Cyclic Copper Uptake and Release from Natural Seawater-A Fully Sustainable Antifouling Technique to Prevent Marine Growth.
Unwanted growth of fouling organisms on underwater surfaces is an omnipresent challenge for the marine industry, costing billions of dollars every year in the transportation sector alone. Copper, the most widely used biocide in antifouling paints, is at the brink of a total ban in being used in antifouling coatings, as it has become an existential threat to nontargeted species due to anthropogenic copper inputs into protected waters. In the current study, using a porous and cross-linked poly(ethylene imine) structure under marine and fouling environments, available copper from natural seawater was absorbed and electrochemically released back as a potent biocide at 1.3 V vs Ag|AgCl, reducing marine growth by 94% compared to the control electrode (coupon) at 0 V. The coating can also function as an electrochemical copper sensor enabling real-time monitoring of the electrochemical uptake and release of copper ions from natural seawater. This allows tailoring of the electrochemical program to the changing marine environments, i.e., when the vessels move from high-copper-contaminated waters to coastal regions with low concentrations of copper.


Quantification of the clinical modifiers impacting high-density lipoprotein cholesterol in the community: Personalized Medicine Research Project.
High-density lipoprotein (HDL) cholesterol levels are inversely correlated with the development of cardiovascular disease. To date, genetic association studies have explained only a small proportion of the overall variance in HDL cholesterol. Further studies are needed, within practice-based cohorts, to place genetic findings into context alongside important clinical variables (eg, age, sex, body mass index, medication use, and clinical comorbidity). The Marshfield Clinic Personalized Medicine Research Project database was designed for large-scale studies of genetic epidemiology in a clinical practice-based setting. Because of its size and its unique practice-based design, this resource will provide adequate statistical power for the assessment of genetic findings related to HDL cholesterol level within the context of covariates known to modify lipid homeostasis. The authors report construction and validation of novel electronic phenotyping algorithms that can be used to model individual baseline HDL cholesterol levels within this practice-based resource. Because these algorithms were developed in a setting that reflects routine clinical care, future genetic studies using these algorithms within practice-based DNA biobanks should facilitate the identification of markers with optimal effect size after adjustment for known clinical factors contributing to the overall variance in HDL cholesterol level within the community.


Audit of conservative management of chronic low back pain in a secondary care setting--part I: facet joint and sacroiliac joint interventions.
The work of a chronic back pain service in secondary care in the West Midlands is reported. The service offers acupuncture, spinal injection procedures, osteopathy and a range of other interventions for patients whose back pain has not responded to conservative management. This section of the report focuses on injection procedures for lumbar facet joint and sacroiliac joint pain, which have been shown to be the cause of chronic low back pain in 16-40% and 13-19% of patients respectively. Diagnosis relies on the use of intra-articular or sensory nerve block injections with local anaesthetic. Possible treatments following diagnosis include intra-articular corticosteroid, radiofrequency denervation (for facet joint pain) or ligament prolotherapy injections (for sacroiliac joint pain). The results of several hospital audits are reported. At six month follow up, 50% of 38 patients undergoing radiofrequency denervation following diagnostic blocks for facet joint pain had improved by more than 50%, compared to 29% of 34 patients treated with intra-articular corticosteroid injection. Sixty three per cent of 19 patients undergoing prolotherapy following diagnostic block injection for sacroiliac joint pain had improved at six months, compared to 33% of 33 who had intra-articular corticosteroid. Both radiofrequency denervation and sacroiliac prolotherapy showed good long-term outcomes at one year.


Climate vs. soil factors in local adaptation of two common plant species.
Evolutionary theory suggests that divergent natural selection in heterogeneous environments can result in locally adapted plant genotypes. To understand local adaptation it is important to study the ecological factors responsible for divergent selection. At a continental scale, variation in climate can be important while at a local scale soil properties could also play a role. We designed an experiment aimed to disentangle the role of climate and (abiotic and biotic) soil properties in local adaptation of two common plant species. A grass (Holcus lanatus) and a legume (Lotus corniculatus), as well as their local soils, were reciprocally transplanted between three sites across an Atlantic-Continental gradient in Europe and grown in common gardens in either their home soil or foreign soils. Growth and reproductive traits were measured over two growing seasons. In both species, we found significant environmental and genetic effects on most of the growth and reproductive traits and a significant interaction between the two environmental effects of soil and climate. The grass species showed significant home site advantage in most of the fitness components, which indicated adaptation to climate. We found no indication that the grass was adapted to local soil conditions. The legume showed a significant home soil advantage for number of fruits only and thus a weak indication of adaptation to soil and no adaptation to climate. Our results show that the importance of climate and soil factors as drivers of local adaptation is species-dependent. This could be related to differences in interactions between plant species and soil biota.


[The meanings of masculinity, sexuality, power and violence among adolescents].
To analyze perceived meanings of masculinity and power related to sexual violence among adolescents. A qualitative study was carried out between 1998 and 2000 in the metropolitan area of Guadalajara, Mexico, among 155 junior high and high school male/female students. Information was collected from 12 focal groups in two-hour sessions. Data collection instruments included: interviews, observation, and instruction guides. Data were recorded using notes and tape recordings. Oral and written information was transcribed, categorized, and coded, in order to construct matrixes and interpret results. Symbolic explanatory concepts related with rape included: constructivism vs. naturalism, heteronomous moral posture, and early exchange towards respect and human rights. Females were perceived as the real and potential victims. Males were perceived as violent by nature or under challenge, and prone to be victimized only if they were children, unmanly, or homosexual. Analysis objects included motives, power, female refusal, accusation, consequences, management, and prevention. Sexual violence is symbolized within the realm of explanatory and moral controversy. The ideological values of masculinity legitimate both legal and judiciary impunity. Social meanings and adolescent participation should be considered in research and interventions.


Self-Reported Long COVID in the General Population: Sociodemographic and Health Correlates in a Cross-National Sample.
We aimed to gain knowledge of possible sociodemographic predictors of long COVID and whether long COVID was associated with health outcomes almost two years after the pandemic outbreak. There were 1649 adults who participated in the study by completing a cross-sectional online survey disseminated openly in Norway, the UK, the USA, and Australia between November 2021 and January 2022. Participants were defined as having long COVID based on self-reports that they had been infected by COVID-19 and were experiencing long-lasting COVID symptoms. Logistic regression analyses were used to examine possible sociodemographic predictors, and multivariate analysis of variance was used to examine whether long COVID status was associated with health outcomes. None of the sociodemographic variables was significantly associated with reporting long COVID. Having long COVID was associated with higher levels of psychological distress, fatigue, and perceived stress. The effect of long COVID on health outcomes was greater among men than among women. In conclusion, long COVID appeared across sociodemographic groups. People with long COVID reported worsened health outcomes compared to those who had had COVID-19 but without long-term symptoms. Men experiencing long COVID appear to be particularly vulnerable to experiencing poorer health outcomes; health services may pay extra attention to potentially unnoticed needs for support among men experiencing long COVID.


Control of sensory fields by stimulation of hypothalamus.
Stimulation of the cat's hypothalamus, which elicits attack, also establishes sensory fields for two reflexes related to biting. Touching a perioral region leads to head movement, bringing the stimulus to the mouth. Touching the lip-line leads to jaw opening. The size of the fields depends on the intensity of stimulation.


Parasitic helminths of the wild rabbit, Oryctolagus cuniculus, in different bioclimatic zones in Tenerife, Canary Islands.
Faunistic and ecological analyses of the wild rabbit helminth fauna were undertaken in Tenerife island (Canary Islands). Rabbits were collected between 1998 and 2000 in seven bioclimatic zones in Tenerife selected by orientation and altitude. Five parasite species were identified, three cestodes (Taenia pisiformis (larvae), Andrya cuniculi and Mosgovoyia ctenoides) and two nematodes (Trichostrongylus retortaeformis and Passalurus ambiguus). Taenia pisiformis presented an irregular distribution with significant differences in prevalences between the zones. Andrya cuniculi was only found in two zones and there were no significant differences in prevalence values. Mosgovoyia ctenoides presented a wide distribution with significant prevalences, which were higher in northern compared to southern zones. Trichostrongylus retortaeformis was absent in the low southern zones of the island. Passalurus ambiguus was found in all zones with no significant difference in the prevalence of infection. The differences in prevalences are likely to be explained by abiotic factors in the case of T. retortaeformis, and by the absence of definitive and intermediate hosts in the case of T. pisiformis and A. cuniculi, respectively. All parasite species in Tenerife are common helminths in the Iberian Peninsula, from which their rabbit hosts originated. No significant differences were recorded in the mean intensities of infection of any of the parasite species identified.


Patterns of horse-rider coordination during endurance race: a dynamical system approach.
In riding, most biomechanical studies have focused on the description of the horse locomotion in unridden condition. In this study, we draw the prospect of how the basic principles established in inter-personal coordination by the theory of Coordination Dynamics may provide a conceptual and methodological framework for understanding the horse-rider coupling. The recent development of mobile technologies allows combined horse and rider recordings during long lasting natural events such as endurance races. Six international horse-rider dyads were thus recorded during a 120 km race by using two tri-axial accelerometers placed on the horses and riders, respectively. The analysis concentrated on their combined vertical displacements. The obtained shapes and angles of Lissajous plots together with values of relative phase between horse and rider displacements at lower reversal point allowed us to characterize four coordination patterns, reflecting the use of two riding techniques per horse's gait (trot and canter). The present study shows that the concepts, methods and tools of self-organizing dynamic system approach offer new directions for understanding horse-rider coordination. The identification of the horse-rider coupling patterns constitutes a firm basis to further study the coalition of multiple constraints that determine their emergence and their dynamics in endurance race.


A Randomized Controlled Trial of Listening to Recorded Music for Heart Failure Patients: Study Protocol.
To describe a conceptual framework and to test the effectiveness of a recorded music-listening protocol on symptom burden and quality of life in heart failure (HF) patients. Heart failure is an important public health problem. Many HF patients experience symptoms burden and poor quality of life, even with current improvements in pharmacological treatments. Recorded music listening has been shown to improve outcomes in cardiovascular patients, but it has never been tested on HF patients and with a specific music protocol and a randomized controlled trial methodology. This study is a multicenter blinded randomized controlled trial that will involve 150 patients. Eligible patients will have a diagnosis of HF, in New York Heart Association functional classification of I to III, and will be recruited from 3 large hospitals in Northern Italy. Patients will be randomly allocated in a 1:1 ratio to receive recorded music-listening intervention with or without standard care for 3 months. Data will be collected at baseline and at the end of the first, second, and third month during the intervention, and at 6 months for follow-up. The following variables will be collected from HF patients with validated protocols: quality of life (primary endpoint), use of emergency services, rehospitalization rates, all cause mortality, self-care, somatic symptoms, quality of sleep, anxiety and depression symptoms, and cognitive function. This study will examine the effect of recorded music listening on HF patients and will inform clinical practice. If the findings are found to be positive, the protocol could be used as a tool for evidence-based applications of recorded music in HF patients. The framework developed in this study may be helpful for future research focused on the effects of music in HF patients.


Socioeconomic inequality in the prevalence of autism spectrum disorder: evidence from a U.S. cross-sectional study.
This study was designed to evaluate the hypothesis that the prevalence of autism spectrum disorder (ASD) among children in the United States is positively associated with socioeconomic status (SES). A cross-sectional study was implemented with data from the Autism and Developmental Disabilities Monitoring Network, a multiple source surveillance system that incorporates data from educational and health care sources to determine the number of 8-year-old children with ASD among defined populations. For the years 2002 and 2004, there were 3,680 children with ASD among a population of 557,689 8-year-old children. Area-level census SES indicators were used to compute ASD prevalence by SES tertiles of the population. Prevalence increased with increasing SES in a dose-response manner, with prevalence ratios relative to medium SES of 0.70 (95% confidence interval [CI] 0.64, 0.76) for low SES, and of 1.25 (95% CI 1.16, 1.35) for high SES, (P<0.001). Significant SES gradients were observed for children with and without a pre-existing ASD diagnosis, and in analyses stratified by gender, race/ethnicity, and surveillance data source. The SES gradient was significantly stronger in children with a pre-existing diagnosis than in those meeting criteria for ASD but with no previous record of an ASD diagnosis (p<0.001), and was not present in children with co-occurring ASD and intellectual disability. The stronger SES gradient in ASD prevalence in children with versus without a pre-existing ASD diagnosis points to potential ascertainment or diagnostic bias and to the possibility of SES disparity in access to services for children with autism. Further research is needed to confirm and understand the sources of this disparity so that policy implications can be drawn. Consideration should also be given to the possibility that there may be causal mechanisms or confounding factors associated with both high SES and vulnerability to ASD.


Extracorporeal membrane oxygenation in patients with severe respiratory failure from COVID-19.
Limited data are available on venovenous extracorporeal membrane oxygenation (ECMO) in patients with severe hypoxemic respiratory failure from coronavirus disease 2019 (COVID-19). We examined the clinical features and outcomes of 190 patients treated with ECMO within 14 days of ICU admission, using data from a multicenter cohort study of 5122 critically ill adults with COVID-19 admitted to 68 hospitals across the United States. To estimate the effect of ECMO on mortality, we emulated a target trial of ECMO receipt versus no ECMO receipt within 7 days of ICU admission among mechanically ventilated patients with severe hypoxemia (PaO2/FiO2 < 100). Patients were followed until hospital discharge, death, or a minimum of 60 days. We adjusted for confounding using a multivariable Cox model. Among the 190 patients treated with ECMO, the median age was 49 years (IQR 41-58), 137 (72.1%) were men, and the median PaO2/FiO2 prior to ECMO initiation was 72 (IQR 61-90). At 60 days, 63 patients (33.2%) had died, 94 (49.5%) were discharged, and 33 (17.4%) remained hospitalized. Among the 1297 patients eligible for the target trial emulation, 45 of the 130 (34.6%) who received ECMO died, and 553 of the 1167 (47.4%) who did not receive ECMO died. In the primary analysis, patients who received ECMO had lower mortality than those who did not (HR 0.55; 95% CI 0.41-0.74). Results were similar in a secondary analysis limited to patients with PaO2/FiO2 < 80 (HR 0.55; 95% CI 0.40-0.77). In select patients with severe respiratory failure from COVID-19, ECMO may reduce mortality.


Brown-Algae Polysaccharides as Active Constituents against Nonalcoholic Fatty Liver Disease.
Nonalcoholic fatty liver disease is a metabolic disorder characterized by lipid overloading in hepatocytes that can progress pathogenically and even end in hepatocellular carcinoma. Nonalcoholic fatty liver disease pharmacological treatment is still limited by unwanted side effects, whereas the use of food components with therapeutic potential is advisable. The culinary use of marine algae is traditional for some populations and reviving worldwide, with promising health outcomes due to the large number of bioactive compounds found in seaweeds. The present review focuses on brown-algae polysaccharides, particularly fucoidan, alginate, and laminarin, and summarizes the experimental evidence of their potential effects against nonalcoholic fatty liver disease onset and progression. In vitro and in vivo studies demonstrate that brown-algae polysaccharides exert beneficial actions on satiety feeling, caloric intake, fat absorption, and modulation of the gut microbiota, which could account for indirect effects on energy and lipid homeostasis, thus diminishing the fat overload in the liver. Specific effects against nonalcoholic fatty liver disease pathogenesis and worsening are also described and sustained by the antioxidant, anti-inflammatory, and antisteatotic properties of brown-algae polysaccharides. Further studies are required to clarify the mechanism of action of brown-algae polysaccharides on liver cells, to determine the composition and bioavailability of brown-algae polysaccharides present in different algal sources and to probe the clinical availability of these compounds in the form of algal foods, food supplements, and regulated therapeutics.


Bilinear sparse coding for invariant vision.
Recent algorithms for sparse coding and independent component analysis (ICA) have demonstrated how localized features can be learned from natural images. However, these approaches do not take image transformations into account. We describe an unsupervised algorithm for learning both localized features and their transformations directly from images using a sparse bilinear generative model. We show that from an arbitrary set of natural images, the algorithm produces oriented basis filters that can simultaneously represent features in an image and their transformations. The learned generative model can be used to translate features to different locations, thereby reducing the need to learn the same feature at multiple locations, a limitation of previous approaches to sparse coding and ICA. Our results suggest that by explicitly modeling the interaction between local image features and their transformations, the sparse bilinear approach can provide a basis for achieving transformation-invariant vision.


China's biggest, most neglected health challenge: Non-communicable diseases.
Over the past two decades, international health policies focusing on the fight against the human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), tuberculosis (TB), malaria, and those diseases that address maternal and child health problems, among others, have skewed disease control priorities in China and other Asian countries. Although these are important health problems, an epidemic of chronic, non-communicable diseases (NCDs) in China has accounted for a much greater burden of disease due to the ongoing rapid socioeconomic and demographic transition. Although NCDs currently account for more than 80% of the overall disease burden in China, they remain very low on the nation's disease control priorities, attracting marginal investment from central and local governments. This leaves the majority of patients with chronic conditions without effective treatment. International organizations and national governments have recognized the devastating social and economic consequences caused by NCDs in low- and middle-income countries, including China. Yet, few donor-funded projects that address NCDs have been implemented in these countries over the past decade. Due to a lack of strong support from international organizations and national governments for fighting against NCDs, affected persons in China, especially the poor and those who live in rural and less developed regions, continue to have limited access to the needed care. Costs associated with frequent health facility visits and regular treatment have become a major factor in medical impoverishment in China. This article argues that although China's ongoing health system reform would provide a unique opportunity to tackle current public health problems, it may not be sufficient to address the emerging threat of NCDs unless targeted steps are taken to assure that adequate financial and human resources are mapped for effective control and management of NCDs in the country. The Chinese government needs to develop a domestically-driven and evidence-based disease control policy and funding priorities that respond appropriately to the country's current epidemiological transition, and rapid sociodemographic and lifestyle changes.


Two types of antibodies are induced by vaccination with A/California/2009 pdm virus: binding near the sialic acid-binding pocket and neutralizing both H1N1 and H5N1 viruses.
Many people have a history of catching the flu several times during childhood but no additional flu in adulthood, even without vaccination. We analyzed the total repertoire of antibodies (Abs) against influenza A group 1 viruses induced in such a flu-resistant person after vaccination with 2009 H1N1 pandemic influenza virus. They were classified into two types, with no exceptions. The first type, the products of B cells newly induced through vaccination, binds near the sialic acid-binding pocket. The second type, the products of long-lived memory B cells established before vaccination, utilizes the 1-69 VH gene, binds to the stem of HA, and neutralizes both H1N1 and H5N1 viruses with few exceptions. These observations indicate that the sialic acid-binding pocket and its surrounding region are immunogenically very potent and majority of the B cells whose growth is newly induced by vaccination produce Abs that recognize these regions. However, they play a role in protection against influenza virus infection for a short period since variant viruses that have acquired resistance to these Abs become dominant. On the other hand, although the stem of HA is immunogenically not potent, the second type of B cells eventually becomes dominant. Thus, a selection system should function in forming the repertoire of long-lived memory B cells and the stability of the epitope would greatly affect the fate of the memory cells. Acquisition of the ability to produce Abs that bind to the stable epitope could be a major factor of flu resistance.


Rationale for dental implants.
The clinical replacement of lost natural teeth by osseointegrated implants has represented one of the most significant advances in restorative dentistry. Two decades ago, a majority of dentists were sceptical about implants and rejected them entirely. Today it is rare to find a practitioner who does not work with dental implants or who is not actively participating in one of the many seminars or courses offered by universities, professional societies and implant manufacturers.


Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice.
Neural cultures derived from Huntington's disease (HD) patient-derived induced pluripotent stem cells were used for 'omics' analyses to identify mechanisms underlying neurodegeneration. RNA-seq analysis identified genes in glutamate and GABA signaling, axonal guidance and calcium influx whose expression was decreased in HD cultures. One-third of gene changes were in pathways regulating neuronal development and maturation. When mapped to stages of mouse striatal development, the profiles aligned with earlier embryonic stages of neuronal differentiation. We observed a strong correlation between HD-related histone marks, gene expression and unique peak profiles associated with dysregulated genes, suggesting a coordinated epigenetic program. Treatment with isoxazole-9, which targets key dysregulated pathways, led to amelioration of expanded polyglutamine repeat-associated phenotypes in neural cells and of cognitive impairment and synaptic pathology in HD model R6/2 mice. These data suggest that mutant huntingtin impairs neurodevelopmental pathways that could disrupt synaptic homeostasis and increase vulnerability to the pathologic consequence of expanded polyglutamine repeats over time.


Reciprocal effects of treatment-induced increases in exercise and improved eating, and their psychosocial correlates, in obese adults seeking weight loss: a field-based trial.
A better understanding of interrelations of exercise and improved eating, and their psychosocial correlates of self-efficacy, mood, and self-regulation, may be useful for the architecture of improved weight loss treatments. Theory-based research within field settings, with samples possessing high probabilities of health risks, might enable rapid application of useful findings. Adult volunteers with severe obesity (body mass index [BMI] 35-50 kg/m²; age = 43.0 ± 9.5 y; 83% female) were randomly assigned to six monthly cognitive-behavioral exercise support sessions paired with either group-based nutrition education (n = 145) or cognitive behavioral methods applied to improved eating (n = 149). After specification of mediation models using a bias-corrected bootstrapping procedure, a series of reciprocal effects analyses assessed: a) the reciprocal effects of changes in exercise and fruit and vegetable intake, resulting from the treatments, b) the reciprocal effects of changes in the three psychosocial variables tested (i.e. self-efficacy, mood, and self-regulation) and fruit and vegetable change, resulting from change in exercise volume, and c) the reciprocal effects of changes in the three psychosocial variables and exercise change, resulting from change in fruit and vegetable intake. Mediation analyses suggested a reciprocal effect between changes in exercise volume and fruit and vegetable intake. After inclusion of psychosocial variables, also found were reciprocal effects between change in fruit and vegetable intake and change in mood, self-efficacy for controlled eating, and self-regulation for eating; and change in exercise volume and change in mood and exercise-related self-regulation. Findings had implications for behavioral weight-loss theory and treatment. Specifically, results suggested that treatments should focus upon, and leverage, the transfer effects from each of the primary weight-loss behaviors (exercise and healthy eating) to the other. Findings on psychosocial correlates of these behavioral processes may also have practical applications.


Supplementation of a suboptimal protein dose with leucine or essential amino acids: effects on myofibrillar protein synthesis at rest and following resistance exercise in men.
Leucine is a nutrient regulator of muscle protein synthesis by activating mTOR and possibly other proteins in this pathway. The purpose of this study was to examine the role of leucine in the regulation of human myofibrillar protein synthesis (MPS). Twenty-four males completed an acute bout of unilateral resistance exercise prior to consuming either: a dose (25 g) of whey protein (WHEY); 6.25 g whey protein with total leucine equivalent to WHEY (LEU); or 6.25 g whey protein with total essential amino acids (EAAs) equivalent to WHEY for all EAAs except leucine (EAA-LEU). Measures of MPS, signalling through mTOR, and amino acid transporter (AAT) mRNA abundance were made while fasted (FAST), and following feeding under rested (FED) and post-exercise (EX-FED) conditions. Leucinaemia was equivalent between WHEY and LEU and elevated compared to EAA-LEU (P=0.001). MPS was increased above FAST at 1–3 h post-exercise in both FED (P <0.001) and EX-FED (P <0.001) conditions with no treatment effect.At 3–5 h, only WHEY remained significantly elevated above FAST in EX-FED(WHEY 184% vs. LEU 55% and EAA-LEU 35%; P =0.036). AAT mRNA abundance was increased above FAST after feeding and exercise with no effect of leucinaemia. In summary, a low dose of whey protein supplemented with leucine or all other essential amino acids was as effective as a complete protein (WHEY) in stimulating postprandial MPS; however only WHEY was able to sustain increased rates of MPS post-exercise and may therefore be most suited to increase exercise-induced muscle protein accretion.


Opioid tolerance--a predictor of increased length of stay and higher readmission rates.
The increasing use of opioids to manage pain in the United States over the last decade has resulted in a subset of our population developing opioid tolerance. While the management of opioid tolerant patients during acute episodes of care is well known to be a challenge amongst health care providers, there is little in the literature that has studied opioid tolerance as a predictor of outcomes. We conducted a review on all admissions to Massachusetts General Hospital over a period of 6 months, from January 2013 to June 2013, and identified opioid tolerant patients at admission using the FDA definition of opioid tolerance. To compare risk adjusted groups, we placed opioid tolerant patients and control patients into groups determined by expected length of stay of less than 2 days, 2 to 5 days, 5 to 10 days, and greater than 10 days. Opioid tolerant patients were then compared to the control for outcomes measures including observed length of stay and readmission rates. Our results show that all opioid tolerant patients have a significantly longer length of stay and a greater 30 day all cause readmission rate than the control group (P < 0.01). This trend was found in the first 3 risk adjusted groups, but not in the fourth group where expected length of stay was greater than 10 days. The opioid tolerant population is at risk given the poorer outcomes and higher health care costs associated with their care. It is imperative that we identify opportunities for improvement and delineate specific pathways for the care of these patients.


Effectiveness of the risk of malignancy index and the risk of ovarian malignancy algorithm in a cohort of women with ovarian cancer: does histotype and stage matter?
To examine the performance of the Risk of Malignancy Index (RMI) and Risk of Ovarian Malignancy Algorithm (ROMA) by histologic subtype and stage of disease in a cohort of women with ovarian cancer. All patients with confirmed ovarian cancer at the Princess Margaret Hospital between February 2011 and January 2013 were eligible for study inclusion. Preoperative cancer antigen 125, human epididymis protein 4, and ultrasound findings were reviewed, and the sensitivity and false-negative rates of the RMI and ROMA were determined by stage of disease and tumor histology. A total of 131 patients with ovarian cancer were identified. High-grade serous (HGS) histology was most frequently associated with stage III/IV disease (n = 46 [72% of stage III/IV]) vs stage I (n = 5 [11% of stage I]; P < 0.0001). Clear cell (CC) and endometrioid (EC) histology presented most commonly with stage I disease (n = 9 [20%] and n = 13 [29% of stage I cases], respectively). Median cancer antigen 125 and human epididymis protein 4 values were significantly higher for HGS than for EC or CC histology. Risk of Malignancy Index II demonstrated the highest sensitivity of the 3 RMI algorithms. All RMIs and ROMA were significantly more sensitive in predicting malignancy in patients with HGS than EC or CC histology. Risk of Malignancy Index II (n = 38) and ROMA (n = 35) exhibited sensitivities of 68% and 54% and false-negative rates of 32% and 46%, respectively, for patients with stage I disease vs sensitivities of 94% and 93% and false-negative rates of 6% and 7% for patients with stage III/IV disease. Both RMI and ROMA performed well for the detection of advanced ovarian cancer and HGS histology. These triaging algorithms do not perform well in patients with stage I disease where EC and CC histologies predominate. Clinicians should be cautious using RMI or ROMA scoring tools to triage isolated adnexal masses because many patients with stage I malignancies would be missed.


Reduced neuronal inhibition and coordination of adolescent prefrontal cortex during motivated behavior.
Adolescence is a time of both cognitive maturation and vulnerability to several major psychiatric illnesses and drug dependence. There is increasing awareness that behavioral or pharmacological intervention during this period may be critical for disease prevention in susceptible individuals. Therefore, we must attain a deeper understanding of how the adolescent brain processes salient events relevant to motivated behavior. To do this, we recorded single-unit and local field potential activity in the orbitofrontal cortex of rats as they performed a simple reward-driven operant task. Adolescents encoded basic elements of the task differently than adults, indicating that neuronal processing of salient events differs in the two age groups. Entrainment of local field potential oscillations, variance in spike timing, and relative proportions of inhibitory and excitatory responses differed in an event-specific manner. Overall adolescent phasic neural activity was less inhibited and more variable through much of the task. Cortical inhibition is essential for efficient communication between neuronal groups, and reduced inhibitory control of cortical activity has been implicated in schizophrenia and other disorders. Thus, these results suggest that reduced inhibitory responses of adolescent cortical neurons to salient events could be a critical mechanism for some of the increased vulnerabilities of this period.


Pervasive purifying selection characterizes the evolution of I2 homologs.
We sampled 384 sequences related to the Solanum pimpinellifolium (=Lycopersicon pimpinellifolium) disease resistance (R) gene 12 from six species, potato, S. demissum, tomato, eggplant, pepper, and tobacco. These species represent increasing phylogenetic distance from potato to tobacco, within the family Solanaceae. Using sequence data from the nucleotide binding site (NBS) region of this gene, we tested models of gene family evolution and inferred patterns of selection acting on the NBS gene region and I2 gene family. We find that the I2 family has diversified within the family Solanaceae for at least 14 million years and evolves through a slow birth-and-death process requiring approximately 12 million years to homogenize gene copies within a species. Analyses of selection resolved a general pattern of strong purifying selection acting on individual codon positions within the NBS and on NBS lineages through time. Surprisingly, we find nine codon positions strongly affected by positive selection and six pairs of codon positions demonstrating correlated amino acid substitutions. Evolutionary analyses serve as bioinformatic tools with which to sort through the vast R gene diversity in plants and find candidates for new resistance specificities or to identify specific amino acid positions important for biochemical function. The slow birth-and-death evolution of I2 genes suggests that some NBS-leucine rich repeat-mediated resistances may not be overcome rapidly by virulence evolution and that the natural diversity of R genes is a potentially valuable source for durable resistance.


Direct assessment of completeness of ascertainment in a stroke incidence study.
Validity of comparisons of stroke incidence between studies or time periods depends on the completeness of ascertainment. Ascertainment cannot be reliably assessed indirectly by statistical methods, such as capture-recapture. We report the first use of direct methods to determine the completeness of different ascertainment strategies in a population-based stroke incidence study (Oxford Vascular Study). We assessed completeness of 2 different ascertainment strategies: the core methods common to most previous incidence studies and core plus supplementary methods used in some studies (including access to carotid and brain imaging referrals and assessment of patients referred as "transient ischemic attack" or "recurrent stroke"). We assessed completeness of ascertainment in 2 ways. First, we searched anonymized primary care electronic patient records of the whole study population (n=90,542). Second, we interviewed and followed-up a high-risk subset of our study population: all patients who had an acute coronary or peripheral vascular event or a related elective investigation or intervention. 126 strokes were ascertained by the core plus supplementary methods, of which only 108 were identified by the core methods alone. Only 2 additional incident strokes were identified by access to primary care electronic patient records of the whole study population. Assessment and follow-up of 1103 high-risk individuals (5.5% of our total study population aged older than 60 years) identified 16 incident strokes. However, all 16 had already been ascertained by the core plus supplementary methods. The core methods of ascertainment used in some stroke incidence studies lead to significant underascertainment. However, direct assessment of ascertainment suggests that the supplementary methods used in recent studies can lead to near-complete ascertainment.


Ultrasensitive techniques and protein misfolding amplification assays for biomarker-guided reconceptualization of Alzheimer's and other neurodegenerative diseases.
The clinical validation and qualification of biomarkers reflecting the complex pathophysiology of neurodegenerative diseases (NDDs) is a fundamental challenge for current drug discovery and development and next-generation clinical practice. Novel ultrasensitive detection techniques and protein misfolding amplification assays hold the potential to optimize and accelerate this process. Here we perform a PubMed-based state of the art review and perspective report on blood-based ultrasensitive detection techniques and protein misfolding amplification assays for biomarkers discovery and development in NDDs. Ultrasensitive assays represent innovative solutions for blood-based assessments during the entire Alzheimer's disease (AD) biological and clinical continuum, for contexts of use (COU) such as prediction, detection, early diagnosis, and prognosis of AD. Moreover, cerebrospinal fluid (CSF)-based misfolding amplification assays show encouraging performance in detecting α-synucleinopathies in prodromal or at-high-risk individuals and may serve as tools for patients' stratification by the presence of α-synuclein pathology. Further clinical research will help overcome current methodological limitations, also through exploring multiple accessible bodily matrices. Eventually, integrative longitudinal studies will support precise definitions for appropriate COU across NDDs.


Circuits, Networks, and Neuropsychiatric Disease: Transitioning From Anatomy to Imaging.
Since the development of cellular and myelin stains, anatomy has formed the foundation for understanding circuitry in the human brain. However, recent functional and structural studies using magnetic resonance imaging have taken the lead in this endeavor. These innovative and noninvasive approaches have the advantage of studying connectivity patterns under different conditions directly in the human brain. They demonstrate dynamic and structural changes within and across networks linked to normal function and to a wide range of psychiatric illnesses. However, these indirect methods are unable to link networks to the hardwiring that underlies them. In contrast, anatomic invasive experimental studies can. Following a brief review of prefrontal cortical, anterior cingulate, and striatal connections and the different methodologies used, this article discusses how data from anatomic studies can help inform how hardwired connections are linked to the functional and structural networks identified in imaging studies.


Oridonin Inhibits Myofibroblast Differentiation and Bleomycin-induced Pulmonary Fibrosis by Regulating Transforming Growth Factor β (TGFβ)/Smad Pathway.
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a progressive disease with unknow. etiology and a high mortality rate. Oridonin is a diterpenoid isolated from the Rabdosia rubesecens with diverse biological functions. However, whether oridonin possess potential protective activity on IPF is still unclear. MATERIAL AND METHODS The aim of the present study was to explore the therapeutic effects of oridonin on IPF. First, TGF-β1-induced MRC-5 cells were employed for the evaluation of inhibitory activity in vitro. Then, a bleomycin (BLM)-induced mice pulmonary fibrosis model was used to verify the activity of oridonin in vivo. Several pathological changes, including alveolar space collapse, emphysema, and infiltration of inflammatory cells, were observed in the BLM‑treated mice. RESULTS Oridonin could significantly inhibit the mRNA and protein expression levels of α-SMA and COL1A1 in TGF-β1-induced MRC-5 cells. Oridonin could attenuate pathological changes, including alveolar space collapse, emphysema, and infiltration of inflammatory cells induced by BLM. In addition, oridonin could significantly inhibit BLM-induced upregulation of α-SMA and COL1A1 and the phosphorylation of Smad2/3 in lung tissues of mice. CONCLUSIONS Oridonin could be used as a potential therapeutic agent in treatment for patients with IPF. The mechanisms of anti-fibrosis effect of oridonin might be inhibition of the TGF-β/Smad pathway.


On the Potential for Open-Endedness in Neural Networks.
Natural evolution gives the impression of leading to an open-ended process of increasing diversity and complexity. If our goal is to produce such open-endedness artificially, this suggests an approach driven by evolutionary metaphor. On the other hand, techniques from machine learning and artificial intelligence are often considered too narrow to provide the sort of exploratory dynamics associated with evolution. In this article, we hope to bridge that gap by reviewing common barriers to open-endedness in the evolution-inspired approach and how they are dealt with in the evolutionary case-collapse of diversity, saturation of complexity, and failure to form new kinds of individuality. We then show how these problems map onto similar ones in the machine learning approach, and discuss how the same insights and solutions that alleviated those barriers in evolutionary approaches can be ported over. At the same time, the form these issues take in the machine learning formulation suggests new ways to analyze and resolve barriers to open-endedness. Ultimately, we hope to inspire researchers to be able to interchangeably use evolutionary and gradient-descent-based machine learning methods to approach the design and creation of open-ended systems.


Search for new phenomena using the invariant mass distribution of same-flavour opposite-sign dilepton pairs in events with missing transverse momentum in s=13 Tepp collisions with the ATLAS detector.
A search for new phenomena in final states containing an e+e- or μ+μ- pair, jets, and large missing transverse momentum is presented. This analysis makes use of proton-proton collision data with an integrated luminosity of 36.1fb-1 , collected during 2015 and 2016 at a centre-of-mass energy s=13TeV with the ATLAS detector at the Large Hadron Collider. The search targets the pair production of supersymmetric coloured particles (squarks or gluinos) and their decays into final states containing an e+e- or μ+μ- pair and the lightest neutralino ( χ~10 ) via one of two next-to-lightest neutralino ( χ~20 ) decay mechanisms: χ~20→Zχ~10 , where the Z boson decays leptonically leading to a peak in the dilepton invariant mass distribution around the Z boson mass; and χ~20→ℓ+ℓ-χ~10 with no intermediate ℓ+ℓ- resonance, yielding a kinematic endpoint in the dilepton invariant mass spectrum. The data are found to be consistent with the Standard Model expectation. Results are interpreted using simplified models, and exclude gluinos and squarks with masses as large as 1.85 and 1.3 Te at 95% confidence level, respectively.


Widely tunable Vernier ring laser on hybrid silicon.
A hybrid silicon tunable Vernier ring laser is designed and fabricated by integration of two intra-cavity ring resonators, hybrid III-V-on-silicon gain elements, and resistive heaters for thermal tuning. Thermal tuning of more than 40 nm is demonstrated with side mode suppression ratio greater than 35 dB and linewidth of 338 kHz.


A database for global soil health assessment.
Field studies have been performed for decades to analyze effects of different management practices on agricultural soils and crop yields, but these data have never been combined together in a way that can inform current and future cropland management. Here, we collected, extracted, and integrated a database of soil health measurements conducted in the field from sites across the globe. The database, named SoilHealthDB, currently focuses on four main conservation management methods: cover crops, no-tillage, agro-forestry systems, and organic farming. These studies represent 354 geographic sites (i.e., locations with unique latitudes and longitudes) in 42 countries around the world. The SoilHealthDB includes 42 soil health indicators and 46 background indicators that describe factors such as climate, elevation, and soil type. A primary goal of this effort is to enable the research community to perform comprehensive analyses, e.g., meta-analyses, of soil health changes related to cropland conservation management. The database also provides a common framework for sharing soil health, and the scientific research community is encouraged to contribute their own measurements.


Structure of mouse major urinary protein genes: different splicing configurations in the 3'-non-coding region.
The multigene family which codes for the mouse major urinary proteins (MUPs) consists of approximately 35 genes. Most of these are members of two different groups, Group 1 and Group 2, which can be distinguished by nucleic acid hybridisation. Here we describe the structure of a Group 1 gene and show that two size classes of MUP mRNA which are found in mouse liver result from different splicing events in the 3'-non-coding region and contain different polyadenylation sites. Short mRNA is approximately 750 nucleotides long, contains six exons, and is the main product of the Group 2 genes. Long mRNA is approximately 880 nucleotides long, contains seven exons and is the main product of the Group 1 genes. Five exons and part of the sixth are common to long and short mRNA and contain the coding region. This codes for an acidic protein of 180 amino acids containing an 18 residue signal peptide. A comparison of the mouse sequence with a homologous rat alpha 2u-globulin sequence shows that the rate of evolutionary divergence of the two proteins has been high. Silent sites have diverged four times more rapidly than replacement sites, showing that there has been selection against change in the protein sequence.


Primary Health Care Consumers' Acceptance, Trust and Gender Preferences towards Omani Doctors.
The percentage of Omani physicians from total number of physicians working in the Sultanate tripled from 9% in 1999 to 27% in 2006 and is expected to increase to 50% by 2010. The study aimed to asses community attitudes towards Omani doctors and to investigate the different socio-demographic variables related to these attitudes. It was done in two selected Primary Health Care (PHC) facilities by simple random technique in Batinah region. Face-to-face interview was made on 305 randomly selected samples of PHC customers by trained researchers from Sultan Qaboos University (SQU). Omani Doctors Acceptance Scale (ODAS) was adapted and used to assess participants acceptance of the communication skills of the Omani doctor, care to the patient, absence of language barrier, competence level, preference to be seen by doctor from the same sex, embarrassment from seeing an Omani doctor, qualification, experience, knowledge and skills of the Omani experience of the Omani doctor, and trust on the Omani doctor. Chi squared tests of significance was used in analysis. Males reported more satisfaction about communication skills of the Omani doctors, whereas female respondents reported higher likelihood of being embarrassed from the latter. Elder age cohort, those reported ever treated by an Omani doctor, married respondents, and those of lower level of education were more likely to report higher level of acceptance than others. Those aged 26-40 and those above 40 years of age were 2.41 and 3.41 times higher than the youngest age cohort respectively. Similarly, older age cohort reported having more trust than the middle age respondents relatively to the youngest age group. The current study showed an accepted level of acceptance to Omani doctors. Looking for crucial issues in patient-doctor relationships as acceptance, satisfaction, trust, gender preference especially for PHC doctors ensure the continuity of care.


Molecular Dynamics Study of Mg2+/Li+ Separation via Biomimetic Graphene-Based Nanopores: The Role of Dehydration in Second Shell.
Residual Mg2+ reduces the performance of lithium-ion batteries. However, separating Mg2+ and Li+ is difficult because of their similar ionic properties. Inspired by the high selectivity of biological Mg2+ channels, this work utilizes atomistic simulations to investigate the ability of graphene-based nanopores with diameters of 0.789, 1.024, and 1.501 nm to separate Mg2+ and Li+ under a series of transmembrane voltages. We analyzed the spatial distribution of molecules in the nanopores' vicinity, structure properties of ionic hydration, and potential of mean force of ions traveling through the nanopores. Separation was mainly caused by the difference in dehydration between the second hydration shells of Mg2+ and Li+. When ions traveled through nanopores, Li+ had to overcome a greater energy barrier than Mg2+ because it had to shed more water molecules and break more hydrogen bonds in the second hydration shell compared with Mg2+. Moreover, the ionic Coulomb blockade of Mg2+ occurred near the pore mouth, impeding Li+ transport and increasing selectivity when the pore diameter decreased to subnanometer.


Bidirectional regulation of osteoclast function by nitric oxide synthase isoforms.
Nitric oxide (NO) produces rapid osteoclast detachment and contraction in vitro, and this effect is accompanied by a profound inhibition of bone resorption. Work by others has confirmed these findings in vivo: inhibition of NO synthase [NOS; L-arginine, NADPH: oxygen oxidoreductase (NO-forming), EC 184.108.40.206] in normal rats is followed by increased bone resorption reflected by a marked loss in bone mineral density. In our present study, immunocytochemistry and Northern blotting show the presence of the constitutive calcium-sensitive NOS isoform (cNOS) in normal rat osteoclasts and in the human preosteoclast cell line (FLG 29.1). The inducible NOS isoform (iNOS) was also clearly demonstrable in the rat cells especially after treatment with gamma interferon (IFN-gamma) and bacterial wall products [lipopolysaccharide (LPS)], while a basal level of transcript was detected in the untreated human preosteoclast line. However NADPH-diaphorase activity was intense only in neonatal rat osteoclasts attached to bone, perhaps reflecting either enhancement of cNOS activity by calcium or increased amounts of the inducible isoform in activated osteoclasts in situ compared with isolated neonatal rat osteoclasts. These actively resorb devitalized bone but the untreated cells contain relatively low levels of NOS; they are extremely sensitive to inhibition by NO. The iNOS inhibitor aminoguanidine markedly enhances in vitro resorption by activated NOS-rich chick osteoclasts and by normal rat osteoclasts treated with LPS or IFN-gamma. In contrast, the nonselective NOS inhibitor NG-monomethyl-L-arginine inhibits resorption by untreated neonatal rat osteoclasts. Thus, osteoclast function may require intermittent calcium-stimulated increases in NO production by cNOS against a basal inhibitory background activity of the iNOS isoform. However, bone resorption depends on precursor replication and on the activity of the mature cells, and we found that the NO donor 3-morpholinosydnonimine (SIN-1) (50 microM) profoundly depressed replication in the human preosteoclast line. Taken together, these results strongly suggest that NO maintains a central control of bone resorption in both avian and mammalian species by exerting a powerful tonic restraint of osteoclast numbers and activity. The presence of NOS in human cells implies a similar function in man and that conventional views of calcium homoeostasis and skeletal metabolism will need substantial revision. Since NO also influences behavior of the osteoblast, the bone-forming cell, in vitro, a similar effect in vivo might imply a general influence on bone remodeling.


Ajoene, a sulfur-rich molecule from garlic, inhibits genes controlled by quorum sensing.
In relation to emerging multiresistant bacteria, development of antimicrobials and new treatment strategies of infections should be expected to become a high-priority research area. Quorum sensing (QS), a communication system used by pathogenic bacteria like Pseudomonas aeruginosa to synchronize the expression of specific genes involved in pathogenicity, is a possible drug target. Previous in vitro and in vivo studies revealed a significant inhibition of P. aeruginosa QS by crude garlic extract. By bioassay-guided fractionation of garlic extracts, we determined the primary QS inhibitor present in garlic to be ajoene, a sulfur-containing compound with potential as an antipathogenic drug. By comprehensive in vitro and in vivo studies, the effect of synthetic ajoene toward P. aeruginosa was elucidated. DNA microarray studies of ajoene-treated P. aeruginosa cultures revealed a concentration-dependent attenuation of a few but central QS-controlled virulence factors, including rhamnolipid. Furthermore, ajoene treatment of in vitro biofilms demonstrated a clear synergistic, antimicrobial effect with tobramycin on biofilm killing and a cease in lytic necrosis of polymorphonuclear leukocytes. Furthermore, in a mouse model of pulmonary infection, a significant clearing of infecting P. aeruginosa was detected in ajoene-treated mice compared to a nontreated control group. This study adds to the list of examples demonstrating the potential of QS-interfering compounds in the treatment of bacterial infections.


Levitation in physics.
Several physical effects allow free floatation of solid and even liquid matter. Materials may be levitated by a jet of gas, by intense sound waves, or by beams of laser light. In addition, conductors levitate in strong radio-frequency fields, charged particles in alternating electric fields, and magnets above superconductors or vice versa. Although levitation by means of ferromagnets is unstable, supper-conductors may be suspended both above and below a magnet as a result of flux pinning. Levitation is used for containerless processing and investigation of materials, for frictionless bearings and high-speed ground transportation, for spectroscopy of single atoms and microparticles, and for demonstrating superconductivity in the new oxide superconductors.


Regulation of rat hepatic sulfotransferase gene expression by glucocorticoid hormones.
Because hormones have been implicated in the molecular regulation of the sulfotransferase multigene family, the effects of glucocorticoid and antiglucocorticoid hormones on rat hepatic hydroxysteroid sulfotransferase-a and aryl sulfotransferase IV gene expression were investigated in vivo and in primary rat hepatocyte culture. Adult male Sprague-Dawley rats were treated for three consecutive days with 2% Tween-20 vehicle, or 100 mg/kg of dexamethasone, betamethasone, hydrocortisone, or triamcinolone acetonide. Betamethasone and triamcinolone acetonide significantly increased hepatic aryl sulfotransferase IV mRNA to levels that were approximately 252% and approximately 452% of control, respectively. Dexamethasone significantly increased hydroxysteroid sulfotransferase-a mRNA and protein to levels that were approximately 150% and approximately 316% of control, respectively. In contrast, in vivo treatment with hydroxysteroid sulfotransferase-a substrate dehydroepiandrosterone significantly decreased hydroxysteroid sulfotransferase-a mRNA levels (by approximately 55% relative to control). To determine if glucocorticoid mediated changes in sulfotransferase expression occurred as a result of direct effects on the hepatocyte, studies were performed in primary rat hepatocyte culture. Triamcinolone acetonide and betamethasone increased sulfotransferase mRNA expression in hepatocyte culture and hydrocortisone proved to be a less effective inducer. Effects of glucocorticoids on sulfotransferase gene expression were compared with glucocorticoid effects on tyrosine aminotransferase expression, a gene known to be regulated by a classical glucocorticoid receptor-mediated mechanism. Dexamethasone produced maximal increases in aryl sulfotransferase IV and tyrosine aminotransferase mRNA levels when added to culture medium at a concentration of 10(-7) M, whereas hydroxysteroid sulfotransferase-a mRNA levels continued to increase through a dexamethasone concentration of 10(-5) M. Treatment of hepatocytes with the antiglucocorticoid RU-486 (10(-5) M) inhibited dexamethasone-stimulated aryl sulfotransferase and tyrosine amino-transferase mRNA expression by approximately 48% and approximately 35%, respectively, but had less effect on hydroxysteroid sulfotransferase mRNA expression. These results suggest that glucocorticoids regulate rat hepatic aryl sulfotransferase IV and hydroxysteroid sulfotransferase-a via classical glucocorticoid receptor-mediated and non-classical mechanisms, respectively.


Crossmodal associations between flavoured milk solutions and musical notes.
A number of crossmodal associations have now been described in the context of food evaluation, such as between tastes or flavours and musical notes (Crisinel & Spence, 2010b). Here we extend these findings by presenting flavoured milk solutions of varying fat contents. The participants in the present study matched a series of milk samples to musical notes. They chose both the pitch and the class of instrument that they felt was most appropriate for each sample. Participants also rated various features of the samples, such as their pleasantness, bitterness, or familiarity. Consistent associations between flavours and both pitch and instruments were confirmed. However, fat content did not influence either the pitch or instrument chosen, although it did have an effect on pleasantness and intensity ratings. These results demonstrate that flavour-sound associations are not restricted to basic tastes and flavours presented individually, but are still present in the context of more complex food stimuli. The present study opens the way for further investigations into the nature and characteristics of crossmodal associations (or correspondences) between more complex stimuli, both in the auditory and gustatory/olfactory modalities. This novel approach could lead to new insights into the representation of chemosensory stimuli in humans.


Effects of gold nanorods modified with antiepidermal growth factor receptor monoclonal antibody on laryngeal cancer cells.
We aimed to evaluate the photothermal effects of gold nanorods (GNRs) modified with antiepidermal growth factor receptor (EGFR) monoclonal antibody (mAb) on laryngeal cancer cells. EGFR protein expressions in HEP-2 cells, and normal laryngeal epithelial and laryngeal cancer tissues were detected by western blot. The cytotoxicity against HEP-2 and BEAS-2B cells was tested by MTT assay, and the photothermal effects were assessed by near-infrared (NIR) irradiation. The apoptosis of HEP-2 cells was detected by flow cytometry. EGFR expression in laryngeal cancer tissues was significantly higher than that in normal tissues (P < 0.05). The inhibitory effects of GNRs and anti-EGFR mAb/GNRs on the apoptosis of HEP-2 and BEAS-2B cells were enhanced with increasing dose. AntiEGFR mAb/GNRs were more cytotoxic to HEP-2 cells and less cytotoxic to BEAS-2B cells than GNRs. NIR irradiation inhibited cell proliferation, which was enhanced with rising power, accompanied by continuously dropping survival rate. The apoptosis rate of the anti-EGFR mAb/GNRs group was significantly higher than that of the GNRs group, and the apoptosis rate of the irradiation + antiEGFR mAb/GNRs group also significantly exceeded that of the irradiation + GNRs group (P < 0.05). Anti-EGFR mAb/GNRs promoted HEP-2 cell apoptosis more evidently than GNRs did. Functional modification of GNRs augmented the targeted specificity to cancer cells, biocompatibility, and stability. Anti-EGFR mAb/GNRs have great potential in biomedical fields.


It's surprisingly nice to hear you: Misunderstanding the impact of communication media can lead to suboptimal choices of how to connect with others.
Positive social connections improve wellbeing. Technology increasingly affords a wide variety of media that people can use to connect with others, but not all media strengthen social connection equally. Optimizing wellbeing, therefore, requires choosing how to connect with others wisely. We predicted that people's preferences for communication media would be at least partly guided by the expected costs and benefits of the interaction-specifically, how awkward or uncomfortable the interaction would be and how connected they would feel to their partner-but that people's expectations would consistently undervalue the overall benefit of more intimate voice-based interactions. We tested this hypothesis by asking participants in a field experiment to reconnect with an old friend either over the phone or e-mail, and by asking laboratory participants to "chat" with a stranger over video, voice, or text-based media. Results indicated that interactions including voice (phone, video chat, and voice chat) created stronger social bonds and no increase in awkwardness, compared with interactions including text (e-mail, text chat), but miscalibrated expectations about awkwardness or connection could lead to suboptimal preferences for text-based media. Misunderstanding the consequences of using different communication media could create preferences for media that do not maximize either one's own or others' wellbeing. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Erythropoietin regulates POMC expression via STAT3 and potentiates leptin response.
The arcuate nucleus of the hypothalamus is essential for metabolic homeostasis and responds to leptin by producing several neuropeptides including proopiomelanocortin (POMC). We previously reported that high-dose erythropoietin (Epo) treatment in mice while increasing hematocrit reduced body weight, fat mass, and food intake and increased energy expenditure. Moreover, we showed that mice with Epo receptor (EpoR) restricted to erythroid cells (ΔEpoRE) became obese and exhibited decreased energy expenditure. Epo/EpoR signaling was found to promote hypothalamus POMC expression independently from leptin. Herein we used WT and ΔEpoRE mice and hypothalamus-derived neural culture system to study the signaling pathways activated by Epo in POMC neurons. We show that Epo stimulation activated STAT3 signaling and upregulated POMC expression in WT neural cultures. ΔEpoRE mice hypothalamus showed reduced POMC levels and lower STAT3 phosphorylation, with and without leptin treatment, compared to in vivo and ex vivo WT controls. Collectively, these data show that Epo regulates hypothalamus POMC expression via STAT3 activation, and provide a previously unrecognized link between Epo and leptin response.


Between a rock and a hard place: Economic expansion and social responsibility in UK media discourses on the global alcohol industry.
Transnational alcohol corporations (TACs) employ a range of strategies to achieve their business objectives, including attempts to frame perceptions of their activities in media debates. TACs aim to achieve a favourable regulatory environment by presenting themselves as socially responsible actors. However, the need to secure financial investment means they must also emphasise their potential for growth. This article investigates tensions between these objectives in coverage of the global alcohol industry in the UK print media. This article examines coverage of the world's four largest TACs in five British daily newspapers and one industry publication between March 2012 and February 2013. 477 articles were identified for analysis through keyword searches of the LexisNexis database. Thematic coding of articles was conducted using Nvivo software. Two conflicting framings of the alcohol industry emerge from our analysis. The first presents TACs as socially responsible actors; key partners to government in reducing alcohol-related harms. This is targeted at policy-makers and the public in an attempt to shape policy debates. The second framing highlights TACs' potential for economic growth by establishing new markets and identifying new customer bases. This is targeted at an audience of potential investors. A fundamental contradiction lies at the heart of these framings, reflecting the tensions that exist between TACs' political and financial strategies. Alcohol industry involvement in policy-making thus involves a fundamental conflict of interests. Consequently, the UK government should reassess the prominence it currently affords to the industry in the development and delivery of alcohol policy.


Mass spectrometric studies of non-covalent compounds: why supramolecular chemistry in the gas phase?
Supramolecular chemistry has progressed quite a long way in recent decades. The examination of non-covalent bonds became the focus of research once the paradigm that the observed properties of a molecule are due to the molecule itself was revised, and researchers became aware of the often quite significant influence of the environment. Mass spectrometry and gas-phase chemistry are ideally suited to study the intrinsic properties of a molecule or a complex without interfering effects from the environment, such as solvation and the effects of counterions present in solution. A comparison of data from the gas phase, i.e. the intrinsic properties, with results from condensed phase, i.e. the properties influenced by the surroundings of the molecule, can consequently contribute significantly to the understanding of non-covalent bonds. This review provides insight into the often-underestimated power of mass spectrometry for the investigation of supramolecules. Through example studies, several aspects are discussed, including determination of structure in solution and the gas phase, ion mobility studies to reveal the formation of zwitterionic structures, stereochemical issues, analysis of reactivity of supramolecular compounds in the condensed and in the gas phase, and the determination of thermochemical data.


Effects from diet-induced gut microbiota dysbiosis and obesity can be ameliorated by fecal microbiota transplantation: A multiomics approach.
Obesity and its comorbidities are currently considered an epidemic, and the involved pathophysiology is well studied. Hypercaloric diets are tightly related to the obesity etiology and also cause alterations in gut microbiota functionality. Diet and antibiotics are known to play crucial roles in changes in the microbiota ecosystem and the disruption of its balance; therefore, the manipulation of gut microbiota may represent an accurate strategy to understand its relationship with obesity caused by diet. Fecal microbiota transplantation, during which fecal microbiota from a healthy donor is transplanted to an obese subject, has aroused interest as an effective approach for the treatment of obesity. To determine its success, a multiomics approach was used that combined metagenomics and metaproteomics to study microbiota composition and function. To do this, a study was performed in rats that evaluated the effect of a hypercaloric diet on the gut microbiota, and this was combined with antibiotic treatment to deplete the microbiota before fecal microbiota transplantation to verify its effects on gut microbiota-host homeostasis. Our results showed that a high-fat diet induces changes in microbiota biodiversity and alters its function in the host. Moreover, we found that antibiotics depleted the microbiota enough to reduce its bacterial content. Finally, we assessed the use of fecal microbiota transplantation as a complementary obesity therapy, and we found that it reversed the effects of antibiotics and reestablished the microbiota balance, which restored normal functioning and alleviated microbiota disruption. This new approach could be implemented to support the dietary and healthy habits recommended as a first option to maintain the homeostasis of the microbiota.


Comparison of Proteomic Responses as Global Approach to Antibiotic Mechanism of Action Elucidation.
New antibiotics are urgently needed to address the mounting resistance challenge. In early drug discovery, one of the bottlenecks is the elucidation of targets and mechanisms. To accelerate antibiotic research, we provide a proteomic approach for the rapid classification of compounds into those with precedented and unprecedented modes of action. We established a proteomic response library of Bacillus subtilis covering 91 antibiotics and comparator compounds, and a mathematical approach was developed to aid data analysis. Comparison of proteomic responses (CoPR) allows the rapid identification of antibiotics with dual mechanisms of action as shown for atypical tetracyclines. It also aids in generating hypotheses on mechanisms of action as presented for salvarsan (arsphenamine) and the antirheumatic agent auranofin, which is under consideration for repurposing. Proteomic profiling also provides insights into the impact of antibiotics on bacterial physiology through analysis of marker proteins indicative of the impairment of cellular processes and structures. As demonstrated for trans-translation, a promising target not yet exploited clinically, proteomic profiling supports chemical biology approaches to investigating bacterial physiology.


A core outcome set for pre-eclampsia research: an international consensus development study.
To develop a core outcome set for pre-eclampsia. Consensus development study. International. Two hundred and eight-one healthcare professionals, 41 researchers and 110 patients, representing 56 countries, participated. Modified Delphi method and Modified Nominal Group Technique. A long-list of 116 potential core outcomes was developed by combining the outcomes reported in 79 pre-eclampsia trials with those derived from thematic analysis of 30 in-depth interviews of women with lived experience of pre-eclampsia. Forty-seven consensus outcomes were identified from the Delphi process following which 14 maternal and eight offspring core outcomes were agreed at the consensus development meeting. Maternal core outcomes: death, eclampsia, stroke, cortical blindness, retinal detachment, pulmonary oedema, acute kidney injury, liver haematoma or rupture, abruption, postpartum haemorrhage, raised liver enzymes, low platelets, admission to intensive care required, and intubation and ventilation. Offspring core outcomes: stillbirth, gestational age at delivery, birthweight, small-for-gestational-age, neonatal mortality, seizures, admission to neonatal unit required and respiratory support. The core outcome set for pre-eclampsia should underpin future randomised trials and systematic reviews. Such implementation should ensure that future research holds the necessary reach and relevance to inform clinical practice, enhance women's care and improve the outcomes of pregnant women and their babies. 281 healthcare professionals, 41 researchers and 110 women have developed #preeclampsia core outcomes @HOPEoutcomes @jamesmnduffy. [Correction added on 29 June 2020, after first online publication: the order has been corrected.].


Hospital marketing and the Internet: the adoption of an innovation.
Given the manner in which the Internet permeates today's society, it is easy to forget that the Internet as we know it is only about a decade old. Due to its newness, the Internet has provided an opportunity to view the manner in which marketers move to adopt such an innovation. To that end, since 1995 a series of studies has tracked the adoption and use of the Internet by hospital marketers. In addition to simply investigating the number of hospitals that utilize the Internet in their marketing efforts, the studies have addressed such questions as: How are hospitals using the Internet to market themselves?, What roadblocks have held hospitals back from adopting the Internet as a marketing tool?, and How happy are hospitals with their Internet investment? This manuscript details the most recent in this series of research studies. In addition, the authors compare the results of this study, conducted in the fall of 2002, with the results from the previous studies. As a result, this study provides a unique opportunity to observe the actual adoption of an innovation, the Internet, by hospital marketing professionals.


Tracking the evolution of a hydrothermal event plume with a RAFOS neutrally buoyant drifter
The migration and evolution of a deep ocean hydrothermal event plume were tracked with a neutrally buoyant RAFOS float. The float remained entrained in the plume for 60 days, and the plume vorticity was calculated directly from the anticyclonic motion of the float. Concentrations of suspended particles, particulate iron, and dissolved manganese in the plume did not decay significantly during the 60 days, which indicates that event plumes would be easily detectable a year after formation.


Engineering Multidimensional Evolutionary Forces to Combat Cancer.
With advances in technology and bioinformatics, we are now positioned to view and manage cancer through an evolutionary lens. This perspective is critical as our appreciation for the role of tumor heterogeneity, tumor immune compartment, and tumor microenvironment on cancer pathogenesis and evolution grows. Here, we explore recent knowledge on the evolutionary basis of cancer pathogenesis and progression, viewing tumors as multilineage, multicomponent organisms whose growth is regulated by subcomponent fitness relationships. We propose reconsidering some current tenets of the cancer management paradigm in order to take better advantage of crucial fitness relationships to improve outcomes of patients with cancer. SIGNIFICANCE: Tumor and tumor immune compartment and microenvironment heterogeneity, and their evolution, are critical disease features that affect treatment response. The impact and interplay of these components during treatment are viable targets to improve clinical response. In this article, we consider how tumor cells, the tumor immune compartment and microenvironment, and epigenetic factors interact and also evolve during treatment. We evaluate the convergence of these factors and suggest innovative treatment concepts that leverage evolutionary relationships to limit tumor growth and drug resistance.


Enteric nervous system stem cells associated with thickened extrinsic fibers in short segment aganglionic Hirschsprung's disease gut are absent in the total colonic and intestinal variants of disease.
Despite current treatments patients with Hirschsprung's disease (HSCR) suffer significant long-term morbidity. Therefore, there is increasing interest in adjunctive therapies, such as using enteric nervous system stem cells (ENSSC), isolated from typical aganglionic bowel. The source of these cells is unclear however it is hypothesized that they are present in the thickened nerve trunks in aganglionic short and long segment HSCR gut. These cells should therefore be absent in total colonic and pan intestinal HSCR where these thickened fibers are absent. Cells were isolated from samples of short segment HSCR gut (n=18) and total colonic and total intestinal HSCR gut (n=2). Acetylcholinesterase histochemistry confirmed the presence/absence of thickened nerve trunks. P75 immunofluorescence highlighted ENSSC at isolation and after 10days in culture in both groups. ENSSC were not isolated or cultured from total colonic and total intestinal HSCR gut where thickened nerve trunks were absent. In contrast 10.0% (+/-1.9 SEM) of cells from short segment HSCR gut were ENSSC at isolation rising to 22.7% (+/-2.9 SEM) after 10days in culture. These results associate ENSCC with thickened nerve trunks and also suggest that the aganglionic bowel segment in total colonic and intestinal HSCR cannot be used as a source of ENSCC for adjunctive therapy.


Transplantation in patients with SCID: mismatched related stem cells or unrelated cord blood?
Pediatric patients with SCID constitute medical emergencies. In the absence of an HLA-identical hematopoietic stem cell (HSC) donor, mismatched related-donor transplantation (MMRDT) or unrelated-donor umbilical cord blood transplantation (UCBT) are valuable treatment options. To help transplantation centers choose the best treatment option, we retrospectively compared outcomes after 175 MMRDTs and 74 UCBTs in patients with SCID or Omenn syndrome. Median follow-up time was 83 months and 58 months for UCBT and MMRDT, respectively. Most UCB recipients received a myeloablative conditioning regimen; most MMRDT recipients did not. UCB recipients presented a higher frequency of complete donor chimerism (P = .04) and faster total lymphocyte count recovery (P = .04) without any statistically significance with the preparative regimen they received. The MMRDT and UCBT groups did not differ in terms of T-cell engraftment, CD4(+) and CD3(+) cell recoveries, while Ig replacement therapy was discontinued sooner after UCBT (adjusted P = .02). There was a trend toward a greater incidence of grades II-IV acute GVHD (P = .06) and more chronic GVHD (P = .03) after UCBT. The estimated 5-year overall survival rates were 62% ± 4% after MMRDT and 57% ± 6% after UCBT. For children with SCID and no HLA-identical sibling donor, both UCBT and MMRDT represent available HSC sources for transplantation with quite similar outcomes.


C-phycocyanin: a biliprotein with antioxidant, anti-inflammatory and neuroprotective effects.
Phycocyanin (Pc) is a phycobiliprotein that has been recently reported to exhibit a variety of pharmacological properties. In this regard, antioxidant, anti-inflammatory, neuroprotective and hepatoprotective effects have been experimentally attributed to Pc. When it was evaluated as an antioxidant in vitro, it was able to scavenge alkoxyl, hydroxyl and peroxyl radicals and to react with peroxinitrite (ONOO(-);) and hypochlorous acid (HOCl). Pc also inhibits microsomal lipid peroxidation induced by Fe(+2)-ascorbic acid or the free radical initiator 2,2' azobis (2-amidinopropane) hydrochloride (AAPH). Furthermore, it reduces carbon tetrachloride (CCl(4))-induced lipid peroxidation in vivo. Pc has been evaluated in twelve experimental models of inflammation and exerted anti-inflammatory effects in a dose-dependent fashion in all of these. Thus, Pc reduced edema, histamine (Hi) release, myeloperoxidase (MPO) activity and the levels of prostaglandin (PGE(2)) and leukotriene (LTB(4)) in the inflamed tissues. These anti-inflammatory effects of Pc can be due to its scavenging properties toward oxygen reactive species (ROS) and its inhibitory effects on cyclooxygenase 2 (COX-2) activity and on Hi release from mast cells. Pc also reduced the levels of tumor necrosis factor (TNF-alpha) in the blood serum of mice treated with endotoxin and it showed neuroprotective effects in rat cerebellar granule cell cultures and in kainate-induced brain injury in rats.


axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase.
Using a sensitive transfection-tumorigenicity assay, we have isolated a novel transforming gene from the DNA of two patients with chronic myelogenous leukemia. Sequence analysis indicates that the product of this gene, axl, is a receptor tyrosine kinase. Overexpression of axl cDNA in NIH 3T3 cells induces neoplastic transformation with the concomitant appearance of a 140-kDa axl tyrosine-phosphorylated protein. Expression of axl cDNA in the baculovirus system results in the expression of the appropriate recombinant protein that is recognized by antiphosphotyrosine antibodies, confirming that the axl protein is a tyrosine kinase. The juxtaposition of fibronectin type III and immunoglobulinlike repeats in the extracellular domain, as well as distinct amino acid sequences in the kinase domain, indicate that the axl protein represents a novel subclass of receptor tyrosine kinases.


Context-specific energy strategies: coupling energy system visions with feasible implementation scenarios.
Conventional energy strategy defines an energy system vision (the goal), energy scenarios with technical choices and an implementation mechanism (such as economic incentives). Due to the lead of a generic vision, when applied in a specific regional context, such a strategy can deviate from the optimal one with, for instance, the lowest environmental impacts. This paper proposes an approach for developing energy strategies by simultaneously, rather than sequentially, combining multiple energy system visions and technically feasible, cost-effective energy scenarios that meet environmental constraints at a given place. The approach is illustrated by developing a residential heat supply strategy for a Swiss region. In the analyzed case, urban municipalities should focus on reducing heat demand, and rural municipalities should focus on harvesting local energy sources, primarily wood. Solar thermal units are cost-competitive in all municipalities, and their deployment should be fostered by information campaigns. Heat pumps and building refurbishment are not competitive; thus, economic incentives are essential, especially for urban municipalities. In rural municipalities, wood is cost-competitive, and community-based initiatives are likely to be most successful. Thus, the paper shows that energy strategies should be spatially differentiated. The suggested approach can be transferred to other regions and spatial scales.


Long-term mortality of hospitalized pneumonia in the EPIC-Norfolk cohort.
Little is known about cause-specific long-term mortality beyond 30 days in pneumonia. We aimed to compare the mortality of patients with hospitalized pneumonia compared to age- and sex-matched controls beyond 30 days. Participants were drawn from the European Prospective Investigation into Cancer (EPIC)-Norfolk prospective population study. Hospitalized pneumonia cases were identified from record linkage (ICD-10: J12-J18). For this study we excluded people with hospitalized pneumonia who died within 30 days. Each case identified was matched to four controls and followed up until the end June 2012 (total 15 074 person-years, mean 6·1 years, range 0·08-15·2 years). Cox regression models were constructed to examine the all-cause, respiratory and cardiovascular mortality using date of pneumonia onset as baseline with binary pneumonia status as exposure. A total of 2465 men and women (503 cases, 1962 controls) [mean age (s.d.) 64·5 (8·3) years] were included in the study. Between a 30-day to 1-year period, hazard ratios (HRs) of all-cause and cardiovascular mortality were 7·3 [95% confidence interval (CI) 5·4-9·9] and 5·9 (95% CI 3·5-9·7), respectively (with very few respiratory deaths within the same period) in cases compared to controls after adjusting for age, sex, asthma, smoking status, pack years, systolic and diastolic blood pressure, diabetes, physical activity, waist-to-hip ratio, prevalent cardiovascular and respiratory diseases. All outcomes assessed also showed increased risk of death in cases compared to controls after 1 year; respiratory cause of death being the most significant during that period (HR 16·4, 95% CI 8·9-30·1). Hospitalized pneumonia was associated with increased all-cause and specific-cause mortality beyond 30 days.


Improving quality of stroke care through benchmarking center performance: why focusing on outcomes is not enough.
Between-center variation in outcome may offer opportunities to identify variation in quality of care. By intervening on these quality differences, patient outcomes may be improved. However, whether observed differences in outcome reflect the true quality improvement potential is not known for many diseases. Therefore, we aimed to analyze the effect of differences in performance on structure and processes of care, and case-mix on between-center differences in outcome after endovascular treatment (EVT) for ischemic stroke. In this observational cohort study, ischemic stroke patients who received EVT between 2014 and 2017 in all 17 Dutch EVT-centers were included. Primary outcome was the modified Rankin Scale, ranging from 0 (no symptoms) to 6 (death), at 90 days. We used random effect proportional odds regression modelling, to analyze the effect of differences in structure indicators (center volume and year of admission), process indicators (time to treatment and use of general anesthesia) and case-mix, by tracking changes in tau2, which represents the amount of between-center variation in outcome. Three thousand two hundred seventy-nine patients were included. Performance on structure and process indicators varied significantly between EVT-centers (P < 0.001). Predicted probability of good functional outcome (modified Rankin Scale 0-2 at 90 days), which can be interpreted as an overall measure of a center's case-mix, varied significantly between 17 and 50% across centers. The amount of between-center variation (tau2) was estimated at 0.040 in a model only accounting for random variation. This estimate more than doubled after adding case-mix variables (tau2: 0.086) to the model, while a small amount of between-center variation was explained by variation in performance on structure and process indicators (tau2: 0.081 and 0.089, respectively). This indicates that variation in case-mix affects the differences in outcome to a much larger extent. Between-center variation in outcome of ischemic stroke patients mostly reflects differences in case-mix, rather than differences in structure or process of care. Since the latter two capture the real quality improvement potential, these should be used as indicators for comparing center performance. Especially when a strong association exists between those indicators and outcome, as is the case for time to treatment in ischemic stroke.


Experimental Onchocerca volvulus infections in mangabey monkeys (Cercocebus atys) compared to infections in humans and chimpanzees (Pan troglodytes).
Three chimpanzees, three mangabey monkeys (Cercocebus atys), and 14 patas monkeys (Erythrocebus patas) were inoculated with L3 Onchocerca volvulus of Guatemalan origin. One chimpanzee and two mangabey monkeys developed antibody activity to at least three different antigens. Both mangabey monkeys recognized a 20 kDa antigen 3.5-5 months post-inoculation, and the monkeys and the chimpanzee developed antibody activity to 14 and 22 kDa antigens 7.5-13 months post-inoculation. One mangabey monkey and the chimpanzee became microfilaria-positive in skin snips at 16 and 21 months post-inoculation, respectively. Antibody activity to the 20 kDa antigen in the mangabey monkeys is noteworthy because of the prominence of this antigen among putatively immune persons living in onchocerciasis-endemic areas. The two mangabey monkeys responded parasitologically in a manner comparable to immune humans. No microfilariae were detected in one monkey and only scant numbers of microfilariae were observed in the second. The mangabey monkey may be a good animal model for the study of onchocerciasis.


Energy-Saving Robust Saturated Control for Active Suspension Systems via Employing Beneficial Nonlinearity and Disturbance.
This article proposes a novel control framework for active suspension systems by purposely employing beneficial nonlinearity and a useful disturbance effect for control performance enhancement. To this aim, a novel amplitude-limited PD-SMC control scheme is established to ensure a stable performance-oriented tracking control of the overall closed-loop system. Importantly, different from most existing control methods, the designed tracking controller purposely employs beneficial nonlinear stiffness and damping of a novel bioinspired reference model and deliberately utilizes useful disturbance response on the active suspension system, so as to improve the convergence speed and reduce control energy cost simultaneously. The asymptotic stability is theoretically proved by a rigorous Lyapunov-based analysis. To the best of our knowledge, this is a unique control scheme for active suspension systems which can technically take several critical control practice issues into account with guaranteed excellent performance simultaneously, including energy savings, actuator saturation, unexpected disturbances, etc. The superior performance is well validated with a series of experiments, and carefully compared to several existing control methods. The results of this study would definitely present a unique insight and an alternative approach to active controller designs via exploiting beneficial nonlinear and disturbance effects for better control performance and lower energy cost simultaneously.


Effect of microencapsulation shear stress on the structural integrity and biological activity of a model monoclonal antibody, trastuzumab.
The aim of the present study was to investigate the influence of process shear stressors on the stability of a model monoclonal antibody, trastuzumab. Trastuzumab, at concentrations of 0.4-4.0 mg/mL, was subjected to sonication, freeze-thaw, lyophilisation, spray drying and was encapsulated into micro- and nanoparticles. The stressed samples were analysed for structural integrity by gel electrophoresis, SDS-PAGE, and size exclusion chromatography (SEC), while the conformational integrity was analysed by circular dichroism (CD). Biological activity of the stressed trastuzumab was investigated by measuring the inhibition of cell proliferation of HER-2 expressing cell lines. Results show that trastuzumab was resistant to the process shear stresses applied and to microencapsulation processes. At the lowest concentration of 0.4 mg/mL, a low percent ( 0.05). The results of this study conclude that trastuzumab may be resistant to various processing stresses. These findings have important implications with respect to pharmaceutical processing of monoclonal antibodies.


De novo transcriptome of Ischnura elegans provides insights into sensory biology, colour and vision genes.
There is growing interest in odonates (damselflies and dragonflies) as model organisms in ecology and evolutionary biology but the development of genomic resources has been slow. So far only one draft genome (Ladona fulva) and one transcriptome assembly (Enallagma hageni) have been published. Odonates have some of the most advanced visual systems among insects and several species are colour polymorphic, and genomic and transcriptomic data would allow studying the genomic architecture of these interesting traits and make detailed comparative studies between related species possible. Here, we present a comprehensive de novo transcriptome assembly for the blue-tailed damselfly Ischnura elegans (Odonata: Coenagrionidae) built from short-read RNA-seq data. The transcriptome analysis in this paper provides a first step towards identifying genes and pathways underlying the visual and colour systems in this insect group. Illumina RNA sequencing performed on tissues from the head, thorax and abdomen generated 428,744,100 paired-ends reads amounting to 110 Gb of sequence data, which was assembled de novo with Trinity. A transcriptome was produced after filtering and quality checking yielding a final set of 60,232 high quality transcripts for analysis. CEGMA software identified 247 out of 248 ultra-conserved core proteins as 'complete' in the transcriptome assembly, yielding a completeness of 99.6%. BLASTX and InterProScan annotated 55% of the assembled transcripts and showed that the three tissue types differed both qualitatively and quantitatively in I. elegans. Differential expression identified 8,625 transcripts to be differentially expressed in head, thorax and abdomen. Targeted analyses of vision and colour functional pathways identified the presence of four different opsin types and three pigmentation pathways. We also identified transcripts involved in temperature sensitivity, thermoregulation and olfaction. All these traits and their associated transcripts are of considerable ecological and evolutionary interest for this and other insect orders. Our work presents a comprehensive transcriptome resource for the ancient insect order Odonata and provides insight into their biology and physiology. The transcriptomic resource can provide a foundation for future investigations into this diverse group, including the evolution of colour, vision, olfaction and thermal adaptation.


Holocene winter climate variability in mid-latitude western North America.
Water resources in western North America depend on winter precipitation, yet our knowledge of its sensitivity to climate change remains limited. Similarly, understanding the potential for future loss of winter snow pack requires a longer perspective on natural climate variability. Here we use stable isotopes from a speleothem in southwestern Oregon to reconstruct winter climate change for much of the past 13,000 years. We find that on millennial time scales there were abrupt transitions between warm-dry and cold-wet regimes. Temperature and precipitation changes on multi-decadal to century timescales are consistent with ocean-atmosphere interactions that arise from mechanisms similar to the Pacific Decadal Oscillation. Extreme cold-wet and warm-dry events that punctuated the Holocene appear to be sensitive to solar forcing, possibly through the influence of the equatorial Pacific on the winter storm tracks reaching the US Pacific Northwest region.


GPU-based fast Monte Carlo dose calculation for proton therapy.
Accurate radiation dose calculation is essential for successful proton radiotherapy. Monte Carlo (MC) simulation is considered to be the most accurate method. However, the long computation time limits it from routine clinical applications. Recently, graphics processing units (GPUs) have been widely used to accelerate computationally intensive tasks in radiotherapy. We have developed a fast MC dose calculation package, gPMC, for proton dose calculation on a GPU. In gPMC, proton transport is modeled by the class II condensed history simulation scheme with a continuous slowing down approximation. Ionization, elastic and inelastic proton nucleus interactions are considered. Energy straggling and multiple scattering are modeled. Secondary electrons are not transported and their energies are locally deposited. After an inelastic nuclear interaction event, a variety of products are generated using an empirical model. Among them, charged nuclear fragments are terminated with energy locally deposited. Secondary protons are stored in a stack and transported after finishing transport of the primary protons, while secondary neutral particles are neglected. gPMC is implemented on the GPU under the CUDA platform. We have validated gPMC using the TOPAS/Geant4 MC code as the gold standard. For various cases including homogeneous and inhomogeneous phantoms as well as a patient case, good agreements between gPMC and TOPAS/Geant4 are observed. The gamma passing rate for the 2%/2 mm criterion is over 98.7% in the region with dose greater than 10% maximum dose in all cases, excluding low-density air regions. With gPMC it takes only 6-22 s to simulate 10 million source protons to achieve ∼1% relative statistical uncertainty, depending on the phantoms and energy. This is an extremely high efficiency compared to the computational time of tens of CPU hours for TOPAS/Geant4. Our fast GPU-based code can thus facilitate the routine use of MC dose calculation in proton therapy.