Diapause, signal and molecular characteristics of overwintering Chilo suppressalis (Insecta: Lepidoptera: Pyralidae).
Diapause is a complex and dynamic process. Chilo suppressalis, an important rice pest in Asia enters facultative diapause as larvae. Our results demonstrated in Yangzhou, China, diapause was initiated between September 4 and 12, 2010. After diapause termination, C. suppressalis remained in quiescence in the field for as long as three months. The average time between collection of field larvae of C. suppressalis and their pupation decreased as the season progressed from fall to next spring. Unexpectedly, the pupated ratio of female to male in the initiation of diapause was 0.22. The abundance of hsp90, hsp70, hsp60 and CsAQP1 all peaked on January 8 or 15, 2011. Nitric oxide (NO) is a secondary messenger that is positively correlated with the diapause of C. suppressalis. Among several geographically separated populations of C. suppressalis, there are no significant differences in the mRNA levels of hsp70, hsp60 or CsAQP1.


Survival and failure modes: platform-switching for internal and external hexagon cemented fixed dental prostheses.
This study evaluated the probability of survival (reliability) of platform-switched fixed dental prostheses (FDPs) cemented on different implant-abutment connection designs. Eighty-four-three-unit FDPs (molar pontic) were cemented on abutments connected to two implants of external or internal hexagon connection. Four groups (n = 21 each) were established: external hexagon connection and regular platform (ERC); external hexagon connection and switched platform (ESC); internal hexagon and regular platform (IRC); and internal hexagon and switched platform (ISC). Prostheses were subjected to step-stress accelerated life testing in water. Weibull curves and probability of survival for a mission of 100,000 cycles at 400 N (two-sided 90% CI) were calculated. The beta values of 0.22, 0.48, 0.50, and 1.25 for groups ERC, ESC, IRC, and ISC, respectively, indicated a limited role of fatigue in damage accumulation, except for group ISC. Survival decreased for both platform-switched groups (ESC: 74%, and ISC: 59%) compared with the regular matching platform counterparts (ERC: 95%, and IRC: 98%). Characteristic strength was higher only for ERC compared with ESC, but not different between internal connections. Failures chiefly involved the abutment screw. Platform switching decreased the probability of survival of FDPs on both external and internal connections. The absence in loss of characteristic strength observed in internal hexagon connections favor their use compared with platform-switched external hexagon connections.


Reporting preclinical anesthesia study (REPEAT): Evaluating the quality of reporting in the preclinical anesthesiology literature.
Poor reporting quality may contribute to irreproducibility of results and failed 'bench-to-bedside' translation. Consequently, guidelines have been developed to improve the complete and transparent reporting of in vivo preclinical studies. To examine the impact of such guidelines on core methodological and analytical reporting items in the preclinical anesthesiology literature, we sampled a cohort of studies. Preclinical in vivo studies published in Anesthesiology, Anesthesia & Analgesia, Anaesthesia, and the British Journal of Anaesthesia (2008-2009, 2014-2016) were identified. Data was extracted independently and in duplicate. Reporting completeness was assessed using the National Institutes of Health Principles and Guidelines for Reporting Preclinical Research. Risk ratios were used for comparative analyses. Of 7615 screened articles, 604 met our inclusion criteria and included experiments reporting on 52 490 animals. The most common topic of investigation was pain and analgesia (30%), rodents were most frequently used (77%), and studies were most commonly conducted in the United States (36%). Use of preclinical reporting guidelines was listed in 10% of applicable articles. A minority of studies fully reported on replicates (0.3%), randomization (10%), blinding (12%), sample-size estimation (3%), and inclusion/exclusion criteria (5%). Statistics were well reported (81%). Comparative analysis demonstrated few differences in reporting rigor between journals, including those that endorsed reporting guidelines. Principal items of study design were infrequently reported, with few differences between journals. Methods to improve implementation and adherence to community-based reporting guidelines may be necessary to increase transparent and consistent reporting in the preclinical anesthesiology literature.


Two mammalian mitotic aurora kinases: who's who?
Several serine-threonine kinases related to the Ipl1p kinase in budding yeast, termed aurora kinases, have been cloned recently. Their characterization revealed them to be important regulators of mitotic functions, including (i) the separation of the centrosome, (ii) assembly of the spindles, and (iii) segregation of the chromosomes. The Perspective by Descamps and Prigent delves into the latest observations on aurora kinases in humans and the specific roles of each kinase within the process of mitosis.


Responsible, Safe, and Effective Use of Antithrombotics and Anticoagulants in Patients Undergoing Interventional Techniques: American Society of Interventional Pain Physicians (ASIPP) Guidelines.
Interventional pain management involves diagnosis and treatment of chronic pain. This specialty utilizes minimally invasive procedures to target therapeutics to the central nervous system and the spinal column. A subset of patients encountered in interventional pain are medicated using anticoagulant or antithrombotic drugs to mitigate thrombosis risk. Since these drugs target the clotting system, bleeding risk is a consideration accompanying interventional procedures. Importantly, discontinuation of anticoagulant or antithrombotic drugs exposes underlying thrombosis risk, which can lead to significant morbidity and mortality especially in those with coronary artery or cerebrovascular disease. This review summarizes the literature and provides guidelines based on best evidence for patients receiving anti-clotting therapy during interventional pain procedures. Best evidence synthesis. To provide a current and concise appraisal of the literature regarding an assessment of the bleeding risk during interventional techniques for patients taking anticoagulant and/or antithrombotic medications. A review of the available literature published on bleeding risk during interventional pain procedures, practice patterns and perioperative management of anticoagulant and antithrombotic therapy was conducted. Data sources included relevant literature identified through searches of EMBASE and PubMed from 1966 through August 2018 and manual searches of the bibliographies of known primary and review articles. 1. There is good evidence for risk stratification by categorizing multiple interventional techniques into low-risk, moderate-risk, and high-risk. Also, their risk should be upgraded based on other risk factors.2. There is good evidence for the risk of thromboembolic events in patients who interrupt antithrombotic therapy. 3. There is good evidence supporting discontinuation of low dose aspirin for high risk and moderate risk procedures for at least 3 days, and there is moderate evidence that these may be continued for low risk or some intermediate risk procedures.4. There is good evidence that discontinuation of anticoagulant therapy with warfarin, heparin, dabigatran (Pradaxa®), argatroban (Acova®), bivalirudin (Angiomax®), lepirudin (Refludan®), desirudin (Iprivask®), hirudin, apixaban (Eliquis®), rivaroxaban (Xarelto®), edoxaban (Savaysa®, Lixiana®), Betrixaban(Bevyxxa®), fondaparinux (Arixtra®) prior to interventional techniques with individual consideration of pharmacokinetics and pharmacodynamics of the drugs and individual risk factors increases safety.5. There is good evidence that diagnosis of epidural hematoma is based on severe pain at the site of the injection, rapid neurological deterioration, and MRI with surgical decompression with progressive neurological dysfunction to avoid neurological sequelae.6. There is good evidence that if thromboembolic risk is high, low molecular weight heparin bridge therapy can be instituted during cessation of the anticoagulant, and the low molecular weight heparin can be discontinued 24 hours before the pain procedure.7. There is fair evidence that the risk of thromboembolic events is higher than that of epidural hematoma formation with the interruption of antiplatelet therapy preceding interventional techniques, though both risks are significant.8. There is fair evidence that multiple variables including anatomic pathology with spinal stenosis and ankylosing spondylitis; high risk procedures and moderate risk procedures combined with anatomic risk factors; bleeding observed during the procedure, and multiple attempts during the procedures increase the risk for bleeding complications and epidural hematoma.9. There is fair evidence that discontinuation of phosphodiesterase inhibitors is optional (dipyridamole [Persantine], cilostazol [Pletal]. However, there is also fair evidence to discontinue Aggrenox [dipyridamole plus aspirin]) 3 days prior to undergoing interventional techniques of moderate and high risk. 10. There is fair evidence to make shared decision making between the patient and the treating physicians with the treating physician and to consider all the appropriate risks associated with continuation or discontinuation of antithrombotic or anticoagulant therapy.11. There is fair evidence that if thromboembolic risk is high antithrombotic therapy may be resumed 12 hours after the interventional procedure is performed.12. There is limited evidence that discontinuation of antiplatelet therapy (clopidogrel [Plavix®], ticlopidine [Ticlid®], Ticagrelor [Brilinta®] and prasugrel [Effient®]) avoids complications of significant bleeding and epidural hematomas.13. There is very limited evidence supporting the continuation or discontinuation of most NSAIDs, excluding aspirin, for 1 to 2 days and some 4 to 10 days, since these are utilized for pain management without cardiac or cerebral protective effect. The continued paucity of the literature with discordant recommendations. Based on the survey of current literature, and published clinical guidelines, recommendations for patients presenting with ongoing antithrombotic therapy prior to interventional techniques are variable, and are based on comprehensive analysis of each patient and the risk-benefit analysis of intervention. Perioperative bleeding, bleeding risk, practice patterns, anticoagulant therapy, antithrombotic therapy, interventional techniques, safety precautions, pain.


Use of hangeul twitter to track and predict human influenza infection.
Influenza epidemics arise through the accumulation of viral genetic changes. The emergence of new virus strains coincides with a higher level of influenza-like illness (ILI), which is seen as a peak of a normal season. Monitoring the spread of an epidemic influenza in populations is a difficult and important task. Twitter is a free social networking service whose messages can improve the accuracy of forecasting models by providing early warnings of influenza outbreaks. In this study, we have examined the use of information embedded in the Hangeul Twitter stream to detect rapidly evolving public awareness or concern with respect to influenza transmission and developed regression models that can track levels of actual disease activity and predict influenza epidemics in the real world. Our prediction model using a delay mode provides not only a real-time assessment of the current influenza epidemic activity but also a significant improvement in prediction performance at the initial phase of ILI peak when prediction is of most importance.


A fundamental, eco-hydrological basis for niche segregation in plant communities.
• Ecologists still puzzle over how plant species manage to coexist with one another while competing for the same essential resources. The classic answer for animal communities is that species occupy different niches, but how plants do this is more difficult to determine. We previously found niche segregation along fine-scale hydrological gradients in European wet meadows and proposed that the mechanism might be a general one, especially in communities that experience seasonal saturation. • We quantified the hydrological niches of 96 species from eight fynbos communities in the biodiversity hotspot of the Cape Floristic Region, South Africa and 99 species from 18 lowland wet meadow communities in the UK. Niche overlap was computed for all combinations of species. • Despite the extreme functional and phylogenetic differences between the fynbos and wet meadow communities, an identical trade-off (i.e. specialization of species towards tolerance of aeration and/or drying stress) was found to cause segregation along fine-scale hydrological gradients. • This study not only confirms the predicted generality of hydrological niche segregation, but also emphasizes its importance for structuring plant communities. Eco-hydrological niche segregation will have implications for conservation in habitats that face changing hydrology caused by water abstraction and climate change.


Child to adult body mass index in the 1958 British birth cohort: associations with parental obesity.
To assess relations between the adiposity of children and their parents and to establish whether tracking of adiposity from childhood to adulthood varies according to the parental body mass index (BMI). Longitudinal data from the 1958 British birth cohort study were used (6540 men and 6207 women). The height and weight of the study subjects were measured at 7, 11, 16, 23 (self reported), and 33 years. Parental height and weight were self reported when their children were 11 years old. The children were classified into six parental BMI (weight/height2) groups. At each age of follow up the mean BMI of the children increased as the parental BMI increased. Higher risks of adult (33 year) obesity were evident among children with overweight or obese parents: the odds for sons and daughters with two obese parents (compared with those with both parents of normal BMI) were 8.4 and 6.8, respectively. The children of two obese parents also showed the strongest child to adult tracking of BMI as indicated by the correlation between ages 7 and 33 (r = 0.46, 0.54, sons and daughters, respectively). The children of obese and overweight parents have an increased risk of obesity. Subjects with two obese parents are fatter in childhood and also show a stronger pattern of tracking from childhood to adulthood. As the prevalence of parental obesity increases in the general population the extent of child to adult tracking of BMI is likely to strengthen.


A proteomic approach to mimic fibrosis disease evolvement by an in vitro cell line.
Subepithelial fibrosis in asthma involves an increase in the thickening of the lamina reticularis and is due to increased deposition of collagen I, III and V, and fibronectin. The cause of the thickening of the reticular layer is not known in detail, however, it is proposed to be caused by bronchial myofibroblasts. The transformation of fibroblasts to myofibroblasts may be contributed by inflammatory cytokines. In this paper we have studied and compared in vivo tissue material with a human fibroblast target cell. A normal primary fetal fibroblast cell line and HFL-1 (human fibroblast lurg cells) were used as a comparison between fibroblasts from human central biopsies regarding morphology and cell proliferation. Both cell morphology and cell proliferation rate was similar between the different set of cell cultures. Furthermore, it could be concluded that fibroblasts cultures from patients with asthma were surrounded by more extracellular matrix molecules compared to the primary cell line HFL-1, which may mimic the in vivo situation during formation of fibrosis. We wanted to investigate if differential protein display by two-dimensional (2-D) gel electrophoresis and subsequent protein identification by matrix assisted laser desorption/ionization-time of flight (MALDI-TOF)-mass spectrometry could reveal proteins induced by cytokine stimulation that can be correlated to the transformation of normal human fetal lungs cells into a more myofibroblast like phenotype. After stimulation with transforming growth factor-beta (TGF-beta) several myofibroblast markers were found to be regulated. Especially cytoskeletal and cytoskeletal-associated proteins like actin isoforms and tropomyosin, proteins that are responsible for contraction as well as transportation of extra cellular matrix proteins, which are overproduced in the formation of fibrosis. These results indicate that TGF-beta, which is increased in a fibrotic process, participates in the transformation of fibroblasts to myofibroblasts.


Hypertension as a Metabolic Disorder and the Novel Role of the Gut.
Hypertension is related to impaired metabolic homeostasis and can be regarded as a metabolic disorder. This review presents possible mechanisms by which metabolic disorders increase blood pressure (BP) and discusses the importance of the gut as a novel modulator of BP. Obesity and high salt intake are major risk factors for hypertension. There is a hypothesis of "salt-induced obesity"; i.e., high salt intake may tie to obesity. Heightened sympathetic nervous system (SNS) activity, especially in the kidney and brain, increases BP in obese patients. Adipokines, including adiponectin and leptin, and renin-angiotensin-aldosterone system (RAAS) contribute to hypertension. Adiponectin induced by a high-salt diet may decrease sodium/glucose cotransporter (SGLT) 2 expression in the kidney, which results in reducing BP. High salt can change secretions of adipokines and RAAS-related components. Evidence has been accumulating linking the gastrointestinal tract to BP. Glucagon-like peptide-1 (GLP-1) and ghrelin decrease BP in both rodents and humans. The sweet taste receptor in enteroendocrine cells increases SGLT1 expression and stimulates sodium/glucose absorption. Roux-en-Y gastric bypass improves glycemic and BP control due to reducing the activity of SGLT1. Na/H exchanger isoform 3 (NHE3) increases BP by stimulating the intestinal absorption of sodium. Gastrin functions as an intestinal sodium taste sensor and inhibits NHE3 activity. Intestinal mineralocorticoid receptors also regulate sodium absorption and BP due to changing ENaC activity. Gastric sensing of sodium induces natriuresis, and gastric distension increases BP. Changes in the composition and function of gut microbiota contribute to hypertension. A high-salt/fat diet may disrupt the gut barrier, which results in systemic inflammation, insulin resistance, and increased BP. Gut microbiota regulates BP by secreting vasoactive hormones and short-chain fatty acids. BP-lowering effects of probiotics and antibiotics have been reported. Bariatric surgery improves metabolic disorders and hypertension due to increasing GLP-1 secretion, decreasing leptin secretion and SNS activity, and changing gut microbiome composition. Strategies targeting the gastrointestinal system may be therapeutic options for improving metabolic abnormalities and reducing BP in humans. SNS, brain, adipocytes, RAAS, the kidney, the gastrointestinal tract, and microbiota play important roles in regulating BP. Most notably, the gut could be a novel target for treatment of hypertension as a metabolic disorder.


Mystery solved: the identification of the two missing Romanov children using DNA analysis.
One of the greatest mysteries for most of the twentieth century was the fate of the Romanov family, the last Russian monarchy. Following the abdication of Tsar Nicholas II, he and his wife, Alexandra, and their five children were eventually exiled to the city of Yekaterinburg. The family, along with four loyal members of their staff, was held captive by members of the Ural Soviet. According to historical reports, in the early morning hours of July 17, 1918 the entire family along with four loyal members of their staff was executed by a firing squad. After a failed attempt to dispose of the remains in an abandoned mine shaft, the bodies were transported to an open field only a few kilometers from the mine shaft. Nine members of the group were buried in one mass grave while two of the children were buried in a separate grave. With the official discovery of the larger mass grave in 1991, and subsequent DNA testing to confirm the identities of the Tsar, the Tsarina, and three of their daughters--doubt persisted that these remains were in fact those of the Romanov family. In the summer of 2007, a group of amateur archeologists discovered a collection of remains from the second grave approximately 70 meters from the larger grave. We report forensic DNA testing on the remains discovered in 2007 using mitochondrial DNA (mtDNA), autosomal STR, and Y-STR testing. Combined with additional DNA testing of material from the 1991 grave, we have virtually irrefutable evidence that the two individuals recovered from the 2007 grave are the two missing children of the Romanov family: the Tsarevich Alexei and one of his sisters.


Framing the doctor-patient relationship in chronic illness: a comparative study of general practitioners' accounts.
How family doctors conceptualise chronic illness in the consultation has important implications for both the delivery of medical care, and its experience by patients. In this paper, we present the results of a re-analysis of qualitative data collected in a series of studies of British family doctors between 1995 and 2001, to explore the ways in which the legitimacy and authority of medical knowledge and practice are organised and worked out in relation to three kinds of chronic illness (menorrhagia; depression; and chronic low back pain/medically unexplained symptoms). We present a comparative analysis of (a). the moral evaluation of the patient (and judgements about the legitimacy of symptom presentation); (b). the possibilities of disposal; and (c). doctors' empathic responses to the patient, in each of these clinical cases. Our analysis defines some of the fundamental conditions through which general practitioners frame their relationships with patients presenting complex but sometimes diffuse combinations of 'social', 'psychological' and 'medical' symptoms. These are fundamental to, yet barely touched by, the increasingly voluminous literature on how doctors should interact with patients. Moving beyond the individual studies from which our data are drawn, we have outlined some of the highly complex and demanding features of what is often seen as routine and unrewarding medical work, and some of the key requirements for the local negotiation of patients' problems and their meanings (for both patients and doctors) in everyday general practice.


Mild cognitive impairment: effect of education on the verbal and nonverbal tasks performance decline.
We sought to longitudinally evaluate the potential association of educational level with performance on verbal and nonverbal tasks in individuals with mild cognitive impairment (MCI). We evaluated patients with MCI, age >50 years, no medication intake, absent vascular risk factors, and no lesions on brain magnetic resonance imaging (MRI). Each patient underwent a clinical assessment packet and a series of neuropsychological tests of the language and constructional praxis subtests of Cambridge Cognitive Examination (CAMGOG) and the Boston naming test (BNT), at baseline, 6 months, and 12 months. Educational levels were defined taking into account the total years of education, the school level, and diplomas. MCI patients with low education level showed a stepwise reduction in scores of naming objects (NO; P = 0.009), definition (DF; P = 0.012), language (LT; P = 0.021), constructional praxis (CD; P = 0.022), confrontation naming skills (BXB; P = 0.033), phonemic help (BFB; P = 0.041), and BNT (P = 0.002). Analysis of covariance, controlling for baseline scores, showed that education was associated with NO score (P = 0.002), DF score (P = 0.005), LT (P = 0.008), CD score (P = 0.008), BXB score (44.36 ± 1.84, P = 0.0001), BFB (P = 0.022), and BNT (P = 0.004). Our findings indicate that education appeared to affect verbal and nonverbal task performance in MCI patients. Despite the fact that higher educated patients are more acquainted with the tasks, slower deterioration in consecutive follow-up examinations could be explained by the cognitive reserve theory. The potential association of this protective effect with delayed onset of symptoms deserves further investigation.


Perturbation of fetal hematopoiesis in a mouse model of Down syndrome's transient myeloproliferative disorder.
Children with Down syndrome develop a unique congenital clonal megakaryocytic proliferation disorder (transient myeloproliferative disorder [TMD]). It is caused by an expansion of fetal megakaryocyte-erythroid progenitors (MEPs) triggered by trisomy of chromosome 21 and is further enhanced by the somatic acquisition of a mutation in GATA1. These mutations result in the expression of a short-isoform GATA1s lacking the N-terminal domain. To examine the hypothesis that the Hsa21 ETS transcription factor ERG cooperates with GATA1s in this process, we generated double-transgenic mice expressing hERG and Gata1s. We show that increased expression of ERG by itself is sufficient to induce expansion of MEPs in fetal livers. Gata1s expression synergizes with ERG in enhancing the expansion of fetal MEPs and megakaryocytic precursors, resulting in hepatic fibrosis, transient postnatal thrombocytosis, anemia, a gene expression profile that is similar to that of human TMD and progression to progenitor myeloid leukemia by 3 months of age. This ERG/Gata1s transgenic mouse model also uncovers an essential role for the N terminus of Gata1 in erythropoiesis and the antagonistic role of ERG in fetal erythroid differentiation and survival. The human relevance of this finding is underscored by the recent discovery of similar mutations in GATA1 in patients with Diamond-Blackfan anemia.


Can race be erased? Coalitional computation and social categorization.
Previous studies have established that people encode the race of each individual they encounter, and do so via computational processes that appear to be both automatic and mandatory. If true, this conclusion would be important, because categorizing others by their race is a precondition for treating them differently according to race. Here we report experiments, using unobtrusive measures, showing that categorizing individuals by race is not inevitable, and supporting an alternative hypothesis: that encoding by race is instead a reversible byproduct of cognitive machinery that evolved to detect coalitional alliances. The results show that subjects encode coalitional affiliations as a normal part of person representation. More importantly, when cues of coalitional affiliation no longer track or correspond to race, subjects markedly reduce the extent to which they categorize others by race, and indeed may cease doing so entirely. Despite a lifetime's experience of race as a predictor of social alliance, less than 4 min of exposure to an alternate social world was enough to deflate the tendency to categorize by race. These results suggest that racism may be a volatile and eradicable construct that persists only so long as it is actively maintained through being linked to parallel systems of social alliance.


Evolutionary trade-offs between reproduction and dispersal in populations at expanding range boundaries.
During recent climate warming, some species have expanded their ranges northwards to keep track of climate changes. Evolutionary changes in dispersal have been demonstrated in these expanding populations and here we show that increased dispersal is associated with reduced investment in reproduction in populations of the speckled wood butterfly, Pararge aegeria. Evolutionary changes in flight versus reproduction will affect the pattern and rate of expansion at range boundaries in the future, and understanding these responses will be crucial for predicting the distribution of species in the future as climates continue to warm.


A rotational and axial motion system load frame insert for in situ high energy x-ray studies.
High energy x-ray characterization methods hold great potential for gaining insight into the behavior of materials and providing comparison datasets for the validation and development of mesoscale modeling tools. A suite of techniques have been developed by the x-ray community for characterizing the 3D structure and micromechanical state of polycrystalline materials; however, combining these techniques with in situ mechanical testing under well characterized and controlled boundary conditions has been challenging due to experimental design requirements, which demand new high-precision hardware as well as access to high-energy x-ray beamlines. We describe the design and performance of a load frame insert with a rotational and axial motion system that has been developed to meet these requirements. An example dataset from a deforming titanium alloy demonstrates the new capability.


BARD1 expression predicts outcome in colon cancer.
BARD1 is a BRCA1-binding partner with tumor suppressive properties. Aberrant splice variants of BARD1 have been detected in various cancers, and it has been postulated that the presence of some splice variants is cancer specific. This is the first study assessing BARD1 expression patterns and correlation with clinical outcome in colon cancer. We analyzed colon cancer samples for the occurrence of BARD1 splice variants, characterized novel BARD1 splice variants, and quantified the mRNA expression levels of these isoforms in primary colon cancers and their corresponding normal tissue. We tested the correlation of full-length BARD1 protein expression and clinical outcome in primary colon cancer samples. In addition to the full-length BARD1 mRNA, we now find 19 distinct BARD1 splice variants in colon cancer. Contrary to previous assumptions, these splice variants also occur in the adjacent normal colon tissue. Although BARD1 splice variants account for a considerable amount of BARD1 mRNA in both cancer and normal colon samples, distinct variants show a cancer-specific regulation pattern. Consistent with its role as tumor suppressor, we further find that the expression of the full-length BARD1 protein predicts outcome in colon cancer and that loss of full-length BARD1 protein is associated with a poor prognosis (P = 0.0002). Taken together, this is the first report to suggest that BARD1 regulation is an important pathway in colon cancer and that the BARD1 full-length protein may be a useful marker to improve risk stratification in colon cancer patients.


Towards understanding two-level-systems in amorphous solids: insights from quantum circuits.
Amorphous solids show surprisingly universal behaviour at low temperatures. The prevailing wisdom is that this can be explained by the existence of two-state defects within the material. The so-called standard tunneling model has become the established framework to explain these results, yet it still leaves the central question essentially unanswered-what are these two-level defects (TLS)? This question has recently taken on a new urgency with the rise of superconducting circuits in quantum computing, circuit quantum electrodynamics, magnetometry, electrometry and metrology. Superconducting circuits made from aluminium or niobium are fundamentally limited by losses due to TLS within the amorphous oxide layers encasing them. On the other hand, these circuits also provide a novel and effective method for studying the very defects which limit their operation. We can now go beyond ensemble measurements and probe individual defects-observing the quantum nature of their dynamics and studying their formation, their behaviour as a function of applied field, strain, temperature and other properties. This article reviews the plethora of recent experimental results in this area and discusses the various theoretical models which have been used to describe the observations. In doing so, it summarises the current approaches to solving this fundamentally important problem in solid-state physics.


Systems and Synthetic Biology of Forest Trees: A Bioengineering Paradigm for Woody Biomass Feedstocks.
Fast-growing forest plantations are sustainable feedstocks of plant biomass that can serve as alternatives to fossil carbon resources for materials, chemicals, and energy. Their ability to efficiently harvest light energy and carbon from the atmosphere and sequester this into metabolic precursors for lignocellulosic biopolymers and a wide range of plant specialized metabolites make them excellent biochemical production platforms and living biorefineries. Their large sizes have facilitated multi-omics analyses and systems modeling of key biological processes such as lignin biosynthesis in trees. High-throughput 'omics' approaches have also been applied in segregating tree populations where genetic variation creates abundant genetic perturbations of system components allowing construction of systems genetics models linking genes and pathways to complex trait variation. With this information in hand, it is now possible to start using synthetic biology and genome editing techniques in a bioengineering approach based on a deeper understanding and rational design of biological parts, devices, and integrated systems. However, the complexity of the biology and interacting components will require investment in big data informatics, machine learning, and intuitive visualization to fully explore multi-dimensional patterns and identify emergent properties of biological systems. Predictive systems models could be tested rapidly through high-throughput synthetic biology approaches and multigene editing. Such a bioengineering paradigm, together with accelerated genomic breeding, will be crucial for the development of a new generation of woody biorefinery crops.


Autophagy is essential for ultrafine particle-induced inflammation and mucus hyperproduction in airway epithelium.
Environmental ultrafine particulate matter (PM) is capable of inducing airway injury, while the detailed molecular mechanisms remain largely unclear. Here, we demonstrate pivotal roles of autophagy in regulation of inflammation and mucus hyperproduction induced by PM containing environmentally persistent free radicals in human bronchial epithelial (HBE) cells and in mouse airways. PM was endocytosed by HBE cells and simultaneously triggered autophagosomes, which then engulfed the invading particles to form amphisomes and subsequent autolysosomes. Genetic blockage of autophagy markedly reduced PM-induced expression of inflammatory cytokines, e.g. IL8 and IL6, and MUC5AC in HBE cells. Mice with impaired autophagy due to knockdown of autophagy-related gene Becn1 or Lc3b displayed significantly reduced airway inflammation and mucus hyperproduction in response to PM exposure in vivo. Interference of the autophagic flux by lysosomal inhibition resulted in accumulated autophagosomes/amphisomes, and intriguingly, this process significantly aggravated the IL8 production through NFKB1, and markedly attenuated MUC5AC expression via activator protein 1. These data indicate that autophagy is required for PM-induced airway epithelial injury, and that inhibition of autophagy exerts therapeutic benefits for PM-induced airway inflammation and mucus hyperproduction, although they are differentially orchestrated by the autophagic flux.


Inhibition of tumor angiogenesis by the matrix metalloproteinase-activated anthrax lethal toxin in an orthotopic model of anaplastic thyroid carcinoma.
Patients with anaplastic thyroid carcinoma (ATC) typically succumb to their disease months after diagnosis despite aggressive therapy. A large percentage of ATCs have been shown to harbor the V600E B-Raf point mutation, leading to the constitutive activation of the mitogen-activated protein kinase pathway. ATC invasion, metastasis, and angiogenesis are in part dependent on the gelatinase class of matrix metalloproteinases (MMP). The explicit targeting of these two tumor markers may provide a novel therapeutic strategy for the treatment of ATC. The MMP-activated anthrax lethal toxin (LeTx), a novel recombinant protein toxin combination, shows potent mitogen-activated protein kinase pathway inhibition in gelatinase-expressing V600E B-Raf tumor cells in vitro. However, preliminary in vivo studies showed that the MMP-activated LeTx also exhibited dramatic antitumor activity against xenografts that did not show significant antiproliferative responses to the LeTx in vitro. Here, we show that the MMP-activated LeTx inhibits orthotopic ATC xenograft progression in both toxin-sensitive and toxin-resistant ATC cells via reduced endothelial cell recruitment and subsequent tumor vascularization. This in turn translates to an improved long-term survival that is comparable with that produced by the multikinase inhibitor sorafenib. Our results also indicate that therapy with the MMP-activated LeTx is extremely effective against advanced tumors with well-established vascular networks. Taken together, these results suggest that the MMP-activated LeTx-mediated endothelial cell targeting is the primary in vivo antitumor mechanism of this novel toxin. Therefore, the MMP-activated LeTx could be used not only in the clinical management of V600E B-Raf ATC but potentially in any solid tumor.


A targeted spatial-temporal proteomics approach implicates multiple cellular trafficking pathways in human cytomegalovirus virion maturation.
The assembly of infectious virus particles is a complex event. For human cytomegalovirus (HCMV) this process requires the coordinated expression and localization of at least 60 viral proteins that comprise the infectious virion. To gain insight into the mechanisms controlling this process, we identified protein binding partners for two viral proteins, pUL99 (also termed pp28) and pUL32 (pp150), which are essential for HCMV virion assembly. We utilized HCMV strains expressing pUL99 or pUL32 carboxyl-terminal green fluorescent protein fusion proteins from their native location in the HCMV genome. Based on the presence of ubiquitin in the pUL99 immunoisolation, we discovered that this viral protein colocalizes with components of the cellular endosomal sorting complex required for transport (ESCRT) pathway during the initial stages of virion assembly. We identified the nucleocapsid and a large number of tegument proteins as pUL32 binding partners, suggesting that events controlling trafficking of this viral protein in the cytoplasm regulate nucleocapsid/tegument maturation. The finding that pUL32, but not pUL99, associates with clathrin led to the discovery that the two viral proteins traffic via distinct pathways during the early stages of virion assembly. Additional investigation revealed that the majority of the major viral glycoprotein gB initially resides in a third compartment. Analysis of the trafficking of these three viral proteins throughout a time course of virion assembly allowed us to visualize their merger into a single large cytoplasmic structure during the late stages of viral assembly. We propose a model of HCMV virion maturation in which multiple components of the virion traffic independently of one another before merging.


TRIP6 regulates p27 KIP1 to promote tumorigenesis.
TRIP6 is an adaptor protein that regulates cell motility and antiapoptotic signaling. Although it has been implicated in tumorigenesis, the underlying mechanism remains largely unknown. Here we provide evidence that TRIP6 promotes tumorigenesis by serving as a bridge to promote the recruitment of p27(KIP1) to AKT in the cytosol. TRIP6 regulates the membrane translocation and activation of AKT and facilitates AKT-mediated recognition and phosphorylation of p27(KIP1) specifically at T157, thereby promoting the cytosolic mislocalization of p27(KIP1). This is required for p27(KIP1) to enhance lysophosphatidic acid (LPA)-induced ovarian cancer cell migration. TRIP6 also promotes serum-induced reduction of nuclear p27(KIP1) expression levels through Skp2-dependent and -independent mechanisms. Consequently, knockdown of TRIP6 in glioblastoma or ovarian cancer xenografts restores nuclear p27(KIP1) expression and impairs tumor proliferation. As TRIP6 is upregulated in gliomas and its levels correlate with poor clinical outcomes in a dose-dependent manner, it may represent a novel prognostic marker and therapeutic target in gliomas.


Origin of biochemical organization.
The problems of the origin of life and biochemical evolution are analyzed in the context of the biochemical organization concept proposed earlier by the authors. The traditional view according to which the evolution of biological systems occurred from lower levels to systems of higher levels is criticized. It is suggested that the formation of the cell and biological systems of lower levels (subcellular structures, supramolecular structures, biomacromolecules) occurred in a coordinated manner. The liposome and inorganic hypotheses of the origin of life are discussed. Regosome model based on ideas of Nussinov and Mekler which combines advantages of the liposome and inorganic hypotheses has been adopted and modernized. It is suggested that the initial metabolism of protocells based itself on C2-C3-compounds. Autodevelopment of catalytic systems of protocells is discussed.


Localization of the gene encoding the human interleukin-2 receptor on chromosome 10.
The human interleukin-2 receptor is an inducible growth factor receptor present on the surface of activated T lymphocytes. The receptor is required for a normal T-cell immune response. High-resolution fluorescence-activated chromosome sorting and DNA spot-blot analysis with complementary DNA's for the interleukin-2 receptor indicated that the receptor gene was located on chromosome 9, 10, 11, or 12. In situ hybridization studies showed that the interleukin-2 receptor gene is on the short arm of chromosome 10, p14----15.


Sex and ethnic differences in 47 candidate proteomic markers of cardiovascular disease: the Mayo Clinic proteomic markers of arteriosclerosis study.
Cardiovascular disease (CVD) susceptibility differs between men and women and varies with ethnicity. This variability is not entirely explained by conventional CVD risk factors. We examined differences in circulating levels of 47 novel protein markers of CVD in 2561 men and women of African-American (AA) and non-Hispanic White (NHW) ethnicity, enrolled at geographically distinct sites. Participants (1,324 AAs, mean age 63.5 y, 71% women; 1,237 NHWs, mean age 58.9 y, 57% women) belonged to sibships ascertained on the basis of hypertension. Solid-phase immunoassays and immunoturbidometric, clot-based, chromogenic, and electrophoretic assays were used to measure the 47 protein markers in plasma or serum. Marker levels were log transformed and outliers were adjusted to within 4 SD. To identify markers independently associated with sex or ethnicity, we employed multivariable regression analyses that adjusted for conventional risk factors, prior history of CVD, medication use and lifestyle factors (physical activity, alcohol consumption and education). Generalized estimating equations were used to correct for intrafamilial correlations. After adjustment for the above covariates, female sex was associated with higher levels of 29 markers and lower levels of 6 markers. Female sex was independently associated with higher levels of several inflammatory markers as well as lipoproteins, adipokines, natriuretic peptides, vasoconstrictor peptides and markers of calcification and thrombosis. AA ethnicity was associated with higher levels of 19 markers and lower levels of 6 markers, including higher levels of several inflammatory makers, higher leptin and lower adiponectin levels, lower levels of vasodilator-natriuretic peptides, higher levels of vasoconstrictor-antidiuretic peptides and markers of calcification and thrombosis. Plasma levels of several novel protein markers of CVD differ significantly in the context of sex and ethnicity. These results have implications for individualized CVD risk assessment.


Field-scale variation in microbial activity and soil properties in relation to mineralization and sorption of pesticides in a sandy soil.
Pesticides applied to agricultural soils are subject to environmental concerns because leaching to groundwater reservoirs and aquatic habitats may occur. Knowledge of field variation of pesticide-related parameters is required to evaluate the vulnerability of pesticide leaching. The mineralization and sorption of the pesticides glyphosate and metribuzin and the pesticide degradation product triazinamin in a field were measured and compared with the field-scale variation of geochemical and microbiological parameters. We focused on the soil parameters clay and organic carbon (C) content and on soil respiratory and enzymatic processes and microbial biomass. These parameters were measured in soil samples taken at two depths (Ap and Bs horizon) in 51 sampling points from a 4-ha agricultural fine sandy soil field. The results indicated that the spatial variation of the soil parameters, and in particular the content of organic C, had a major influence on the variability of the microbial parameters and on sorption and pesticide mineralization in the soil. For glyphosate, with a co-metabolic pathway for degradation, the mineralization was increased in soils with high microbial activity. The spatial variability, expressed as the CV, was about five times higher in the Bs horizon than in the Ap horizon, and the local-scale variation within 100 m(2) areas were two to three times lower than the field-scale variation within the entire field of about 4 ha.


Fluoride Exposure Induces Inhibition of Sodium-and Potassium-Activated Adenosine Triphosphatase (Na+, K+-ATPase) Enzyme Activity: Molecular Mechanisms and Implications for Public Health.
In this study, several lines of evidence are provided to show that Na + , K + -ATPase activity exerts vital roles in normal brain development and function and that loss of enzyme activity is implicated in neurodevelopmental, neuropsychiatric and neurodegenerative disorders, as well as increased risk of cancer, metabolic, pulmonary and cardiovascular disease. Evidence is presented to show that fluoride (F) inhibits Na + , K + -ATPase activity by altering biological pathways through modifying the expression of genes and the activity of glycolytic enzymes, metalloenzymes, hormones, proteins, neuropeptides and cytokines, as well as biological interface interactions that rely on the bioavailability of chemical elements magnesium and manganese to modulate ATP and Na + , K + -ATPase enzyme activity. Taken together, the findings of this study provide unprecedented insights into the molecular mechanisms and biological pathways by which F inhibits Na + , K + -ATPase activity and contributes to the etiology and pathophysiology of diseases associated with impairment of this essential enzyme. Moreover, the findings of this study further suggest that there are windows of susceptibility over the life course where chronic F exposure in pregnancy and early infancy may impair Na + , K + -ATPase activity with both short- and long-term implications for disease and inequalities in health. These findings would warrant considerable attention and potential intervention, not to mention additional research on the potential effects of F intake in contributing to chronic disease.


The use of and obstacles to social learning in climate change adaptation initiatives in South Africa.
Global environmental change will have major impacts on ecosystems and human livelihoods while challenging the adaptive capacity of individuals and communities. Social learning, an ongoing adaptive process of knowledge generation, reflection and synthesis, may enhance people's awareness about climate change and its impacts, with positive outcomes for their adaptive capacity. The objectives of this study were to assess the prevalence of factors promoting social learning in climate change adaptation initiatives in South Africa. An online survey was used to obtain the views of decision makers in government and non-governmental organisations about the presence of personal factors and organisational factors that promote social learning. Descriptive analysis was used to assess these issues. The findings provide some evidence of social learning in climate change adaptation projects in South Africa, with the majority of respondents indicating that personal social learning indicators were present. Mechanisms for improved conflict resolution were, however, less prevalent. The organisational and governance-related barriers to implementation also presented significant challenges. Some of the main organisational barriers were short timeframes for implementing projects, inadequate financial resources, political interference, shortcomings in governance systems and lack of knowledge and expertise in organisations. There is a need for organisations to promote social learning by ensuring that their organisational environment and governance structures are conducive for their employees to embrace social learning. This will help contribute to the overall success of climate change adaptation initiatives.


Clinical and video-assisted examination of the vestibulo-ocular reflex: a comparative study.
The assessment of the vestibulo-ocular reflex (VOR) is one of the main steps in clinically evaluating patients with dizziness. It can be performed at the bedside with common head-impulse test in which eye position is analysed at the end of the head-thrust. It is an important test due to its high specificity but low sensitivity. We studied 179 patients with different types of balance- affecting disorders. The results were analysed in contingency tables. The clinical test was classified as normal or abnormal according to the absence or existence, respectively, of fixation saccades once the head-thrust was ended. The video head-impulse test (vHIT) was classified according to vestibulo-ocular reflex (VOR) gain and presence of fixation saccades. The speed of the slow phase of spontaneous nystagmus was also quantified, as well as the caloric test results. There were significant differences (Chi-square test, P=0.00) for the findings in the clinical evaluation and with the vHIT: 32.1% of the tests performed yielded different findings in both tests. In the vHIT, the differences were due to the finding of normal gain with saccades; in these patients, the mean canal paresis was significantly abnormal: 39% ± 10%. The distribution of findings for the VOR bedside examination and for that with the help of a video system are significantly different; as such, the video head-impulse examination is not simply an added VOR detection and registration system. The difference relies mainly on a vHIT response characterised as of normal gain but with fixation saccades. These have been considered as the cause for the low sensitivity of the bedside VOR examination and sometimes regarded as normal responses; we have demonstrated that these findings are abnormal according to the findings of higher canal paresis in the caloric test.


The effect of real-time teleconsultations between hospital-based nurses and patients with severe COPD discharged after an exacerbation.
We investigated the effect of daily real-time teleconsultations for one week between hospital-based nurses specialised in respiratory diseases and patients with severe COPD discharged after acute exacerbation. Patients admitted with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) at two hospitals were recruited at hospital discharge. They were randomly assigned to intervention or control. The telemedicine equipment consisted of a briefcase with built-in computer including a web camera, microphone and measurement equipment. The primary outcome was the mean number of total hospital readmissions within 26 weeks of discharge. A total of 266 patients (mean age 72 years) were allocated to either intervention (n = 132) or control (n = 134). There was no significant difference in the unconditional total mean number of hospital readmissions after 26 weeks: mean 1.4 (SD 2.1) in the intervention group and 1.6 (SD 2.4) in the control group. In a secondary analysis, there was no significant difference between the two groups in mortality, time to readmission, mean number of total hospital readmissions, mean number of readmissions with AECOPD, mean number of total hospital readmission days or mean number of readmission days with AECOPD calculated at 4, 8, 12 and 26 weeks. Thus the addition of one week of teleconsultations between hospital-based nurses and patients with severe COPD discharged after hospitalisation did not significantly reduce readmissions or affect mortality.


HE4 (WFDC2) Promotes Tumor Growth in Endometrial Cancer Cell Lines.
HE4, also known as WFDC2, is a useful biomarker for ovarian cancer when either used alone or in combination with CA125. HE4 is also overexpressed in endometrial cancer (EC), but its function in cancer cells is not clear. In this study, we investigate the role of HE4 in EC progression. An HE4-overexpression system was established by cloning the HE4 prototypic mRNA variant (HE4-V0) into a eukaryotic expression vector. Following transfection, stable clones in two EC cell lines were selected. The effects of HE4 overexpression on cell growth and function were measured with the use of cell proliferation assay, matrigel invasion, and soft agar gel colony formation assays. HE4-induced cancer cell proliferation in vivo was examined in a mouse xenograft model. HE4 overexpression significantly enhanced EC cell proliferation, matrigel invasion, and colony formation in soft agar. Moreover, HE4 overexpression promoted tumor growth in the mouse xenograft model. HE4 overexpression enhanced several malignant phenotypes in cell culture and in a mouse model. These results are consistent with our previous observation that high levels of serum HE4 closely correlate with the stage, myometrial invasion and tumor size in patients with EC. This study provides evidence that HE4 overexpression directly impacts tumor progression in endometrial cancer.


Prior-entry: a review.
The law of prior entry was one of E.B. Titchener's seven fundamental laws of attention. According to Titchener (1908, p. 251): "the object of attention comes to consciousness more quickly than the objects which we are not attending to." Although researchers have been studying prior entry for more than a century now, progress in understanding the effect has been hindered by the many methodological confounds present in early research. As a consequence, it is unclear whether the behavioral effects reported in the majority of published studies in this area should be attributed to attention, decisional response biases, and/or, in the case of exogenous spatial cuing studies of the prior-entry effect, to sensory facilitation effects instead. In this article, the literature on the prior-entry effect is reviewed, the confounds present in previous research highlighted, current consensus summarized, and some of the key questions for future research outlined. In particular, recent research has now provided compelling psychophysical and electrophysiological evidence to support the claim that attending to a sensory modality, spatial location, or stimulus feature/attribute can all give rise to a relative speeding-up of the time of arrival of attended, as compared to relatively less attended (or unattended) stimuli. Prior-entry effects have now been demonstrated following both the endogenous and exogenous orienting of attention, though prior-entry effects tend to be smaller in magnitude when assessed by means of participants' performance on SJ tasks than when assessed by means of their performance on TOJ tasks.


Knowledge, attitudes, and practices related to salt consumption in Nepal: Findings from the community-based management of non-communicable diseases project in Nepal (COBIN).
High salt/sodium intake is associated with an increased risk of hypertension, which is a major risk factor for cardiovascular diseases. This paper aims to examine the association between salt consumption and salt-related knowledge, attitudes, and practices (KAP) in Nepal. The cross-sectional data used in this study were collected as part of the community-based management of non-communicable diseases project (COBIN) to understand the amount and KAP related to salt consumption in Nepal. Multivariate hierarchical logistic regression was performed to assess the association of salt-related KAP and determinants of high salt consumption in Nepal. The mean per capita salt intake was 8.0 (±3.7) g/day, with 81.6% of the population reporting higher intake than the WHO recommendation of <5 g/day. People of upper castes [adjusted odds ratio (aOR) = 0.7; 95% confidence interval (CI): 0.5-0.9], people in large families (aOR = 0.6; 95% CI: 0.5-0.7), respondents who were advised to lower salt intake (aOR = 0.6; 95% CI: 0.4-0.9) and who checked salt/sodium labels in food (aOR = 0.6; 95% CI: 0.4-0.9) were less likely to consume higher amounts of salt. Similarly, people who added extra salt to their food at the table (aOR = 1.4; 95 CI: 1.1-1.9) and who reported consuming high amounts of salt (aOR = 1.5; 95% CI: 1.1-2.3) were more likely to have high salt intake. High salt intake was documented in this population. This study suggests the need for culturally tailored community-based behavior modification through health education and dietary counseling to effectively reduce salt consumption and thereby support a reduction in hypertension and cardiovascular diseases in Nepal.


Effect of water on the molecular mobility of elastin.
Purified and hydrated elastin is studied by both thermal and dielectric techniques to have insight into the chain dynamics of this protein. By differential scanning calorimetry, the glassy behavior of elastin is highlighted; the glass transition temperature (T(g)) of elastin is found to be widely dependent on hydration, falling from 200 degrees C in the dehydrated state to 30 degrees C for 30% hydration. A limit of T(g) at around 0 degrees C is found when crystallizable water is present in the system, that is, when the formation of ice prevents motions of some 10 nm along the polypeptidic chains. The technique of thermally stimulated currents, carried out in the -180 to 0 degrees C temperature range, is useful to detect localized motions. In this case, too, the localized motions vary considerably according to hydration: a first relaxation mode is observed at -145 degrees C and it is associated with the reorientation of crystallizable water in ice I; a second relaxation mode, more complex and cooperative, occurs at around -80 degrees C and could be attributed to the complex constituted by the dipolar groups of the polypeptidic chain and noncrystallizable water, behaving as a glassy system.


Measurement of bone lengthening forces; an experimental model in the lamb.
OBJECTIVE: To obtain the mechanical behaviour pattern of the lengthening process. DESIGN. IN VIVO: measurement of forces during bone lengthening in lambs. BACKGROUND: A series of parameters of a mechanical and biological nature have a bearing on all lengthening processes, and most of them are not fully understood. METHODS: A strain-gauge-monitored unilateral fixator was designed and used to obtain data about the changes which took place in the forces of elongation at a rate of 1 mm/day in four lambs while a 3 cm progressive lengthening of the left tibia was being performed, analysing how these forces behaved from day to day, and how they changed in the course of a single day. RESULTS: The maximum forces in all the animals each day occur after distraction, and the forces reach their greatest magnitude between days 21 and 25 after surgery, attaining values of slightly over 8 kg (40-50% of the animal's weight). The maximum daily force starts to drop 1 h after distraction, and continues to decrease gradually throughout the day until it reaches a value slightly greater than the initial force on the previous day. CONCLUSION: This pattern is due to the distraction of soft tissues which gradually adapt to their new situation, thereby reducing the level of stress. RELEVANCE: In the daily bone lengthening procedure, the greatest forces are produced in a short period of time immediately after lengthening. they could be reduced to decrease pain in the patient and loads on the device by performing lengthening over a greater number of steps or using dynamic equipment able to absorb these forces.


Increased sensitivity to chemotherapy induced by CpG-ODN treatment is mediated by microRNA modulation.
We recently reported that peritumoral CpG-ODN treatment, activating TLR-9 expressing cells in tumor microenvironment, induces modulation of genes involved in DNA repair and sensitizes cancer cells to DNA-damaging cisplatin treatment. Here, we investigated whether this treatment induces modulation of miRNAs in tumor cells and their relevance to chemotherapy response. Array analysis identified 20 differentially expressed miRNAs in human IGROV-1 ovarian tumor cells from CpG-ODN-treated mice versus controls (16 down- and 4 up-regulated). Evaluation of the role of the 3 most differentially expressed miRNAs on sensitivity to cisplatin of IGROV-1 cells revealed significantly increased cisplatin cytotoxicity upon ectopic expression of hsa-miR-302b (up-modulated in our array), but no increased effect upon reduced expression of hsa-miR-424 or hsa-miR-340 (down-modulated in our array). Accordingly, hsa-miR-302b expression was significantly associated with time to relapse or overall survival in two data sets of platinum-treated ovarian cancer patients. Use of bio-informatics tools identified 19 mRNAs potentially targeted by hsa-miR-302b, including HDAC4 gene, which has been reported to mediate cisplatin sensitivity in ovarian cancer. Both HDAC4 mRNA and protein levels were significantly reduced in IGROV-1 cells overexpressing hsa-miR-302b. Altogether, these findings indicate that hsa-miR-302b acts as a "chemosensitizer" in human ovarian carcinoma cells and may represent a biomarker able to predict response to cisplatin treatment. Moreover, the identification of miRNAs that improve sensitivity to chemotherapy provides the experimental underpinning for their possible future clinical use.


Global impact of oncogenic Src on a phosphotyrosine proteome.
Elevated activity of Src, the first characterized protein-tyrosine kinase, is associated with progression of many human cancers, and Src has attracted interest as a therapeutic target. Src is known to act in various receptor signaling systems to impact cell behavior, yet it remains likely that the spectrum of Src protein substrates relevant to cancer is incompletely understood. To better understand the cellular impact of deregulated Src kinase activity, we extensively applied a mass spectrometry shotgun phosphotyrosine (pTyr) proteomics strategy to obtain global pTyr profiles of Src-transformed mouse fibroblasts as well as their nontransformed counterparts. A total of 867 peptides representing 563 distinct pTyr sites on 374 different proteins were identified from the Src-transformed cells, while 514 peptides representing 275 pTyr sites on 167 proteins were identified from nontransformed cells. Distinct characteristics of the two profiles were revealed by spectral counting, indicative of pTyr site relative abundance, and by complementary quantitative analysis using stable isotope labeling with amino acids in cell culture (SILAC). While both pTyr profiles are replete with sites on signaling and adhesion/cytoskeletal regulatory proteins, the Src-transformed profile is more diverse with enrichment in sites on metabolic enzymes and RNA and protein synthesis and processing machinery. Forty-three pTyr sites (32 proteins) are predicted as major biologically relevant Src targets on the basis of frequent identification in both cell populations. This select group, of particular interest as diagnostic biomarkers, includes well-established Src sites on signaling/adhesion/cytoskeletal proteins, but also uncharacterized sites of potential relevance to the transformed cell phenotype.


The possible role of sphincteroplasty and surgical sphincterotomy in the pathogenesis of recurrent common duct brown stones.
The hypothesis has been tested that postcholecystectomy common duct stones of the brown subtype are a consequence of three factors: bile infection, old age and previous sphincterotomy. It was found that: (i) 27 of 39 consecutive patients with recurrent common duct stones had brown stones. Nineteen of these 27 patients (70.3%) had previous sphincterotomy or sphincteroplasty: (ii) six of 15 patients with stone and bile analysis both at the time of cholecystectomy and at the second operation and who had sterile operative bile and non brown stones at the first operation, formed brown stones after T-tube drainage and after the onset of bile infection; (iii) patients with both intra and postoperative negative bile culture (n = 39 out of 137) had a lower mean age (50.5 years) and less frequently had a sphincterotomy than did individuals with a negative culture at operation, who subsequently had bile infection (n = 37; mean age 58.5 years; sphincterotomy in 88.8% of cases). In addition, in a follow up study of 105 patients with sphincterotomy and with sphincteroplasty (including ERCP or i.v. cholangiography in all cases), mean follow-up interval 6.1 years, 11.3% of patients had brown recurrent common duct stones. It is suggested that, since brown recurrent common duct stones are secondary to bile stasis and infection and the duodenum is going to be colonized by bacteria with increasing age, sphincterotomy (and subsequent stricture), facilitating bile contamination and bacterial overgrowth, could be one of the major determinants of brown recurrent common duct stones (RCS) formation. In particular, more than 11% of the patients with a sphincterotomy are going to form in the future RCS of the brown subtype.


CJCheck Stage 1: development and testing of a checklist for reporting community juries - Delphi process and analysis of studies published in 1996-2015.
Opportunities for community members to actively participate in policy development are increasing. Community/citizen's juries (CJs) are a deliberative democratic process aimed to illicit informed community perspectives on difficult topics. But how comprehensive these processes are reported in peer-reviewed literature is unknown. Adequate reporting of methodology enables others to judge process quality, compare outcomes, facilitate critical reflection and potentially repeat a process. We aimed to identify important elements for reporting CJs, to develop an initial checklist and to review published health and health policy CJs to examine reporting standards. Using the literature and expertise from CJ researchers and policy advisors, a list of important CJ reporting items was suggested and further refined. We then reviewed published CJs within the health literature and used the checklist to assess the comprehensiveness of reporting. CJCheck was developed and examined reporting of CJ planning, juror information, procedures and scheduling. We screened 1711 studies and extracted data from 38. No studies fully reported the checklist items. The item most consistently reported was juror numbers (92%, 35/38), while least reported was the availability of expert presentations (5%, 2/38). Recruitment strategies were described in 66% of studies (25/38); however, the frequency and timing of deliberations was inadequately described (29%, 11/38). Currently CJ publications in health and health policy literature are inadequately reported, hampering their use in policy making. We propose broadening the CJCheck by creating a reporting standards template in collaboration with international CJ researchers, policy advisors and consumer representatives to ensure standardized, systematic and transparent reporting.


Simultaneous rate-synchrony codes in populations of spiking neurons.
Firing rates and synchronous firing are often simultaneously relevant signals, and they independently or cooperatively represent external sensory inputs, cognitive events, and environmental situations such as body position. However, how rates and synchrony comodulate and which aspects of inputs are effectively encoded, particularly in the presence of dynamical inputs, are unanswered questions. We examine theoretically how mixed information in dynamic mean input and noise input is represented by dynamic population firing rates and synchrony. In a subthreshold regime, amplitudes of spatially uncorrelated noise are encoded up to a fairly high input frequency, but this requires both rate and synchrony output channels. In a suprathreshold regime, means and common noise amplitudes can be simultaneously and separately encoded by rates and synchrony, respectively, but the input frequency for which this is possible has a lower limit.


The antiproliferative effect of pinostrobin on human umbilical vein endothelial cells (HUVEC).
Atherosclerosis and stent re-stenosis are problems that are accompanied with high morbidity and mortality. Endothelial cell proliferation plays a role in both diseases, so the quest for potent inhibitors is still ongoing. The flavonoid pinostrobin previously showed cytotoxic effects on different cell lines. In this investigation, we tested the antiproliferative effect of pinostrobin on human umbilical vein endothelial cells (HUVEC). The effect of pinostrobin on human umbilical vein endothelial cells after 1 hour and after 48 hours of treatment was tested. A dose- and time-dependent antiproliferative effect of pinostrobin was observed. After 1 hour of treatment, no significant differences between the control group and the cells treated with pinostrobin could be detected. After 48 h of pinostrobin treatment, the number of cells decreased significantly. Higher doses had stronger inhibitory effects on the proliferation. Furthermore, we tested the change of membrane potential on cells that were treated with different concentrations of pinostrobin. We could show that the change of membrane potential was also time- as well as dose-dependent. Our hypothesis is that pinostrobin leads to depolarisation of the cell potential of endothelial cells. Since the membrane potential remains less negative, this could lead to instability of the membrane, resulting in cell death.


Discussions by elders and adult children about end-of-life preparation and preferences.
In the United States, 73% of deaths occur among people aged 65 years or older. Although most would prefer to die at home after a short illness, most actually die in institutions after prolonged declines. Despite this discrepancy, elders and their adult children often do not discuss end-of-life preferences. Use of advance directives has not been widespread, and people often avoid the subject until a crisis. This project focused on informal family communication about end-of-life preparation and preferences, about which little is known. In May 2006, we conducted in-depth exploratory interviews with 15 older adults about their end-of-life preparation and preferences and with 15 younger adults about their parents' end-of-life preparation and preferences. The interview included an item rating the depth of discussion. Participants in both groups were primarily female and white. Mean age of older adults was 78.6 years (range, 70-88 years). Mean age of younger adults was 53.1 years (range, 42-63 years); mean age of their parents was 82.6 years (range, 68-99 years). Nine older adults reported discussing end-of-life preparation and preferences with their adult children; six had barely discussed the topic at all. Ten younger adults reported having talked with their parents about end-of-life preparation and preferences; five had not discussed it. Barriers to discussions about end-of-life preparation and preferences were fear of death, trust in others to make decisions, family dynamics, and uncertainty about preferences. Facilitators for discussion were acceptance of the reality of death, prior experience with death, religion or spirituality, and a desire to help the family. Successful strategies included casually approaching the topic and writing down end-of-life preparation and preferences. Knowing the obstacles to and facilitators for discussion can help health care and public health professionals target approaches to encouraging elders and their families to discuss end-of-life preparation and preferences before a crisis.


Phytoestrogen consumption and breast cancer risk in a multiethnic population: the Bay Area Breast Cancer Study.
Research on the relation between phytoestrogens and breast cancer risk has been limited in scope. Most epidemiologic studies have involved Asian women and have examined the effects of traditional soy foods (e.g., tofu), soy protein, or urinary excretion of phytoestrogens. The present study extends this research by examining the effects of a spectrum of phytoestrogenic compounds on breast cancer risk in non-Asian US women. African-American, Latina, and White women aged 35-79 years, who were diagnosed with breast cancer between 1995 and 1998, were compared with women selected from the general population via random digit dialing. Interviews were conducted with 1,326 cases and 1,657 controls. Usual intake of specific phytoestrogenic compounds was assessed via a food frequency questionnaire and a newly developed nutrient database. Phytoestrogen intake was not associated with breast cancer risk (odds ratio = 1.0, 95% confidence interval: 0.80, 1.3 for the highest vs. lowest quartile). Results were similar for pre- and postmenopausal women, for women in each ethnic group, and for all seven phytoestrogenic compounds studied. Phytoestrogens appear to have little effect on breast cancer risk at the levels commonly consumed by non-Asian US women: an average intake equivalent to less than one serving of tofu per week.


Serotonin transporter polyadenylation polymorphism modulates the retention of fear extinction memory.
Growing evidence suggests serotonin's role in anxiety and depression is mediated by its effects on learned fear associations. Pharmacological and genetic manipulations of serotonin signaling in mice alter the retention of fear extinction learning, which is inversely associated with anxious temperament in mice and humans. Here, we test whether genetic variation in serotonin signaling in the form of a common human serotonin transporter polyadenylation polymorphism (STPP/rs3813034) is associated with spontaneous fear recovery after extinction. We show that the risk allele of this polymorphism is associated with impaired retention of fear extinction memory and heightened anxiety and depressive symptoms. These STPP associations in humans mirror the phenotypic effects of serotonin transporter knockout in mice, highlighting the STPP as a potential genetic locus underlying interindividual differences in serotonin transporter function in humans. Furthermore, we show that the serotonin transporter polyadenylation profile associated with the STPP risk allele is altered through the chronic administration of fluoxetine, a treatment that also facilitates retention of extinction learning. The propensity to form persistent fear associations due to poor extinction recall may be an intermediate phenotype mediating the effects of genetic variation in serotonergic function on anxiety and depression. The consistency and specificity of these data across species provide robust support for this hypothesis and suggest that the little-studied STPP may be an important risk factor for mood and anxiety disorders in humans.


Bacteria and tumours: causative agents or opportunistic inhabitants?
Associations between different bacteria and various tumours have been reported in patients for decades. Studies involving characterisation of bacteria within tumour tissues have traditionally been in the context of tumourigenesis as a result of bacterial presence within healthy tissues, and in general, dogma holds that such bacteria are causative agents of malignancy (directly or indirectly). While evidence suggests that this may be the case for certain tumour types and bacterial species, it is plausible that in many cases, clinical observations of bacteria within tumours arise from spontaneous infection of established tumours. Indeed, growth of bacteria specifically within tumours following deliberate systemic administration has been demonstrated for numerous bacterial species at preclinical and clinical levels. We present the available data on links between bacteria and tumours, and propose that besides the few instances in which pathogens are playing a pathogenic role in cancer, in many instances, the prevalent relationship between solid tumours and bacteria is opportunistic rather than causative, and discuss opportunities for exploiting tumour-specific bacterial growth for cancer treatment.


Health behaviour change of people living with HIV after a comprehensive community-based HIV stigma reduction intervention in North-West Province in South Africa.
Abstract All over the world, health behaviour is considered a complex, far reaching and powerful phenomenon. People's lives are influenced by their own or others' health behaviour on a daily basis. Whether it has to do with smoking, drinking, pollution, global warming or HIV management, it touches lives and it challenges personal and community responses. Health behaviour, and health behaviour change, probably holds the key to many a person's immediate or prolonged life or death outcomes. The same can be said about communities, culture groups and nations. This SANPAD-funded study focused on research questions relating to health behaviour change for people living with HIV (PLWH) in the North-West Province in South Africa. It investigated whether a comprehensive community-based HIV stigma reduction intervention caused health behaviour change in PLWH. An quantitative single system research design with one pre- and four repetitive post-tests utilizing purposive sampling was used to test change-over-time in the health behaviour of 18 PLWH. The results of the study indicated statistical and/or practical significant change-over-time. The intervention not only addressed the health behaviour of PLWH, but also their HIV stigma experiences, HIV signs and symptoms and their quality of life in the context of being HIV positive. The recommendations include popularization of the comprehensive community-based HIV stigma reduction intervention and extending it to include a second intervention to strengthen health behaviour and quality of life for PLWH in the community at large.


Direct observation of multimer stabilization in the mechanical unfolding pathway of a protein undergoing oligomerization.
Understanding how protein oligomerization affects the stability of monomers in self-assembled structures is crucial to the development of new protein-based nanomaterials and protein cages for drug delivery. Here, we use single-molecule force spectroscopy (AFM-SMFS), protein engineering, and computer simulations to evaluate how dimerization and tetramerization affects the stability of the monomer of Streptavidin, a model homotetrameric protein. The unfolding force directly relates to the folding stability, and we find that monomer of Streptavidin is mechanically stabilized by 40% upon dimerization, and that it is stabilized an additional 24% upon tetramerization. We also find that biotin binding increases stability by another 50% as compared to the apo-tetrameric form. We used the distribution of unfolding forces to extract properties of the underlying energy landscape and found that the distance to the transition state is decreased and the barrier height is increased upon multimerization. Finally, we investigated the origin of the strengthening by ligand binding. We found that, rather than being strengthened through intramolecular contacts, it is strengthened due to the contacts provided by the biotin-binding loop that crosses the interface between the dimers.


SU-E-J-78: Enhance Patient Positioning Accuracy with Optically Guided Frameless Target Localization Technique for Intracranial Radiation Therapy.
To make use of the optical guided frameless stereotactic target localization technique to detect the interfraction and intrafraction patient positioning errors and correct the patient position for fractional intracranial therapy, therefore, to enhance the patient positioning accuracy. Four patients who underwent fractionated intracranial intensity modulated radiation therapy (IMRT) were studied. For each patient, in addition to the thermoplastic head mask, frameless array and bite-block were used for patient positioning. Optical guided frameless planning was utilized to define the coordinates of the isocenter during the treatment planning procedure. In each treatment fraction, the patient was first set up by matching the room lasers to the BB markers attached on the mask. The optical guided frameless system then captured the patient position and reported displacements of the current patient position to the planned patient position. These displacements were called interfraction errors. The treatment plan was designed to have up to 8 non-coplanar fields. Dose delivery of the non-coplanar fields required couch rotation which introduced isocenter displacements called intrafraction errors. Population statistics of interfraction and intrafraction errors (4 patient, 110 fractions) were calculated. The optical guided frameless system monitored the patient positioning errors and provided guidance for correction prior to the dose delivery. Among all patients and radiation treatment fractions, the overall detected interfraction error was 3.6±1.3 mm (mean ±SD) and the intrafraction error was 1.4±0.8 mm. Both types of errors were online corrected with the guidance of optical guided frameless system. Conventional laser guided thermoplastic mask patient position for intracranial therapy has interfraction and intrafraction errors. The optical guided frameless target localization technique allows clinicians to dectect and correct these errors online, therefore, to enhance the patient positioning accuracy for intracranial radiation therapy.


HCV and HIV prevalences strongly correlated in Asian communities with reservoirs of HIV in high-risk groups.
In some Asian communities, HIV epidemics initially concentrated in high-risk groups develop into generalized epidemics, while in others HIV epidemics remain confined to high-risk groups. We examined whether blood exposures in a community, as indicated by hepatitis C virus (HCV) prevalence, can account for the variability in HIV prevalence in Asia. We searched the published literature for temporally comparable HCV and HIV prevalence estimates for pregnant women and other "low-risk" population segments in Asian communities with established HIV epidemics in injection drug users or prostitute women. We assessed the correlation between HCV and HIV prevalences in these communities. HCV and HIV prevalences were strongly correlated (r = .97, p < .001). This finding suggests that blood-borne transmission drives generalized HIV epidemics in Asia and highlights the need for appropriately designed investigations of transmission modes.


Coinfection of HPV-11 and HPV-16 in a case of laryngeal squamous papillomas with severe dysplasia.
Human papillomavirus (HPV) types 6 and 11 have been associated with benign laryngeal papilloma, while HPV-16 is occasionally associated with laryngeal carcinoma. In this study, a case of laryngeal squamous papillomas with severe dysplasia was evaluated for the presence of HPV infection. The biopsy specimens were taken from a 58-year-old female patient at two different time points 3 months apart. Architecturally, the tumor showed papillary configuration reminiscent of squamous papilloma. Cytologically, the lesion showed morphologic features characteristic of severe squamous epithelial dysplasia. HPV infection was determined by DNA in situ hybridization using type-specific HPV-DNA probes. HPV-11 probes demonstrated homogeneous nuclear staining, suggesting productive viral replication. In contrast, HPV-16 probe produced a speckled pattern, suggesting HPV-16 DNA integration. Normal laryngeal epithelium did not yield specific hybridization. The presence of HPV-11 and HPV-16 was confirmed by PCR using HPV type-specific primers. Immunocytochemical staining was performed to detect Ki-67, a proliferation marker, and p53. Ki-67 expression was demonstrated throughout the whole thickness of epithelium. Staining for p53 was negative. This study suggests that multiple HPV infections can occur in the same lesion and that HPV-16 infection and its DNA integration may contribute to the occurrence of severe dysplasia in the lesion described.


Predicted limited redistribution of T cells to secondary lymphoid tissue correlates with increased risk of haematological malignancies in asplenic patients.
The spleen, a secondary lymphoid tissue (SLT), has an important role in generation of adaptive immune responses. Although splenectomy remains a common procedure, recent studies reported poor prognosis and increased risk of haematological malignancies in asplenic patients. The high baseline trafficking of T lymphocytes to splenic tissue suggests splenectomy may lead to loss of blood-borne malignant immunosurveillance that is not compensated for by the remaining SLT. To date, no quantitative analysis of the impact of splenectomy on the human T cell trafficking dynamics and tissue localisation has been reported. We developed a quantitative computational model that describes organ distribution and trafficking of human lymphocytes to explore the likely impact of splenectomy on immune cell distributions. In silico splenectomy resulted in an average reduction of T cell numbers in SLT by 35% (95%CI 0.12-0.97) and a comparatively lower, 9% (95%CI 0.17-1.43), mean decrease of T cell concentration in SLT. These results suggest that the surveillance capacity of the remaining SLT insufficiently compensates for the absence of the spleen. This may, in part, explain haematological malignancy risk in asplenic patients and raises the question of whether splenectomy has a clinically meaningful impact on patient responses to immunotherapy.


Action of antimicrobial substances produced by different oil reservoir Bacillus strains against biofilm formation.
Microbial colonization of petroleum industry systems takes place through the formation of biofilms, and can result in biodeterioration of the metal surfaces. In a previous study, two oil reservoir Bacillus strains (Bacillus licheniformis T6-5 and Bacillus firmus H(2)O-1) were shown to produce antimicrobial substances (AMS) active against different Bacillus strains and a consortium of sulfate-reducing bacteria (SRB) on solid medium. However, neither their ability to form biofilms nor the effect of the AMS on biofilm formation was adequately addressed. Therefore, here, we report that three Bacillus strains (Bacillus pumilus LF4 -- used as an indicator strain, B. licheniformis T6-5, and B. firmus H(2)O-1), and an oil reservoir SRB consortium (T6lab) were grown as biofilms on glass surfaces. The AMS produced by strains T6-5 and H(2)O-1 prevented the formation of B. pumilus LF4 biofilm and also eliminated pre-established LF4 biofilm. In addition, the presence of AMS produced by H(2)O-1 reduced the viability and attachment of the SRB consortium biofilm by an order of magnitude. Our results suggest that the AMS produced by Bacillus strains T6-5 and H(2)O-1 may have a potential for pipeline-cleaning technologies to inhibit biofilm formation and consequently reduce biocorrosion.


Independent effects of testosterone on lipid oxidation and VLDL-TG production: a randomized, double-blind, placebo-controlled, crossover study.
Low testosterone (T) levels in men have been shown to predict development of the metabolic syndrome, but the effects of T on lipid metabolism are incompletely understood. In a randomized, double-blind, placebo-controlled, crossover study, 12 healthy, young males received gonadotropin-releasing hormone agonist treatment 1 month prior to 3 of 4 trial days to induce castrate levels of T. On trial days, T gel was applied to the body containing either high or low physiological T dose or placebo. On the 4th trial day, participants constituted their own eugonadal controls. Each study comprised a 5-h basal period and a 3-h hyperinsulinemic-euglycemic clamp. Short-term hypogonadism did not affect VLDL triglyceride (TG) secretion, nor did it affect VLDL-TG concentrations. It was, however, characterized by lower total lipid oxidation. In addition, acute rescue with high physiological T increased VLDL-TG secretion during both basal and clamp conditions. These data show that T can act through fast nongenomic pathways in the liver. In addition, the early hypogonadal state is characterized by decreased total lipid oxidation, but whether these changes represent early hypogonadal metabolic dysfunction warrants further investigations. T is not a major determinant of resting VLDL-TG kinetics in men.


Expression Patterns in Reductive Iron Assimilation and Functional Consequences during Phagocytosis of Lichtheimia corymbifera, an Emerging Cause of Mucormycosis.
Iron is an essential micronutrient for most organisms and fungi are no exception. Iron uptake by fungi is facilitated by receptor-mediated internalization of siderophores, heme and reductive iron assimilation (RIA). The RIA employs three protein groups: (i) the ferric reductases (Fre5 proteins), (ii) the multicopper ferroxidases (Fet3) and (iii) the high-affinity iron permeases (Ftr1). Phenotyping under different iron concentrations revealed detrimental effects on spore swelling and hyphal formation under iron depletion, but yeast-like morphology under iron excess. Since access to iron is limited during pathogenesis, pathogens are placed under stress due to nutrient limitations. To combat this, gene duplication and differential gene expression of key iron uptake genes are utilized to acquire iron against the deleterious effects of iron depletion. In the genome of the human pathogenic fungus L. corymbifera, three, four and three copies were identified for FRE5, FTR1 and FET3 genes, respectively. As in other fungi, FET3 and FTR1 are syntenic and co-expressed in L. corymbifera. Expression of FRE5, FTR1 and FET3 genes is highly up-regulated during iron limitation (Fe-), but lower during iron excess (Fe+). Fe- dependent upregulation of gene expression takes place in LcFRE5 II and III, LcFTR1 I and II, as well as LcFET3 I and II suggesting a functional role in pathogenesis. The syntenic LcFTR1 I-LcFET3 I gene pair is co-expressed during germination, whereas LcFTR1 II- LcFET3 II is co-expressed during hyphal proliferation. LcFTR1 I, II and IV were overexpressed in Saccharomyces cerevisiae to represent high and moderate expression of intracellular transport of Fe3+, respectively. Challenge of macrophages with the yeast mutants revealed no obvious role for LcFTR1 I, but possible functions of LcFTR1 II and IVs in recognition by macrophages. RIA expression pattern was used for a new model of interaction between L. corymbifera and macrophages.


Advances in materials and concepts in fixed prosthodontics: a selection of possible treatment modalities.
The introduction of adhesive techniques in combination with translucent restorative materials has greatly influenced treatment concepts in fixed prosthodontics. Modern production technologies offer access to new polymer materials that provide innovative pre-treatment options for complex prosthetic rehabilitations. Additionally, computer-aided design and manufacturing (CAD/CAM) provides access to new ceramic types and thus extends the range of indications for metal-free restorative options. With these developments, important changes of treatment concepts in fixed prosthodontics have occurred which affect the professional life of dental practitioners with a focus on prosthetic dentistry. This article gives an overview of the advances in selected fields of fixed prosthodontics and provides support in material selection for different kinds of indications, from single-tooth restorations to fixed dental prostheses.


IL-2 coordinates IL-2-producing and regulatory T cell interplay.
Many species of bacteria use quorum sensing to sense the amount of secreted metabolites and to adapt their growth according to their population density. We asked whether similar mechanisms would operate in lymphocyte homeostasis. We investigated the regulation of the size of interleukin-2 (IL-2)-producing CD4(+) T cell (IL-2p) pool using different IL-2 reporter mice. We found that in the absence of either IL-2 or regulatory CD4(+) T (T reg) cells, the number of IL-2p cells increases. Administration of IL-2 decreases the number of cells of the IL-2p cell subset and, pertinently, abrogates their ability to produce IL-2 upon in vivo cognate stimulation, while increasing T reg cell numbers. We propose that control of the IL-2p cell numbers occurs via a quorum sensing-like feedback loop where the produced IL-2 is sensed by both the activated CD4(+) T cell pool and by T reg cells, which reciprocally regulate cells of the IL-2p cell subset. In conclusion, IL-2 acts as a self-regulatory circuit integrating the homeostasis of activated and T reg cells as CD4(+) T cells restrain their growth by monitoring IL-2 levels, thereby preventing uncontrolled responses and autoimmunity.


The effect of cathodal transcranial direct current stimulation during rapid eye-movement sleep on neutral and emotional memory.
Sleep-dependent memory consolidation has been extensively studied. Neutral declarative memories and serial reaction time task (SRTT) performance can benefit from slow-wave activity, characterized by less than 1 Hz frequency cortical slow oscillations (SO). Emotional memories can benefit from theta activity, characterized by 4-8 Hz frequency cortical oscillations. Applying transcranial direct current stimulation (tDCS) during sleep entrains specific frequencies to alter sleep architecture. When applying cathodal tDCS (CtDCS), neural inhibition or excitation may depend on the waveform at the applied frequency. A double dissociation was predicted, with CtDCS at SO frequency improving neutral declarative memory and SRTT performance, and theta frequency CtDCS inhibiting negative emotional memory. Participants completed three CtDCS conditions (Theta: 5 Hz, SO: 0.75 Hz and control: sham) and completed an SRTT and word recognition task pre- and post-sleep, comprising emotional and neutral words to assess memory. In line with predictions, CtDCS improved neutral declarative memory when applied at SO frequency. When applied at theta frequency, no negative emotional word memory impairment was found but a positive association was found between post-stimulation theta power and emotional word recognition. SRTT performance was also not altered by either CtDCS frequency. Future studies should investigate overnight theta CtDCS and examine the effects of CtDCS during and after stimulation.


A case of splenic rupture: a rare event after laparoscopic cholecystectomy.
Laparoscopic cholecystectomy (LC) is generally safe and well-accepted. In rare cases, it is associated with complications (intra- e postoperative bleeding, visceral injury and surgical site infection). Splenic lesion has been reported only after direct trauma. We report an unusual case of splenic rupture presenting after "uncomplicated" LC. A 77-year-old woman presented with distended abdomen, tenderness in the left upper quadrant and severe anemia 12 hours after LC. Clinical examination revealed hypovolemic shock. Abdominal computed tomography confirmed the diagnosis of splenic rupture, and the patient required an urgent splenectomy through midline incision. The post-operative course was uneventful and the patient was discharged on 7th postoperative day.Splenic injury rarely complicates LC. We postulate that congenital or post-traumatic adhesions of the parietal peritoneum to the spleen may have been stretched from the splenic capsule during pneumoperitoneum establishment, resulting in subcapsular hematoma and subsequent delayed rupture. Splenic rupture is an unusual but life-threatening complication of LC. Direct visualization of the spleen at the end of LC might be a useful procedure to aid early recognition and management in such cases.


Counting low-copy number proteins in a single cell.
We have designed a microfluidic device in which we can manipulate, lyse, label, separate, and quantify the protein contents of a single cell using single-molecule fluorescence counting. Generic labeling of proteins is achieved through fluorescent-antibody binding. The use of cylindrical optics enables high-efficiency (approximately 60%) counting of molecules in micrometer-sized channels. We used this microfluidic device to quantify beta2 adrenergic receptors expressed in insect cells (SF9). We also analyzed phycobiliprotein contents in individual cyanobacterial cells (Synechococcus sp. PCC 7942) and observed marked differences in the levels of specific complexes in cell populations that were grown under nitrogen-depleted conditions.


The use of magnetic resonance imaging in predicting the clinical outcome of spinal arteriovenous fistula.
Magnetic resonance imaging (MRI) has been used to screen and follow-up spinal dural arteriovenous fistulae (SDAVF). The purpose of this study was to evaluate the association between MRI findings and neurologic function in SDAVF. This study also investigated clinical features and treatment results of SDAVF. A total of 15 consecutive patients who underwent embolization or surgery for SDAVF were included. We treated seven (60%) patients with embolization and six (40%) with surgery. We analysed clinical features, MRI findings, treatment results, and neurologic function. Neurologic function was measured by the Aminoff-Logue disability scale (ALS). Patients with longer levels of intramedullary high signal intensity in preoperative T2-weighted images (T2WI) exhibited worse pre- and postoperative ALS scores (r=0.557, p=0.031; r=0.530, p=0.042, Pearson correlation). Preoperative ALS score was significantly correlated with postoperative ALS score (r=0.908, p=0.000, Pearson correlation). The number of levels showing intramedullary high signal intensity in T2WI decreased significantly postoperatively (5.2±3.1 vs. 1.0±1.4, p=0.001, Wilcoxon ranked test). The number of involved levels of high signal intensity in preoperative T2WI is useful for predicting pre- and postoperative neurologic function in SDAVF.