histories involving genetic material introduced by multiple discrete admixture pulses. The new method facilitates the exploration of admixture and its contribution to adaptation, ecological divergence, and speciation.


A cyclic nucleotide-gated channel inhibits sensory axon outgrowth in larval and adult Caenorhabditis elegans: a distinct pathway for maintenance of sensory axon structure.
The tax-2 and tax-4 genes of C. elegans encode two subunits of a cyclic nucleotide-gated channel that is required for chemosensation, thermosensation and normal axon outgrowth of some sensory neurons. Here we show that, in tax-2 and tax-4 mutants, young larvae have superficially normal axons, but axon outgrowth resumes in inappropriate regions in late larval stages. Using a temperature-sensitive mutation in tax-2, we find that tax-2 activity is required during the adult stage to preserve normal axon morphology. These results indicate that tax-2 and tax-4 are required for the maintenance of correct axon structure, and reveal an unexpected plasticity that allows C. elegans axons to be remodeled long after their initial connections have been established. TAX-2 and TAX-4 have been proposed to form a transduction channel for chemosensation and thermosensation, and tax-2 activity is required in the adult stage for normal chemotaxis to NaCl and odorants. Animals mutant for the daf-11 gene have axon phenotypes that are similar to those of tax-2 and tax 4 mutants; this axon phenotype also has a late time of action. daf-11 regulates a developmental process called dauer larva formation that is controlled by sensory stimuli, and tax-2 and tax-4 can either stimulate or inhibit dauer larva formation in different contexts.


Tuning the Senses: How the Pupil Shapes Vision at the Earliest Stage.
The pupil responds reflexively to changes in brightness and focal distance to maintain the smallest pupil (and thus the highest visual acuity) that still allows sufficient light to reach the retina. The pupil also responds to a wide variety of cognitive processes, but the functions of these cognitive responses are still poorly understood. In this review, I propose that cognitive pupil responses, like their reflexive counterparts, serve to optimize vision. Specifically, an emphasis on central vision over peripheral vision results in pupil constriction, and this likely reflects the fact that central vision benefits most from the increased visual acuity provided by small pupils. Furthermore, an intention to act with a bright stimulus results in preparatory pupil constriction, which allows the pupil to respond quickly when that bright stimulus is subsequently brought into view. More generally, cognitively driven pupil responses are likely a form of sensory tuning: a subtle adjustment of the eyes to optimize their properties for the current situation and the immediate future.


Hypersensitive to red and blue 1 and its modification by protein phosphatase 7 are implicated in the control of Arabidopsis stomatal aperture.
The stomatal pores are located on the plant leaf epidermis and regulate CO(2) uptake for photosynthesis and the loss of water by transpiration. Their stomatal aperture therefore affects photosynthesis, water use efficiency, and agricultural crop yields. Blue light, one of the environmental signals that regulates the plant stomatal aperture, is perceived by the blue/UV-A light-absorbing cryptochromes and phototropins. The signal transduction cascades that link the perception of light to the stomatal opening response are still largely unknown. Here, we report two new players, Hypersensitive to Red and Blue 1 (HRB1) and Protein Phosphatase 7 (PP7), and their genetic and biochemical interactions in the control of stomatal aperture. Mutations in either HRB1 or PP7 lead to the misregulation of the stomatal aperture and reduce water loss under blue light. Both HRB1 and PP7 are expressed in the guard cells in response to a light-to-dark or dark-to-light transition. HRB1 interacts with PP7 through its N-terminal ZZ-type zinc finger motif and requires a functional PP7 for its stomatal opening response. HRB1 is phosphorylated in vivo, and PP7 can dephosphorylate HRB1. HRB1 is mostly dephosphorylated in a protein complex of 193 kDa in the dark, and blue light increases complex size to 285 kDa. In the pp7 mutant, this size shift is impaired, and HRB1 is predominately phosphorylated. We propose that a modification of HRB1 by PP7 under blue light is essential to acquire a proper conformation or to bring in new components for the assembly of a functional HRB1 protein complex. Guard cells control stomatal opening in response to multiple environmental or biotic stimuli. This study may furnish strategies that allow plants to enjoy the advantages of both constitutive and ABA-induced protection under water-limiting conditions.


Characterization of structural features that mediate the tethering of Caenorhabditis elegans protein kinase A to a novel A kinase anchor protein. Insights into the anchoring of PKAI isoforms.
Caenorhabditis elegans protein kinase A (PKAI(CE)) is tethered to organelles in vivo. A unique A kinase anchor protein (AKAP(CE)) avidly binds the RI-like regulatory subunits (R(CE)) of PKAI(CE) and stringently discriminates against RIIalpha and RIIbeta subunits, the preferred ligands for classical AKAPs. We elucidated structural features that stabilize AKAP(CE).R(CE) complexes and confer atypical R isoform specificity on the anchor protein. Three large aliphatic amino acids (Leu(236), Ile(248), and Leu(252)) in the tethering domain of AKAP(CE) (residues 236-255) are crucial for ligation of R(CE). Their side chains apparently generate a precisely configured hydrophobic binding pocket that accommodates an apolar surface on R(CE) dimers. Basic residues (His(254)-Arg(255)-Lys(256)) at the C terminus of the tethering site set an upper limit on affinity for R(CE.) A central dipeptide (Phe(243)-Ser(244)) contributes critical and distinctive properties of the tethering site. Ser(244) is essential for selective binding of R(CE) and exclusion of RII isoforms. The aromatic hydrophobic character of Phe(243) ensures maximal R(CE) binding activity, thereby supporting a "gatekeeper" function of Ser(244). Substitution of Phe(243)-Ser(244) with Leu-Val generated an RII-specific AKAP. R(CE) and RII subunits contain similar dimerization domains. AKAP-binding domains of R(CE) (residues 23-47) and RII differ markedly in size, amino acid sequence, and docking specificity. Four hydrophobic residues (Cys(23), Val(27), Ile(32), and Cys(44)) in R(CE) are crucial for avid binding with AKAP(CE), whereas side chains from Leu(20), Leu(35), Val(36), Ile(40), and Ile(41) have little impact on complex formation. Tyr(26) is embedded in the docking domain, but its aromatic ring is required for R(CE)-R(CE) dimerization. Residues 236-255 in AKAP(CE) also constitute a binding site for mammalian RIalpha. RIalpha (PKAIalpha) is tightly sequestered by AKAP(CE) in vitro (K(D) = approximately 10 nM) and in the environment of intact cells. The tethering domain of AKAP(CE) provides a molecular module for manipulating intracellular localization of RI and elucidating functions of anchored PKAI in eukaryotes.


Comprehensive Study of Mediterranean (Croatian) Propolis Peculiarity: Headspace, Volatiles, Anti-Varroa-Treatment Residue, Phenolics, and Antioxidant Properties.
Eight propolis samples from Croatia were analyzed in detail, to study the headspace, volatiles, anti-Varroa-treatment residue, phenolics, and antioxidant properties. The samples exhibited high qualitative/quantitative variability of the chemical profiles, total phenolic content (1,589.3-14,398.3 mg GAE (gallic acid equivalent)/l EtOH extract), and antioxidant activity (11.1-133.5 mmol Fe(2+) /l extract and 6.2-65.3 mmol TEAC (Trolox® equivalent antioxidant capacity)/l extract). The main phenolics quantified by HPLC-DAD at 280 and 360 nm were vanillin, p-coumaric acid, ferulic acid, chrysin, galangin, and caffeic acid phenethyl ester. The major compounds identified by headspace solid-phase microextraction (HS-SPME), simultaneous distillation extraction (SDE), and subsequent GC-FID and GC/MS analyses were α-eudesmol (up to 19.9%), β-eudesmol (up to 12.6%), γ-eudesmol (up to 10.5%), benzyl benzoate (up to 28.5%), and 4-vinyl-2-methoxyphenol (up to 18.1%). Vanillin was determined as minor constituent by SDE/GC-FID/MS and HPLC-DAD. The identified acaricide residue thymol was ca. three times more abundant by HS-SPME/GC-FID/MS than by SDE/GC-FID/MS and was not detected by HPLC-DAD.


Electrochemically prepared oxides for resistive switching memories.
Redox-based resistive switching memories (ReRAMs) are the strongest candidates for next generation nonvolatile memories. These devices are commonly composed of metal/solid electrolyte/metal junctions, where the solid electrolyte is usually an oxide layer. A key aspect in the ReRAMs development is the solid electrolyte engineering, since it is crucial to tailor the material properties for obtaining excellent switching properties (e.g. retention, endurance, etc.). Here we present an anodizing process as a non vacuum and low temperature electrochemical technique for growing oxides with tailored structural and electronic properties. The effect of the anodizing conditions on the solid state properties of the anodic oxides is studied in relation to the final ReRAM device performances demonstrating the great potentiality of this technique to produce high quality oxide thin films for resistive switching memories.


Middle-aged female rats lack changes in histone H3 acetylation in the anterior hypothalamus observed in young females on the day of a luteinizing hormone surge.
Histone acetylation has recently been implicated in gene transcription and estradiol (E2) actions in the hypothalamus. This study aims to determine the involvement of histone acetylation in mediating E2-induced luteinizing hormone (LH) surge to understand the mechanism underlying LH surge dysfunction in female reproductive aging. Young and middle-aged female rats were ovariectomized (OVX) and treated with hormone or oil once per day for two days. At the time of the expected LH surge, blood samples were taken for LH assay. The anterior and posterior hypothalami were dissected, histone H3/H4 acetylation and histone deacetylases (HDACs) 4, -5, -10 and -11 protein expressions were measured using Western blotting. Our results show that in the young females, E2 markedly increased histone H3 acetylation while significantly reducing HDAC10 protein expression in the anterior hypothalamus. Notably, E2-induced alterations of histone H3 acetylation and HDAC10 in the anterior hypothalamus were absent in middle-aged females, associated with a reduced LH release. However, age alters histone H4 acetylation in both the anterior and posterior hypothalamus and significantly increased HDAC 4 and -5 protein expression in the anterior hypothalamus. Taken together, these data suggest that histone H3 acetylation in the anterior hypothalamus may mediate E2 regulation of LH surge and the process possibly through decreasing HDAC10. The missed responsiveness of histone H3 acetylation and HDAC10 expression to E2 in the anterior hypothalamus may contribute to LH surge failure that occurs in female reproductive aging.


Implementation of a fast method for high resolution phase contrast tomography.
We report the implementation of a method which can yield the 3D distribution of the phase (refractive index) of a weakly absorbing object from a single tomographic data set. In order to reduce the residual absorption artifact (due to the fact that only one data set is used) the original algorithm presented by A. V. Bronnikov is amended by adding in the filter a factor found by using a semi empirical approach. The quality of the reconstruction is largely sufficient for optimal segmentation and further postprocessing even though the filter correction is based on assumption of constant absorption. This one step approach allows keeping radiation dose to the minimum. Spatial resolution is comparable to the conventional absorption based technique. The performance of the method is validated by using an established phase contrast technique.


RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma.
A series of 88 conventional follicular and Hürthle cell thyroid tumors were analyzed for RAS mutations and PAX8-PPAR gamma rearrangements using molecular methods and for galectin-3 and HBME-1 expression by immunohistochemistry. A novel LightCycler technology-based method was developed to detect point mutations in codons 12/13 and 61 of the H-RAS, K-RAS, and N-RAS genes. Forty-nine percent of conventional follicular carcinomas had RAS mutations, 36% had PAX8-PPAR gamma rearrangement, and only one (3%) had both. In follicular adenomas, 48% had RAS mutations, 4% had PAX8-PPAR gamma rearrangement, and 48% had neither. Follicular carcinomas with PAX8-PPAR gamma typically showed immunoreactivity for galectin-3 but not for HBME-1, tended to present at a younger patient age and be smaller size, and were almost always overtly invasive. In contrast, follicular carcinomas with RAS mutations most often displayed an HBME-1-positive/galectin-3-negative immunophenotype and were either minimally or overtly invasive. Hürthle cell tumors infrequently had PAX8-PPAR gamma rearrangement or RAS mutations. These results suggest that conventional follicular thyroid carcinomas develop through at least two distinct and virtually nonoverlapping molecular pathways initiated by either RAS point mutation or PAX8-PPAR gamma rearrangement.