Src regulates sequence-dependent beta-2 adrenergic receptor recycling via cortactin phosphorylation.
The recycling of internalized signaling receptors, which has direct functional consequences, is subject to multiple sequence and biochemical requirements. Why signaling receptors recycle via a specialized pathway, unlike many other proteins that recycle by bulk, is a fundamental unanswered question. Here, we show that these specialized pathways allow selective control of signaling receptor recycling by heterologous signaling. Using assays to visualize receptor recycling in living cells, we show that the recycling of the beta-2 adrenergic receptor (B2AR), a prototypic signaling receptor, is regulated by Src family kinases. The target of Src is cortactin, an essential factor for B2AR sorting into specialized recycling microdomains on the endosome. Phosphorylation of a single cortactin residue, Y466, regulates the rate of fission of B2AR recycling vesicles from these microdomains and, therefore, the rate of delivery of B2AR to the cell surface. Together, our results indicate that actin-stabilized microdomains that mediate signaling receptor recycling can serve as a functional point of convergence for crosstalk between signaling pathways.


Was there compression of disability for older Americans from 1992 to 2003?
Medical advances and the growth of the elderly population have focused interest on trends in the health of the elderly. Three theories have been advanced to describe these trends: compression of morbidity, expansion of morbidity, and dynamic equilibrium. We applied multistate life table methods to the Medicare Current Beneficiary Survey to estimate active and disabled life expectancy from 1992 to 2003, defining disability as having difficulty with instrumental activities of daily living or activities of daily living. We found increases in active life expectancy past age 65 and decreases in life expectancy with severe disability. These trends are consistent with elements of both the theory of compression of morbidity and the theory of dynamic equilibrium.


Multiannual effects of induced plant defenses: Are defended plants good or bad neighbors?
Defenses induced by herbivore feeding or phytohormones such as methyl jasmonate (MeJA) can affect growth, reproduction, and herbivory, not only on the affected individual but also in its neighboring plants. Here, we report multiannual defense, growth, and reproductive responses of MeJA-treated bilberry (Vaccinium myrtillus) and neighboring ramets. In a boreal forest in western Norway, we treated bilberry ramets with MeJA and water (control) and measured responses over three consecutive years. We observed the treatment effects on variables associated with herbivory, growth, and reproduction in the MeJA-treated and untreated ramet and neighboring ramets distanced from 10 to 500 cm. MeJA-treated ramets had fewer grazed leaves and browsed shoots compared to control, with higher effects in 2014 and 2015, respectively. In 2013, growth of control ramets was greater than MeJA-treated ramets. However, MeJA-treated ramets had more flowers and berries than control ramets 2 years after the treatment. The level of insect and mammalian herbivory was also lower in untreated neighboring ramets distanced 10-150 cm and, consistent with responses of MeJA-treated ramets, the stronger effect was also one and 2 years delayed, respectively. The same neighboring ramets had fewer flowers and berries than untreated ramets, indicating a trade-off between defense and reproduction. Although plant-plant effects were observed across all years, the strength varied by the distance between the MeJA-treated ramets and its untreated neighbors. We document that induced defense in bilberry reduces both insect and mammalian herbivory, as well as growth, over multiple seasons. The defense responses occurred in a delayed manner with strongest effects one and 2 years after the induction. Additionally, our results indicate defense signaling between MeJA-treated ramets and untreated neighbors. In summary, this study shows that induced defenses are important ecological strategies not only for the induced individual plant but also for neighboring plants across multiple years in boreal forests.


Recent advances in the development of a chemically synthesised anti-malarial vaccine.
Obtaining an effective antimalarial vaccine has represented one of the biggest public health challenges over the last 50 years. Despite efforts by many laboratories around the world using whole-organism, recombinant proteins and genome-based approaches, the results have been disappointing. One of the main problems when designing an antimalarial vaccine is the poor immunogenicity induced by the functionally relevant and conserved protein regions of the parasite. This review focuses on the logical and rational methodology followed to identify Plasmodium falciparum conserved functional regions with the ability to bind to target cells conserved high activity binding peptides (cHABPs) and the physicochemical and immunological characteristics that should be taken into account for modifying them into highly immunogenic and protection-inducing peptides (mHABPs) into highly immunogenic and protection-inducing in Aotus monkeys. The functional approach taken to develop a fully protective, minimal subunit-based, multiantigenic, multistage and synthetic peptide-based antimalarial vaccine has shown promising results. The clear relationship observed between mHABPs structure and their immunological properties highlights the challenges and opportunities arising from this methodology, as well as the universal principles and rules derived therefrom.


Low frequency fluctuations reveal integrated and segregated processing among the cerebral hemispheres.
Resting-state functional magnetic resonance imaging (fMRI) has provided a novel approach for examining interhemispheric interaction, demonstrating a high degree of functional connectivity between homotopic regions in opposite hemispheres. However, heterotopic resting-state functional connectivity (RSFC) remains relatively uncharacterized. In the present study, we examine non-homotopic regions, characterizing heterotopic RSFC and comparing it to intrahemispheric RSFC, to examine the impact of hemispheric separation on the integration and segregation of processing in the brain. Resting-state fMRI scans were acquired from 59 healthy participants to examine inter-regional correlations in spontaneous low frequency fluctuations in BOLD signal. Using a probabilistic atlas, we correlated probability-weighted time series from 112 regions (56 per hemisphere) distributed throughout the entire cerebrum. We compared RSFC for pairings of non-homologous regions located in different hemispheres (heterotopic connectivity) to RSFC for the same pairings when located within hemisphere (intrahemispheric connectivity). For positive connections, connectivity strength was greater within each hemisphere, consistent with integrated intrahemispheric processing. However, for negative connections, RSFC strength was greater between the hemispheres, consistent with segregated interhemispheric processing. These patterns were particularly notable for connections involving frontal and heteromodal regions. The distribution of positive and negative connectivity was nearly identical within and between the hemispheres, though we demonstrated detailed regional variation in distribution. We discuss implications for leading models of interhemispheric interaction. The future application of our analyses may provide important insight into impaired interhemispheric processing in clinical and aging populations.


Do United States' teachers know and adhere to the national guidelines on asthma management in the classroom? A systematic review.
Proper asthma management in schools is important in achieving optimum asthma control in children with asthma. The National Heart, Lung, and Blood Institute (NHLBI) has developed guidelines on classroom asthma management. We conducted a systematic review to examine teacher knowledge of the NHLBI guidelines on asthma management in the classroom. We searched PubMed and EMBASE using search terms "asthma management," "teacher(s)," "school teacher," and "public school." The inclusion criteria were articles published in English from 1994 to May 2014 that focus on schools in the United States (US). From 535 titles and abstracts, 9 studies met inclusion criteria. All studies reported that school teachers did not know the policies and procedures of asthma management. Teachers relied on school nurses to handle medical emergencies. Some studies identified that lack of full-time school nurses was a barrier to asthma management. Only one study showed directly that classroom teachers were not following the NHLBI guidelines on asthma management. Our literature review revealed that US teachers do not know the NHLBI guidelines on asthma management in the classroom. Future research should focus on interventions targeted toward training classroom teachers on asthma management as per NHLBI guidelines to ultimately improve asthma management in schools.


C3orf58, a novel paracrine protein, stimulates cardiomyocyte cell-cycle progression through the PI3K-AKT-CDK7 pathway.
The regenerative capacity of the heart is markedly diminished shortly after birth, coinciding with overall withdrawal of cardiomyocytes from cell cycle. Consequently, the adult mammalian heart has limited capacity to regenerate after injury. The discovery of factors that can induce cardiomyocyte proliferation is, therefore, of high interest and has been the focus of extensive investigation throughout the past years. We have recently identified C3orf58 as a novel hypoxia and Akt induced stem cell factor (HASF) secreted from mesenchymal stem cells, which can promote cardiac repair through cytoprotective mechanisms. Here, we tested the hypothesis that HASF can also contribute to cardiac regeneration by stimulating cardiomyocyte division and proliferation. Neonatal ventricular cardiomyocytes were stimulated in culture for 7 days with purified recombinant HASF protein. Compared with control untreated cells, HASF-treated neonatal cardiomyocytes exhibited 60% increase in DNA synthesis as measured by bromodeoxyuridine incorporation. These results were confirmed by immunofluorescence confocal microscopy showing a 50% to 100% increase in the number of cardiomyocytes in the mitotic and cytokinesis phases. Importantly, in vivo cardiac overexpression of HASF in a transgenic mouse model resulted in enhanced level of DNA synthesis and cytokinesis in neonatal and adult cardiomyocytes. These proliferative effects were modulated by a phosphoinositide 3-kinase-protein kinase B-cycle-dependent kinase 7 pathway as revealed by the use of phosphoinositide 3-kinase -pathway-specific inhibitors and silencing of the Cdk7 gene. Our studies support the hypothesis that HASF induces cardiomyocyte proliferation via a phosphoinositide 3-kinase-protein kinase B-cycle-dependent kinase 7 pathway. The implications of this finding may be significant for cardiac regeneration biology and therapeutics.


Historical Relationships among Wild Boar Populations of the Ryukyu Archipelago and Other Eurasian regions, as Inferred from Mitochondrial Cytochrome b Gene Sequences.
The Ryukyu wild boar (Sus scrofa riukiuanus) is an endemic, morphologically defined subspecies of the Eurasian wild boar (S. scrofa) found on five islands of the Ryukyu Archipelago (a group of small islands stretching from mainland Japan to Taiwan). Two hypothetical scenarios have been proposed regarding the origin of the current Ryukyu wild boar populations: 1) natural dispersal and 2) transportation and subsequent release by prehistoric humans. To test these two hypotheses, we compared the mitochondrial cytochrome b gene sequence (1140 base pairs) in 352 individual wild boar samples that included representatives of all five insular populations of the Ryukyu wild boar and populations of other conspecific subspecies in insular East and Southeast Asia and the Eurasian Continent. A total of 68 haplotypes were recognized, of which 12 were unique to the Ryukyu wild boar populations. The results of Bayesian phylogenetic analyses supported monophyly of the five Ryukyu populations (posterior probability value of 92), confirming the validity of the subspecies as a natural group. Coalescent analysis estimated the divergence times between the Ryukyu wild boar and the other conspecific subspecies as 144-465 thousand years ago (Kya), with a 95% HPD (highest posterior density) range of 51-837 Kya, and with no significant migration. Taking the broadly accepted date of initial human migration to the Ryukyus (no earlier than 50 Kya) into consideration, our results strongly suggest that the ancestral form of the Ryukyu wild boar first entered the Ryukyu Archipelago by natural dispersal prior to the arrival of prehistoric humans.


Use of mental health care for nonpsychotic conditions by immigrants in different admission classes and by refugees in Ontario, Canada.
Most Canadian newcomers are admitted in the economic, family, or refugee class, each of which has its own selection criteria and experiences. Evidence has shown various risks for mental health disorders across admission classes, but the respective service-use patterns for people in these classes are unknown. In this study, we compared service use for nonpsychotic mental health disorders by newcomers in various admission classes with that of long-term residents (i.e., Canadian-born persons or immigrants before 1985) in urban Ontario. In this population-based matched cross-sectional study, we linked health service databases to the Ontario portion of the Citizenship and Immigration Canada database. Outcomes were mental health visits to primary care physicians, mental health visits to psychiatrists, and emergency department visits or hospital admissions. We measured service use for recent immigrants (those who arrived in Ontario between 2002 and 2007; n = 359 673). We compared service use by immigrants in each admission class during the first 5 years in Canada with use by age- and sex-matched long-term residents. We measured likelihood of access to each service and intensity of use of each service using conditional logistic regression and negative binomial models. Economic and family class newcomers were less likely than long-term residents to use primary mental health care. The use of primary mental health care by female refugees did not differ from that of matched long-term residents, but use of such care by male refugees was higher (odds ratio 1.14, 95% confidence interval 1.09-1.19). Immigrants in all admission classes were less likely to use psychiatric services and hospital services for mental health care. Exceptions were men in the economic and family classes, whose intensity of hospital visits was similar to that of matched long-term residents. Immigrants in all admission classes generally used less care for nonpsychotic disorders than longterm residents, although male refugees used more primary care. Future research should examine how mental health needs align with service use, particularly for more vulnerable groups such as refugees.


UAV-Based Estimation of Carbon Exports from Heterogeneous Soil Landscapes--A Case Study from the CarboZALF Experimental Area.
The advantages of remote sensing using Unmanned Aerial Vehicles (UAVs) are a high spatial resolution of images, temporal flexibility and narrow-band spectral data from different wavelengths domains. This enables the detection of spatio-temporal dynamics of environmental variables, like plant-related carbon dynamics in agricultural landscapes. In this paper, we quantify spatial patterns of fresh phytomass and related carbon (C) export using imagery captured by a 12-band multispectral camera mounted on the fixed wing UAV Carolo P360. The study was performed in 2014 at the experimental area CarboZALF-D in NE Germany. From radiometrically corrected and calibrated images of lucerne (Medicago sativa), the performance of four commonly used vegetation indices (VIs) was tested using band combinations of six near-infrared bands. The highest correlation between ground-based measurements of fresh phytomass of lucerne and VIs was obtained for the Enhanced Vegetation Index (EVI) using near-infrared band b899. The resulting map was transformed into dry phytomass and finally upscaled to total C export by harvest. The observed spatial variability at field- and plot-scale could be attributed to small-scale soil heterogeneity in part.


Chemical Solution Route for High-Quality Multiferroic BiFeO3 Thin Films.
Bismuth ferrite (BiFeO3 ) has recently become interesting as a room-temperature multiferroic material, and a variety of prototype devices have been designed based on its thin films. A low-cost and simple processing technique for large-area and high-quality BiFeO3 thin films that is compatible with current semiconductor technologies is therefore urgently needed. Development of BiFeO3 thin films is summarized with a specific focus on the chemical solution route. By a systematic analysis of the recent progress in chemical-route-derived BiFeO3 thin films, the challenges of these films are highlighted. An all-solution chemical-solution deposition (AS-CSD) for BiFeO3 thin films with different orientation epitaxial on various oxide bottom electrodes is introduced and a comprehensive study of the growth, structure, and ferroelectric properties of these films is provided. A facile low-cost route to prepare large-area high-quality epitaxial BFO thin films with a comprehensive understanding of the film thickness, stoichiometry, crystal orientation, ferroelectric properties, and bottom electrode effects on evolutions of microstructures is provided. This work paves the way for the fabrication of devices based on BiFeO3 thin films.


Indicators of transitions in biological systems.
In the face of global biodiversity declines, predicting the fate of biological systems is a key goal in ecology. One popular approach is the search for early warning signals (EWSs) based on alternative stable states theory. In this review, we cover the theory behind nonlinearity in dynamic systems and techniques to detect the loss of resilience that can indicate state transitions. We describe the research done on generic abundance-based signals of instability that are derived from the phenomenon of critical slowing down, which represent the genesis of EWSs research. We highlight some of the issues facing the detection of such signals in biological systems - which are inherently complex and show low signal-to-noise ratios. We then document research on alternative signals of instability, including measuring shifts in spatial autocorrelation and trait dynamics, and discuss potential future directions for EWSs research based on detailed demographic and phenotypic data. We set EWSs research in the greater field of predictive ecology and weigh up the costs and benefits of simplicity vs. complexity in predictive models, and how the available data should steer the development of future methods. Finally, we identify some key unanswered questions that, if solved, could improve the applicability of these methods.


Fluoride induced mitochondrial impairment and PINK1-mediated mitophagy in Leydig cells of mice: In vivo and in vitro studies.
It is very important to explore the potential harm and underlying mechanism of fluoride due to the extensive distribution and the significant health risks of fluoride in environment. The objective of this study to investigate whether fluoride can induce mitochondrial impairment and mitophagy in testicular cells. For this, 40 male mice were randomly divided into four groups treated with 0, 0.6, 1.2, 2.4 mM NaF deionized water, respectively, for 90 days continuously. The results showed that mitophagy was triggered by F in testicular tissues, especially in the Leydig cells by transmission electron microscopy and mitophagy receptor PHB2 locations by immunofluorescence. Furthermore, TM3 Leydig cells line was employed and treated with 0, 0.125, 0.25, and 0.5 mM NaF for 24 h. The mitochondrial function indicators and mitophagy maker PHB2, COX IV and regulator PINK1 in transcript and protein levels in Leydig cells were examined by the methods of qRT-PCR, western blotting, and immunofluorescence co-localization. The results showed that fluoride decreased the mitochondrial membrane potential with a concomitant increase in the number of lysosomes. Meanwhile, fluoride exposure also increased the expressions of PINK1 and PHB2 in TM3 Leydig cells. These results revealed that fluoride could induce mitochondrial impairment and excessive PINK1/Parkin-mediated mitophagy in testicular cells, especially in Leydig cells, which could contribute to the elucidation of the mechanisms of F-induced male reproductive toxicity.


How many dendritic cells are required to initiate a T-cell response?
T-cell activation in lymph nodes relies on encounters with antigen (Ag)-bearing dendritic cells (DCs) but the number of DCs required to initiate an immune response is unknown. Here we have used a combination of flow cytometry, 2-photon imaging, and computational modeling to quantify the probability of T cell-DC encounters. We calculated that the chance for a T cell residing 24 hours in a murine popliteal lymph nodes to interact with a DC was 8%, 58%, and 99% in the presence of 10, 100, and 1000 Ag-bearing DCs, respectively. Our results reveal the existence of a threshold in DC numbers below which T-cell responses fail to be elicited for probabilistic reasons. In mice and probably humans, we estimate that a minimum of 85 DCs are required to initiate a T-cell response when starting from precursor frequency of 10(-6). Our results have implications for the rational design of DC-based vaccines.


Association between urologist characteristics and radiation oncologist consultation for patients with locoregional prostate cancer.
Physicians managing patients with prostate cancer play a critical role in subsequent specialist consultations and initial treatment choice, especially in cases for which no consensus exists regarding optimal treatment strategy. The NCCN Guidelines for Prostate Cancer recommend radiation as a therapy option for patients with locoregional prostate cancer. The authors examined the association of urologist characteristics with the likelihood that patients would consult radiation oncologists. A retrospective cohort of 39,934 patients aged 66 years or older who were diagnosed with locoregional prostate cancer between 2004 and 2007, and the 2405 urologists who performed the patient diagnostic biopsies were constructed using the SEER-Medicare linked database and the American Medical Association Physician Masterfile. Logistic multilevel regression analysis was used to evaluate the influence of urologists' characteristics on radiation oncologist consultation within 9 months of locoregional prostate cancer diagnosis. Overall, 24,549 (61.5%) patients consulted a radiation oncologist. After adjusting for patient and urologist characteristics, patients diagnosed by urologists in noninstitutional settings (eg, physician office) were significantly more likely to consult a radiation oncologist (odds ratio [OR], 1.40; 95% CI, 1.17-1.67; P=.0002) compared with those diagnosed by urologists in institutional settings with a major medical school affiliation. In addition, patients diagnosed by urologists older than 57 years were significantly more likely to consult a radiation oncologist (OR, 1.21; 95% CI, 1.07-1.38, P=.003).


Cytomegalovirus papillitis in an immunocompetent patient.
A 22-year-old immunocompetent woman who presented with a 3-week history of fever, headache, and visual loss and was found to have subnormal visual acuity and bilateral optic disc swelling. Serum cytomegalovirus (CMV) IgM and IgG and polymerase chain reaction results were positive, indicating an acute CMV infection. No cause of immunocompromise was found. After treatment with intravenous ganciclovir, the papillitis and systemic CMV illness resolved with no residual deficit. This is the first reported case of primary CMV papillitis to be successfully treated with ganciclovir alone.


Availability of rural Minnesota obstetric services: is it a problem?
In the late 1980s several published articles predicted a crisis in the availability of obstetric care due to declining numbers of rural obstetrical providers. Several state and national studies documented the adverse impact of malpractice and time demands on both urban and rural physicians. But only limited information is available to document current trends in rural obstetrical practice and assess whether or not the predicted crisis occurred. This study sought to provide that updated information for rural Minnesota. A telephone survey of all rural Minnesota obstetrical providers was used to document the number, location, and specialty of rural obstetrical providers, their practice limitations, and plans for future practice. This data was combined with state perinatal statistics for each county to further assess obstetrical care availability and perinatal outcomes. All rural Minnesota obstetricians and certified nurse midwives provide obstetrical care as did 69 percent of all rural family physicians. Only 27 percent of rural obstetrical providers put any type of restrictions on their obstetrical practices. During the past year, 67 currently practicing rural physicians have stopped providing obstetrical care while 55 new obstetrical providers have begun rural practice. Two to 3 percent of current rural providers plan to retire or discontinue obstetrical services during the next five years. The provider demographics from the survey identified eight counties with no prenatal providers, and 12 additional communities of decreased provider availability. However, only two of the counties with no prenatal providers and five of the counties with areas of limited providers had increased percentages of adverse prenatal outcomes such as low birthweight or late prenatal care. This study concluded that Minnesota does not have a serious statewide problem with availability of rural obstetrical providers. However, a few isolated regions of the state have limited provider availability, including limited availability of local high-risk services and consultants.


Race by Gender Group Differences in the Protective Effects of Socioeconomic Factors Against Sustained Health Problems Across Five Domains.
Despite the existing literature on the central role of socioeconomic status (SES; education and income) for maintaining health, less is known about group differences in this effect. Built on the intersectionality approach, this study compared race by gender groups for the effects of baseline education and income on sustained health problems in five domains: depressive symptoms, insomnia, physical inactivity, body mass index (BMI), and self-rated health (SRH). Data came from waves 7, 8, and 10 of the Health and Retirement Study (HRS), which were collected in 2004, 2006, and 2010, respectively. The study followed 37,495 white and black men and women above age 50 for up to 6 years. This number included 12,495 white men, 15,581 white women, 3839 black men, and 5580 black women. Individuals reported their depressive symptoms (Center for Epidemiological Studies-Depression (CES-D) 11), insomnia, physical inactivity, BMI, and SRH across all waves. Multigroup structural equation modeling (SEM) was used to compare black men, black women, white men, and white women for the effects of education and income in 2004 on sustained health problems from 2004 to 2010. In the pooled sample, higher education and income at baseline were associated with lower sustained health problems across all five domains. However, race by gender group differences were found in the effects of education and income on sustained insomnia, physical inactivity, and BMI, but not depressive symptoms and SRH. The protective effects of education against insomnia, physical inactivity, and BMI were not found for black men. For black women, the effect of education on BMI was not found. Income had a protective effect against sustained high BMI among white and black women but not white and black men. The intersection of race and gender alters the protective effects of social determinants on sustained health problems such as insomnia, physical inactivity, and BMI. Social groups particularly vary in the operant mechanisms by which SES contributes to maintaining health over time. The health effects are less universal for education than income. Race by gender groups differ more in SES determinants of BMI, insomnia, and physical inactivity than depressive symptoms and SRH.


High-dimensional dynamics in a single-transistor oscillator containing Feynman-Sierpiński resonators: Effect of fractal depth and irregularity.
Fractal structures pervade nature and are receiving increasing engineering attention towards the realization of broadband resonators and antennas. We show that fractal resonators can support the emergence of high-dimensional chaotic dynamics even in the context of an elementary, single-transistor oscillator circuit. Sierpiński gaskets of variable depth are constructed using discrete capacitors and inductors, whose values are scaled according to a simple sequence. It is found that in regular fractals of this kind, each iteration effectively adds a conjugate pole/zero pair, yielding gradually more complex and broader frequency responses, which can also be implemented as much smaller Foster equivalent networks. The resonators are instanced in the circuit as one-port devices, replacing the inductors found in the initial version of the oscillator. By means of a highly simplified numerical model, it is shown that increasing the fractal depth elevates the dimension of the chaotic dynamics, leading to high-order hyperchaos. This result is overall confirmed by SPICE simulations and experiments, which however also reveal that the non-ideal behavior of physical components hinders obtaining high-dimensional dynamics. The issue could be practically mitigated by building the Foster equivalent networks rather than the verbatim fractals. Furthermore, it is shown that considerably more complex resonances, and consequently richer dynamics, can be obtained by rendering the fractal resonators irregular through reshuffling the inductors, or even by inserting a limited number of focal imperfections. The present results draw attention to the potential usefulness of fractal resonators for generating high-dimensional chaotic dynamics, and underline the importance of irregularities and component non-idealities.


MiR-184 expression is regulated by AMPK in pancreatic islets.
AMPK is a critical energy sensor and target for widely used antidiabetic drugs. In β cells, elevated glucose concentrations lower AMPK activity, and the ablation of both catalytic subunits [β-cell-specific AMPK double-knockout (βAMPKdKO) mice] impairs insulin secretion in vivo and β-cell identity. MicroRNAs (miRNAs) are small RNAs that silence gene expression that are essential for pancreatic β-cell function and identity and altered in diabetes. Here, we have explored the miRNAs acting downstream of AMPK in mouse and human β cells. We identified 14 down-regulated and 9 up-regulated miRNAs in βAMPKdKO vs. control islets. Gene ontology analysis of targeted transcripts revealed enrichment in pathways important for β-cell function and identity. The most down-regulated miRNA was miR-184 (miR-184-3p), an important regulator of β-cell function and compensatory expansion that is controlled by glucose and reduced in diabetes. We demonstrate that AMPK is a potent regulator and an important mediator of the negative effects of glucose on miR-184 expression. Additionally, we reveal sexual dimorphism in miR-184 expression in mouse and human islets. Collectively, these data demonstrate that glucose-mediated changes in AMPK activity are central for the regulation of miR-184 and other miRNAs in islets and provide a link between energy status and gene expression in β cells.-Martinez-Sanchez, A., Nguyen-Tu, M.-S., Cebola, I., Yavari, A., Marchetti, P., Piemonti, L., de Koning, E., Shapiro, A. M. J., Johnson, P., Sakamoto, K., Smith, D. M., Leclerc, I., Ashrafian, H., Ferrer, J., Rutter, G. A. MiR-184 expression is regulated by AMPK in pancreatic islets.


Aspirin as a promoter of ephedrine-induced thermogenesis: potential use in the treatment of obesity.
Chronic administration of aspirin to obese mice had no effect on energy balance and body composition. In contrast, ephedrine increased energy expenditure by 9% and reduced body weight and body fat by 18% and 50%, respectively: obesity, however, was reduced but not reversed. In the presence of both ephedrine and aspirin, increase in energy expenditure found during treatment with ephedrine alone was doubled, and the obese group lost greater than 75% of body fat: obesity was reversed. These studies indicate that although aspirin administered alone has no influence on energy balance it can markedly potentiate thermogenic properties of ephedrine, effects which led to a normalization of body composition of the obese to that of the lean. Such ephedrine-aspirin mixtures, often found in over-the-counter preparations for asthma and bronchial disorders, could be put to new use as aids for treatment of human obesity.


Perceptions on the sexual harassment of female nurses in a state hospital in Sri Lanka: a qualitative study.
Sexual harassment occurs within the nursing profession globally, challenging the health and safety of nurses and the quality and efficiency of health systems. In Sri Lanka, no studies have explored this issue in the health sector; however, female employees face sexual harassment in other workplace settings. To explore female nurses' perceptions of workplace sexual harassment in a large state hospital in Sri Lanka. This is a qualitative study conducted in an urban, mainly Buddhist and Singhalese context. We invited all female senior and ward nurses working in the hospital to participate in the study. We conducted individual in-depth interviews with four senior nurses and focus group discussions with 29 nurses in three groups. The nurses described a variety of perceived forms of sexual harassment in the hospital. They discussed patient-perpetrated incidents as the most threatening and the clearest to identify compared with incidents involving doctors and other co-workers. There was significant ambiguity regarding sexual consent and coercion in relationships between female nurses and male doctors, which were described as holding potential for exploitation or harassment. The nurses reported that typical reactions to sexual harassment were passive. Alternatively, they described encountering inaction or victim blaming when they attempted to formally report incidents. They perceived that workplace sexual harassment has contributed to negative societal attitudes about the nursing profession and discussed various informal strategies, such as working in teams, to protect themselves from sexual harassment in the hospital. Sexual harassment was a perceived workplace concern for nurses in this hospital. To develop effective local prevention and intervention responses, further research is required to determine the magnitude of the problem and explore differences in responses to and consequences of sexual harassment based on perpetrator type and intent, and personal vulnerabilities of the victims, among other factors.


High diversity of Diaporthe species associated with pear shoot canker in China.
Species of Diaporthe (syn. Phomopsis) are important endophytes, saprobes and pathogens, infecting a wide range of plants and resulting in important crop diseases. However, the species occurring on pear remain largely unresolved. In this study, a total of 453 Diaporthe isolates were obtained from branches of Pyrus plants (including P. bretschneideri, P. communis, P. pyrifolia and P. ussuriensis collected from 12 provinces in China) showing shoot canker symptoms. Phylogenetic analyses based on five loci (ITS, TEF, CAL, HIS, and TUB) coupled with morphology of 113 representative isolates revealed that 19 Diaporthe species were isolated, representing 13 known species (including D. caryae, D. cercidis, D. citrichinensis, D. eres, D. fusicola, D. ganjae, D. hongkongensis, D. padina, D. pescicola, D. sojae, D. taoicola, D. unshiuensis and D. velutina) and six new species described here as D. acuta, D. chongqingensis, D. fulvicolor, D. parvae, D. spinosa and D. zaobaisu. Although Koch's postulates confirmed all species to be pathogenic, a high degree of variation in aggressiveness was observed. Moreover, these species have a high diversity, plasticity, and prevalence related to the geographical location and pear species involved.


Using a Quality Improvement Model to Implement Distress Screening in a Community Cancer Setting.
Quality cancer care includes routine screening for psychosocial distress. This quality improvement project focused on the implementation of distress screening at a licensed affiliate of Cancer Support Community, a community-based non-profit organization that provides professionally led cancer support. An advanced practice oncology nurse assisted the staff in implementing and evaluating the process of distress screening. CancerSupportSource (CSS), a validated web-based distress screening program developed by Cancer Support Community for use in community cancer settings, was employed to screen for distress, identify potential resources, and improve in-house and community referrals. For purposes of this quality improvement project, CSS was administered in interview format by staff. The Plan-Do-Study-Act (PDSA) quality improvement approach was used to implement CSS. To implement the practice of distress screening, 21 patient participants were initially screened and evaluated for distress, including risk for clinically significant levels of depression, using CSS. The tool identified participant concerns and flagged thirteen persons as at risk for depression. After implementation and evaluation of distress screening using PDSA, in a year, 51 participants were screened. Participants stated that distress screening allowed for discussion of intimate questions that may not have otherwise occurred in an intake interview. It was demonstrated that CSS identified psychosocial and practical needs, facilitating the referral process and identification of community resources. Application of the PDSA model was an effective quality improvement model that can be used for the implementation and sustainability of distress screening across settings.


Dynamic tensile forces drive collective cell migration through three-dimensional extracellular matrices.
Collective cell migration drives tissue remodeling during development, wound repair, and metastatic invasion. The physical mechanisms by which cells move cohesively through dense three-dimensional (3D) extracellular matrix (ECM) remain incompletely understood. Here, we show directly that migration of multicellular cohorts through collagenous matrices occurs via a dynamic pulling mechanism, the nature of which had only been inferred previously in 3D. Tensile forces increase at the invasive front of cohorts, serving a physical, propelling role as well as a regulatory one by conditioning the cells and matrix for further extension. These forces elicit mechanosensitive signaling within the leading edge and align the ECM, creating microtracks conducive to further migration. Moreover, cell movements are highly correlated and in phase with ECM deformations. Migrating cohorts use spatially localized, long-range forces and consequent matrix alignment to navigate through the ECM. These results suggest biophysical forces are critical for 3D collective migration.


The Challenge of Combining Chemo- and Radiotherapy with Checkpoint Kinase Inhibitors.
Preclinical models of cancer have demonstrated enhanced efficacy of cell-cycle checkpoint kinase inhibitors when used in combination with genotoxic agents. This combination therapy is predicted to be exquisitely toxic to cells with a deficient G1-S checkpoint or cells with a genetic predisposition leading to intrinsic DNA replication stress, as these cancer cells become fully dependent on the intra-S and G2-M checkpoints for DNA repair and cellular survival. Therefore, abolishing remaining cell-cycle checkpoints after damage leads to increased cell death in a tumor cell-specific fashion. However, the preclinical success of these drug combinations is not consistently replicated in clinical trials. Here, we provide a perspective on the translation of preclinical studies into rationally designed clinical studies. We will discuss successes and failures of current treatment combinations and drug regimens and provide a detailed overview of all clinical trials using ATR, CHK1, or WEE1 inhibitors in combination with genotoxic agents. This highlights the need for revised patient stratification and the use of appropriate pharmacodynamic biomarkers to improve the success rate of clinical trials.


Rituals of infant death: defining life and Islamic personhood.
This article is about the recognition of personhood when death occurs in early life. Drawing from anthropological perspectives on personhood at the beginnings and ends of life, it examines the implications of competing religious and customary definitions of personhood for a small sample of young British Pakistani Muslim women who experienced miscarriage and stillbirth. It suggests that these women's concerns about the lack of recognition given to the personhood of their fetus or baby constitute a challenge to customary practices surrounding burial as a Muslim. The article suggests that these women's concerns cannot be adequately glossed as a clash of Islamic belief versus Western medicine. Rather, they represent a renegotiation of Islamic opinion and customary practices within the broader context of changes in the medical and social norms surrounding pregnancy loss and infant death in multi-ethnic British society.


A new spatiotemporal filtering method for single-trial estimation of correlated ERP subcomponents.
A novel spatiotemporal filtering method for single trial estimation of event-related potential (ERP) subcomponents is proposed here. Unlike some previous works in ERP estimation [1], , the proposed method is able to estimate temporally correlated ERP subcomponents such as P3a and P3b. A new cost function is, therefore, defined which can deflate one of the correlated subcomponents. The method is applied to both simulated and real data and has shown to perform very well even in low signal-to-noise ratio situations. In addition, the method is compared to spatial principal component analysis and its superiority has been confirmed by using simulated signals. The approach can be especially useful in mental fatigue analysis where the relative variability of P300 subcomponents is the key factor in detecting the level of fatigue.


Whole-genome duplication and the functional diversification of teleost fish hemoglobins.
Subsequent to the two rounds of whole-genome duplication that occurred in the common ancestor of vertebrates, a third genome duplication occurred in the stem lineage of teleost fishes. This teleost-specific genome duplication (TGD) is thought to have provided genetic raw materials for the physiological, morphological, and behavioral diversification of this highly speciose group. The extreme physiological versatility of teleost fish is manifest in their diversity of blood-gas transport traits, which reflects the myriad solutions that have evolved to maintain tissue O(2) delivery in the face of changing metabolic demands and environmental O(2) availability during different ontogenetic stages. During the course of development, regulatory changes in blood-O(2) transport are mediated by the expression of multiple, functionally distinct hemoglobin (Hb) isoforms that meet the particular O(2)-transport challenges encountered by the developing embryo or fetus (in viviparous or oviparous species) and in free-swimming larvae and adults. The main objective of the present study was to assess the relative contributions of whole-genome duplication, large-scale segmental duplication, and small-scale gene duplication in producing the extraordinary functional diversity of teleost Hbs. To accomplish this, we integrated phylogenetic reconstructions with analyses of conserved synteny to characterize the genomic organization and evolutionary history of the globin gene clusters of teleosts. These results were then integrated with available experimental data on functional properties and developmental patterns of stage-specific gene expression. Our results indicate that multiple α- and β-globin genes were present in the common ancestor of gars (order Lepisoteiformes) and teleosts. The comparative genomic analysis revealed that teleosts possess a dual set of TGD-derived globin gene clusters, each of which has undergone lineage-specific changes in gene content via repeated duplication and deletion events. Phylogenetic reconstructions revealed that paralogous genes convergently evolved similar functional properties in different teleost lineages. Consistent with other recent studies of globin gene family evolution in vertebrates, our results revealed evidence for repeated evolutionary transitions in the developmental regulation of Hb synthesis.


Glycaemic risk assessment in children and young people with Type 1 diabetes mellitus.
To ascertain if those with diabetes (and their carers) ascribe a similar level of risk to blood glucose control as healthcare professionals. We used a structured questionnaire to ask fifty healthcare professionals how 'dangerous' a given blood glucose value was. Their answers were modelled to produce an algorithm of assessed risk. To examine if patients (and their carers) would apportion a similar level of risk to that of healthcare professionals, the same questionnaire was issued to fifty children and adolescents with Type 1 diabetes. For patients under 8 years old the carers completed the questionnaires (n = 23). Both patient and carers together completed the questionnaire for those aged 8-11 years (n = 15) and patients over the age of 11 years completed the questionnaire themselves (n = 12). The median results and interquartile range of the assessed level of risk, as determined by the two groups, were compared using a generalized linear model. A significant difference (P < 0.0001) was identified between the median risk assessments of the two groups. The zero level of assessed risk was upward shifted in the patient group by 0.8 mmol/l and indicated the patients' view of risk increased. Patients with Type 1 diabetes (and their carers) evaluate the risk from blood glucose values differently from healthcare professionals. The euglycaemic state (zero ascribed risk) that patients chose was 0.8 mmol/l greater than that of healthcare professionals, indicating, perhaps, hypoglycaemia avoidance, a more pragmatic approach or less exposure to current trends in glycaemic control.


Awakening: Predicting external stimulation to force transitions between different brain states.
A fundamental problem in systems neuroscience is how to force a transition from one brain state to another by external driven stimulation in, for example, wakefulness, sleep, coma, or neuropsychiatric diseases. This requires a quantitative and robust definition of a brain state, which has so far proven elusive. Here, we provide such a definition, which, together with whole-brain modeling, permits the systematic study in silico of how simulated brain stimulation can force transitions between different brain states in humans. Specifically, we use a unique neuroimaging dataset of human sleep to systematically investigate where to stimulate the brain to force an awakening of the human sleeping brain and vice versa. We show where this is possible using a definition of a brain state as an ensemble of "metastable substates," each with a probabilistic stability and occurrence frequency fitted by a generative whole-brain model, fine-tuned on the basis of the effective connectivity. Given the biophysical limitations of direct electrical stimulation (DES) of microcircuits, this opens exciting possibilities for discovering stimulation targets and selecting connectivity patterns that can ensure propagation of DES-induced neural excitation, potentially making it possible to create awakenings from complex cases of brain injury.


Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors.
The generation of functional hepatocytes independent of donor liver organs is of great therapeutic interest with regard to regenerative medicine and possible cures for liver disease. Induced hepatic differentiation has been achieved previously using embryonic stem cells or induced pluripotent stem cells. Particularly, hepatocytes generated from a patient's own induced pluripotent stem cells could theoretically avoid immunological rejection. However, the induction of hepatocytes from induced pluripotent stem cells is a complicated process that would probably be replaced with the arrival of improved technology. Overexpression of lineage-specific transcription factors directly converts terminally differentiated cells into some other lineages, including neurons, cardiomyocytes and blood progenitors; however, it remains unclear whether these lineage-converted cells could repair damaged tissues in vivo. Here we demonstrate the direct induction of functional hepatocyte-like (iHep) cells from mouse tail-tip fibroblasts by transduction of Gata4, Hnf1α and Foxa3, and inactivation of p19(Arf). iHep cells show typical epithelial morphology, express hepatic genes and acquire hepatocyte functions. Notably, transplanted iHep cells repopulate the livers of fumarylacetoacetate-hydrolase-deficient (Fah(-/-)) mice and rescue almost half of recipients from death by restoring liver functions. Our study provides a novel strategy to generate functional hepatocyte-like cells for the purpose of liver engineering and regenerative medicine.


Evolving and combining facial composites: between-witness and within-witness morphs compared.
Student participant-witnesses produced 4 composites of unfamiliar faces with a system that uses a genetic algorithm to evolve appearance of artificial faces. Morphs of 4 composites produced by different witnesses (between-witness morphs) were judged better likenesses (Experiment 1) and were more frequently named (Experiment 2) by participants who were familiar with the target actors than were morphs of 4 composites produced by a single witness (within-witness morphs). Within-witness morphs were judged better likenesses and more frequently named than the best or the first-produced individual composites. The same results for likeness judgments were observed after possible artifacts in the comparison of between- and within-witness morphs were eliminated (Experiment 3). Experiment 4 showed that both internal and external features were better represented in morphs than in the original composites, although the representation of internal features improved more. The results suggest that morphing improves the representation of faces by reducing random error. Between-witness morphs yield more benefit than within-witness morphs by reducing consistent but idiosyncratic errors of individual witnesses. The experiments provide the first demonstration of an advantage for within-witness morphs produced using a single system. Experiment 2 provides the first demonstration of a reliable advantage for between-witness morphs in the most forensically relevant task: naming a composite of a familiar person produced by a witness who was unfamiliar with the target. Morphing would enhance the recognition of facial composites of criminals. Within-witness morphing provides a methodology for use in crimes in which the victim is the only witness.


Methicillin-resistant Staphylococcus aureus as a uropathogen in an Irish setting.
Urinary tract infections are one of the most common infectious diseases diagnosed in the community and in the hospital setting. Their treatment is complicated by drug-resistant pathogens and the colonization by microbes of indwelling urinary catheters. This study assessed the occurrence and antimicrobial susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) uropathogens isolated for 5 consecutive years at University Hospital Waterford between 2010 and 2014. We created 4 clinically relevant subdivisions, based on urine source: hospital inpatients, patients from the Emergency Department, patients referred from their General Practitioner, and Nursing Home patients. We performed a retrospective review from the hospital's electronic microbiological system and calculated resistance rates for each of the standard antimicrobial agents. During the 5-year study period, we studied 151 urine isolates obtained from 128 patients who had an MRSA cultured in their urine sample. There was 100% resistance of all MRSA isolates to Flucloxacillin and Coamoxiclav. Ninety-eight percent of isolates were resistant to Ciprofloxacin. The resistance rate for Trimethoprim was 7.4% and there was only 2.7% resistance for Nitrofurantoin. For a clinical subset of patients, we also demonstrated 100% sensitivity for samples tested against Teicoplanin and Vancomycin. Urinary MRSA is an infrequently studied phenomenon, but with the rising trend of hospital superbugs nationally, its management is of critical importance. Suitable agents to address this within our population include Nitrofurantoin in the well patient requiring urinary MRSA eradication or Vancomycin/Teicoplanin in the unwell patient requiring intravenous therapy. In all groups, fluoroquinolones should be avoided due to significant resistance rates.


The amino acid sequence of Neurospora NADP-specific glutamate dehydrogenase. The tryptic peptides.
The NADP-specific glutamate dehydrogenase of Neurospora crassa was digested with trypsin, and peptides accounting for 441 out of the 452 residues of the polypeptide chain were isolated and substantially sequenced. Additional experimental detail has been deposited as Supplementary Publication SUP 50052 (11 pages) with the British Library (Lending Division), Boston Spa, Wetherby, W. Yorkshire LS23 7BQ, U.K., from whom copies may be obtained under the terms given in Biochem J. (1975) 145, 5.


Low-dose oral sirolimus and the risk of menstrual-cycle disturbances and ovarian cysts: analysis of the randomized controlled SUISSE ADPKD trial.
Sirolimus has been approved for clinical use in non proliferative and proliferative disorders. It inhibits the mammalian target of rapamycin (mTOR) signaling pathway which is also known to regulate ovarian morphology and function. Preliminary observational data suggest the potential for ovarian toxicity but this issue has not been studied in randomized controlled trials. We reviewed the self-reported occurrence of menstrual cycle disturbances and the appearance of ovarian cysts post hoc in an open label randomized controlled phase II trial conducted at the University Hospital Zürich between March 2006 and March 2010. Adult females with autosomal dominant polycystic kidney disease, an inherited kidney disease not known to affect ovarian morphology and function, were treated with 1.3 to 1.5 mg sirolimus per day for a median of 19 months (N = 21) or standard care (N = 18). Sirolimus increased the risk of both oligoamenorrhea (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.1 to 29) and ovarian cysts (HR 4.4, CI 1.1 to 26); one patient was cystectomized five months after starting treatment with sirolimus. We also studied mechanisms of sirolimus-associated ovarian toxicity in rats. Sirolimus amplified signaling in rat ovarian follicles through the pro-proliferative phosphatidylinositol 3-kinase pathway. Low dose oral sirolimus increases the risk of menstrual cycle disturbances and ovarian cysts and monitoring of sirolimus-associated ovarian toxicity is warranted and might guide clinical practice with mammalian target of rapamycin inhibitors. ClinicalTrials.gov NCT00346918.


Significance of apoptotic cell death in systemic complications with severe acute pancreatitis.
In severe acute pancreatitis, multiple organ failure in the early stage after onset, and sepsis in the late stage, due to infection of pancreatic or peripancreatic devitalized tissue, contribute to its high mortality. In analogy with sepsis, evidence has accumulated of the significance of apoptotic cell death in the systemic manifestations associated with acute pancreatitis. Since we identified apoptosis-inducing activity in pancreatitis-associated ascitic fluid in 1995, a number of investigators, including our group, have reported, through animal experiments, that apoptosis occurred in the parenchymal cells constituting organs, such as alveolar epithelial cells in the lung, renal tubular cells in the kidney, and hepatocytes in the liver, and this apoptosis was involved in organ dysfunction with severe acute pancreatitis. Moreover, through clinical and experimental investigations, apoptosis has been revealed to be involved in the mechanism of infectious complications in acute pancreatitis. Namely, apoptosis in lymphatic tissues and peripherally circulating lymphocytes is involved in the impairment of cellular immunity, and apoptosis in gut epithelial cells is implicated in bacterial translocation. These results suggest that apoptotic cell death may play a considerable role in affecting mortality and morbidity in severe acute pancreatitis. Control of apoptosis could be a potent strategy for improvement of the clinical outcome in severe acute pancreatitis.


Endothelial Expression of Endothelin Receptor A in the Systemic Capillary Leak Syndrome.
Idiopathic systemic capillary leak syndrome (SCLS) is a rare and potentially fatal vascular disorder characterized by reversible bouts of hypotension and edema resulting from fluid and solute escape into soft tissues. Although spikes in permeability-inducing factors have been linked to acute SCLS flares, whether or not they act on an inherently dysfunctional endothelium is unknown. To assess the contribution of endothelial-intrinsic mechanisms in SCLS, we derived blood-outgrowth endothelial cells (BOEC) from patients and healthy controls and examined gene expression patterns. Ednra, encoding Endothelin receptor A (ETA)-the target of Endothelin 1 (ET-1)-was significantly increased in SCLS BOEC compared to healthy controls. Although vasoconstriction mediated by ET-1 through ETA activation on vascular smooth muscle cells has been well characterized, the expression and function of ETA receptors in endothelial cells (ECs) has not been described. To determine the role of ETA and its ligand ET-1 in SCLS, if any, we examined ET-1 levels in SCLS sera and functional effects of endothelial ETA expression. ETA overexpression in EAhy926 endothelioma cells led to ET-1-induced hyper-permeability through canonical mechanisms. Serum ET-1 levels were elevated in acute SCLS sera compared to remission and healthy control sera, suggesting a possible role for ET-1 and ETA in SCLS pathogenesis. However, although ET-1 alone did not induce hyper-permeability of patient-derived BOEC, an SCLS-related mediator (CXCL10) increased Edrna quantities in BOEC, suggesting a link between SCLS and endothelial ETA expression. These results demonstrate that ET-1 triggers classical mechanisms of vascular barrier dysfunction in ECs through ETA. Further studies of the ET-1-ETA axis in SCLS and in more common plasma leakage syndromes including sepsis and filovirus infection would advance our understanding of vascular integrity mechanisms and potentially uncover new treatment strategies.


Comparison Between Franz Diffusion Cell and a novel Micro-physiological System for In Vitro Penetration Assay Using Different Skin Models.
In vitro diffusive models are an important tool to screen the penetration ability of active ingredients in various formulations. A reliable assessment of skin penetration enhancing properties, mechanism of action of carrier systems, and an estimation of a bioavailability are essential for transdermal delivery. Given the importance of testing the penetration kinetics of different compounds across the skin barrier, several in vitro models have been developedThe aim of this study was to compare the Franz Diffusion Cell (FDC) with a novel fluid-dynamic platform (MIVO) by evaluating penetration ability of caffeine, a widely used reference substance, and LIP1, a testing molecule having the same molecular weight but a different lipophilicity in the two diffusion chamber systems. A 0.7% caffeine or LIP1 formulation in either water or propylene glycol (PG) containing oleic acid (OA) was topically applied on the Strat-M® membrane or pig ear skin, according to the infinite-dose experimental condition (780 ul/cm2). The profile of the penetration kinetics was determined by quantify the amount of molecule absorbed at different time-points (1, 2, 4, 6, 8 hours), by means of HPLC analysis. Both diffusive systems show a similar trend for caffeine and LIP1 penetration kinetics. The Strat-M® skin model shows a lower barrier function than the pig skin biopsies, whereby the PGOA vehicle exhibits a higher penetration, enhancing the effect for both diffusive chambers and skin surrogates. Most interestingly, MIVO diffusive system better predicts the lipophilic molecules (i.e. LIP1) permeation through highly physiological fluid flows resembled below the skin models.


Mediterranean diet and cognitive decline.
To investigate the possible role of diet in age-related cognitive decline (ARCD) and cognitive impairment of both degenerative (Alzheimer's disease, AD) and vascular (vascular dementia, VaD) origin. Literature review. In an elderly population of southern Italy with a typical Mediterranean diet, high energy intake of monounsaturated fatty acids (MUFA) appeared to be associated with a high level of protection against ARCD. In addition, dietary fat and energy in the elderly seem to be risk factors, while fish consumption and cereals are found to reduce the prevalence of AD in European and North American countries. Finally, the relative risk of dementia (AD and VaD) was lower in the subjects of a French cohort who drank three or four glasses of red wine each day compared with total abstainers. Essential components of the Mediterranean diet--MUFA, cereals and wine--seem to be protective against cognitive decline. As such, dietary antioxidants and supplements, specific macronutrients of the Mediterranean diet, oestrogens and anti-inflammatory drugs may act synergistically with other protective factors, opening up new therapeutic interventions for cognitive decline.


Clostridial dermatitis and cellulitis: an emerging disease of turkeys.
Clostridial dermatitis of turkeys (CDT) has emerged as a major issue across most geographic regions of the United States. The prevalence and severity of dermatitis has increased over the last several years, since the time it was first reported in 1993. Cellulitis in poultry can be associated with Staphylococcus aureus or Escherichia coli, but the more recent field situation in turkeys is specifically associated with Clostridium spp. The prevalence of cellulitis is relatively low; however, the disease can be devastating in the individual flocks affected. Clostridium septicum, Clostridium perfringens, Clostridium sordelli, and S. aureus can cause cellulitis. Escherichia coli, Streptococcus spp., and other bacteria have occasionally been isolated from birds diagnosed with cellulitis. CDT appears as excessive mortality in older birds around 16-18 weeks of age. It has been reported from field experience as early as 7 wk of age. Clinical signs of CDT can range from sudden death to inappetence, depression, leg weakness, recumbency, and ataxia. The disease is characterized by reddish to dark or greenish discoloration of the skin around the thighs, abdomen, keel, tail region, back, and wings. The lesions can extend into the underlying muscles, and there can be gas bubbles under the skin which result in crepitation. Some cases present with dead birds having "bubbly tail," fluid-filled blisters associated with broken feather follicles around the base of the tail. Bubbly tail in breeder toms might not cause excessive mortality, but the lesions are so severe that the birds cannot be used for semen collection. Incidence of mortality from this condition can be severe and acute (i.e., rapid onset of high mortality). The dead birds decompose very quickly. Microscopically, there is necrosis, with or without inflammation of the skin, especially in the dermis and occasionally in the skeletal muscles, associated with large numbers of rod-shaped bacteria. Overcrowding, aggressive birds, poor-wet litter, decreased down time, a contaminated environment including feed and water, poor hygienic conditions, and contaminated vaccines and vaccine equipment, etc., can predispose birds for CDT. Preventative measures and treatment are discussed extensively in this review.


Prioritizing breast imaging services during the COVID pandemic: A survey of breast imaging facilities within the Breast Cancer Surveillance Consortium.
The COVID-19 pandemic disrupted breast cancer screening and diagnostic imaging in the United States. We sought to evaluate how medical facilities prioritized breast imaging services during periods of reduced capacity or upon re-opening after closures. In fall 2020, we surveyed 77 breast imaging facilities within the Breast Cancer Surveillance Consortium in the United States. The survey ascertained the pandemic's impact on clinical practices during March-September 2020. Nearly all facilities (97%) reported closing or operating at reduced capacity at some point during this period. All facilities were open by August 2020, though 14% were still operating at reduced capacity in September 2020. During periods of re-opening or reduced capacity, 93% of facilities reported prioritizing diagnostic breast imaging over breast cancer screening. For diagnostic imaging, facilities prioritized based on rescheduling canceled appointments (89%), specific indication for diagnostic imaging (89%), patient demand (84%), individual characteristics and risk factors (77%), and time since last imaging examination (72%). For screening mammography, facilities prioritized based on rescheduled cancelations (96%), patient demand (83%), individual characteristics and risk factors (73%), and time since last mammogram (71%). For biopsy services, more than 90% of facilities reported prioritization based on rescheduling of canceled exams, patient demand, patient characteristics and risk factors and level of suspicion on imaging. The observed patterns from this large and geographically diverse sample of facilities in the United States indicate that multiple factors were commonly used to prioritize breast imaging services during periods of reduced capacity.


Nonribosomal peptide synthase gene clusters for lipopeptide biosynthesis in Bacillus subtilis 916 and their phenotypic functions.
Bacillus cyclic lipopeptides (LPs) have been well studied for their phytopathogen-antagonistic activities. Recently, research has shown that these LPs also contribute to the phenotypic features of Bacillus strains, such as hemolytic activity, swarming motility, biofilm formation, and colony morphology. Bacillus subtilis 916 not only coproduces the three families of well-known LPs, i.e., surfactins, bacillomycin Ls (iturin family), and fengycins, but also produces a new family of LP called locillomycins. The genome of B. subtilis 916 contains four nonribosomal peptide synthase (NRPS) gene clusters, srf, bmy, fen, and loc, which are responsible for the biosynthesis of surfactins, bacillomycin Ls, fengycins, and locillomycins, respectively. By studying B. subtilis 916 mutants lacking production of one, two, or three LPs, we attempted to unveil the connections between LPs and phenotypic features. We demonstrated that bacillomycin Ls and fengycins contribute mainly to antifungal activity. Although surfactins have weak antifungal activity in vitro, the strain mutated in srfAA had significantly decreased antifungal activity. This may be due to the impaired productions of fengycins and bacillomycin Ls. We also found that the disruption of any LP gene cluster other than fen resulted in a change in colony morphology. While surfactins and bacillomycin Ls play very important roles in hemolytic activity, swarming motility, and biofilm formation, the fengycins and locillomycins had little influence on these phenotypic features. In conclusion, B. subtilis 916 coproduces four families of LPs which contribute to the phenotypic features of B. subtilis 916 in an intricate way.


Sinomenine, a natural dextrorotatory morphinan analog, is anti-inflammatory and neuroprotective through inhibition of microglial NADPH oxidase.
The mechanisms involved in the induction and regulation of inflammation resulting in dopaminergic (DA) neurotoxicity in Parkinson's disease (PD) are complex and incompletely understood. Microglia-mediated inflammation has recently been implicated as a critical mechanism responsible for progressive neurodegeneration. Mesencephalic neuron-glia cultures and reconstituted cultures were used to investigate the molecular mechanisms of sinomenine (SN)-mediated anti-inflammatory and neuroprotective effects in both the lipopolysaccharide (LPS)- and the 1-methyl-4-phenylpyridinium (MPP+)-mediated models of PD. SN showed equivalent efficacy in protecting against DA neuron death in rat midbrain neuron-glial cultures at both micro- and sub-picomolar concentrations, but no protection was seen at nanomolar concentrations. The neuroprotective effect of SN was attributed to inhibition of microglial activation, since SN significantly decreased tumor necrosis factor-alpha (TNF-alpha, prostaglandin E2 (PGE2) and reactive oxygen species (ROS) production by microglia. In addition, from the therapeutic point of view, we focused on sub-picomolar concentration of SN for further mechanistic studies. We found that 10(-14) M of SN failed to protect DA neurons against MPP+-induced toxicity in the absence of microglia. More importantly, SN failed to show a protective effect in neuron-glia cultures from mice lacking functional NADPH oxidase (PHOX), a key enzyme for extracellular superoxide production in immune cells. Furthermore, we demonstrated that SN reduced LPS-induced extracellular ROS production through the inhibition of the PHOX cytosolic subunit p47phoxtranslocation to the cell membrane. Our findings strongly suggest that the protective effects of SN are most likely mediated through the inhibition of microglial PHOX activity. These findings suggest a novel therapy to treat inflammation-mediated neurodegenerative diseases.


The performance of low-cost commercial cloud computing as an alternative in computational chemistry.
The growth of commercial cloud computing (CCC) as a viable means of computational infrastructure is largely unexplored for the purposes of quantum chemistry. In this work, the PSI4 suite of computational chemistry programs is installed on five different types of Amazon World Services CCC platforms. The performance for a set of electronically excited state single-point energies is compared between these CCC platforms and typical, "in-house" physical machines. Further considerations are made for the number of cores or virtual CPUs (vCPUs, for the CCC platforms), but no considerations are made for full parallelization of the program (even though parallelization of the BLAS library is implemented), complete high-performance computing cluster utilization, or steal time. Even with this most pessimistic view of the computations, CCC resources are shown to be more cost effective for significant numbers of typical quantum chemistry computations. Large numbers of large computations are still best utilized by more traditional means, but smaller-scale research may be more effectively undertaken through CCC services.


Four new vaccines for routine immunization in India: what about hemophilus influenza B and pneumococcal vaccine?
Immunization is the process whereby a person is made immune or resistant to an infectious disease, typically by the administration of a vaccine. The Expanded Program on Immunization (EPI) was flagged off in India in 1978. According to the recommendation of National technical advisory group of India (NATGI), Government of India is going to include four new vaccines in the UIP for whole India. The four new vaccines are Inactivated Poliomyelitis Vaccine (IPV) for polio, rota viral vaccine, vaccine against rubella, and Japanese encephalitis vaccine (179 districts in India). Here, authors have tried to show a comparative descriptive analysis of the hemophilus influenza and pneumococcal pneumonia with rota virus, so that in near future Government of India can also consider their inclusion in the national UIP. In India, 39.2% of all diarrheal death are due to rota virus, whereas 0.72 million deaths are due to hemophilus influenza B and 1.3 million are due to pneumococcal pneumonia in <5 years age-group. India's indigenous developed rota viral vaccine's (Rotavac) efficacy is 56% in 1(st) year compared to H influenza B (Hib) efficacy 95% and PCV13 vaccine "3 + 1" dose efficacy 100% (South Africa). Rotarix incremental cost-effectiveness ratio is US $21.4 to US $34 per disability-adjusted life years (DALYs) compared to Hib US $ 819 per DALYs in India. In case of pneumococcal vaccine, India needs more trails on the serotype specificity, efficacy, and cost-effectiveness but there is enough evidence that hemophilus influenza burden is high in India and the present Hib vaccine is safe and highly effective. In future with the help of donor agencies, India should include the hemophilus influenza B and pneumococcal pneumonia vaccine in national UIP which will save millions of poor children's life.


Potential Risk of Higenamine Misuse in Sports: Evaluation of Lotus Plumule Extract Products and a Human Study.
Since 2017, higenamine has been added to the World Anti-Doping Agency (WADA) prohibited list as a β2-agonist prohibited at all times for sportspersons. According to WADA's report, positive cases of higenamine misuse have been increasing yearly. However, higenamine occurs naturally in the Chinese herb lotus plumule-the green embryo of lotus (Nelumbo nucifera Gaertn) seeds-commercially available as concentrated powder on the Asian market. This study evaluated the major phytochemical components of lotus plumule products using an appropriate extraction method, followed by a human study in which the products were orally administered in multiple doses to investigate the risk of doping violations. Comparing various extraction methods revealed that optimized microwave-assisted extraction exhibited the highest extraction efficiency (extraction time, 26 min; power, 1046 W; and temperature, 120 °C). Subsequently, the alkaloids in lotus plumule products were quantitatively confirmed and compared. Human study participants (n = 6) consumed 0.8 g of lotus plumule (equivalent to 679.6 μg of higenamine) three times daily for three consecutive days. All participants' urinary higenamine concentrations exceeded the WADA reporting cut-off of 10.0 ng/mL. Accordingly, lotus plumule consumption may engender adverse analytical findings regarding higenamine. Athletes should avoid consuming lotus plumule-containing products during in- and out-of-competition periods.


Interleukin 2 receptor antagonists for kidney transplant recipients.
Interleukin 2 receptor antagonists (IL2Ra) are used as induction therapy for prophylaxis against acute rejection in kidney transplant recipients. Use of IL2Ra has increased steadily since their introduction, but the proportion of new transplant recipients receiving IL2Ra differs around the globe, with 27% of new kidney transplant recipients in the United States, and 70% in Australasia receiving IL2Ra in 2007. To systematically identify and summarise the effects of using an IL2Ra, as an addition to standard therapy, or as an alternative to another immunosuppressive induction strategy. We searched the Cochrane Renal Group's specialised register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE to identify new records, and authors of included reports were contacted for clarification where necessary. Randomised controlled trials (RCTs) in all languages comparing IL2Ra to placebo, no treatment, other IL2Ra or other antibody therapy. Data was extracted and assessed independently by two authors, with differences resolved by discussion. Dichotomous outcomes are reported as relative risk (RR) and continuous outcomes as mean difference (MD) with 95% confidence intervals (CI). We included 71 studies (306 reports, 10,537 participants). Where IL2Ra were compared with placebo (32 studies; 5,784 patients) graft loss including death with a functioning graft was reduced by 25% at six months (16 studies: RR 0.75, 95% CI 0.58 to 0.98) and one year (24 studies: RR 0.75, 95% CI 0.62 to 0.90), but not beyond this. At one year biopsy-proven acute rejection was reduced by 28% (14 studies: RR 0.72, 95% CI 0.64 to 0.81), and there was a 19% reduction in CMV disease (13 studies: RR 0.81, 95% CI 0.68 to 0.97). There was a 64% reduction in early malignancy within six months (8 studies: RR 0.36, 95% CI 0.15 to 0.86), and creatinine was lower (7 studies: MD -8.18 micromol/L 95% CI -14.28 to -2.09) but these differences were not sustained.When IL2Ra were compared to ATG (16 studies, 2211 participants), there was no difference in graft loss at any time point, or for acute rejection diagnosed clinically, but the was benefit of ATG therapy over IL2Ra for biopsy-proven acute rejection at one year (8 studies:, RR 1.30 95% CI 1.01 to 1.67), but at the cost of a 75% increase in malignancy (7 studies: RR 0.25 95% CI 0.07 to 0.87) and a 32% increase in CMV disease (13 studies: RR 0.68 95% CI 0.50 to 0.93). Serum creatinine was significantly lower for IL2Ra treated patients at six months (4 studies: MD -11.20 micromol/L 95% CI -19.94 to -2.09). ATG patients experienced significantly more fever, cytokine release syndrome and other adverse reactions to drug administration and more leucopenia but not thrombocytopenia. There were no significant differences in outcomes according to cyclosporine or tacrolimus use, azathioprine or mycophenolate, or to the study populations baseline risk for acute rejection. There was no evidence that effects were different according to whether equine or rabbit ATG was used. Given a 38% risk of rejection, per 100 recipients compared with no treatment, nine recipients would need treatment with IL2Ra to prevent one recipient having rejection, 42 to prevent one graft loss, and 38 to prevent one having CMV disease over the first year post-transplantation. Compared with ATG treatment, ATG may prevent some experiencing acute rejection, but 16 recipients would need IL2Ra to prevent one having CMV, but 58 would need IL2Ra to prevent one having malignancy. There are no apparent differences between basiliximab and daclizumab. IL2Ra are as effective as other antibody therapies and with significantly fewer side effects.


Mitochondrial DNA and the peopling of South America.
The initial peopling of South America is largely unresolved, in part because of the unique distribution of genetic diversity in native South Americans. On average, genetic diversity estimated within Andean populations is higher than that estimated within Amazonian populations. Yet there is less genetic differentiation estimated among Andean populations than estimated among Amazonian populations. One hypothesis is that this pattern is a product of independent migrations of genetically differentiated people into South America. A competing hypothesis is that there was a single migration followed by regional isolation. In this study we address these hypotheses using mtDNA hypervariable region 1 sequences representing 21 South American groups and include new data sets for four native Peruvian communities from Tupe, Yungay, and Puno. An analysis of variance that compared the combined data from western South America to the combined data from eastern South America determined that these two regional data sets are not significantly different. As a result, a migration from a single source population into South America serves as the simplest explanation of the data.


The human AC133 hematopoietic stem cell antigen is also expressed in epithelial cells and targeted to plasma membrane protrusions.
The human AC133 antigen and mouse prominin are structurally related plasma membrane proteins. However, their tissue distribution is distinct, with the AC133 antigen being found on hematopoietic stem and progenitor cells and prominin on various epithelial cells. To determine whether the human AC133 antigen and mouse prominin are orthologues or distinct members of a protein family, we examined the human epithelial cell line Caco-2 for the possible expression of the AC133 antigen. By both immunofluorescence and immunoprecipitation, the AC133 antigen was found to be expressed on the surface of Caco-2 cells. Interestingly, immunoreactivity for the AC133 antigen, but not its mRNA level, was down-regulated upon differentiation of Caco-2 cells. The AC133 antigen was specifically located at the apical rather than basolateral plasma membrane. An apical localization of the AC133 antigen was also observed in various human embryonic epithelia including the neural tube, gut, and kidney. Electron microscopy revealed that, within the apical plasma membrane of Caco-2 cells, the AC133 antigen was confined to microvilli and absent from the planar, intermicrovillar regions. This specific subcellular localization did not depend on an epithelial phenotype, because the AC133 antigen on hematopoietic stem cells, as well as that ectopically expressed in fibroblasts, was selectively found in plasma membrane protrusions. Hence, the human AC133 antigen shows the features characteristic of mouse prominin in epithelial and transfected non-epithelial cells, i.e. a selective association with apical microvilli and plasma membrane protrusions, respectively. Conversely, flow cytometry of murine CD34(+) bone marrow progenitors revealed the cell surface expression of prominin. Taken together, the data strongly suggest that the AC133 antigen is the human orthologue of prominin.


Cytoreductive surgery and HIPEC improve survival compared to palliative chemotherapy for biliary carcinoma with peritoneal metastasis: A multi-institutional cohort from PSOGI and BIG RENAPE groups.
Peritoneal metastasis from biliary carcinoma (PMC) is associated with poor prognosis when treated with chemotherapy. To evaluate the impact on survival of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), and compare with conventional palliative chemotherapy for patients with PMC. A prospective multicenter international database was retrospectively searched to identify all patients with PMC treated with a potentially curative CRS/HIPEC (CRS/HIPEC group). The overall survival (OS) was compared to patients with PMC treated with palliative chemotherapy (systemic chemotherapy group). Survival was analyzed using Kaplan-Meier method and compared with Log-Rank test. Between 1995 and 2015, 34 patients were included in the surgical group, and compared to 21 in the systemic chemotherapy group. In the surgical group, median peritoneal cancer index was 9 (range 3-26), macroscopically complete resection was obtained for 25 patients (73%). There was more gallbladder localization in the surgical group compared to the chemotherapy group (35% vs. 18%, p = 0.001). Median OS was 21.4 and 9.3 months for surgical and chemotherapy group, respectively (p=0.007). Three-year overall survival was 30% and 10% for surgical and chemotherapy group, respectively. Treatment with CRS and HIPEC for biliary carcinoma with peritoneal metastasis is feasible and may provide survival benefit when compared to palliative chemotherapy.


Aggregate versus day level association between methamphetamine use and HIV medication non-adherence among gay and bisexual men.
Methamphetamine use is associated with HIV infection, especially among gay and bisexual men. Methamphetamine use contributes to disease progression both directly, by increasing viral load and damaging the immune system, and indirectly, by decreasing medication adherence. Research examining the association of methamphetamine use and non-adherence has traditionally compared groups of users and nonusers on adherence, compared methamphetamine use between participants above or below some threshold level of adherence (e.g. >90 % dose adherence), or examined aggregate relationships. Using Timeline Follow-back procedures, the present study examined aggregate, threshold, and day-level associations of methamphetamine use with non-adherence in 210 HIV-positive gay and bisexual methamphetamine-using men. Methamphetamine use was not associated with adherence behavior at the aggregate-level, but methamphetamine use on a given day was associated with 2.3 times the odds of non-adherence on that day. Threshold results were equivocal. These data suggest that the methamphetamine and non-adherence relationship is complicated: non-adherence is more likely to occur on days in which methamphetamine is used, but participants reported more non-adherence days in which methamphetamine was not used. This seeming paradox generates questions about the selection of analytical techniques and has important implications for behavioral interventions targeting substance use and adherence among HIV-positive individuals.


Systematic functional prioritization of protein posttranslational modifications.
Protein function is often regulated by posttranslational modifications (PTMs), and recent advances in mass spectrometry have resulted in an exponential increase in PTM identification. However, the functional significance of the vast majority of these modifications remains unknown. To address this problem, we compiled nearly 200,000 phosphorylation, acetylation, and ubiquitination sites from 11 eukaryotic species, including 2,500 newly identified ubiquitylation sites for Saccharomyces cerevisiae. We developed methods to prioritize the functional relevance of these PTMs by predicting those that likely participate in cross-regulatory events, regulate domain activity, or mediate protein-protein interactions. PTM conservation within domain families identifies regulatory "hot spots" that overlap with functionally important regions, a concept that we experimentally validated on the HSP70 domain family. Finally, our analysis of the evolution of PTM regulation highlights potential routes for neutral drift in regulatory interactions and suggests that only a fraction of modification sites are likely to have a significant biological role.


Deep-penetrating photodynamic therapy with KillerRed mediated by upconversion nanoparticles.
The fluorescent protein KillerRed, a new type of biological photosensitizer, is considered as a promising substitute for current synthetic photosensitizes used in photodynamic therapy (PDT). However, broad application of this photosensitiser in treating deep-seated lesions is challenging due to the limited tissue penetration of the excitation light with the wavelength falling in the visible spectral range. To overcome this challenge, we employ upconversion nanoparticles (UCNPs) that are able to convert deep-penetrating near infrared (NIR) light to green light to excite KillerRed locally, followed by the generation of reactive oxygen species (ROS) to kill tumour cells under centimetre-thick tissue. The photosensitizing bio-nanohybrids, KillerRed-UCNPs, are fabricated through covalent conjugation of KillerRed and UCNPs. The resulting KillerRed-UCNPs exhibit excellent colloidal stability in biological buffers and low cytotoxicity in the dark. Cross-comparison between the conventional KillerRed and UCNP-mediated KillerRed PDT demonstrated superiority of KillerRed-UCNPs photosensitizing by NIR irradiation, manifested by the fact that ∼70% PDT efficacy was achieved at 1-cm tissue depth, whereas that of the conventional KillerRed dropped to ∼7%. KillerRed is a protein photosensitizer that holds promise as an alternative for the existing hydrophobic photosensitizers that are widely used in clinical photodynamic therapy (PDT). However, applications of KillerRed to deep-seated tumours are limited by the insufficient penetration depth of the excitation light in highly scattering and absorbing biological tissues. Herein, we reported the deployment of upconversion nanoparticles (UCNPs) to enhance the treatment depth of KillerRed by converting the deep-penetrating near-infrared (NIR) light to upconversion photoluminescence and activating the PDT effect of KillerRed under deep tissues. This work demonstrated clear potential of UCNPs as the NIR-to-visible light converter to overcome the light penetration limit that has plagued PDT application for many years.


Epidemic investigation of the jaundice outbreak in girdharnagar, ahmedabad, gujarat, India, 2008.
Since 1976, seven outbreaks of hepatitis E occurred in Ahmedabad. Clusters of jaundice cases were reported on June 19, 2008, by a civic center, Girdharnagar ward, Ahmedabad. THE OBJECTIVES WERE AS FOLLOWS: (1) to identify the etiological agent, source of outbreak, and mode of transmission; (2) to propose a control measure based on the outbreak investigation. We defined a case as an acute illness with (a) a discrete onset of symptoms and (b) jaundice or elevated serum aminotransferase levels, from March to September 2008 in the households of the Girdharnagar ward. We collected data through a door-to-door survey and hospital records. We described the outbreak in terms of time, place, and person. We collected laboratory investigation reports of case patients admitted to the civil hospital. To test our hypothesis we conducted a retrospective cohort study to find out the relative risk for hepatitis. We conducted environment investigation to find out the source of contamination of water supply. A total 233 case patients of hepatitis were identified with the attack rate of 10.9/1000 population. Cases were reported in all the age groups with a higher attack rate in the age group of 20-29 years (18.5/1000). Out of 17 case patients, 16 were positive for the hepatitis E IgM antibody. The attack rate was two times more among those who were exposed to the leaking pipeline than the non-exposed (RR=2.3, 95% CI 1.76, 2.98). Environmental investigation also confirmed the sewage contamination of drinking water in the distribution system. The outbreak was due to hepatitis E virus. We recommended a temporary alternative water supply, repair of the leakages, and water quality surveillance.


Characterization of the role of dendritic cells in prion transfer to primary neurons.
TSEs (transmissible spongiform encephalopathies) are neurodegenerative diseases caused by pathogenic isoforms (PrPSc) of the host-encoded PrPc (cellular prion protein). After consumption of contaminated food, PrPSc deposits rapidly accumulate in lymphoid tissues before invasion of the CNS (central nervous system). However, the mechanisms of prion spreading from the periphery to the nervous system are still unclear. In the present study, we investigated the role of DCs (dendritic cells) in the spreading of prion infection to neuronal cells. First, we determined that BMDCs (bone-marrow-derived DCs) rapidly uptake PrPSc after exposure to infected brain homogenate. Next, we observed a progressive catabolism of the internalized prion aggregates. Similar experiments performed with BMDCs isolated from KO (knockout) mice or mice overexpressing PrP (tga20) indicate that both PrPSc uptake and catabolism are independent of PrPc expression in these cells. Finally, using co-cultures of prion-loaded BMDCs and cerebellar neurons, we characterized the transfer of the prion protein and the resulting infection of the neuronal cultures. Interestingly, the transfer of PrPSc was triggered by direct cell-cell contact. As a consequence, BMDCs retained the prion protein when cultured alone, and no transfer to the recipient neurons was observed when a filter separated the two cultures or when neurons were exposed to the BMDC-conditioned medium. Additionally, fixed BMDCs also failed to transfer prion infectivity to neurons, suggesting an active transport of prion aggregates, in accordance with a role of TNTs (tunnelling nanotubes) observed in the co-cultures.


Chronic nicotine and mecamylamine treatment increase brain nicotinic receptor binding without changing alpha 4 or beta 2 mRNA levels.
It has recently been shown using regionally dissected tissue that both chronic mecamylamine treatment and chronic nicotine treatment increase the number of [3H]-nicotine binding sites in mouse brain, and that additive increases in the number of binding sites is observed after cotreatment with the two drugs. The studies reported here extend these findings by using quantitative autoradiographic methods to analyze the brains of chronically treated mice at a finer anatomical level of resolution. DBA/2 mice were chronically infused (i.v.) with saline, 4.0 mg/ kg/hr nicotine, 4.0 mg/kg/hr mecamylamine or both drugs for 7 days. The brains of these mice were subsequently analyzed to determine the effects of chronic drug treatment on [3H]-nicotine binding and on the levels of mRNA encoding the nicotinic receptor subunits, alpha 4 and beta 2. [3H]-Nicotine binding was increased in 37 of 46 brain regions after chronic nicotine treatment (average increase = 66.5%), in 41 of 46 regions after chronic mecamylamine treatment (average increase = 56.5%), and in 45 of 46 brain regions after chronic treatment with both drugs (average increase = 107.1%). The changes in [3H]-nicotine binding produced by the two drugs across brain regions were highly (r = 0.98) and significantly correlated. These results are consistent with the proposal that the same receptors are affected by agonist or antagonist treatment. Chronic treatment had no significant effect on the levels of alpha 4 or beta 2 mRNA as measured by in situ hybridization. Therefore, the increases in [3H]-nicotine binding do not arise from changes in the steady-state levels of either alpha 4 or beta 2 mRNA which are believed to encode the subunits of this nicotinic receptor subtype.


Association study of dietary non-enzymatic antioxidant capacity (NEAC) and colorectal cancer risk in the Spanish Multicase-Control Cancer (MCC-Spain) study.
Studies attempting to link dietary non-enzymatic antioxidant activity (NEAC) and colorectal cancer (CRC) risk have reported mixed results. We examined this association in the Spanish Multicase-Control Study considering the likely influence of coffee and other dietary factors. 1718 CRC cases and 3312 matched-controls provided information about diet through a validated 140-item food frequency questionnaire. Dietary NEAC was estimated for three methods [total radical-trapping antioxidant parameters (TRAP), ferric reducing/antioxidant power (FRAP) and TEAC-ABTS] using published values of NEAC content in food, with and without coffee's NEAC. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated through unconditional logistic regression models adjusted for lifestyle and dietary factors. Overall dietary intake of NEAC was significantly lower in cases compared to controls and associated with a significantly reduced CRC risk, in both men (ORQ5vsQ1 = 0.67, 95% CI 0.47-0.96 for FRAP) and women (ORQ5vsQ1 = 0.53, 95% CI 0.32-085 for FRAP), in multivariate models with and without the antioxidant contribution from coffee. The effect was similar for all the NEAC methods evaluated and for both colon and rectum. The association between dietary NEAC and CRC risk became non-significant when adjusting for fiber intake. However, intakes of NEAC and fiber were correlated. This study indicates that intake of an antioxidant-rich plant-based diet, both with and without NEAC from coffee, is associated with decreased CRC risk.


Rethinking the measurement of energy poverty in Europe: A critical analysis of indicators and data.
Energy poverty - which has also been recognised via terms such as 'fuel poverty' and 'energy vulnerability' - occurs when a household experiences inadequate levels of energy services in the home. Measuring energy poverty is challenging, as it is a culturally sensitive and private condition, which is temporally and spatially dynamic. This is compounded by the limited availability of appropriate data and indicators, and lack of consensus on how energy poverty should be conceptualised and measured. Statistical indicators of energy poverty are an important and necessary part of the research and policy landscape. They carry great political weight, and are often used to guide the targeting of energy poverty measures - due to their perceived objectivity - with important consequences for both the indoor and built environment of housing. Focussing on the European Union specifically, this paper critically assesses the available statistical options for monitoring energy poverty, whilst also presenting options for improving existing data. This is examined through the lens of vulnerability thinking, by considering the ways in which policies and institutions, the built fabric and everyday practices shape energy use, alongside the manner in which energy poor households experience and address the issue on a day-to-day basis.