Kinematics of foraging dives and lunge-feeding in fin whales.
Fin whales are among the largest predators on earth, yet little is known about their foraging behavior at depth. These whales obtain their prey by lunge-feeding, an extraordinary biomechanical event where large amounts of water and prey are engulfed and filtered. This process entails a high energetic cost that effectively decreases dive duration and increases post-dive recovery time. To examine the body mechanics of fin whales during foraging dives we attached high-resolution digital tags, equipped with a hydrophone, a depth gauge and a dual-axis accelerometer, to the backs of surfacing fin whales in the Southern California Bight. Body pitch and roll were estimated by changes in static gravitational acceleration detected by orthogonal axes of the accelerometer, while higher frequency, smaller amplitude oscillations in the accelerometer signals were interpreted as bouts of active fluking. Instantaneous velocity of the whale was determined from the magnitude of turbulent flow noise measured by the hydrophone and confirmed by kinematic analysis. Fin whales employed gliding gaits during descent, executed a series of lunges at depth and ascended to the surface by steady fluking. Our examination of body kinematics at depth reveals variable lunge-feeding behavior in the context of distinct kinematic modes, which exhibit temporal coordination of rotational torques with translational accelerations. Maximum swimming speeds during lunges match previous estimates of the flow-induced pressure needed to completely expand the buccal cavity during feeding.


Behavioral and toxicological effects of propofol.
There is increasing concern about abuse of propofol, a widely-used surgical anesthetic and sedative that is currently not a controlled substance. The purpose of this study was to establish a rat model of the psychoactive effect of subanesthetic doses of propofol that could be useful for confirming abuse liability and for studying mechanisms of propofol abuse. Sprague-Dawley rats were trained to discriminate propofol (10 mg/kg, intraperitoneally) from vehicle (2% methylcellulose). Carisoprodol (100 mg/kg), chlordiazepoxide (10 mg/kg), and dizocilpine (0.1 mg/kg) were tested for substitution for the discriminative-stimulus effects of propofol (10 mg/kg), whereas pentylenetetrazol (10 mg/kg) was tested for antagonism of the discriminative-stimulus effects. Propofol (10 mg/kg) was tested for substitution in rats trained to discriminate carisoprodol from vehicle. Carisoprodol produced 59% propofol-appropriate responding, chlordiazepoxide produced 65% propofol-appropriate responding, and dizocilpine produced 34% propofol-appropriate responding. Pentylenetetrazol decreased propofol-appropriate responding to 41%. Propofol produced 52% carisoprodol-appropriate responding. Mortality rate during training of propofol (10 mg/kg) was 38%. Postmortem examination revealed cardiovascular abnormalities similar to those observed in propofol-infusion syndrome in humans. The results demonstrate that propofol can be trained as a discriminative stimulus. Its discriminative-stimulus effects were more similar to compounds promoting γ-aminobutyric acid-A receptor activity than to a compound inhibiting N-methyl-d-aspartate receptor activity. As propofol has discriminative-stimulus effects similar to known drugs of abuse, and occasions a high-mortality rate, its potential for continued abuse is of particular concern.


Comparative Effectiveness of Treatment Choices for Graves' Hyperthyroidism: A Historical Cohort Study.
The optimum therapy for Graves' disease (GD) is chosen following discussion between physician and patient regarding benefits, drawbacks, potential side effects, and logistics of the various treatment options, and it takes into account patient values and preferences. This cohort study aimed to provide useful information for this discussion regarding the usage, efficacy, and adverse-effect profile of radioactive iodine (RAI), antithyroid drugs (ATDs), and thyroidectomy in a tertiary healthcare facility. The cohort included consecutive adults diagnosed with GD from January 2002 to December 2008, who had complete follow-up after treatment at the Mayo Clinic, Rochester, Minnesota. Data on treatment modalities, disease relapses, and adverse effects were extracted manually and electronically from the electronic medical records. Kaplan-Meier analyses were performed to evaluate the association of treatments with relapse-free survival. The cohort included 720 patients with a mean age of 49.3 years followed for a mean of 3.3 years. Of these, 76.7% were women and 17.1% were smokers. The initial therapy was RAI in 75.4%, ATDs in 16.4%, and thyroidectomy in 2.6%, while 5.6% opted for observation. For the duration of follow-up, ATDs had an overall failure rate of 48.3% compared with 8% for RAI (hazard ratio = 7.6; p < 0.0001). Surgery had a 100% success rate; 80% of observed patients ultimately required therapy. Adverse effects developed in 43 (17.3%) patients treated with ATDs, most commonly dysgeusia (4.4%), rash (2.8%), nausea/gastric distress (2.4%), pruritus (1.6%), and urticaria (1.2%). Eight patients treated with RAI experienced radiation thyroiditis (1.2%). Thyroidectomy resulted in one (2.9%) hematoma and one (2.85%) superior laryngeal nerve damage, with no permanent hypocalcemia. RAI was the most commonly used modality within the cohort and demonstrated the best efficacy and safety profile. Surgery was also very effective and relatively safe in the hands of experienced surgeons. While ATDs allow preservation of thyroid function, a high relapse rate combined with a significant adverse-effect profile was documented. These data can inform discussion between physician and patient regarding choice of therapy for GD.


Repurposing drugs for the treatment and control of helminth infections.
Helminth infections are responsible for a considerable public health burden, yet the current drug armamentarium is small. Given the high cost of drug discovery and development, the high failure rates and the long duration to develop novel treatments, drug repurposing circumvents these obstacles by finding new uses for compounds other than those they were initially intended to treat. In the present review, we summarize in vivo and clinical trial findings testing clinical candidates and marketed drugs against schistosomes, food-borne trematodes, soil-transmitted helminths, Strongyloides stercoralis, the major human filariases lymphatic filariasis and onchocerciasis, taeniasis, neurocysticercosis and echinococcosis. While expanding the applications of broad-spectrum or veterinary anthelmintics continues to fuel alternative treatment options, antimalarials, antibiotics, antiprotozoals and anticancer agents appear to be producing fruitful results as well. The trematodes and nematodes continue to be most investigated, while cestodal drug discovery will need to be accelerated. The most clinically advanced drug candidates include the artemisinins and mefloquine against schistosomiasis, tribendimidine against liver flukes, oxantel pamoate against trichuriasis, and doxycycline against filariasis. Preclinical studies indicate a handful of promising future candidates, and are beginning to elucidate the broad-spectrum activity of some currently used anthelmintics. Challenges and opportunities are further discussed.


Cardiovascular health, traffic-related air pollution and noise: are associations mutually confounded? A systematic review.
This review assessed the confounding effect of one traffic-related exposure (noise or air pollutants) on the association between the other exposure and cardiovascular outcomes. A systematic review was conducted with the databases Medline and Embase. The confounding effects in studies were assessed by using change in the estimate with a 10 % cutoff point. The influence on the change in the estimate of the quality of the studies, the exposure assessment methods and the correlation between road noise and air pollutions were also assessed. Nine publications were identified. For most studies, the specified confounders produced changes in estimates <10 %. The correlation between noise and pollutants, the quality of the study and of the exposure assessment do not seem to influence the confounding effects. Results from this review suggest that confounding of cardiovascular effects by noise or air pollutants is low, though with further improvements in exposure assessment, the situation may change. More studies using pollution indicators specific to road traffic are needed to properly assess if noise and air pollution are subjected to confounding.


Discrimination of tones during reinforcing brain stimulation.
Hungry animals were trained to press a lever for brain stimulation. Different tones were presented concurrently with the stimulation. A second lever delivered food only during critical tone periods. Animals were able to discriminate tones presented concurrently with rewarding intracranial stimulation, and they also interrupted self-stimulation behavior to respond appropriately under other reinforcements.


Clinical and molecular characterization of 17q21.31 microdeletion syndrome in 14 French patients with mental retardation.
Chromosome 17q21.31 microdeletion was one of the first genomic disorders identified by chromosome microarrays. We report here the clinical and molecular characterization of a new series of 14 French patients with this microdeletion syndrome. The most frequent clinical features were hypotonia, developmental delay and facial dysmorphism, but scaphocephaly, prenatal ischemic infarction and perception deafness were also described. Genotyping of the parents showed that the parent from which the abnormality was inherited carried the H2 inversion polymorphism, confirming that the H2 allele is necessary, but not sufficient to generate the 17q21.31 microdeletion. Previously reported molecular analyses of patients with 17q21.31 microdeletion syndrome defined a 493 kb genomic fragment that was deleted in most patients after taking into account frequent copy number variations in normal controls, but the deleted interval was significantly smaller (205 kb) in one of our patients, encompassing only the MAPT, STH and KIAA1267 genes. As this patient presents the classical phenotype of 17q21.31 syndrome, these data make it possible to define a new minimal critical region of 160.8 kb, strengthening the evidence for involvement of the MAPT gene in this syndrome.


Job interview training targeting nonverbal communication using an android robot for individuals with autism spectrum disorder.
Job interviews are significant barriers for individuals with autism spectrum disorder because these individuals lack good nonverbal communication skills. We developed a job interview training program using an android robot. The job interview training program using an android robot consists the following three stages: (1) tele-operating an android robot and conversing with others through the android robot, (2) a face-to-face mock job interview with the android robot, and (3) feedback based on the mock job interview and nonverbal communication exercises using the android robot. The participants were randomly assigned to the following two groups: one group received a combined intervention with "interview guidance by teachers and job interview training program using an android robot" (n = 13), and the other group received an intervention with interview guidance by teachers alone (n = 16). Before and after the intervention, the participants in both groups underwent a mock job interview with a human interviewer, who provided outcome measurements of nonverbal communication, self-confidence, and salivary cortisol. After the training sessions, the participants who received the combined interview guidance by teachers and the job interview training program using an android robot intervention displayed improved nonverbal communication skills and self-confidence and had significantly lower levels of salivary cortisol than the participants who only received interview guidance by teachers. The job interview training program using an android robot improved various measures of job interview skills in individuals with autism spectrum disorder.


Isolation, culture and characterization of cardiac progenitor cells derived from human embryonic heart tubes.
A variety of studies have reported on the isolation and expansion of cardiac stem cells from adult hearts. However, there is little information concerning cardiac stem/progenitor cells derived from embryonic hearts/heart tubes. To provide more evidence for embryonic heart-derived stem/progenitor cells, Nkx2.5+ human cardiac progenitorcells (hCPCs) were isolated and cloned from human heart tubes. The cells stained positive for Nkx2.5 and Oct-4, and negative for alpha-smooth muscle actin (alpha-SMA), cytokeratin, factor-VIII, alpha-sarcomeric actin and c-Kit. GATA-4 expression of Nkx2.5+ hCPCs was higher than that of embryonic limb bud mesenchymal cells of the control group (p < 0.05). These cells were passaged continuously for >3 months (23 passages) and proliferated actively in vitro. After being treated with 5-azacytidine, Nkx2.5+ hCPCs underwent cardiomyogenic differentiation. Ultrastructural observation confirmed that the longitudinal section of these cardiomyogenic differentiation cells clearly revealed typical sarcomeres and intercalated discs. alpha-MHC, alpha-sarcomeric actin and GATA-4 levels were increased in Nkx2.5+ hCPCs treated with 5-azacytidine compared to untreated cells. Nkx2.5+ hCPCs exhibited positive staining and had a higher expression for alpha-SMA when cocultured with canine vascular endothelial cells. After Nkx2.5+ hCPCs were treated with endothelin-1, all cells displayed spontaneous electrical activity and spontaneous beating. Connexin-40 and -45 were stained positive in the treated cells. In conclusion, Nkx2.5+ hCPCs derived from heart tubes have been isolated and cloned in vitro. These cells are capable of long-term self-renewal and possess a potential to differentiate into cardiac muscle-like cells, cardiac pacemaking cells and smooth muscle-like cells. They could have a significant impact on cardiac regeneration medicine and developmental biology.


Discrimination, racial bias, and telomere length in African-American men.
Leukocyte telomere length (LTL) is an indicator of general systemic aging, with shorter LTL being associated with several chronic diseases of aging and earlier mortality. Identifying factors related to LTL among African Americans may yield insights into mechanisms underlying racial disparities in health. To test whether the combination of more frequent reports of racial discrimination and holding a greater implicit anti-black racial bias is associated with shorter LTL among African-American men. Cross-sectional study of a community sample of 92 African-American men aged between 30 and 50 years. Participants were recruited from February to May 2010. Ordinary least squares regressions were used to examine LTL in kilobase pairs in relation to racial discrimination and implicit racial bias. Data analysis was completed in July 2013. After controlling for chronologic age and socioeconomic and health-related characteristics, the interaction between racial discrimination and implicit racial bias was significantly associated with LTL (b=-0.10, SE=0.04, p=0.02). Those demonstrating a stronger implicit anti-black bias and reporting higher levels of racial discrimination had the shortest LTL. Household income-to-poverty threshold ratio was also associated with LTL (b=0.05, SE=0.02, p<0.01). Results suggest that multiple levels of racism, including interpersonal experiences of racial discrimination and the internalization of negative racial bias, operate jointly to accelerate biological aging among African-American men. Societal efforts to address racial discrimination in concert with efforts to promote positive in-group racial attitudes may protect against premature biological aging in this population.


A heterogeneous human tissue mimicking phantom for RF heating and MRI thermal monitoring verification.
This paper describes a heterogeneous phantom that mimics a human thigh with a deep-seated tumor, for the purpose of studying the performance of radiofrequency (RF) heating equipment and non-invasive temperature monitoring with magnetic resonance imaging (MRI). The heterogeneous cylindrical phantom was constructed with an outer fat layer surrounding an inner core of phantom material mimicking muscle, tumor and marrow-filled bone. The component materials were formulated to have dielectric and thermal properties similar to human tissues. The dielectric properties of the tissue mimicking phantom materials were measured with a microwave vector network analyzer and impedance probe over the frequency range of 80-500 MHz and at temperatures of 24, 37 and 45 °C. The specific heat values of the component materials were measured using a differential scanning calorimeter over the temperature range of 15-55 °C. The thermal conductivity value was obtained from fitting the curves obtained from one-dimensional heat transfer measurement. The phantom was used to verify the operation of a cylindrical four-antenna annular phased array extremity applicator (140 MHz) by examining the proton resonance frequency shift (PRFS) thermal imaging patterns for various magnitude/phase settings (including settings to focus heating in tumors). For muscle and tumor materials, MRI was also used to measure T1/T2* values (1.5 T) and to obtain the slope of the PRFS phase change versus temperature change curve. The dielectric and thermal properties of the phantom materials were in close agreement to well-accepted published results for human tissues. The phantom was able to successfully demonstrate satisfactory operation of the tested heating equipment. The MRI-measured thermal distributions matched the expected patterns for various magnitude/phase settings of the applicator, allowing the phantom to be used as a quality assurance tool. Importantly, the material formulations for the various tissue types may be used to construct customized phantoms that are tailored for different anatomical sites.


Neuroprotection by association of palmitoylethanolamide with luteolin in experimental Alzheimer's disease models: the control of neuroinflammation.
Alzheimer's disease (AD) is the most common neurodegenerative disorder. Its neuropathological hallmarks include deposition of beta amyloid (Aβ) fibrils in senile plaques. Numerous biochemical events, leading to Aβ neurotoxicity in AD, have been proposed and it seems that neuroinflammation plays a prominent role among these. Thus, since inflammatory processes and oxidative stress are considered to play an important role in neuroinflammatory disorders and in AD pathology, in the present work we decided to test a new composite, which is a formulation constituted of an anti-inflammatory compound such as palmitoylethanolamide (PEA) and the well recognized antioxidant flavonoid luteolin (Lut), subjected to an ultra-micronization process, here designated co-ultraPEALut. We investigated the effect of co-ultraPEALut in both an in vitro and ex vivo organotypic model of AD. For the in vitro model, we used human neuronal cells, obtained by differentiating SH-SY5Y neuroblastoma cells into sustainable neuronal morphology. These well differentiated cells express features specific to mature neurons, such as synaptic structures and functional axonal vesicle transport, making this new concept for in vitro differentiation valuable for many neuroscientific research areas, including AD. Differentiated SH-SY5Y cells were pre-treated with co-ultraPEALut (reference concentrations: 27, 2.7 and 0.27 µM PEA) for 2 h. AD features were induced by Aβ₁₋₄₂ stimulation (1 µM). Twenty-four hours later cell vitality was evaluated by the colorimetric MTT assay, whereas the neuroinflammation underling AD was observed by Western blot analysis for IκBα degradation and nuclear factor-κB traslocation, as well as glial fibrillary acidic protein expression. For the organotypic model of AD, hippocampal slice cultures were prepared from mice at postnatal day 6 and after 21 days of culturing the slices were pre-treated with co-ultraPEALut (reference concentrations: 27, 2.7 and 0.27 µM PEA) for 2 h and then incubated with Aβ₁₋₄₂ (1 µg/ml) for 24 h. Pre-treatment with co-ultraPEALut significantly reduced inducible nitric oxide synthase and glial fibrillary acidic protein expression, restored neuronal nitric oxide synthase and brainderived neurotrophic factor and reduced the apoptosis. Taken together our results clearly showed that co-ultraPEALut is able to blunt Aβ-induced astrocyte activation and to exert a marked protective effect on glial cells. These findings suggest that the association of co-ultraPEALut may provide an effective strategy for AD.


Noncoding RNAs as potential biomarkers to predict the outcome in pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC), a common digestive system cancer, is highly malignant and has a poor disease outcome. Currently, all available examination and detection methods cannot accurately predict the clinical outcome. Therefore, it is extremely important to identify novel molecular biomarkers for personalized medication and to significantly improve the overall outcome. The "noncoding RNAs" (ncRNAs) are a group of RNAs that do not code for proteins, and they are categorized as structural RNAs and regulatory RNAs. It has been shown that microRNAs and long ncRNAs function as regulatory RNAs to affect the progression of various diseases. Many studies have confirmed a role for ncRNAs in the progression of PDAC during the last few years. Because of the significant role of ncRNAs in PDAC, ncRNA profiling may be used to predict PDAC outcome with high accuracy. This review comprehensively analyzes the value of ncRNAs as potential biomarkers to predict the outcome in PDAC and the possible mechanisms thereof.


Effect of tumor necrosis factor inhibition on spinal inflammation and spinal ankylosis in SKG mice.
To prevent spinal progression in ankylosing spondylitis, initiating TNF-inhibitor treatment as early as possible is suggested. However, the outcomes are inconsistent in previous clinical studies. Here, we investigated the effect of TNF inhibition alone on spinal progression when used during arthritis development in a murine model. We injected 8-week-old SKG mice with curdlan (curdlan group). We injected adalimumab at 3 and 9 weeks after the first curdlan injection (ADA group). The clinical scores of peripheral arthritis decreased in the ADA group at 3 weeks after first adalimumab injection. Using positron emission tomography-magnetic resonance imaging and histologic examination, spinal inflammation was observed in the curdlan group, and was significantly deceased in the ADA group. However, spinal osteoblast activities by imaging using OsteoSense 680 EX and bone metabolism-related cytokines such as receptor activator of nuclear factor-kappa B ligand, osteoprotegerin, Dickkopf-1, and sclerostin levels except IL-17A level were not different between the two groups. We conclude that treating TNF inhibitor alone reduced peripheral arthritis score and spinal inflammation in curdlan-injected SKG mice but did not decrease the spinal osteoblast activity, suggesting little effect on spinal ankylosis.


Validating child vaccination status in a demographic surveillance system using data from a clinical cohort study: evidence from rural South Africa.
Childhood vaccination coverage can be estimated from a range of sources. This study aims to validate vaccination data from a longitudinal population-based demographic surveillance system (DSS) against data from a clinical cohort study. The sample includes 821 children in the Vertical Transmission cohort Study (VTS), who were born between December 2001 and April 2005, and were matched to the Africa Centre DSS, in northern KwaZulu-Natal. Vaccination information in the surveillance was collected retrospectively, using standardized questionnaires during bi-annual household visits, when the child was 12 to 23 months of age. DSS vaccination information was based on extraction from a vaccination card or, if the card was not available, on maternal recall. In the VTS, vaccination data was collected at scheduled maternal and child clinic visits when a study nurse administered child vaccinations. We estimated the sensitivity of the surveillance in detecting vaccinations conducted as part of the VTS during these clinic visits. Vaccination data in matched children in the DSS was based on the vaccination card in about two-thirds of the cases and on maternal recall in about one-third. The sensitivity of the vaccination variables in the surveillance was high for all vaccines based on either information from a South African Road-to-Health (RTH) card (0.94-0.97) or maternal recall (0.94-0.98). Addition of maternal recall to the RTH card information had little effect on the sensitivity of the surveillance variable (0.95-0.97). The estimates of sensitivity did not vary significantly, when we stratified the analyses by maternal antenatal HIV status. Addition of maternal recall of vaccination status of the child to the RTH card information significantly increased the proportion of children known to be vaccinated across all vaccines in the DSS. Maternal recall performs well in identifying vaccinated children aged 12-23 months (both in HIV-infected and HIV-uninfected mothers), with sensitivity similar to information extracted from vaccination cards. Information based on both maternal recall and vaccination cards should be used if the aim is to use surveillance data to identify children who received a vaccination.


SCN5A variant that blocks fibroblast growth factor homologous factor regulation causes human arrhythmia.
Nav channels are essential for metazoan membrane depolarization, and Nav channel dysfunction is directly linked with epilepsy, ataxia, pain, arrhythmia, myotonia, and irritable bowel syndrome. Human Nav channelopathies are primarily caused by variants that directly affect Nav channel permeability or gating. However, a new class of human Nav channelopathies has emerged based on channel variants that alter regulation by intracellular signaling or cytoskeletal proteins. Fibroblast growth factor homologous factors (FHFs) are a family of intracellular signaling proteins linked with Nav channel regulation in neurons and myocytes. However, to date, there is surprisingly little evidence linking Nav channel gene variants with FHFs and human disease. Here, we provide, to our knowledge, the first evidence that mutations in SCN5A (encodes primary cardiac Nav channel Nav1.5) that alter FHF binding result in human cardiovascular disease. We describe a five*generation kindred with a history of atrial and ventricular arrhythmias, cardiac arrest, and sudden cardiac death. Affected family members harbor a novel SCN5A variant resulting in p.H1849R. p.H1849R is localized in the central binding core on Nav1.5 for FHFs. Consistent with these data, Nav1.5 p.H1849R affected interaction with FHFs. Further, electrophysiological analysis identified Nav1.5 p.H1849R as a gain-of-function for INa by altering steady-state inactivation and slowing the rate of Nav1.5 inactivation. In line with these data and consistent with human cardiac phenotypes, myocytes expressing Nav1.5 p.H1849R displayed prolonged action potential duration and arrhythmogenic afterdepolarizations. Together, these findings identify a previously unexplored mechanism for human Nav channelopathy based on altered Nav1.5 association with FHF proteins.


Analysis of potentially mobile phosphorus in arable soils using solid state nuclear magnetic resonance.
In many intensive agroecosystems continued inputs of phosphorus (P) over many years can significantly increase soil P concentrations and the risk of P loss to surface waters. For this study we used solid-state 31P nuclear magnetic resonance (NMR) spectroscopy, high-power decoupling with magic angle spinning (HPDec-MAS) NMR, and cross polarization with magic angle spinning (CP-MAS) NMR to determine the chemical nature of potentially mobile P associated with aluminum (Al) and calcium (Ca) in selected arable soils. Three soils with a range of bicarbonate-extractable Olsen P concentrations (40-102 mg P kg(-1)) were obtained from a long-term field experiment on continuous root crops at Rothamsted, UK, established in 1843 (sampled 1958). This soil has a threshold or change point at 59 mg Olsen P kg(-1), above which potentially mobile P (as determined by extraction with water or 0.01 M CaCl2) increases much more per unit increase in Olsen P than below this point. Results showed that CaCl2 and water preferentially extracted Al-P and Ca-P forms, respectively, from the soils. Comparison among the different soils also indicated that potentially mobile P above the threshold was largely present as a combination of soluble and loosely adsorbed (protonated-cross polarized) P forms largely associated with Ca, such as monetite (CaHPO4) and dicalcium phosphate dihydrate (CaHPO4-2H2O), and some Al-associated P as wavellite. The findings of this study demonstrate that solid-state NMR has the potential to provide accurate information on the chemical nature of soil P species and their potential mobility.


CUB-domain containing protein 1 represses the epithelial phenotype of pancreatic cancer cells.
The prognosis of pancreatic cancer is dismal due to the frequent metastasis and invasion to surrounding organs. Numerous molecules are involved in the malignant behavior of pancreatic cancer cells, but the entire process remains unclear. Several reports have suggested that CUB-domain containing protein-1 (CDCP1) is highly expressed in pancreatic cancer, but its impact on the invasive growth and the upstream regulator remain elusive. To clarify the role of CDCP1 in pancreatic cancer, we here examined the effects of CDCP1 knockdown on the cell behaviors of pancreatic cancer cells. Knockdown of CDCP1 expression in Panc-1 resulted in reduced cellular migration accompanied by the increased expression of E-cadherin and decreased expression of N-cadherin. Knockdown of CDCP1 attenuated the spheroid formation and resistance against gemcitabine, which are some of the cancer stem cell-related phenotypes. Bone morphogenetic protein 4 (BMP4) was found to induce CDCP1 expression via the extracellular signal regulated kinase pathway, suggesting that CDCP1 has a substantial role in the BMP4-induced epithelial-mesenchymal transition. These results indicate that CDCP1 represses the epithelial phenotype of pancreatic cancer cells.


Frailty, Inflammation, and Mortality Among Persons Aging With HIV Infection and Injection Drug Use.
Serum markers of inflammation increase with age and have been strongly associated with adverse clinical outcomes among both HIV-infected and uninfected adults. Yet, limited data exist on the predictive and clinical utility of aggregate measures of inflammation. This study sought to evaluate the relationship of a recently validated aggregate inflammatory index with frailty and mortality among aging HIV-infected and uninfected injection drug users. Frailty was assessed among HIV-infected and uninfected participants in the AIDS Linked to the IntraVenous Experience (ALIVE) cohort study using the five Fried phenotypic criteria: weight loss, exhaustion, low physical activity, decreased grip strength, and slow gait. The aggregate inflammatory index was constructed from serum measures of interleukin-6 and soluble tumor necrosis factor-α receptor-1. Multinomial logistic regression was used to assess the relationship of frailty with inflammation. Cox proportional hazards models were used to estimate risk for all-cause mortality. Among 1,326 subjects, the median age was 48 years and 29% were HIV-infected. Adjusting for sociodemographics, comorbidity, and HIV status, frailty was significantly associated with each standard deviation increase in log interleukin-6 (odds ratio 1.33; 95% CI, 1.09-1.61), log tumor necrosis factor-α receptor-1 (odds ratio 1.25; 95% CI, 1.04-1.51) and inflammatory index score (odds ratio 1.39; 95% CI, 1.14-1.68). Adjusting for sociodemographics, comorbidity, HIV status, and frailty, the inflammatory index score was independently associated with increased mortality (HR 1.65; 95% CI, 1.44-1.89). A recently validated, simple, biologically informed inflammatory index is independently associated with frailty and mortality risk among aging HIV-infected and uninfected injection drug users.


A role for milk proteins and their peptides in cancer prevention.
A role for the amount and type of dietary protein in the etiology of cancer has not been studied extensively. Nevertheless, there is no compelling evidence from epidemiological studies to indicate that protein, at levels usually consumed, is a risk factor for cancer. On the other hand, animal studies suggest that certain peptides and amino acids derived from dietary proteins may influence carcinogenesis. The predominant protein in milk, casein, its peptides, but not liberated amino acids, have antimutagenic properties. Animal models, usually for colon and mammary tumorigenesis, nearly always show that whey protein is superior to other dietary proteins for suppression of tumour development. This benefit is attributed to its high content of cystine/cysteine and gamma-glutamylcyst(e)ine dipeptides, which are efficient substrates for the synthesis of glutathione. Glutathione is an ubiquitous cellular antioxidant that directly or through its associated enzymes destroys reactive oxygen species, detoxifies carcinogens, maintains proteins in a reduced state and ensures a competent immune system. Various experiments showed that tumour prevention by dietary whey protein was accompanied by increased glutathione levels in serum and tissues as well as enhanced splenic lymphocyte proliferation, phagocytosis and natural killer, T helper and cytotoxic T cell activity. Whey protein components, beta-lactoglobulin, alpha-lactalbumin and serum albumin were studied infrequently, but results suggest they have anticancer potential. The minor component lactoferrin has received the most attention; it inhibits intestinal tumours and perhaps tumours at other sites. Lactoferrin acts by induction of apoptosis, inhibition of angiogenesis, modulation of carcinogen metabolising enzymes and perhaps acting as an iron scavenger. Supplementing cows with selenium increases the content of selenoproteins in milk, which on isolation inhibited colon tumorigenesis in rats.


Association of Impact Velocity with Risks of Serious Injuries and Fatalities to Pedestrians in Commercial Truck-Pedestrian Accidents.
This study aimed to clarify the relationship between truck-pedestrian crash impact velocity and the risks of serious injury and fatality to pedestrians. We used micro and macro truck-pedestrian accident data from the Japanese Institute for Traffic Accident Research and Data Analysis (ITARDA) database. We classified vehicle type into five categories: heavy-duty trucks (gross vehicle weight [GVW] ≥11 × 103 kg [11 tons (t)], medium-duty trucks (5 × 103 kg [5 t] ≤ GVW < 11 × 103 kg [11 t]), light-duty trucks (GVW <5 × 103 kg [5 t]), box vans, and sedans. The fatality risk was ≤5% for light-duty trucks, box vans, and sedans at impact velocities ≤ 30 km/h and for medium-duty trucks at impact velocities ≤20 km/h. The fatality risk was ≤10% for heavy-duty trucks at impact velocities ≤10 km/h. Thus, fatality risk appears strongly associated with vehicle class. The results also revealed that a 10 km/h reduction in impact velocities could mitigate the severity of pedestrian injuries at impact velocities ≥30 km/h for all five analyzed vehicle types. Therefore, serious injuries and fatalities to pedestrians could be decreased by the development and deployment of collision mitigation systems (CMSs) to all vehicles, including to commercial trucks, because CMSs can detect pedestrians in even severe conditions, such as when the drive's view is obstructed, and can reduce the impact velocity. The present results indicate that CMS design specifications should differ between vehicle types because of the strong dependence of seriousinjury and fatality risks on vehicle type.


Ultrastructural modifications of intestinal and colonic mucosa induced by free or bound bile acids.
There is substantial evidence that bile acids may enhance the colon tumorigenesis induced by chemical carcinogens and that agents stimulating increased bile acid excretion may show similar promoting or enhancing activity. To test the premise that these agents might modify topographical ultrastructure of the small intestine and colon in the absence of carcinogens, rats were fed for 6 weeks on chemically defined diets containing 2% levels of three commercial bile acid sequestrants or 15% levels of wheat brain, cellulose, pectin, or alfalfa. Major qualitative and quantitative deviations from normal morphology were observed with each of the three sequestrants. Similar but less dramatic modifications occurred with diets containing alfalfa or pectin, both of which either "bind" bile acids in vitro or result in increased bile acid excretion. Bran and cellulose which neither "bind" bile acids nor increase their fecal excretion, were without significant effects on intestinal or colonic morphology. The morphological deviations observed with bile acid sequestrants were shown to be a direct response to free or bound bile acids by comparing the morphological modifications resulting from daily intracolonic infusions of free bile acids, sequestrant-bound bile acids, or the sequestrant alone.


Extreme challenges: psychiatric inpatients with severe self-harming behavior in Norway: a national screening investigation.
Extreme self-harming behavior is a major challenge for patients and health services. Nevertheless, this patient population is poorly described in research literature. The aim of this study was to assess the volume of patients with extensive psychiatric hospitalization due to extreme self-harming behaviors, the extent of severe medical sequelae, and collaboration problems within health services. In a national screening investigation, department managers in 83 adult psychiatric inpatient institutions across all health regions in Norway were invited to participate in a brief, prepared, telephone interview. Sixty-one interviews were completed. Extensive hospitalization (prolonged or multiple) due to extreme self-harm was reported for the last year in all health regions and in 427 individual cases. Mean number of cases did not differ by region. Psychiatric hospitalizations were more frequent in hospital units than mental health centers. In 109 of the cases, self-harming behavior had severe medical consequences, including five deaths. In 122 of the cases, substantial collaboration problems within the health services were reported (disagreements on diagnosis, treatment needs and resources). Extensive (long-term) hospitalization was particularly associated with the combination of severe medical sequelae and collaboration problems. This investigation confirms a noteworthy, nationwide, population of severely self-harming inpatients with extensive health service use, prevalent severe medical complications, and unsatisfactory collaboration within health services. These preliminary results are alarming, and indicate a need for more profound understanding of highly complex and severe cases.


Predictive distributions for between-study heterogeneity and simple methods for their application in Bayesian meta-analysis.
Numerous meta-analyses in healthcare research combine results from only a small number of studies, for which the variance representing between-study heterogeneity is estimated imprecisely. A Bayesian approach to estimation allows external evidence on the expected magnitude of heterogeneity to be incorporated. The aim of this paper is to provide tools that improve the accessibility of Bayesian meta-analysis. We present two methods for implementing Bayesian meta-analysis, using numerical integration and importance sampling techniques. Based on 14,886 binary outcome meta-analyses in the Cochrane Database of Systematic Reviews, we derive a novel set of predictive distributions for the degree of heterogeneity expected in 80 settings depending on the outcomes assessed and comparisons made. These can be used as prior distributions for heterogeneity in future meta-analyses. The two methods are implemented in R, for which code is provided. Both methods produce equivalent results to standard but more complex Markov chain Monte Carlo approaches. The priors are derived as log-normal distributions for the between-study variance, applicable to meta-analyses of binary outcomes on the log odds-ratio scale. The methods are applied to two example meta-analyses, incorporating the relevant predictive distributions as prior distributions for between-study heterogeneity. We have provided resources to facilitate Bayesian meta-analysis, in a form accessible to applied researchers, which allow relevant prior information on the degree of heterogeneity to be incorporated.


Synapse- and stimulus-specific local translation during long-term neuronal plasticity.
Long-term memory and synaptic plasticity require changes in gene expression and yet can occur in a synapse-specific manner. Messenger RNA localization and regulated translation at synapses are thus critical for establishing synapse specificity. Using live-cell microscopy of photoconvertible fluorescent protein translational reporters, we directly visualized local translation at synapses during long-term facilitation of Aplysia sensory-motor synapses. Translation of the reporter required multiple applications of serotonin, was spatially restricted to stimulated synapses, was transcript- and stimulus-specific, and occurred during long-term facilitation but not during long-term depression of sensory-motor synapses. Translational regulation only occurred in the presence of a chemical synapse and required calcium signaling in the postsynaptic motor neuron. Thus, highly regulated local translation occurs at synapses during long-term plasticity and requires trans-synaptic signals.


In Comparison to Pathological Q Waves, Selvester Score is a Superior Diagnostic Indicator of Increased Long-Term Mortality Risk in ST Elevation Myocardial Infarction Patients Treated with Primary Coronary Intervention.
The development of pathological Q waves has long been correlated with worsened outcome in patients with ST elevation myocardial infarction (STEMI). In this study, we investigated long-term mortality of STEMI patients treated by primary percutaneous coronary intervention (PPCI) and compared predictive values of Q waves and of Selvester score for infarct volume estimation. Data of 283 consecutive STEMI patients (103 females) treated by PPCI were analysed. The presence of pathological Q wave was evaluated in pre-discharge electrocardiograms (ECGs) recorded ≥72 h after the chest pain onset (72 h Q). The Selvester score was evaluated in acute ECGs (acute Selvester score) and in the pre-discharge ECGs (72 h Selvester score). The results were related to total mortality and to clinical and laboratory variables. A 72 h Q presence and 72 h Selvester score ≥6 was observed in 184 (65.02%) and 143 (50.53%) patients, respectively. During a follow-up of 5.69 ± 0.66 years, 36 (12.7%) patients died. Multivariably, 72 h Selvester score ≥6 was a strong independent predictor of death, while a predictive value of the 72 h Q wave was absent. In high-risk subpopulations defined by clinical and laboratory variables, the differences in total mortality were highly significant (p < 0.01 for all subgroups) when stratified by 72 h Selvester score ≥6. On the contrary, the additional risk-prediction by 72 h Q presence was either absent or only borderline. In contemporarily treated STEMI patients, Selvester score is a strong independent predictor of long-term all-cause mortality. On the contrary, the prognostic value of Q-wave presence appears limited in contemporarily treated STEMI patients.


Amorphous silica nanoparticle-induced pulmonary inflammatory response depends on particle size and is sex-specific in rats.
Due to mass production and extensive use, the potential adverse health effects of amorphous silica nanoparticles (ASiNPs) have received a significant attention from the public and researchers. However, the relationship between physicochemical properties of ASiNPs and their health effects is still unclear. In this study, we manufactured two types of ASiNPs of different diameters (20 and 50 nm) and compared the toxic response induced in rats after intratracheal instillation (75, 150 or 300 μg/rat). There were no dose-related differences in mortality, body weight gain or organ weight between the groups. However both types of ASiNPs significantly decreased the proportion of neutrophils in male rats, whereas the levels of hemoglobin and hematocrit were markedly reduced only in female rats instilled with 20 nm-ASiNPs. ASiNPs-induced lung tissue damage seemed to be more evident in the 20 nm ASiNP-treated group and in female rats than male rats. Similarly, expression of caveolin-1 and matrix metalloproteinase-9 seemed to be most notably enhanced in female rats treated with 20 nm-ASiNPs. The total number of bronchial alveolar lavage cells significantly increased in rats instilled with 20 nm-ASiNPs, accompanying a decrease in the proportion of macrophages and an increase in polymorphonuclear leukocytes. Moreover, secretion of inflammatory mediators clearly increased in human bronchial epithelial cells treated with 20 nm-ASiNPs, but not in those treated with 50 nm-ASiNPs. These results suggest that pulmonary effects of ASiNPs depend on particle size. Sex-dependent differences should also be carefully considered in understanding nanomaterial-induced adverse health effects.


RS3PE syndrome: a clinical and immunogenetical study.
This study analyses the clinical, radiological, evolutive, and immunogenetical characteristics of a series of patients diagnosed with remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome. Reviewed were the clinical charts and human leukocyte antigen (HLA) profiles of all patients treated at a single teaching hospital fulfilling the features of this syndrome according to the definition of McCarty. Twelve cases were detected in ten men and two women aged from 62 to 85 years. Rheumatoid factor was negative in all cases, and antinuclear antibodies (ANA) were positive in two. All patients achieved complete resolution of their condition within 1 year with glucocorticoid (GC) use. Two relapsed after remission but responded again to low doses of GC. Four patients showed clinical and electrodiagnostic studies consistent with carpal tunnel syndrome. No specific HLA association could be found in this report. To date, none of these patients has developed definite rheumatic diseases, infections, or malignant diseases. Although the real nature of the syndrome is still a matter of debate, at least in our context, RS3PE remains a definite condition with an excellent prognosis.


Pharmacokinetics of hydroxyurea 1,000 mg coated breakable tablets and 500 mg capsules in pediatric and adult patients with sickle cell disease.
Little is known about the pharmacokinetics of hydroxyurea in patients with sickle cell disease (SCD). Our aims were to evaluate bioequivalence between standard hydroxyurea capsules and a new formulation of 1,000 mg coated breakable tablets in adults and to compare pharmacokinetic parameters in adults and children with SCD. Fifteen adults received hydroxyurea capsules and tablets in a randomized cross-over study. Eleven children received hydroxyurea tablets. The results showed bioequivalence between capsules and tablets in adults. Pharmacokinetic parameters were not significantly different between adults and children. Considerable inter-individual variability was noted.


Variable-density parallel imaging with partially localized coil sensitivities.
Partially parallel imaging with localized sensitivities is a fast parallel image reconstruction method for both Cartesian and non-Cartesian trajectories, but suffers from aliasing artifacts when there are deviations from the assumption of perfect localization. Such reconstructions would normally crop the individual coil images to remove the artifacts prior to combination. However, the sampling densities in variable-density k-space trajectories support different field-of-views for separate regions in k -space. In fact, the higher sampling density of low frequencies can be used to reconstruct a bigger field-of-view without introducing aliasing artifacts and the resulting image signal-to-noise ratio (SNR) can be improved. A novel, fast variable-density parallel imaging method is presented, which reconstructs different field-of-views from separate frequencies according to the local sampling density in k-space. Aliasing-suppressed images can be produced with high SNR-efficiency without the need for accurate estimation of coil sensitivities and complex or iterative computations.


Co-occurrence of histone H3 K27M and BRAF V600E mutations in paediatric midline grade I ganglioglioma.
Ganglioglioma (GG) is a grade I tumor characterized by alterations in the MAPK pathway, including BRAF V600E mutation. Recently, diffuse midline glioma with an H3 K27M mutation was added to the WHO 2016 classification as a new grade IV entity. As co-occurrence of H3 K27M and BRAF V600E mutations has been reported in midline tumors and anaplastic GG, we searched for BRAF V600E and H3 K27M mutations in a series of 54 paediatric midline grade I GG (midline GG) to determine the frequency of double mutations and its relevance for prognosis. Twenty-seven patients (50%) possessed the BRAF V600E mutation. The frequency of the co-occurrence of H3F3A/BRAF mutations at diagnosis was 9.3%. No H3 K27M mutation was detected in the absence of the BRAF V600E mutation. Double-immunostaining revealed that BRAF V600E and H3 K27M mutant proteins were present in both the glial and neuronal components. Immunopositivity for the BRAF V600E mutant protein correlated with BRAF mutation status as detected by massARRAY or digital droplet PCR. The median follow-up of patients with double mutation was 4 years. One patient died of progressive disease 8 years after diagnosis, whereas the four other patients were all alive with stable disease at the last clinical follow-up (at 9 months, 1 year and 7 years) without adjuvant therapy. We demonstrate in this first series of midline GGs that the H3 K27M mutation can occur in association with the BRAF V600E mutation in grade I glioneuronal tumors. Despite the presence of H3 K27M mutations, these cases should not be graded and treated as grade IV tumors because they have a better spontaneous outcome than classic diffuse midline H3 K27M-mutant glioma. These data suggest that H3 K27M cannot be considered a specific hallmark of grade IV diffuse gliomas and highlight the importance of integrated histomolecular diagnosis in paediatric brain tumors.


Anaerobic utilization of alkylbenzenes and n-alkanes from crude oil in an enrichment culture of denitrifying bacteria affiliating with the beta-subclass of Proteobacteria.
Denitrifying bacteria were enriched from freshwater sediment with added nitrate as electron acceptor and crude oil as the only source of organic substrates. The enrichment cultures were used as laboratory model systems for studying the degradative potential of denitrifying bacteria with respect to crude oil constituents, and the phylogenetic affiliation of denitrifiers that are selectively enriched with crude oil. The enrichment culture exhibited two distinct growth phases. During the first phase, bacteria grew homogeneously in the aqueous phase, while various C1-C3 alkylbenzenes, but no alkanes, were utilized from the crude oil. During the second phase, bacteria also grew that formed aggregates, adhered to the crude oil layer and emulsified the oil, while utilization of n-alkanes (C5 to C12) from the crude oil was observed. During growth, several alkylbenzoates accumulated in the aqueous phase, which were presumably formed from alkylbenzenes. Application of a newly designed, fluorescently labelled 16S rRNA-targeted oligonucleotide probe specific for the Azoarcus/Thauera group within the beta-subclass of Proteobacteria revealed that the majority of the enriched denitrifiers affiliated with this phylogenetic group.


Factors leading to under-reporting of tuberculosis in the private sector in Korea.
To identify factors associated with under-reporting of tuberculosis (TB) in the private sector in Korea. A cross-sectional study of 37,820 cases in whom treatment was initiated between January and December 2008 using data from the Nationwide Medical Records Survey of Patients with TB. Adjusted odds ratios (aOR) for under-reporting with respect to socio-demographic and clinical factors were estimated. Among the 37,820 identified cases, 21,611 (57.1%) were reported to the Korean TB Surveillance System. Factors associated with under-reporting on univariate analysis included young children, foreign-born persons, non-multidrug-resistant TB, persons prescribed fewer than four anti-tuberculosis drugs, non-performance of or negative result on sputum smear and extra-pulmonary TB (particularly abdominal or genitourinary TB). For pulmonary TB, cases with no sputum smear results vs. smear-positive patients (aOR 2.23, P < 0.001) and those prescribed <4 drugs vs. those who were prescribed ≥4 drugs (aOR 1.60, P < 0.001) were strongly related to under-reporting on multivariate analysis. The extent of under-reporting was greater among young children, persons who had not received sputum smear testing and those who had been prescribed fewer than four drugs. Furthermore, TB diagnostic investigations were often inadequate. Education on reporting requirements, including the importance of following guidelines on TB management, and a stricter enforcement of the existing TB Prevention Law, are needed.


Microtubule polarity confers direction to pigment transport in chromatophores.
The cellular mechanisms used to direct translocating organelles are poorly understood. It is believed that the intrinsic structural polarity of microtubules may play a role in this process. We have examined the effects that differently oriented microtubules have upon the direction of pigment transport in surgically severed melanophore arms. In a previous paper (McNiven, M. A., M. Wang, and K. R. Porter, 1984, Cell, 37:753-765) we reported that after isolation, arms repolarized and reoriented their microtubules outward from their centers as if to form new "microcells." Pigment aggregation in these arms was toward a new focal point located at the arm centers. In this study we monitored pigment movement in isolated arms containing taxol-stabilized microtubules to test if the reversal in direction of pigment transport is dependent upon the repolarization of microtubules. We report that taxol delays both the microtubule reorientation and reversal in transport direction in a concentration-dependent manner. These and other presented data suggest that the polarity of the microtubule population within a melanophore confers direction on pigment transport.


Enhancing quality and integrity in biomedical research in Africa: an international call for greater focus, investment and standardisation in capacity strengthening for frontline staff.
The integrity of biomedical research depends heavily on the quality of research data collected. In turn, data quality depends on processes of data collection, a task undertaken by frontline research staff in many research programmes in Africa and elsewhere. These frontline research staff often have additional responsibilities including translating and communicating research in local languages, seeking informed consent for study participation and maintaining supportive relationships between research institutions and study participants and wider communities. The level of skills that fieldworkers need to undertake these responsibilities clearly affects the quality of data collected, the ethics of research 'on the ground' and the short and long term acceptability of research.We organised an international workshop in Kenya in July 2014 to discuss the role of frontline staff in scientific research. A total of 25 field managers from 9 African countries and the UK met for 2.5 days to discuss the relationship between data quality and institutional performance management systems and how they affect career progression and supportive supervision policies of research frontline staff.From this workshop, and supporting an expanding literature on the role of fieldworkers in international health research, participants agreed that fieldworkers' roles present them with practical and ethical challenges that their routine training does not adequately prepare them for. We argue that the common and complex challenges facing fieldworkers should in part be addressed through increased investment and collaborative agreements across types of research institutions in Africa. We call for standardization of core elements of training for this critically important cadre of research staff who perform similar roles and encounter similar challenges in many African settings. Although many valuable training elements are offered in institutions, there is a need to develop broader, more grounded and innovative strategies to address complex realities for fieldworkers, and support the integrity and ethics of health research in these settings.


Scaling of the size of the first agonist EMG burst during rapid wrist movements in patients with Parkinson's disease.
Rapid wrist flexion movements were studied in a group of 10 patients with Parkinson's disease both on and off their normal drug therapy, and were compared with the same movements made by a group of eight normal individuals. When normal subjects made movements through 60 degrees, the first agonist burst of EMG activity in the wrist flexor muscles was longer and larger than that seen in movements of 15 degrees. If a large opposing load of 2.2 Nm was added, this also increased the size and duration of the first agonist EMG burst. Although the movements made by the patients were slower than those of normals, the size and duration of the first agonist EMG burst changed with movement size and added load in the normal way. This shows that patients can produce large, long bursts of EMG activity, but that there is a failure to match these parameters appropriately to the size of movement required. The effect of levodopa therapy on the movements was not dramatic. Although patients produced faster wrist movements when on medication than when off, the change was relatively small compared with the change seen in their overall clinical rating. Changes in the velocity of movements at a single joint are not a good reflection of the overall clinical state of patients with Parkinson's disease.


Hypolestes hatuey sp. nov.: a new species of the enigmatic genus Hypolestes (Odonata, Hypolestidae) from Hispaniola.
Both sexes of Hypolestes hatuey Torres-Cambas, sp. nov. (Odonata: Zygoptera: Hypolestidae) from Hispaniola are described and illustrated here. This newly described species differs from H. trinitatis and H. clara, the other two species within the genus, by the morphology of the genital ligula and male cerci. Females of H. hatuey sp. nov. differ from H. clara by the shape of the female antehumeral stripe and wing venation. Morphological distinctiveness in males is supported by genetic differences in the 16S mitochondrial gene. Following the categories and criteria of the IUCN Red List of Threatened Species, we suggest this species should be listed as Data Deficient (DD), given that available data on its distribution are too limited to assess its risk of extinction.


Detection and stability of Japanese encephalitis virus RNA and virus viability in dead infected mosquitoes under different storage conditions.
A semi-nested polymerase chain reaction (PCR) was evaluated for detection of Japanese encephalitis (JE) virus in infected mosquitoes stored under simulated northern Australian summer conditions. The effect of silica gel, thymol, and a combination of the two on RNA stability and virus viability in dead mosquitoes were also examined. While JE virus RNA was relatively stable in mosquitoes held for up to 14 days after death, viable virus was not detected after day 1. Thymol vapor inhibited fungal contamination. Detection of single mosquitoes infected with JE virus in large pools of mosquitoes was also investigated. Single laboratory-infected mosquitoes were detected in pools of < or = 200 mosquitoes and in pools diluted to 0.2/100 and 0.1/100 mosquitoes, using the semi-nested PCR. However, the ability to detect live virus decreased as pool size increased. The semi-nested PCR proved more expensive than virus isolation for pools of 100 mosquitoes. However, the semi-nested PCR was faster and more economical using larger pools. Results indicate that surveillance of JE virus in mosquitoes using the semi-nested PCR is an alternative to monitoring seroconversions in sentinel pigs.


Value and appropriate use of rating scales and apparative measurements in quantification of disability in Parkinson's disease.
Despite widespread use in pharmacotherapeutical trials, in the majority of rating scales used in Parkinson's disease (PD) validity, reliability and appropriate use have never been confirmed by statistical data. For this reason 350 unselected PD-pats. were investigated by an extensive standardized test-battery including registration of basis data, Columbia University Rating Scale (CURS), scale for assessment of functional disability (ADL), SCAG-scale, Hoehn & Jahr-scale (HY), mod. Webster step second-test (WSST), Purdue-pegboard, questionnaire for subjective complaints (SC), WDG, LPS1/2, 3/4, 6, 7, 10, clinical assessment of dementia, v. Zerssen-scale and orthostatic hypotension (60 degrees tilt up). For CURS, SCAG and ADL instrumental reliability was calculated by Cronbach's alpha. For CURS, SCAG, ADL and the total data of complete test battery (CTB) principal component analysis (PCA) was performed for data reduction. CURS, SCAG and ADL showed high internal consistency (alpha approximately > or = 0.9). For CURS 5 factors accounting for 66% total variance could be extracted by PCA. They represent gait, rigidity, tremor, right/left dexterity (eigenvalues > 1). For SCAG 3 factors (61% of total variance) representing dementia, depression and change of personality were extracted. For ADL 3 factors (67% of total variance) could be extracted, representing overall functional disability, handwriting and disability by pain. PCA of the CTB identified 8 interpretable factors (66% of total variance) characterizing at least partially the clinical profile of PD: 1. motor disability (assessment by rating-scales) 2. dementia, 3. motor-disability (assessment by apparative measurements), 4. depression, 5. orthostatic hypotension, 6. WDG, 7. tremor and 8. pain. Our data confirm the suitability of the investigated scales and give a rational base for their appropriate use in a sense of data reduction and economical evaluation.


The hyperplastic cholecystoses: cholesterolosis and adenomyomatosis.
Cholesterolosis and adenomyomatosis, two diseases of the gallbladder that are unrelated to cholelithiasis or cholecystitis, are detected on oral cholecystograms with considerable frequency. These disorders are of uncertain etiology, and it is also unclear if they cause clinical symptoms. Cholesterolosis is the result of the accumulation of triglycerides and esterified sterols in macrophages in the lamina propria. The abnormality is unassociated with cholesterol gallstones, supersaturation of bile with cholesterol, hyperlipidemia, obesity, or atherosclerosis. Adenomyomatosis involves hyperplasia of the tissues of the gallbladder wall with outpouches of the mucosa similar to diverticula of the colon. In this report, the pathology, etiology, clinical and radiologic features, and treatment of these two entities are reviewed.


Transradial access for primary percutaneous coronary intervention: the next standard of care?
Primary percutaneous coronary intervention (PPCI) has been acknowledged by the most recent European guidelines to be the preferred treatment for ST elevation myocardial infarction (STEMI). Patients undergoing PPCI are expected to receive a broad spectrum of anticoagulants and antiplatelet agents, which increases the risk of bleedings, in most cases, at the site of vascular access. The burden of bleeding complications after PPCI is as negative as that of ischemic complications not only on in-hospital morbidity, but also on mid- and long-term survival. Owing to the unique features of the radial artery, transradial approach (TRA) seems able to overcome most of the problems related to vascular access particularly in case of STEMI. In this short review we discuss the results of the latest studies and we highlight not only the safety and feasibility of TRA-PPCI, but also the advantages in terms of morbidity and mortality. We finally report on our experience at OLVG Amsterdam, and how TRA can also change the logistics in case of a PPCI programme (short stay).


Inhibition of melanogenesis by 5,7-dihydroxyflavone (chrysin) via blocking adenylyl cyclase activity.
Due to its multiple biological activities, 5,7-dihydroxyflavone (chrysin) in propolis has gained attention as potentially useful therapeutics for various diseases. However, the efficacy of chrysin for the use of dermatological health has not been fully explored. To clarify the action mechanism of the skin protecting property of chrysin, we firstly investigated the molecular docking property of chrysin on the mammalian adenylyl cyclase, which is the key enzyme of cAMP-induced melanogenesis. We also examined the involvement of chrysin in alpha-MSH and forskolin-induced cAMP signaling within a cell based assay. In addition, we inquired into the inhibitory effect of chrysin on melanogenesis and found that the pretreatment with chrysin inhibited the forskolin-induced melanin contents significantly without annihilating the cell viability. These results strongly suggest that chrysin directly inhibits the activity of adenylyl cyclase, downregulates forskolin-induced cAMP-production pathway, consequently inhibiting melanogenesis. Thus, chrysin may also be used as an effective inhibitor of hyperpigmentation.


Structure and inhibitor specificity of the PCTAIRE-family kinase CDK16.
CDK16 (also known as PCTAIRE1 or PCTK1) is an atypical member of the cyclin-dependent kinase (CDK) family that has emerged as a key regulator of neurite outgrowth, vesicle trafficking and cancer cell proliferation. CDK16 is activated through binding to cyclin Y via a phosphorylation-dependent 14-3-3 interaction and has a unique consensus substrate phosphorylation motif compared with conventional CDKs. To elucidate the structure and inhibitor-binding properties of this atypical CDK, we screened the CDK16 kinase domain against different inhibitor libraries and determined the co-structures of identified hits. We discovered that the ATP-binding pocket of CDK16 can accommodate both type I and type II kinase inhibitors. The most potent CDK16 inhibitors revealed by cell-free and cell-based assays were the multitargeted cancer drugs dabrafenib and rebastinib. An inactive DFG-out binding conformation was confirmed by the first crystal structures of CDK16 in separate complexes with the inhibitors indirubin E804 and rebastinib, respectively. The structures revealed considerable conformational plasticity, suggesting that the isolated CDK16 kinase domain was relatively unstable in the absence of a cyclin partner. The unusual structural features and chemical scaffolds identified here hold promise for the development of more selective CDK16 inhibitors and provide opportunity to better characterise the role of CDK16 and its related CDK family members in various physiological and pathological contexts.


Shaping emission spectra of fluorescent molecules with single plasmonic nanoresonators.
We show that plasmonic nanoresonators composed of two gold nanoparticles change not only the intensity but also the spectral shape of the emission of fluorescent molecules. The plasmonic resonance frequency can be tuned by varying the distance between the nanoparticles, which allows us to selectively favor transitions of a fluorescent molecule to a specific vibrational ground state. Experimental data from correlated scattering and fluorescence microscopy agree well with calculations in the framework of generalized Mie theory. Our results show that the widely used description of a dye molecule near a metal surface as a mere two-level system is inadequate.


Identifying periodically expressed transcripts in microarray time series data.
Microarray experiments are now routinely used to collect large-scale time series data, for example to monitor gene expression during the cell cycle. Statistical analysis of this data poses many challenges, one being that it is hard to identify correctly the subset of genes with a clear periodic signature. This has lead to a controversial argument with regard to the suitability of both available methods and current microarray data. We introduce two simple but efficient statistical methods for signal detection and gene selection in gene expression time series data. First, we suggest the average periodogram as an exploratory device for graphical assessment of the presence of periodic transcripts in the data. Second, we describe an exact statistical test to identify periodically expressed genes that allows one to distinguish periodic from purely random processes. This identification method is based on the so-called g-statistic and uses the false discovery rate approach to multiple testing. Using simulated data it is shown that the suggested method is capable of identifying cell-cycle-activated genes in a gene expression data set even if the number of the cyclic genes is very small and regardless the presence of a dominant non-periodic component in the data. Subsequently, we re-examine 12 large microarray time series data sets (in part controversially discussed) from yeast, human fibroblast, human HeLa and bacterial cells. Based on the statistical analysis it is found that a majority of these data sets contained little or no statistical significant evidence for genes with periodic variation linked to cell cycle regulation. On the other hand, for the remaining data the method extends the catalog of previously known cell-cycle-specific transcripts by identifying additional periodic genes not found by other methods. The problem of distinguishing periodicity due to generic cell cycle activity and to artifacts from synchronization is also discussed. The approach has been implemented in the R package GeneTS available from http://www.stat.uni-muenchen.de/~strimmer/software.html under the terms of the GNU General Public License.


Circumcision of privately insured males aged 0 to 18 years in the United States.
Male circumcision confers protection against HIV, sexually transmitted infections, and urinary tract infections. Compared with circumcision of postneonates (>28 days), circumcision of neonates is associated with fewer complications and usually performed with local rather than general anesthesia. We assessed circumcision of commercially insured males during the neonatal or postneonatal period. We analyzed 2010 MarketScan claims data from commercial health plans, using procedural codes to identify circumcisions performed on males aged 0 to 18 years, and diagnostic codes to assess clinical indications for the procedure. Among circumcisions performed in the first year of life, we estimated rates for neonates and postneonates. We estimated the percentage of circumcisions by age among males who had circumcisions in 2010, and the mean payment for neonatal and postneonatal procedures. We found that 156,247 circumcisions were performed, with 146,213 (93.6%) in neonates and 10,034 (6.4%) in postneonates. The neonatal circumcision rate was 65.7%, and 6.1% of uncircumcised neonates were circumcised by their first birthday. Among postneonatal circumcisions, 46.6% were performed in males younger than 1 year and 25.1% were for nonmedical indications. The mean payment was $285 for a neonatal and $1885 for a postneonatal circumcision. The large number of nonmedical postneonatal circumcisions suggests that neonatal circumcision might be a missed opportunity for these boys. Delay of nonmedical circumcision results in greater risk for the child, and a more costly procedure. Discussions with parents early in pregnancy might help them make an informed decision about circumcision of their child.


Seeing the Invisible-Ultrasound Molecular Imaging.
Ultrasound molecular imaging has been developed in the past two decades with the goal of non-invasively imaging disease phenotypes on a cellular level not depicted on anatomic imaging. Such techniques already play a role in pre-clinical research for the assessment of disease mechanisms and drug effects, and are thought to in the future contribute to earlier diagnosis of disease, assessment of therapeutic effects and patient-tailored therapy in the clinical field. In this review, we first describe the chemical composition and structure as well as the in vivo behavior of the ultrasound contrast agents that have been developed for molecular imaging. We then discuss the strategies that are used for targeting of contrast agents to specific cellular targets and protocols used for imaging. Next we describe pre-clinical data on imaging of thrombosis, atherosclerosis and microvascular inflammation and in oncology, including the pathophysiological principles underlying the selection of targets in each area. Where applicable, we also discuss efforts that are currently underway for translation of this technique into the clinical arena.


Honokiol induces apoptosis and autophagy via the ROS/ERK1/2 signaling pathway in human osteosarcoma cells in vitro and in vivo.
Osteosarcoma is the most common primary malignant tumor of bone, the long-term survival of which has stagnated in the past several decades. In the present study, we investigated the anticancer effect of honokiol (HNK), an active component isolated and purified from the magnolia officinalis on human osteosarcoma cells. Our results showed that honokiol caused dose-dependent and time-dependent cell death in human osteosarcoma cells. The types of cell death induced by honokiol were primarily autophagy and apoptosis. Furthermore, honokiol induced G0/G1 phase arrest, elevated the levels of glucose-regulated protein (GRP)-78, an endoplasmic reticular stress (ERS)-associated protein, and increased the production of intracellular reactive oxygen species (ROS). In contrast, reducing production of intracellular ROS using N-acetylcysteine, a scavenger of ROS, concurrently suppressed honokiol-induced cellular apoptosis, autophagy, and cell cycle arrest. Consequently, honokiol stimulated phosphorylation of extracellular signal-regulated kinase (ERK)1/2. Furthermore, pretreatment of osteosarcoma cells with PD98059, an inhibitor of ERK1/2, inhibited honokiol-induced apoptosis and autophagy. Finally, honokiol suppressed tumor growth in the mouse xenograft model. Taken together, our results revealed that honokiol caused G0/G1 phase arrest, induced apoptosis, and autophagy via the ROS/ERK1/2 signaling pathway in human osteosarcoma cells. Honokiol is therefore a promising candidate for development of antitumor drugs targeting osteosarcoma.


Potential drug-drug interactions in prescriptions to patients over 45 years of age in primary care, southern Brazil.
Few cross-sectional studies involving adults and elderly patients with major DDIs have been conducted in the primary care setting. The study aimed to investigate the prevalence of potential drug-drug interactions (DDIs) in patients treated in primary care. A cross-sectional study involving patients aged 45 years or older was conducted at 25 Basic Health Units in the city of Maringá (southern Brazil) from May to December 2010. The data were collected from prescriptions at the pharmacy of the health unit at the time of the delivery of medication to the patient. After delivery, the researcher checked the electronic medical records of the patient. A total of 827 patients were investigated (mean age: 64.1; mean number of medications: 4.4). DDIs were identified in the Micromedex® database. The prevalence of potential DDIs and major DDIs was 63.0% and 12.1%, respectively. In both the univariate and multivariate analyses, the number of drugs prescribed was significantly associated with potential DDIs, with an increasing risk from three to five drugs (OR = 4.74; 95% CI: 2.90-7.73) to six or more drugs (OR = 23.03; 95% CI: 10.42-50.91). Forty drugs accounted for 122 pairs of major DDIs, the most frequent of which involved simvastatin (23.8%), captopril/enalapril (16.4%) and fluoxetine (16.4%). This is the first large-scale study on primary care carried out in Latin America. Based on the findings, the estimated prevalence of potential DDIs was high, whereas clinically significant DDIs occurred in a smaller proportion. Exposing patients to a greater number of prescription drugs, especially three or more, proved to be a significant predictor of DDIs. Prescribers should be more aware of potential DDIs. Future studies should assess potential DDIs in primary care over a longer period of time.


On the relationship of synaptic activity to macroscopic measurements: does co-registration of EEG with fMRI make sense?
A two-scale theoretical description outlines relationships between brain current sources and the resulting extracranial electric field, recorded as EEG. Finding unknown sources of EEG, the so-called "inverse problem", is discussed in general terms, with emphasis on the fundamental non-uniqueness of inverse solutions. Hemodynamic signatures, measured with fMRI, are expressed as voxel integrals to facilitate comparisons with EEG. Two generally distinct cell groups (1 and 2), generating EEG and fMRI signals respectively, are embedded within the much broader class of synaptic action fields. Cell groups 1 and 2 may or may not overlap in specific experiments. Implications of this incomplete overlap for co-registration studies are considered. Each experimental measure of brain function is generally sensitive to a different kind of source activity and to different spatial and temporal scales. Failure to appreciate such distinctions can exacerbate conflicting views of brain function that emphasize either global integration or functional localization.


Acute pancreatitis due to pravastatin therapy.
Few data exist about the incidence of drug-induced pancreatitis in the general population. Drugs are related to the etiology of pancreatitis in about 1.4-2% of cases. Statins are generally well tolerated. Acute pancreatitis has been reported in a few cases treated with atorvastatin, fluvastatin, lovastatin and simvastatin. We report the case of a 56-year-old patient who, after 6 months of treatment with pravastatin 20 mg once daily for hypercholesterolemia, presented with acute pancreatitis. Other causes of the disease were ruled out. Five months later, the patient, on his own initiative, reintroduced pravastatin and acute pancreatitis recurred after 3 days. To our knowledge this is the first report of pravastatin-induced pancreatitis and further strengthens the fact that statins may cause acute pancreatitis.


Multilocus analysis of a taxonomically densely sampled dataset reveal extensive non-monophyly in the avian family Locustellidae.
The phylogeny of most of the species in the avian passerine family Locustellidae is inferred using a Bayesian species tree approach (Bayesian Estimation of Species Trees, BEST), as well as a traditional Bayesian gene tree method (MrBayes), based on a dataset comprising one mitochondrial and four nuclear loci. The trees inferred by the different methods agree fairly well in topology, although in a few cases there are marked differences. Some of these discrepancies might be due to convergence problems for BEST (despite up to 1×10(9) iterations). The phylogeny strongly disagrees with the current taxonomy at the generic level, and we propose a revised classification that recognizes four instead of seven genera. These results emphasize the well known but still often neglected problem of basing classifications on non-cladistic evaluations of morphological characters. An analysis of an extended mitochondrial dataset with multiple individuals from most species, including many subspecies, suggest that several taxa presently treated as subspecies or as monotypic species as well as a few taxa recognized as separate species are in need of further taxonomic work.


Defective alpha-polymerization in the conversion of fibrinogen Baltimore to fibrin.
The subunit structure of fibrinogen Baltimore and fibrin formed from this inherited dysfibrinogenemia was analyzed by polyacrylamide gel electrophoresis in sodium dodecyl sulfate. The molecular weights of the alpha-, b- and gamma-chains of fibrinogen Baltimore were found to be identical to those of normal fibrinogen. Noncross-linked fibrin formed from both purified fibrinogen Baltimore as well as normal fibrinogen contained two alpha-monomers (alpha1 and alpha2). alpha2 was presumed to be alpha-monomer from which fibrinopeptide A had been released. The evolution of alpha2 during clotting of fibrinogen Baltimore was delayed and appeared to be quantitatively reduced when compared to normal. Crosslinked fibrin formed from fibrinogen Baltimore possessed an abnormal subunit structure. alpha-polymers were not generated in thrombin-induced, factor XIII-rich clots of fibrinogen Baltimore under conditions of pH and calcium concentration suitable for complete alpha-polymerization in normal fibrin. If clotting was carried out with calcium concentrations twice that required for normal clots or at pH 6.4, fibrin from fibrinogen Baltimore was completely cross-linked. These structural analyses of fibrin formed from fibrinogen Baltimore substantiate earlier findings that indicate a defect in the alpha-chain of this dysfibrinogenemia.


Identification of casein kinase Ialpha interacting protein partners.
Casein kinase Ialpha (CKIalpha) belongs to a family of serine/threonine protein kinases involved in membrane trafficking, RNA processing, mitotic spindle formation and cell cycle progression. In this report, we identified several CKIalpha interacting proteins including RCC1, high mobility group proteins 1 and 2 (HMG1, HMG2), Erf, centaurin-alpha1, synaptotagmin IX and CPI-17 that were isolated from brain as CKIalpha co-purifying proteins. Actin, importin-alpha(1), importin-beta, PP2Ac, centaurin-alpha1, and HMG1 were identified by affinity chromatography using a peptide column comprising residues 214-233 of CKIalpha. We have previously shown that centaurin-alpha1 represents a CKIalpha partner both in vitro and in vivo. The nuclear protein regulator of chromosome condensation 1 (RCC1) is a guanosine nucleotide exchange factor for Ran which is involved in nuclear transport and mitotic spindle formation. Here we show that CKIalpha and RCC1 interact in brain and in cultured cells. However, the interaction does not involve residues 217-233 of CKIalpha which are proposed from X-ray structures to represent an anchoring site for CKI partners. Formation of the RCC1/CKIalpha complex is consistent with the association of the kinase with mitotic spindles. In conclusion, we have identified a number of novel CKIalpha protein partners and their relations to CKI are discussed.


I Am Aware of My Inconsistencies but Can Tolerate Them: The Effect of High Quality Listening on Speakers' Attitude Ambivalence.
We examined how listeners characterized by empathy and a non-judgmental approach affect speakers' attitude structure. We hypothesized that high quality listening decreases speakers' social anxiety, which in turn reduces defensive processing. This reduction in defensive processing was hypothesized to result in an awareness of contradictions (increased objective-attitude ambivalence), and decreased attitude extremity. Moreover, we hypothesized that experiencing high quality listening would enable speakers to tolerate contradictory responses, such that listening would attenuate the association between objective- and subjective-attitude ambivalence. We obtained consistent support for our hypotheses across four laboratory experiments that manipulated listening experience in different ways on a range of attitude topics. The effects of listening on objective-attitude ambivalence were stronger for higher dispositional social anxiety and initial objective-attitude ambivalence (Study 4). Overall, the results suggest that speakers' attitude structure can be changed by a heretofore unexplored interpersonal variable: merely providing high quality listening.


Locomotion without a brain: physical reservoir computing in tensegrity structures.
Embodiment has led to a revolution in robotics by not thinking of the robot body and its controller as two separate units, but taking into account the interaction of the body with its environment. By investigating the effect of the body on the overall control computation, it has been suggested that the body is effectively performing computations, leading to the term morphological computation. Recent work has linked this to the field of reservoir computing, allowing one to endow morphologies with a theory of universal computation. In this work, we study a family of highly dynamic body structures, called tensegrity structures, controlled by one of the simplest kinds of "brains." These structures can be used to model biomechanical systems at different scales. By analyzing this extreme instantiation of compliant structures, we demonstrate the existence of a spectrum of choices of how to implement control in the body-brain composite. We show that tensegrity structures can maintain complex gaits with linear feedback control and that external feedback can intrinsically be integrated in the control loop. The various linear learning rules we consider differ in biological plausibility, and no specific assumptions are made on how to implement the feedback in a physical system.


Structural basis for Fullerene geometry in a human endogenous retrovirus capsid.
The HML2 (HERV-K) group constitutes the most recently acquired family of human endogenous retroviruses, with many proviruses less than one million years old. Many maintain intact open reading frames and provirus expression together with HML2 particle formation are observed in early stage human embryo development and are associated with pluripotency as well as inflammatory disease, cancers and HIV-1 infection. Here, we reconstruct the core structural protein (CA) of an HML2 retrovirus, assemble particles in vitro and employ single particle cryogenic electron microscopy (cryo-EM) to determine structures of four classes of CA Fullerene shell assemblies. These icosahedral and capsular assemblies reveal at high-resolution the molecular interactions that allow CA to form both pentamers and hexamers and show how invariant pentamers and structurally plastic hexamers associate to form the unique polyhedral structures found in retroviral cores.


Evaluation of Complications and Costs During Overlapping Transsphenoidal Surgery in the Treatment of Pituitary Adenoma.
Pituitary adenomas are among the most common primary brain tumors. Recently, overlapping surgery has been curbed in many institutions because of the suggestion there might be more significant adverse events, despite several studies showing that complication rates are equivalent. To assess complications and costs associated with overlapping surgery during the transsphenoidal resection of pituitary adenomas. A single-center, retrospective cohort study was performed to evaluate the cases of patients who underwent a transsphenoidal approach for pituitary tumor resection. Patient, surgical, complication, and cost (value-driven outcome) variables were analyzed. A total of 629 patients (302 nonoverlapping, 327 overlapping cases) were identified. No significant differences in age (P = .6), sex (P = .5), tumor type (P = .5), or prior rates of pituitary adenoma resection (P = .5) were seen. Similar presenting symptoms were observed in the 2 groups, and follow-up length was comparable (P = .3). No differences in tumor sizes (P = .5), operative time (P = .4), fat/fascia use (P = .4), or cerebrospinal fluid diversion (P = .8) were seen between groups. The gross total resection rate was not significantly different (P = .9), and no difference in recurrence rate was seen (P = .4). A comparable complication rate was seen between groups (P = .6). No differences in total or subtotal costs were seen either. The results of this study offer additional evidence that overlapping surgery does not result in worsened complications, lengthened surgery, or increased patient cost for patients undergoing transsphenoidal resection of pituitary adenomas. Thus, studies and policy aiming to improve patient safety and cost should focus on optimizing other aspects of healthcare delivery.


The Golgi-resident protease Kex2 acts in conjunction with Prm1 to facilitate cell fusion during yeast mating.
The molecular machines that mediate cell fusion are unknown. Previously, we identified a multispanning transmembrane protein, Prm1 (pheromone-regulated membrane protein 1), that acts during yeast mating (Heiman, M.G., and P. Walter. 2000. J. Cell Biol. 151:719-730). Without Prm1, a substantial fraction of mating pairs arrest with their plasma membranes tightly apposed yet unfused. In this study, we show that lack of the Golgi-resident protease Kex2 strongly enhances the cell fusion defect of Prm1-deficient mating pairs and causes a mild fusion defect in otherwise wild-type mating pairs. Lack of the Kex1 protease but not the Ste13 protease results in similar defects. Deltakex2 and Deltakex1 fusion defects were suppressed by osmotic support, a trait shared with mutants defective in cell wall remodeling. In contrast, other cell wall mutants do not enhance the Deltaprm1 fusion defect. Electron microscopy of Deltakex2-derived mating pairs revealed novel extracellular blebs at presumptive sites of fusion. Kex2 and Kex1 may promote cell fusion by proteolytically processing substrates that act in parallel to Prm1 as an alternative fusion machine, as cell wall components, or both.


Integrated Optic Surface Plasmon Resonance Measurements in a Borosilicate Glass Substrate.
The surface plasmon resonance (SPR) technique is a well-known optical method that can be used to measure the refractive index of organic nano-layers adsorbed on a thin metal film. Although there are many configurations for measuring biomolecular interactions, SPR-based techniques play a central role in many current biosensing experiments, since they are the most suited for sensitive and quantitative kinetic measurements. Here we give some results from the analysis and numerical elaboration of SPR data from integrated optics experiments in a particular borosilicate glass, chosen for its composition offering the rather low refractive index of 1.4701 at 633 nm wavelength. These data regard the flow over the sensing region (metal window) of different solutions with refractive indexes in the range of interest (1.3÷1.5) for the detection of contaminants in aqueous solutions. After a discussion of the principles of SPR, of the metal window design optimization by means of optical interaction numerical modeling, and of waveguide fabrication techniques, we give a description of system setup and experimental results. Optimum gold film window thickness and width in this guided-wave configuration has been for the first time derived and implemented on an integrated optic prototype device. Its characterization is given by means of the real time waveguide output intensity measurements, which correspond to the interaction between the sensing gold thin film window and the flowing analyte. The SPR curve was subsequently inferred. Finally, a modified version of the device is reported, with channel waveguides arranged in a Y-junction optical circuit, so that laser source stability requirements are lowered by a factor of 85 dB, making possible the use of low cost sources in practical applications.


Multiple distance cues do not prevent systematic biases in reach to grasp movements.
The perceived distance of objects is biased depending on the distance from the observer at which objects are presented, such that the egocentric distance tends to be overestimated for closer objects, but underestimated for objects further away. This leads to the perceived depth of an object (i.e., the perceived distance from the front to the back of the object) also being biased, decreasing with object distance. Several studies have found the same pattern of biases in grasping tasks. However, in most of those studies, object distance and depth were solely specified by ocular vergence and binocular disparities. Here we asked whether grasping objects viewed from above would eliminate distance-dependent depth biases, since this vantage point introduces additional information about the object's distance, given by the vertical gaze angle, and its depth, given by contour information. Participants grasped objects presented at different distances (1) at eye-height and (2) 130 mm below eye-height, along their depth axes. In both cases, grip aperture was systematically biased by the object distance along most of the trajectory. The same bias was found whether the objects were seen in isolation or above a ground plane to provide additional depth cues. In two additional experiments, we verified that a consistent bias occurs in a perceptual task. These findings suggest that grasping actions are not immune to biases typically found in perceptual tasks, even when additional cues are available. However, online visual control can counteract these biases when direct vision of both digits and final contact points is available.


Workplace observation of work stressors, catecholamines and musculoskeletal pain among male employees.
Prolonged activation of the sympathetic-adrenal medullary system during work and the lack of recovery after work may indicate a risk for musculoskeletal pain (ie, neck, shoulder, or low-back pain). This field study tested whether a high level of work stressors are associated with musculoskeletal pain and higher urinary norepinephrine excretion rates at work, after work, and on Sundays. Altogether 32 male employees working in adult education took part in a three-phase repeated-measures field study including workplace observation, self-report of musculoskeletal pain, and measurement of urinary catecholamine at work, in the evening after work, and at corresponding times on Sundays. In univariate analyses, work stressors and workday levels of norepinephrine were significantly higher in the participants with high levels of musculoskeletal pain. Moreover, regressing workday norepinephrine excretion rates on predictor variables in the multilevel regression analysis showed a significant interaction between work stressors and musculoskeletal pain (P=0.011) with elevated excretion rates of norepinephrine in those exposed to a high level of work stressors and, at the same time, reporting higher levels of musculoskeletal pain. High work stressors turned out to be associated with musculoskeletal pain and norepinephrine concentration in male employees. Increased activity of the sympathetic-adrenal medullary system seems to play an important role in work-related musculoskeletal pain.


Response to ocean acidification in larvae of a large tropical marine fish, Rachycentron canadum.
Currently, ocean acidification is occurring at a faster rate than at any time in the last 300 million years, posing an ecological challenge to marine organisms globally. There is a critical need to understand the effects of acidification on the vulnerable larval stages of marine fishes, as there is potential for large ecological and economic impacts on fish populations and the human economies that rely on them. We expand upon the narrow taxonomic scope found in the literature today, which overlooks many life history characteristics of harvested species, by reporting on the larvae of Rachycentron canadum (cobia), a large, highly mobile, pelagic-spawning, widely distributed species with a life history and fishery value contrasting other species studied to date. We raised larval cobia through the first 3 weeks of ontogeny under conditions of predicted future ocean acidification to determine effects on somatic growth, development, otolith formation, swimming ability, and swimming activity. Cobia exhibited resistance to treatment effects on growth, development, swimming ability, and swimming activity at 800 and 2100 μatm pCO2 . However, these scenarios resulted in a significant increase in otolith size (up to 25% larger area) at the lowest pCO2 levels reported to date, as well as the first report of significantly wider daily otolith growth increments. When raised under more extreme scenarios of 3500 and 5400 μatm pCO2 , cobia exhibited significantly reduced size-at-age (up to 25% smaller) and a 2-3 days developmental delay. The robust nature of cobia may be due to the naturally variable environmental conditions this species currently encounters throughout ontogeny in coastal environments, which may lead to an increased acclimatization ability even during long-term exposure to stressors.