Effects of interactive physical-activity video-game training on physical and cognitive function in older adults.
The purpose of the present study was to assess the potential of exergame training based on physically simulated sport play as a mode of physical activity that could have cognitive benefits for older adults. If exergame play has the cognitive benefits of conventional physical activity and also has the intrinsic attractiveness of video games, then it might be a very effective way to induce desirable lifestyle changes in older adults. To examine this issue, the authors developed an active video game training program using a pretest-training-posttest design comparing an experimental group (24 × 1 hr of training) with a control group without treatment. Participants completed a battery of neuropsychological tests, assessing executive control, visuospatial functions, and processing speed, to measure the cognitive impact of the program. They were also given a battery of functional fitness tests to measure the physical impact of the program. The trainees improved significantly in measures of game performance. They also improved significantly more than the control participants in measures of physical function and cognitive measures of executive control and processing speed, but not on visuospatial measures. It was encouraging to observe that, engagement in physically simulated sport games yielded benefits to cognitive and physical skills that are directly involved in functional abilities older adults need in everyday living (e.g., Hultsch, Hertzog, Small, & Dixon, 1999).


Differences in distribution of esterase between cell fractions of rat liver homogenates prepared in various media. Relevance to the lysosomal location of the enzyme in the intact cell.
The distribution of esterase in subcellular fractions of rat liver homogenates was compared with that of the lysosomal enzyme acid phosphatase and the microsomal enzyme glucose 6-phosphatase. Most of the esterase from sucrose homogenate sediments with glucose 6-phosphatase and about 8% is recovered in the supernatant. However, up to 53% of the esterase can be washed from microtome sections of unfixed liver, in which less cellular damage would be expected than that caused by homogenization. About 40% of both esterase and acid phosphatase are recovered in the soluble fraction after homogenization in aqueous glycerol or in a two-phase system (Arcton 113-0.25m-sucrose), although glucose 6-phosphatase is still recovered in the microsomal fraction of such homogenates. The esterase of the microsomal fraction prepared from a sucrose homogenate is much more readily released by treatment with 0.26% deoxycholate than are other constituents of this fraction. The release of esterase from the microsomal fraction by the detergent and its concomitant release with acid phosphatase after homogenization in glycerol or the two-phase system suggests that a greater proportion of esterase may be present in lysosomes of the intact cell than is indicated by the results of standard fractionation procedures.


Analysis of historical negative control group data from the rat in vivo micronucleus assay.
A database of micronuclei counts for historical negative control data from rat in vivo micronuclei tests performed in 10 different laboratories was established. Data were available from over 4000 negative control rats from 10 laboratories. The mean frequency of micronucleated cells (MN)/1000 cells ranged from 0.44 to 2.22, a 5-fold range. Overall there were no major sex or strain differences in frequency, although there were some small but statistically significant differences within laboratories. There was appreciable variability between experiments compared with variability within experiments in some laboratories. No specific factor was identified which could explain this variability although it was noted that many different vehicles were used in the experiments. It is hoped that these data will help laboratories beginning studies with the rat micronucleus assay and those involved in the assessment of micronucleus assay results.


Characterization of Innate Responses Induced by PLGA Encapsulated- and Soluble TLR Ligands In Vitro and In Vivo in Chickens.
Natural or synthetic Toll-like receptor (TLR) ligands trigger innate responses by interacting with distinct TLRs. TLR ligands can thus serve as vaccine adjuvants or stand-alone antimicrobial agents. One of the limitations of TLR ligands for clinical application is their short half-life and rapid clearance from the body. In the current study, encapsulation of selected TLR ligands in biodegradable poly(D,L-lactide-co-glycolide) polymer nanoparticles (PLGA NPs) was examined in vitro and in vivo as a means to prolong innate responses. MQ-NCSU cells (a chicken macrophage cell line) were treated with encapsulated or soluble forms of TLR ligands and the resulting innate responses were evaluated. In most cases, encapsulated forms of TLR ligands (CpG ODN 2007, lipopolysaccharide and Pam3CSK4) induced comparable or higher levels of nitric oxide and cytokine gene expression in macrophages, compared to the soluble forms. Encapsulated CpG ODN, in particular the higher dose, induced significantly higher expression of interferon (IFN)-γ and IFN-β until at least 18 hr post-treatment. Cytokine expression by splenocytes was also examined in chickens receiving encapsulated or soluble forms of lipopolysaccharide (a potent inflammatory cytokine inducer in chickens) by intramuscular injection. Encapsulated LPS induced more sustained innate responses characterized by higher expression of IFN-γ and IL-1β until up to 96 hr. The ability of TLR ligands encapsulated in polymeric nanoparticles to maintain prolonged innate responses indicates that this controlled-release system can extend the use of TLR ligands as vaccine adjuvants or as stand-alone prophylactic agents against pathogens.


PRGmatic: an efficient pipeline for collating genome-enriched second-generation sequencing data using a 'provisional-reference genome'.
Second-generation sequencing is increasingly being used in combination with genome-enrichment techniques to amplify a large number of loci in many individuals for the purpose of population genetic and phylogeographic analysis. Compiling all the necessary tools to analyse these data is complex and time-consuming. Here, we assemble a set of programs and pipe them together with Perl, enabling research laboratories without a dedicated bioinformatician to utilize second-generation sequencing. User input is a folder of the second-generation sequencing reads sorted by individual (in FASTA format) and pipeline output is a folder of multi-FASTA files that correspond to loci (with 2 alleles called per individual). Additional output includes a summary file of the number of individuals per locus, observed and expected heterozygosity for each locus, distribution of multiple hits and summary statistics (θ, Tajima's D, etc.). This user-friendly, open source pipeline, which requires no a priori reference genome because it constructs its own, allows the user to set various parameters (e.g. minimum coverage) in the dependent programs (CAP3, BWA, SAMtools and VarScan) and facilitates evaluation of the nature and quality of data collected prior to analysis in software packages.


Spatial discounting of food and social rewards in guppies (poecilia reticulata).
In temporal discounting, animals trade off the time to obtain a reward against the quality of a reward, choosing between a smaller reward available sooner versus a larger reward available later. Similar discounting can apply over space, when animals choose between smaller and closer versus larger and more distant rewards. Most studies of temporal and spatial discounting in non-human animals use food as the reward, and it is not established whether animals trade off other preferred stimuli in similar ways. Here, we offered female guppies (Poecilia reticulata) a spatial discounting task in which we measured preferences for a larger reward as the distance to it increased relative to a closer but smaller reward. We tested whether the fish discounted reward types differently by offering subjects either food items or same-sex conspecifics as rewards. Before beginning the discounting tasks, we conducted validation tests to ensure that subjects equally valued the food and social stimuli in the quantities provided. In the discounting task, subjects switched their preferences from the larger to the smaller reward as the distance to the larger reward increased (spatial discounting), but the pattern and magnitude of discounting did not differ across the two reward types. These findings indicate that guppies show similar patterns of discounting for food and social rewards in a spatial task. In an examination of travel times, however, the fish swam faster to food rewards than to shoaling partners. Analysis of travel times suggests that fish temporally discounted social rewards less steeply than food rewards. Thus, reward type influences temporal discounting, suggesting a dissociation between temporal and spatial discounting. Our results illustrate how animals adjust choices and travel times depending on both the type of cost (time, distance) and benefits (food, social partners).


Health system reform in the Emirate of Abu Dhabi, United Arab Emirates.
The desire to achieve the best outcomes in the provision of healthcare has driven health system reforms in many countries across the globe, including the Emirate of Abu Dhabi, United Arab Emirates. As a young state (the United Arab Emirates was founded as an independent state in 1971) with a diverse (with 78% expatriates) and young population (40.23% of the national Emirati population is under 15 years of age), the government of the Emirate of Abu Dhabi has embarked on a journey to reform their healthcare system. This reform focuses on the redesign, financing, regulation and provision of healthcare with the aim of delivering accessible, affordable and high quality health care. We will describe and review the health system reform in Abu Dhabi to date: its background, history and characteristics. The review looks at whether the main components of the reform (mandatory health insurance; enhanced competition and a centralized regulatory system) have had the desired effects in terms of improving quality, enhancing access and ensuring affordability. Looking toward the future for the health system in Abu Dhabi we conclude that it is too early to tell whether the reform programme is having the desired effects in terms of achieving its goals of quality, access and affordability.


Nutrition agenda setting, policy formulation and implementation: lessons from the Mainstreaming Nutrition Initiative.
Undernutrition is the single largest contributor to the global burden of disease and can be addressed through a number of highly efficacious interventions. Undernutrition generally has not received commensurate attention in policy agendas at global and national levels, however, and implementing these efficacious interventions at a national scale has proven difficult. This paper reports on the findings from studies in Bangladesh, Bolivia, Guatemala, Peru and Vietnam which sought to identify the challenges in the policy process and ways to overcome them, notably with respect to commitment, agenda setting, policy formulation and implementation. Data were collected through participant observation, documents and interviews. Data collection, analysis and synthesis were guided by published conceptual frameworks for understanding malnutrition, commitment, agenda setting and implementation capacities. The experiences in these countries provide several insights for future efforts: (a) high-level political attention to nutrition can be generated in a number of ways, but the generation of political commitment and system commitment requires sustained efforts from policy entrepreneurs and champions; (b) mid-level actors from ministries and external partners had great difficulty translating political windows of opportunity for nutrition into concrete operational plans, due to capacity constraints, differing professional views of undernutrition and disagreements over interventions, ownership, roles and responsibilities; and (c) the pace and quality of implementation was severely constrained in most cases by weaknesses in human and organizational capacities from national to frontline levels. These findings deepen our understanding of the factors that can influence commitment, agenda setting, policy formulation and implementation. They also confirm and extend upon the growing recognition that the heavy investment to identify efficacious nutrition interventions is unlikely to reduce the burden of undernutrition unless or until these systemic capacity constraints are addressed, with an emphasis initially on strategic and management capacities.


An evolutionary explanation of female-biased sexual size dimorphism in North Sea plaice, Pleuronectes platessa L.
Sexual size dimorphism (SSD) is caused by differences in selection pressures and life-history trade-offs faced by males and females. Proximate causes of SSD may involve sex-specific mortality, energy acquisition, and energy expenditure for maintenance, reproductive tissues, and reproductive behavior. Using a quantitative, individual-based, eco-genetic model parameterized for North Sea plaice, we explore the importance of these mechanisms for female-biased SSD, under which males are smaller and reach sexual maturity earlier than females (common among fish, but also arising in arthropods and mammals). We consider two mechanisms potentially serving as ultimate causes: (a) Male investments in male reproductive behavior might evolve to detract energy resources that would otherwise be available for somatic growth, and (b) diminishing returns on male reproductive investments might evolve to reduce energy acquisition. In general, both of these can bring about smaller male body sizes. We report the following findings. First, higher investments in male reproductive behavior alone cannot explain the North Sea plaice SSD. This is because such higher reproductive investments require increased energy acquisition, which would cause a delay in maturation, leading to male-biased SSD contrary to observations. When accounting for the observed differential (lower) male mortality, maturation is postponed even further, leading to even larger males. Second, diminishing returns on male reproductive investments alone can qualitatively account for the North Sea plaice SSD, even though the quantitative match is imperfect. Third, both mechanisms can be reconciled with, and thus provide a mechanistic basis for, the previously advanced Ghiselin-Reiss hypothesis, according to which smaller males will evolve if their reproductive success is dominated by scramble competition for fertilizing females, as males would consequently invest more in reproduction than growth, potentially implying lower survival rates, and thus relaxing male-male competition. Fourth, a good quantitative fit with the North Sea plaice SSD is achieved by combining both mechanisms while accounting for sex-specific costs males incur during their spawning season. Fifth, evolution caused by fishing is likely to have modified the North Sea plaice SSD.


L-carnosine affects the growth of Saccharomyces cerevisiae in a metabolism-dependent manner.
The dipeptide L-carnosine (β-alanyl-L-histidine) has been described as enigmatic: it inhibits growth of cancer cells but delays senescence in cultured human fibroblasts and extends the lifespan of male fruit flies. In an attempt to understand these observations, the effects of L-carnosine on the model eukaryote, Saccharomyces cerevisiae, were examined on account of its unique metabolic properties; S. cerevisiae can respire aerobically, but like some tumor cells, it can also exhibit a metabolism in which aerobic respiration is down regulated. L-Carnosine exhibited both inhibitory and stimulatory effects on yeast cells, dependent upon the carbon source in the growth medium. When yeast cells were not reliant on oxidative phosphorylation for energy generation (e.g. when grown on a fermentable carbon source such as 2% glucose), 10-30 mM L-carnosine slowed growth rates in a dose-dependent manner and increased cell death by up to 17%. In contrast, in media containing a non-fermentable carbon source in which yeast are dependent on aerobic respiration (e.g. 2% glycerol), L-carnosine did not provoke cell death. This latter observation was confirmed in the respiratory yeast, Pichia pastoris. Moreover, when deletion strains in the yeast nutrient-sensing pathway were treated with L-carnosine, the cells showed resistance to its inhibitory effects. These findings suggest that L-carnosine affects cells in a metabolism-dependent manner and provide a rationale for its effects on different cell types.


Treatment practice in the elderly patient with chronic lymphocytic leukemia-analysis of the combined SEER and Medicare database.
The median age at diagnosis of chronic lymphocytic leukemia (CLL) is 72, but patients enrolled in randomized trials are often a decade younger. Therapy selection and outcomes in the older, comorbid population are less understood. We evaluated treatment patterns and outcomes among 2,985 first primary CLL patients from the linked Surveillance, Epidemiology, and End Results-Medicare database. There were 151 chlorambucil (CLB), 594 rituximab monotherapy (R-mono), 696 rituximab + intravenous chemotherapy (R + IV Chemo), and 1,544 IV chemo-only patients. Patients administered CLB and R-mono were the oldest and had the highest comorbidity burden while patients receiving R + IV Chemo were the youngest and had the lowest comorbidity burden (p < 0.0001). In the multivariate survival analysis, receipt of R + IV Chemo was associated with significantly lower mortality risk vs. IV Chemo-only (hazard ratio (HR) = 0.73; 95 % confidence interval (CI) 0.62-0.87) and a non-significant mortality risk reduction with R-mono vs. CLB (HR = 0.47; 95 % CI: 0.21-1.05). Older age and increasing comorbidity score were significantly associated with higher mortality. These findings suggest that chemoimmunotherapy is more effective than chemotherapy in an elderly population with a high prevalence of comorbidity, and this extends the conclusions from clinical trials in younger, medically fit patients.


Sterile cerebrospinal fluid pleocytosis in young febrile infants with urinary tract infections.
To determine the prevalence of and to identify risk factors for sterile cerebrospinal fluid (CSF) pleocytosis in a large sample of febrile young infants with urinary tract infections (UTIs) and to describe the clinical courses of those patients. Secondary analysis of a multicenter retrospective review. Emergency departments of 20 North American hospitals. Patients Infants aged 29 to 60 days with temperatures of 38.0°C or higher and culture-proven UTIs who underwent a nontraumatic lumbar puncture from January 1, 1995, through May 31, 2006. Febrile UTI. Presence of sterile CSF pleocytosis defined as CSF white blood cell count of 10/μL or higher in the absence of bacterial meningitis and clinical course and treatment (ie, presence of adverse events, time to defervescence, duration of parenteral antibiotic treatment, and length of hospitalization). A total of 214 of 1190 infants had sterile CSF pleocytosis (18.0%; 95% confidence interval, 15.9%-20.3%). Only the peripheral white blood cell count was independently associated with sterile CSF pleocytosis, and patients with a peripheral white blood cell count of 15/μL or higher had twice the odds of having sterile CSF pleocytosis (odds ratio, 1.97; 95% confidence interval, 1.32-2.94; P = .001). In the subset of patients at very low risk for adverse events (ie, not clinically ill in the emergency department and without a high-risk medical history), patients with and without sterile CSF pleocytosis had similar clinical courses; however, patients with CSF pleocytosis had longer parenteral antibiotics courses (median length, 4 days [interquartile range, 3-6 days] vs 3 days [interquartile range, 3-5 days]) (P = .04). Sterile CSF pleocytosis occurs in 18% of young infants with UTIs. Patients with CSF pleocytosis at very low risk for adverse events may not require longer treatment with antibiotics.


Differential functional genomic effects of anti-inflammatory phytocompounds on immune signaling.
Functional comparative genomic analysis of the cellular immunological effects of different anti-inflammatory phytocompounds is considered as a helpful approach to distinguish the complex and specific bioactivities of candidate phytomedicines. Using LPS-stimulated THP-1 monocytes, we characterize here the immunomodulatory activities of three single phytocompounds (emodin, shikonin, and cytopiloyne) and a defined phytocompound mixture extracted from Echinacea plant (BF/S+L/Ep) by focused DNA microarray analysis of selected immune-related genes. Shikonin and emodin significantly inhibited the early expression (within 0.5 h) of approximately 50 genes, notably cytokines TNF-α, IL-1β and IL-4, chemokines CCL4 and CCL8, and inflammatory modulators NFATC3 and PTGS2. In contrast, neither cytopiloyne nor BF/S+L/Ep inhibited the early expression of these 50 genes, but rather inhibited most late-stage expression (~12 h) of another immune gene subset. TRANSPATH database key node analysis identified the extracellular signal-regulated kinase (ERK) 1/2 activation pathway as the putative target of BF/S+L/Ep and cytopiloyne. Western blot confirmed that delayed inactivation of the ERK pathway was indeed demonstrable for these two preparations during the mid-stage (1 to 4 h) of LPS stimulation. We further identified ubiquitin pathway regulators, E6-AP and Rad23A, as possible key regulators for emodin and shikonin, respectively. The current focused DNA microarray approach rapidly identified important subgenomic differences in the pattern of immune cell-related gene expression in response to specific anti-inflammatory phytocompounds. These molecular targets and deduced networks may be employed as a guide for classifying, monitoring and manipulating the molecular and immunological specificities of different anti-inflammatory phytocompounds in key immune cell systems and for potential pharmacological application.


Dynamic distribution of seqa protein across the chromosome of escherichia coli K-12.
The bacterial SeqA protein binds to hemi-methylated GATC sequences that arise in newly synthesized DNA upon passage of the replication machinery. In Escherichia coli K-12, the single replication origin oriC is a well-characterized target for SeqA, which binds to multiple hemi-methylated GATC sequences immediately after replication has initiated. This sequesters oriC, thereby preventing reinitiation of replication. However, the genome-wide DNA binding properties of SeqA are unknown, and hence, here, we describe a study of the binding of SeqA across the entire Escherichia coli K-12 chromosome, using chromatin immunoprecipitation in combination with DNA microarrays. Our data show that SeqA binding correlates with the frequency and spacing of GATC sequences across the entire genome. Less SeqA is found in highly transcribed regions, as well as in the ter macrodomain. Using synchronized cultures, we show that SeqA distribution differs with the cell cycle. SeqA remains bound to some targets after replication has ceased, and these targets locate to genes encoding factors involved in nucleotide metabolism, chromosome replication, and methyl transfer.


Optimal Monitoring For Coronary Heart Disease Risk in Patients with Systemic Lupus Erythematosus: A Systematic Review.
Premature coronary heart disease (CHD) significantly affects morbidity and mortality in systemic lupus erythematosus (SLE). Several studies have detected factors influencing the atherosclerotic process, as well as methods to quantify the atherosclerotic burden in subclinical stages. The aim of this systematic review was to identify the minimum investigations to optimally monitor CHD risk in SLE. English-restricted literature review was performed using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines through Ovid Medline, Embase, and Cochrane Central databases, from inception until May 2014 (Medline until October 2014). Specific search terms included, among others, "SLE," "atherosclerosis," "CHD," "myocardial ischemia," "acute coronary syndrome," "myocardial infarction," and "angina pectoris." We identified 101 eligible articles, 23 with cardiovascular events (CVE) as endpoints and 78 with measures of subclinical atherosclerosis. The Newcastle-Ottawa scale was used for quality assessment. Certain traditional and disease-specific factors were identified as independent predictors for CHD. Among the former were age (particularly postmenopausal state), male sex, arterial hypertension, dyslipidemia, and smoking. Disease activity and duration, cumulative damage, antiphospholipid antibodies, high sensitivity C-reactive protein, and renal disease were the most consistent disease-related factors. Corticosteroids were linked to increased CHD risk whereas antimalarials were protective. Concerning imaging techniques, carotid ultrasonography (intima-media thickness and plaque) was shown to independently predict CVE. Premature CHD in SLE is multifactorial; modifiable variables should be monitored at frequent intervals to ensure prompt management. Disease-specific factors also affect the atherogenic process and should be evaluated regularly. Carotid ultrasonography may hold promise in predicting CVE in selected high-risk patients.


Assessment of sample handling practices on microbial activity in sputum samples from patients with cystic fibrosis.
The aim of this study was to quantitatively and qualitatively assess the effect of sample storage on the metabolically active microbial community found in sputum samples from patients with cystic fibrosis (CF). Sputum samples were collected and split in two equal aliquots one of which was immersed in RNAlater and refrigerated immediately, the second stored at room temperature for 24 h and RNAlater was subsequently added. mRNA was extracted, and RT-PCR-DGGE and qPCR analysis of the bacterial and fungal communities was carried out. Significant differences in the bacterial communities between the two protocols were observed but there were no significant difference seen in the fungal community analyses. Analysis by qPCR demonstrated that room temperature storage gave statistically significant increases in eubacteria and Pseudomonas spp. and a statistically significant decrease in those of Haemophilus influenzae. The analysis of metabolically active microbial communities from CF sputum using molecular techniques indicated that samples should be stored at 4 degrees C upon addition of RNAlater to obtain an accurate depiction of the CF lung microbiota. Also, storing respiratory samples at room temperature may cause an over representation of Pseudomonas aeruginosa and mask the presence of other clinically significant organisms.


Industry-Led Access-To-Medicines Initiatives In Low- And Middle-Income Countries: Strategies And Evidence.
Global biopharmaceutical companies are increasingly establishing access-to-medicines (AtM) initiatives in low- and middle-income countries. We reviewed the initiatives of twenty-one research-based global biopharmaceutical companies to assess their strategies for improving access and the quality of evidence on the impact of their initiatives. The number of operating initiatives increased from 17 in 2000 to 102 in 2015. Of the 120 different AtM initiatives identified, 48 percent used a medicine donation strategy, and 44 percent used a price reduction strategy. While companies have frequently claimed that their initiatives have had positive impacts, we found published evaluations for only seven initiatives, and nearly all of the evaluations were of low (62 percent) or very low (32 percent) quality. It is clear that the biopharmaceutical industry has increased its commitment to improving access to medicines in low- and middle-income countries. However, companies should do more to generate high-quality evidence on their initiatives, and the global health community should do more to assist the developing of evidence about the initiatives.


Volition and conflict in human medial frontal cortex.
Controversy surrounds the role of human medial frontal cortex in controlling actions. Although damage to this area leads to severe difficulties in spontaneously initiating actions, the precise mechanisms underlying such "volitional" deficits remain to be established. Previous studies have implicated the medial frontal cortex in conflict monitoring and the control of voluntary action, suggesting that these key processes are functionally related or share neural substrates. Here, we combine a novel behavioral paradigm with functional imaging of the oculomotor system to reveal, for the first time, a functional subdivision of the pre-supplementary motor area (pre-SMA) into anatomically distinct areas that respond exclusively to either volition or conflict. We also demonstrate that activity in the supplementary eye field (SEF) distinguishes between success and failure in changing voluntary action plans during conflict, suggesting a role for the SEF in implementing the resolution of conflicting actions. We propose a functional architecture of human medial frontal cortex that incorporates the generation of action plans and the resolution of conflict.


Speech-language pathology findings in patients with mouth breathing: multidisciplinary diagnosis according to etiology.
The purpose of this study was to identify and compare the results of the findings from speech-language pathology evaluations for orofacial function including tongue and lip rest postures, tonus, articulation and speech, voice and language, chewing, and deglutition in children who had a history of mouth breathing. The diagnoses for mouth breathing included: allergic rhinitis, adenoidal hypertrophy, allergic rhinitis with adenoidal hypertrophy; and/or functional mouth breathing. This study was conducted with on 414 subjects of both genders, from 2 to 16-years old. A team consisting of 3 speech-language pathologists, 1 pediatrician, 1 allergist, and 1 otolaryngologist, evaluated the patients. Multidisciplinary clinical examinations were carried out (complete blood counting, X-rays, nasofibroscopy, audiometry). The two most commonly found etiologies were allergic rhinitis, followed by functional mouth breathing. Of the 414 patients in the study, 346 received a speech-language pathology evaluation. The most prevalent finding in this group of 346 subjects was the presence of orofacial myofunctional disorders. The most frequently orofacial myofunctional disorder identified in these subjects who also presented mouth breathing included: habitual open lips rest posture, low and forward tongue rest posture and lack of adequate muscle tone. There were also no statistically significant relationships identified between etiology and speech-language diagnosis. Therefore, the specific type of etiology of mouth breathing does not appear to contribute to the presence, type, or number of speech-language findings which may result from mouth breathing behavior.


Improvement of corneal fluorescein staining in post cataract surgery of diabetic patients by an oral aldose reductase inhibitor, ONO-2235.
While the mechanism in the pathogenesis of diabetic corneal disease is unclear, aldose reductase has been implicated in corneal disease. The effects of an oral aldose reductase inhibitor (ARI) on the ocular surface of diabetic patients after cataract surgery were studied. This clinical trial was designed to be randomised, double blinded, and placebo controlled. Pseudophakic patients with diabetes were randomly assigned to treatment with either oral ARI (ONO-2235) (n=12) or placebo (n=9) for 12 weeks. The vital staining of the ocular surface, tear production and clearance, break up time in tears (BUT), corneal and conjunctival sensation, and symptom score before treatments were examined as well as 4, 8, 12 weeks after the administration. Specular microscopic evaluation was also performed. After a 12 week period of oral ARI administration, fluorescein staining scores (from 2.04 (SD 1.12) to 1.46 (1.18); p=0.016), conjunctival sensation (from 1.15 (0.37) to 1.36 (0.31); p=0.0006), and symptom scores (from 5.38 (1.932) to 4.00 (2.07); p=0.0002) recovered significantly. Fluorescein staining of oral ARI administration also decreased compared with placebo (p=0.017). Rose bengal staining, tear clearance, and corneal sensation were improved although this increase was minor. Tear production, BUT, and specular microscopic evaluation of the corneal epithelium and endothelium did not demonstrate a significant change. Oral ARI opposes the ocular surface changes caused by diabetes, by recovery of ocular surface sensitivity as demonstrated through an improvement in vital staining.


Glomerular size reduction associated with severe cardiorenal syndrome.
Pathologic changes that are associated with the cardiorenal syndrome (CRS) are seldom described. The two theories that address renal physiology in CRS include chronic indolent ischemia from renal vasoconstriction and chronic glomerular venous congestion from increased venous pressures. We report on the glomerular histologic changes that occur with long standing heart failure. To examine whether CRS causes renal ischemia that manifests as glomerular size reduction. We performed a case-control study where we measured total glomerular areas in 16 adult cases with end-stage heart disease and compared them with matched controls. Control biopsy samples were obtained from renal tissue included in nephrectomies. Glomerular size was measured using the BioQuant Image Analysis program. Cases and controls were matched on the following variables: age (within 10 years), race, body mass index (BMI), diabetes mellitus (DM), glomerular filtration rate (GFR) (within 10 mL/min/1.73 m2), and history of tobacco use. The age range of all patients at the time of biopsy was 40 - 73 years. Nine of the case patients had DM. Estimated GFR ranged from 29 to 55 mL/min/1.73 m2. Mean BMI was 30.8 (SD 4.7) kg/m2. The average median glomerular area in the case patients was 23,944 pixels (1 pixel = 1 μm2), (IQR 22,549 - 27,990) vs. in controls 38,566 pixels (IQR 31, 227 - 45,938) (p = 0.004). This case-controlled cohort study demonstrates that patients with long standing heart failure have smaller glomerular size as compared with controls matched for relevant clinical variables but not for heart failure.


Effects of insulin and sulphonylureas on insulin-like growth factor-I levels in streptozotocin-induced diabetic rats.
Diabetes Mellitus is associated with decreased insulin-like growth factor-I (IGF-I) levels and also, poor growth in diabetes is related with low circulating levels of IGF-I. Insulin acts via an increase of IGF-I synthesis on growth. We studied the effects of insulin and sulphonylureas on serum IGF-I levels and aimed to evaluate the restoration of IGF-I in different therapeutic strategies. Thirty male rats were used in the study and diabetes was induced by a single intraperitoneal injection of streptozotocin (35 mg/kg body weight). After confirmation of hyperglycemia, rats were divided into three groups. The first group was treated with insulin, and second group with glimepiride, third group was not treated (control group). IGF-I levels were measured at basal, after streptozotocin and at the end of the treatment period. Serum IGF-I levels were found to decrease from 577.2 ng/ml to 253.0 ng/ml after streptozotocin (p<0.005). After 1 month, IGF-1 levels were found 524.0 ng/ml in insulin group, 449.3 ng/ml in sulphonylurea group, and 313.1 ng/ml in control group. The increase in IGF-I was statistically significant in insulin group (p<0.005), and in sulphonylurea group (p<0.05), but it was not significant in control group (p>0.05). Serum IGF-I levels decrease in diabetes and insulin treatment restores IGF-I depletion significantly. And although less effective, treatment with glimepiride restores IGF-I levels significantly.


Neural coding: higher-order temporal patterns in the neurostatistics of cell assemblies.
Recent advances in the technology of multiunit recordings make it possible to test Hebb's hypothesis that neurons do not function in isolation but are organized in assemblies. This has created the need for statistical approaches to detecting the presence of spatiotemporal patterns of more than two neurons in neuron spike train data. We mention three possible measures for the presence of higher-order patterns of neural activation--coefficients of log-linear models, connected cumulants, and redundancies--and present arguments in favor of the coefficients of log-linear models. We present test statistics for detecting the presence of higher-order interactions in spike train data by parameterizing these interactions in terms of coefficients of log-linear models. We also present a Bayesian approach for inferring the existence or absence of interactions and estimating their strength. The two methods, the frequentist and the Bayesian one, are shown to be consistent in the sense that interactions that are detected by either method also tend to be detected by the other. A heuristic for the analysis of temporal patterns is also proposed. Finally, a Bayesian test is presented that establishes stochastic differences between recorded segments of data. The methods are applied to experimental data and synthetic data drawn from our statistical models. Our experimental data are drawn from multiunit recordings in the prefrontal cortex of behaving monkeys, the somatosensory cortex of anesthetized rats, and multiunit recordings in the visual cortex of behaving monkeys.


How does job dissatisfaction interact with self-rated health in determining the risk of health-related job loss? Prospective findings from the Health and Employment After Fifty (HEAF) study.
Health and job satisfaction are key independent determinants of ability to work to older ages. We investigated the interaction of these two important factors on health-related job loss (HRJL) over 2 years of follow-up comparing male and female older workers. A population sample of adults aged 50-64 years, recruited from 24 English general practices in the Health and Employment After Fifty (HEAF) study, completed questionnaires at baseline with follow-ups at 12 and 24 months. Multiple-record Cox proportional hazards models were performed to explore the main effects of, and potential interactions between, job satisfaction and self-rated health (SRH) as predictors of time to first HRJL. Of the initial 8134 participants, 5143 were ever in work in the study period. Among men, 5.7% and 14.3% reported job dissatisfaction (those in good and poor SRH, respectively), while among women these percentages were 4.6 and 12.9. HRJL was reported by 106 men and 176 women. Men in good health dissatisfied with their job had a sixfold (HR=6.4; 95% CI 3.3 to 12.4) increased risk of HRJL compared with men satisfied with their job (significant multiplicative interaction). Women dissatisfied with their job were more likely to have an HRJL within 2 years of follow-up irrespective of their SRH. SRH and job dissatisfaction have important individual effects on the risk of stopping work for health among older workers. These findings point to the importance of job satisfaction in reducing health-related exit from paid work among older workers.


Kinetics and mechanism of autohydrolysis of hardwoods.
Autohydrolysis using water is a promising method to extract hemicelluloses from wood prior to pulping in order to make co-products such as ethanol and acetic acid besides pulp. Many studies have been carried out on the kinetics and mechanism of autohydrolysis using batch reactors. The present study was performed in a continuous mixed flow reactor where the wood chips are retained in a basket inside the reactor. This reactor is well suited to determine intrinsic kinetics of hemicellulose dissolution because the dissolved products are rapidly removed from the reactor, thus minimizing further hydrolysis and degradation of the hemicelluloses in solution. The xylan removal rate follows an S-shaped behavior. GPC analysis of the continuously removed extract shows that the dissolved xylan oligomers have a DP smaller than about 25. Lignin-free xylan oligomers and cellulose oligomers are the major components dissolved in the initial stage of autohydrolysis, while xylan covalently bound to lignin (i.e. an LCC) is the major component removed during the later stage of autohydrolysis. The molecular weight of the dissolved components decreases with time in the second stage. The kinetics of xylan removal are explained in terms of a mechanism based on recent knowledge of the ultrastructure of the cell fibre wall.


Vpr is preferentially targeted by CTL during HIV-1 infection.
The HIV-1 accessory proteins Vpr, Vpu, and Vif are essential for viral replication, and their cytoplasmic production suggests that they should be processed for recognition by CTLs. However, the extent to which these proteins are targeted in natural infection, as well as precise CTL epitopes within them, remains to be defined. In this study, CTL responses against HIV-1 Vpr, Vpu, and Vif were analyzed in 60 HIV-1-infected individuals and 10 HIV-1-negative controls using overlapping peptides spanning the entire proteins. Peptide-specific IFN-gamma production was measured by ELISPOT assay and flow-based intracellular cytokine quantification. HLA class I restriction and cytotoxic activity were confirmed after isolation of peptide-specific CD8(+) T cell lines. CD8(+) T cell responses against Vpr, Vpu, and Vif were found in 45%, 2%, and 33% of HIV-1-infected individuals, respectively. Multiple CTL epitopes were identified in functionally important regions of HIV-1 Vpr and Vif. Moreover, in infected individuals in whom the breadth of HIV-1-specific responses was assessed comprehensively, Vpr and p17 were the most preferentially targeted proteins per unit length by CD8(+) T cells. These data indicate that despite the small size of these proteins Vif and Vpr are frequently targeted by CTL in natural HIV-1 infection and contribute importantly to the total HIV-1-specific CD8(+) T cell responses. These findings will be important in evaluating the specificity and breadth of immune responses during acute and chronic infection, and in the design and testing of candidate HIV vaccines.


Electrodialytic remediation of polychlorinated biphenyls contaminated soil with iron nanoparticles and two different surfactants.
Polychlorinated biphenyls (PCB) are persistent organic pollutants (POP) that strongly adsorb in soils and sediments. There is a need to develop new and cost-effective solutions for the remediation of PCB contaminated soils. The suspended electrodialytic remediation combined with zero valent iron nanoparticles (nZVI) could be a competitive alternative to the commonly adapted solutions of incineration or landfilling. Surfactants can enhance the PCB desorption, dechlorination, and the contaminated soil cleanup. In this work, two different surfactants (saponin and Tween 80) were tested to enhance PCB desorption and removal from a soil sampled at a polluted site, in a two-compartment cell where the soil was stirred in a slurry with 1% surfactant, 10mL of nZVI commercial suspension, and a voltage gradient of 1Vcm(-1). The highest PCB removal was obtained with saponin. Higher chlorinated PCB congeners (penta, hexa, hepta and octachlorobiphenyl) showed removal percentages between 9% and 96%, and the congeners with highest removal were PCB138, PCB153 and PCB180. The use of low level direct current enhanced PCB removal, especially with saponin. Electrodechlorination of PCB with surfactants and nZVI showed encouraging tendencies and a base is thus formed for further optimization towards a new method for remediation of PCB polluted soils.


Pituitary adenylate cyclase-activating peptide as a neurotransmitter in the canine ileal circular muscle.
Pituitary adenylate cyclase-activating peptide (PACAP)1-27, PACAP1-38, and vasoactive intestinal peptide (VIP) initiated dose-dependent contractions of canine ileal circular muscle after intra-arterial injection in vivo or ex vivo. PACAP1-27- and VIP-induced contractions approached the tissue maximum; VIP was 100-fold less potent. PACAP1-38 was more potent than VIP. PACAP1-27 contractions in vivo were unaffected by hexamethonium, reduced equally by atropine or atropine plus hexamethonium, and abolished by tetrodotoxin (TTX), suggesting that PACAP released acetylcholine and another excitatory neurotransmitter from postganglionic cholinergic enteric nerves. In myenteric plexus-free circular muscle strips, PACAP1-27 at 10(-9) M and PACAP1-38 or VIP at 10(-7) M increased [3H]acetylcholine release during nerve stimulation, suggesting the locus of one postganglionic site at which PACAP1-27 acts. All agonists inhibited nerve-mediated contractions in vivo with a potency rank order similar to that for excitation. Inhibition of nitric oxide (NO) synthetase or TTX decreased the duration and amplitude of PACAP1-27- but not PACAP1-38-induced inhibition. Inhibition of NO synthetase abolished VIP-induced inhibition, but TTX did not. Submaximal contractions to acetylcholine were amplified by PACAP1-27 or VIP before TTX and inhibited after TTX. Thus, both PACAP molecules and VIP directly inhibit and indirectly excite smooth muscle contractions. PACAP1-27 and VIP also release NO. The functional potency differences between PACAP1-27 and VIP suggest PAC1 receptors mediate all responses, likely through the stimulation of adenylate cyclase.


Enhanced bandgap in annular photonic-crystal silicon-on-insulator asymmetric slabs.
Photonic band structures of annular photonic-crystal (APC) silicon-on-insulator (SOI) asymmetric slabs with finite thickness were investigated by the three-dimensional plane-wave expansion method. The results show that for a broad range of air-volume filling factors, APC slabs can exhibit a significantly larger bandgap than conventional circular-hole photonic-crystal (PC) slabs. Bandgap enhancements over conventional air hole PC SOI slabs as large as twofold are predicted for low air-volume filling factors below 15%. This desirable behavior suggests a potential for APC SOI slabs to serve as the basis of various optical cavities, waveguides, and mirrors.


Functional Amyloids.
When protein/peptides aggregate, they usually form the amyloid state consisting of cross β-sheet structure built by repetitively stacked β-strands forming long fibrils. Amyloids are usually associated with disease including Alzheimer's. However, amyloid has many useful features. It efficiently transforms protein from the soluble to the insoluble state in an essentially two-state process, while its repetitive structure provides high stability and a robust prion-like replication mechanism. Accordingly, amyloid is used by nature in multifaceted and ingenious ways of life, ranging from bacteria and fungi to mammals. These include (1) Structure: Templating for small chemical molecules (Pmel17), biofilm formation in bacteria (curli), assisting aerial hyphae formation in streptomycetes (chaplins) or monolayer formation at a surface (hydrophobins). (2) Reservoirs: A storage state for peptide/proteins to protect them from their surroundings or vice versa (storage of peptide hormones in mammalian secretory granules or major basic protein in eosinophils). (3) Information carriers: The fungal immune system (HET-s prion in Podospora anserina, yeast prions) or long-term memory (e.g., mnemons in yeast, cytoplasmic polyadenylation element-binding protein in aplysia). Aggregation is also used to (4) "suppress" the function of the soluble protein (e.g., Cdc19 in yeast stress granules), or (5) "signaling" through formation of oligomers (e.g., HET-s prion, necroptosis-related proteins RIP1/RIP3). This review summarizes current knowledge on functional amyloids with a focus on the amyloid systems curli in bacteria, HET-s prion in P. anserina, and peptide hormone storage in mammals together with an attempt to highlight differences between functional and disease-associated amyloids.


Peritoneal adhesion and angiogenesis in ovarian carcinoma are inversely regulated by hyaluronan: the role of gonadotropins.
Ovarian carcinoma is the leading cause of death among gynecologic cancers. Although transformation of the outer ovarian epithelium was linked with ovulation, the disease is significantly more prevalent and severe in postmenopausal women. We postulated that menopause could augment ovarian cancer progression through the effects of gonadotropins on multifocal seeding to the mesothelial layer lining the peritoneum. This seeding is mediated by integrins as well as by CD44 interaction with hyaluronan (HA). Here, we report the effect of gonadotropins on HA synthesis and degradation and on peritoneal adhesion. A significant concentration- and time-dependent induction in expression levels of HA synthases (HASs) and hyaluronidases (Hyals) was observed in vitro on stimulation of human epithelial ovarian carcinoma cells by gonadotropins. Hormonal regulation of HA-mediated adhesion was manifested in vivo as well, by fluorescence microscopy of stained MLS multicellular tumor spheroids. The number of spheroids adhered to the mesothelium of ovariectomized CD-1 nude mice 9.5 hours after intraperitoneal insertion was significantly higher than in nonovariectomized mice. Inhibition of HA synthesis by 6-diazo-5-oxo-1-norleucine (DON) both in spheroids and ovariectomized mice significantly reduced the number of adhered spheroids. Thus, the change in the hormonal environment during menopause assists in HA-dependent adherence of ovarian cancer spheroids onto the peritoneum. However, HA is antiangiogenic and it can significantly suppress tumor progression. Accordingly, angiogenesis of the adhered spheroids was significantly elevated in DON-treated tumors. These results can explain the selective pressure that can lead to simultaneously increased tumor expression of both HASs and Hyals.


Tumor vessel normalization by chloroquine independent of autophagy.
Chloroquine (CQ) has been evaluated as an autophagy blocker for cancer treatment, but it is unknown if it acts solely by inhibiting cancer cell autophagy. We report that CQ reduced tumor growth but improved the tumor milieu. By normalizing tumor vessel structure and function and increasing perfusion, CQ reduced hypoxia, cancer cell invasion, and metastasis, while improving chemotherapy delivery and response. Inhibiting autophagy in cancer cells or endothelial cells (ECs) failed to induce such effects. CQ's vessel normalization activity relied mainly on alterations of endosomal Notch1 trafficking and signaling in ECs and was abrogated by Notch1 deletion in ECs in vivo. Thus, autophagy-independent vessel normalization by CQ restrains tumor invasion and metastasis while improving chemotherapy, supporting the use of CQ for anticancer treatment.


High power Er:YAG laser with radially-polarized Laguerre-Gaussian (LG01) mode output.
A simple method for conditioning the pump beam in an end-pumped solid-state laser to allow direct excitation of the first order Laguerre-Gaussian doughnut (LG01) mode is reported. This approach has been applied to a hybrid (fiber-laser-pumped) Er:YAG laser yielding 13.1 W of continuous-wave output at 1645 nm in a radially-polarized LG01 doughnut beam with beam propagation factor (M(2)) < 2.4 for 34 W of incident pump power at 1532 nm. The corresponding slope efficiency with respect to incident pump power was 48%. The prospects of further power scaling and improved laser performance are discussed.


Effect of flock size on dioxin levels in eggs from chickens kept outside.
To decrease dioxin uptake by the general population the European Union (EU) has set limits to the dioxin content of many foodstuffs including eggs. Eggs from free foraging chickens are known to have a higher dioxin content compared with confined laying hens, and the question is whether these eggs can adhere to current EU regulations. The aim of the study was to investigate parameters that are involved in the contamination of eggs from chickens raised under organic conditions. Samples from 34 organic farms including soil and earthworm samples were collected between September and December of the year 2003. Dioxin levels were assayed by gas chromatography-mass spectrometry. Various parameters were collected by on farm interviews. Egg dioxin content varied between 0.4 and 8.1 pg of toxic equivalents (TEQ)/g of egg fat with a mean of 2.2 pg of TEQ/g of egg fat. Nine out of 34 farms exceeded the EU limit of 3 pg of TEQ/g of egg fat. In addition, dioxin-like polychlorinated biphenyls (DL-PCB) were measured, and 8 samples exceeded the limit for the sum of dioxins and DL-PCB. Overall, egg samples from 10 farms were noncompliant with the dioxin or total TEQ limits. No statistically significant relation could be observed between egg dioxin levels and the concentration observed in soil or earthworms. A statistically significant association was observed between flock size and egg dioxin and DL-PCB content. This effect is most likely attributable to the fact that flock size is related to the time chickens spend outside. Restricting outdoor run use on one of the farms resulted in a decrease of the egg dioxin content to a level that was within the EU limits. This demonstrates that the most likely contamination source is the soil or soil organisms but that the behavior of the hens determines the extent of the contamination. Following the completion of this study, a dioxin monitoring protocol has been set up in the Netherlands to prevent marketing of eggs with raised dioxin levels.


Characteristics of multidrug resistance in Plasmodium and Leishmania: detection of P-glycoprotein-like components.
Multidrug-resistance (MDR) in neoplastic cells is frequently characterized by the overexpression of P-glycoprotein (PGP), a 170 kDa transmembrane glycoprotein that binds multiple cytotoxic drugs as well as calcium channel antagonists. Chloroquine resistance in Plasmodium falciparum appears to be analogous to MDR in neoplastic cells, where the induction of resistance with one drug confers resistance to other structurally and functionally unrelated drugs. To test the hypothesis that chloroquine resistance in P. falciparum and antimony resistance in Leishmania is mediated by a similar mechanism of MDR in mammalian neoplastic cells, a PGP-specific monoclonal antibody (C219) was used to determine the presence of PGP genes in resistant and sensitive Plasmodium and Leishmania parasites by indirect immunofluorescence assays and Western blotting procedures. These PGP-like components were detected in both drug-sensitive and -resistant Plasmodium and Leishmania cells. A 40-42 kDa component was observed to be greater in a chloroquine-resistant P. berghei (C line) than in a chloroquine-susceptible P line. Differences observed between Pentostam-resistant and -sensitive Leishmania promastigote clones and isolates included the increased expression of 96-106 and 23-25 kDa peptides in drug-resistant L. enrietti, and increased amounts of two different peptides in two drug-resistant L. panamensis clones (i.e., 96-106 and 43-45 kDa in WR-746-CL4, and 53 and 23-25 kDa in kDa) in amastigotes as in MDR KB carcinoma cells (KB-V1). Comparative indirect immunofluorescent studies suggested that a correlation existed between the degree of antimony susceptibility and the concentration of the moiety recognized by C219 in two L. panamensis clones. Binding of the C219 monoclonal antibody to the PGP-like component of Leishmania was blocked by Pentostam, while the binding of C219 to multiple-drug resistant KB-V1 PGP was not inhibited by Pentostam, regardless of the PGP concentration. This suggests some degree of specificity in the binding of Pentostam to the Leishmania PGP-like components. In addition, these studies have demonstrated that drug-sensitive Leishmania accumulate two to five times more 125Sb-Pentostam than resistant clones.


Blending materials composed of boron, nitrogen and carbon to transform approaches to liquid hydrogen stores.
Mixtures of hydrogen storage materials containing the elements of boron, nitrogen, carbon, i.e., isomers of BN cyclopentanes are examined to find a 'fuel blend' that remains a liquid phase throughout hydrogen release, maximizes hydrogen storage density, minimizes impurities and remains thermally stable at ambient temperatures. We find that the mixture of ammonia borane dissolved in 3-methyl-1,2-dihydro-1,2-azaborolidine (compound B) provide a balance of these properties and provides ca. 5.6 wt% hydrogen. The two hydrogen storage materials decompose at a faster rate than either individually and products formed are a mixture of molecular trimers. Digestion of the product mixture formed from the decomposition of the AB + B fuel blend with methanol leads to the two corresponding methanol adducts of the starting material and not a complex mixture of adducts. The work shows the utility of using blends of materials to reduce volatile impurities and preserve liquid phase.


Downregulation of splicing factor SRSF3 induces p53β, an alternatively spliced isoform of p53 that promotes cellular senescence.
Most human pre-mRNA transcripts are alternatively spliced, but the significance and fine-tuning of alternative splicing in different biological processes is only starting to be understood. SRSF3 (SRp20) is a member of a highly conserved family of splicing factors that have critical roles in key biological processes, including tumor progression. Here, we show that SRSF3 regulates cellular senescence, a p53-mediated process to suppress tumorigenesis, through TP53 alternative splicing. Downregulation of SRSF3 was observed in normal human fibroblasts undergoing replicative senescence, and was associated with the upregulation of p53β, an alternatively spliced isoform of p53 that promotes p53-mediated senescence. Knockdown of SRSF3 by short interfering RNA (siRNA) in early-passage fibroblasts induced senescence, which was associated with elevated expression of p53β at mRNA and protein levels. Knockdown of p53 partially rescued SRSF3-knockdown-induced senescence, suggesting that SRSF3 acts on p53-mediated cellular senescence. RNA pulldown assays demonstrated that SRSF3 binds to an alternatively spliced exon uniquely included in p53β mRNA through the consensus SRSF3-binding sequences. RNA crosslinking and immunoprecipitation assays (CLIP) also showed that SRSF3 in vivo binds to endogenous p53 pre-mRNA at the region containing the p53β-unique exon. Splicing assays using a transfected TP53 minigene in combination with siRNA knockdown of SRSF3 showed that SRSF3 functions to inhibit the inclusion of the p53β-unique exon in splicing of p53 pre-mRNA. These data suggest that downregulation of SRSF3 represents an endogenous mechanism for cellular senescence that directly regulates the TP53 alternative splicing to generate p53β. This study uncovers the role for general splicing machinery in tumorigenesis, and suggests that SRSF3 is a direct regulator of p53.


Oxygen concentration determines the biological effects of NOTCH-1 signaling in adenocarcinoma of the lung.
NOTCH signaling is an evolutionarily conserved signaling pathway that regulates cell fate during development and postnatal life. It has been increasingly linked to carcinogenesis, although its role in cancer seems to be highly context and tissue specific. Although NOTCH signaling is required for lung development, little is known about its role in lung cancer. In this study, we show that NOTCH signaling, as measured by the gamma-secretase cleavage product N(IC)-1, is active in both normal human and lung tumor samples; however, downstream NOTCH readouts (i.e., HES-1 and HES-5) are elevated in lung tumors. Levels of NOTCH signaling components in primary human lung cells reflect observations in tissue samples, yet lung tumor cell lines showed little NOTCH signaling. Because oxygen concentrations are important in normal lung physiology and lung tumors are hypoxic, the effect of low oxygen on these lung tumor cell lines was evaluated. We found that hypoxia dramatically elevates NOTCH signaling (especially NOTCH-1) in lung tumor cell lines and concomitantly sensitizes them to inhibition via small-molecule gamma-secretase inhibitors or NOTCH-1 RNA interference. gamma-Secretase inhibitor-induced apoptosis of lung tumor cells grown under hypoxic conditions could be rescued by reintroduction of active NOTCH-1. Our data strengthen the role of NOTCH in lung cancer and as a therapeutic target for the treatment of lung and other hypoxic tumor types.


Gene expression signatures as a guide to treatment strategies for in-transit metastatic melanoma.
In-transit metastatic melanoma, which typically presents as multifocal lesions, provides a unique setting to evaluate the utility of gene signatures for defining optimal regional therapeutic strategies and assessing the efficacy of treatment. The goal of this study was to determine whether a single multifocal lesion is representative of residual tumor burden in terms of gene expression signatures predictive of response to therapy. Using microarray-based gene expression profiling, we examined 55 in-transit melanoma lesions across 29 patients with multifocal disease. Principal component analysis, unsupervised hierarchical clustering, one-way ANOVA, binary regression analysis, and gene signatures predictive of oncogenic pathway activation were used to compare patterns of gene expression across all multifocal lesions from a patient. Patterns of gene expression were highly similar (P < 0.006; average r = 0.979) across pretreatment lesions from a single patient compared with the significantly different patterns observed across patients (P < 0.05). The findings presented in this study show that individual melanoma tumor nodules in patients with multifocal disease harbor similar patterns of gene expression and a single lesion can be used to predict response to chemotherapy, evaluate the activation status of oncogenic signaling pathways, and characterize other aspects of the biology of an individual patient's disease. These results will facilitate the use of gene expression profiling in melanoma regional therapy clinical trials to not only select optimal regional chemotherapeutic agents but to also allow for a more rational identification of candidates for specific targeted therapies and evaluation of their therapeutic efficacy. Mol Cancer Ther; 9(4); 779-90. (c)2010 AACR.


Predicting evolutionary site variability from structure in viral proteins: buriedness, packing, flexibility, and design.
Several recent works have shown that protein structure can predict site-specific evolutionary sequence variation. In particular, sites that are buried and/or have many contacts with other sites in a structure have been shown to evolve more slowly, on average, than surface sites with few contacts. Here, we present a comprehensive study of the extent to which numerous structural properties can predict sequence variation. The quantities we considered include buriedness (as measured by relative solvent accessibility), packing density (as measured by contact number), structural flexibility (as measured by B factors, root-mean-square fluctuations, and variation in dihedral angles), and variability in designed structures. We obtained structural flexibility measures both from molecular dynamics simulations performed on nine non-homologous viral protein structures and from variation in homologous variants of those proteins, where they were available. We obtained measures of variability in designed structures from flexible-backbone design in the Rosetta software. We found that most of the structural properties correlate with site variation in the majority of structures, though the correlations are generally weak (correlation coefficients of 0.1-0.4). Moreover, we found that buriedness and packing density were better predictors of evolutionary variation than structural flexibility. Finally, variability in designed structures was a weaker predictor of evolutionary variability than buriedness or packing density, but it was comparable in its predictive power to the best structural flexibility measures. We conclude that simple measures of buriedness and packing density are better predictors of evolutionary variation than the more complicated predictors obtained from dynamic simulations, ensembles of homologous structures, or computational protein design.


Cooperative Binding of Cyclodextrin Dimers to Isoflavone Analogues Elucidated by Free Energy Calculations.
Dimerization of cyclodextrin (CD) molecules is an elementary step in the construction of CD-based nanostructured materials. Cooperative binding of CD cavities to guest molecules facilitates the dimerization process and, consequently, the overall stability and assembly of CD nanostructures. In the present study, all three dimerization modes (head-to-head, head-to-tail, and tail-to-tail) of β-CD molecules and their binding to three isoflavone drug analogues (puerarin, daidzin, and daidzein) were investigated in explicit water surrounding using molecular dynamics simulations. Total and individual contributions from the binding partners and solvent environment to the thermodynamics of these binding reactions are quantified in detail using free energy calculations. Cooperative drug binding to two CD cavities gives an enhanced binding strength for daidzin and daidzein, whereas for puerarin no obvious enhancement is observed. Head-to-head dimerization yields the most stable complexes for inclusion of the tested isoflavones (templates) and may be a promising building block for construction of template-stabilized CD nanostructures. Compared to the case of CD monomers, the desolvation of CD dimers and entropy changes upon complexation prove to be influential factors of cooperative binding. Our results shed light on key points of the design of CD-based supramolecular assemblies. We also show that structure-based calculation of binding thermodynamics can quantify stabilization caused by cooperative effects in building blocks of nanostructured materials.


Efficiency of porcine endothelial cell infection with human cytomegalovirus depends on both virus tropism and endothelial cell vascular origin.
Human cytomegalovirus (HCMV) infection or reactivation has been linked to allograft rejection resulting from endothelial injury and immune activation. In pig-to-human xenotransplantation, currently investigated to circumvent the shortage of human organs in transplantation medicine, the porcine endothelium will inevitably be exposed to human pathogens such as HCMV. We investigated the susceptibility of porcine endothelial cells (pEC) to HCMV infection. Immortalized porcine aortic (PEDSV15) and porcine microvascular bone-marrow derived EC (2A2) as well as a panel of primary pEC originated from different vascular beds were inoculated with the endotheliotropic (TB40/E) and the fibroblast propagated (TB40/F) HCMV strains at multiplicity of infection (MOI) ranging from 0.1 to 5. Viral replication kinetics, development of cytopathology and release of viral progeny were analyzed. All viral strains infected pEC with differences in both infection efficiency and kinetics of cytopathology. Moreover, differences in susceptibility of pEC derived from distinct vascular beds were observed. HCMV underwent a complete replication cycle in about 5% of the infected pEC. Comparing the permissiveness of pEC to human aortic EC (HAEC) revealed differences in strain susceptibility and lower rates of late antigen expression in pEC. Finally, HCMV-infected pEC released viral particles but with a lower efficiency than infected HAEC. Our data demonstrate that HCMV productively infects pEC, therefore finding strategies to render pEC resistant to HCMV infection will be of interest to reduce the potential risk carried by HCMV reactivation in xenotransplantation.


Effects of growth implants on consumer perceptions of meat tenderness in beef steers.
Anabolic steroid implants are routinely used to increase growth performance and profitability; however, there are concerns that the use of implants, particularly those containing trenbolone acetate, may have detrimental effects on carcass quality and beef tenderness. Thus, the objectives of the current study were to determine the effects of various commonly used implant regimens on shear force values, sensory properties, and consumer satisfaction of beef top loin steaks from cattle of Bos indicus influence. Cattle were supplied by producers that agreed to provide sire and dam information in exchange for carcass and sensory data. Steers (n = 2,748) were assigned randomly to one of three implant treatments (12/sire; four steers from each sire were placed into each treatment group): 1) unimplanted controls (n = 1,368); 2) Synovex-S followed by another Synovex-S (n = 660); or 3) Synovex-S followed by Revalor-S (n = 720). Steaks sampled after 3, 7, and 14 d of aging indicated that unimplanted cattle had lower (P < 0.05) Warner-Bratzler Shear force values than those from implanted animals. No differences (P > 0.05) in shear force values were found between the two treatments or the control groups for steaks sampled following a 21-d aging period. Steaks from implanted animals sampled after 3, 7, and 14 d aging were rated lower (P < 0.05) for initial and sustained trained sensory panel tenderness scores. Consumers failed to detect any differences in steak samples related to implant treatment after 7 and 14 d of aging. Consumer education level and family income did not affect overall acceptability (P > 0.10 and 0.18, respectively) or tenderness acceptability (P > 0.11 and 0.68, respectively); however, consumers with postgraduate degrees recorded lower (P < 0.05) overall quality, beef flavor, juiciness, and tenderness scores than consumers in all other education classifications. Additionally, family income had no effect on overall quality (P > 0.21), beef flavor (P > 0.28), juiciness (P > 0.58), or tenderness (P > 0.45) scores. Results indicate that using a moderate implant program in Bos indicus-influenced cattle has no detrimental effects on beef tenderness and consumer acceptability.


Cultural and community determinants of subjective social status among Cherokee and White youth.
. Subjective social status (SSS) is associated with physical and mental health in diverse samples. However, community, cultural, and ethnic influences on SSS are poorly understood, especially among rural and American Indian populations. We aimed to examine similarities and differences in how community poverty, family context, and life course attainment predict SSS among Cherokee and White youth in Appalachia. We assessed culturally and developmentally appropriate aspects of life course attainment among 344 Cherokee and White youth (age 19-24) using the Life Trajectory Interview for Youth (Brown et al. 2006. International Journal of Methods in Psychiatric Research, 15, 192-206). Combined with information regarding community context and family history, these data were used to examine common patterns and ethnic differences in community, family, and cultural influences on SSS. Overall, both Cherokee and White youth rank their families lower in SSS than previously studied US youth. Family poverty during childhood and low parental education negatively influence family SSS, Cherokee youth rank higher on subjective socioeconomic status (SES) than Whites, as do participants in high poverty areas. However, White youth rank higher on peer SSS. Ethnographically generated items perform better than standard demographic markers in predicting SSS. Educational attainment is associated with peer SSS among Cherokee (but not White) youths. Cultural identity, community context, and local reference groups are crucial determinants of SSS. Both White and Cherokee youth in Appalachia exhibit SSS rankings consistent with socioeconomic and cultural marginalization. On a local scale, however, living in high poverty areas or minority communities may buffer individuals from some negative social comparisons regarding subjectively perceived SES. Meanwhile, social monitoring in small minority communities may constrain optimistic bias in assessments of peer popularity and status. Social ecology, family context, and individual attainment appear to exert distinctive influences on SSS across different cultural and ethnic groups.


Rebuilding the Damaged Heart: Mesenchymal Stem Cells, Cell-Based Therapy, and Engineered Heart Tissue.
Mesenchymal stem cells (MSCs) are broadly distributed cells that retain postnatal capacity for self-renewal and multilineage differentiation. MSCs evade immune detection, secrete an array of anti-inflammatory and anti-fibrotic mediators, and very importantly activate resident precursors. These properties form the basis for the strategy of clinical application of cell-based therapeutics for inflammatory and fibrotic conditions. In cardiovascular medicine, administration of autologous or allogeneic MSCs in patients with ischemic and nonischemic cardiomyopathy holds significant promise. Numerous preclinical studies of ischemic and nonischemic cardiomyopathy employing MSC-based therapy have demonstrated that the properties of reducing fibrosis, stimulating angiogenesis, and cardiomyogenesis have led to improvements in the structure and function of remodeled ventricles. Further attempts have been made to augment MSCs' effects through genetic modification and cell preconditioning. Progression of MSC therapy to early clinical trials has supported their role in improving cardiac structure and function, functional capacity, and patient quality of life. Emerging data have supported larger clinical trials that have been either completed or are currently underway. Mechanistically, MSC therapy is thought to benefit the heart by stimulating innate anti-fibrotic and regenerative responses. The mechanisms of action involve paracrine signaling, cell-cell interactions, and fusion with resident cells. Trans-differentiation of MSCs to bona fide cardiomyocytes and coronary vessels is also thought to occur, although at a nonphysiological level. Recently, MSC-based tissue engineering for cardiovascular disease has been examined with quite encouraging results. This review discusses MSCs from their basic biological characteristics to their role as a promising therapeutic strategy for clinical cardiovascular disease.


Influence of gas packing and orientation on FTIR activity for CO chemisorption to the Cu paddlewheel.
In situ Fourier-transform infrared (FTIR) spectroscopy is able to probe structural defects via site-specific adsorption of CO to the Cu-BTC (BTC = 1,3,5-benzenetricarboxylate) metal-organic framework (MOF). The temperature-programmed desorption (TPD) of CO chemisorbed to Cu-TDPAT (TDPAT = 2,4,6-tris(3,5-dicarboxylphenylamino)-1,3,5-triazine) is virtually identical to Cu-BTC, suggesting CO chemisorbs to the open metal site at the axial position of the copper paddlewheel that is the building unit of both MOFs. Yet, despite an increased gravimetric CO : Cu ratio, CO chemisorbed to Cu-TDPAT is FTIR inactive. We rule out the presence of residual solvent, thermal degradation, adsorption temperature, and ligand-induced electronic effects at the adsorption site. TPD at increased pressure suggests the multiple CO per Cu site rearrange in Cu-TDPAT as a dynamic function of temperature and pressure. Thus, the FTIR inactivity of CO chemisorbed to Cu-TDPAT is attributed to orientation and/or packing of the CO relative to the Cu binding site. The results suggest dynamic chemisorption complicate extension of a site-specific in situ FTIR probe of gas adsorption. For both Cu-BTC and Cu-TDPAT, the in situ FTIR probe is a less sensitive probe of defects than X-ray photoelectron spectroscopy and nitrogen adsorption.


Speckle-reduction algorithm for ultrasound images in complex wavelet domain using genetic algorithm-based mixture model.
Compared with other medical-imaging modalities, ultrasound (US) imaging is a valuable way to examine the body's internal organs, and two-dimensional (2D) imaging is currently the most common technique used in clinical diagnoses. Conventional 2D US imaging systems are highly flexible cost-effective imaging tools that permit operators to observe and record images of a large variety of thin anatomical sections in real time. Recently, 3D US imaging has also been gaining popularity due to its considerable advantages over 2D US imaging. It reduces dependency on the operator and provides better qualitative and quantitative information for an effective diagnosis. Furthermore, it provides a 3D view, which allows the observation of volume information. The major shortcoming of any type of US imaging is the presence of speckle noise. Hence, speckle reduction is vital in providing a better clinical diagnosis. The key objective of any speckle-reduction algorithm is to attain a speckle-free image while preserving the important anatomical features. In this paper we introduce a nonlinear multi-scale complex wavelet-diffusion based algorithm for speckle reduction and sharp-edge preservation of 2D and 3D US images. In the proposed method we use a Rayleigh and Maxwell-mixture model for 2D and 3D US images, respectively, where a genetic algorithm is used in combination with an expectation maximization method to estimate mixture parameters. Experimental results using both 2D and 3D synthetic, physical phantom, and clinical data demonstrate that our proposed algorithm significantly reduces speckle noise while preserving sharp edges without discernible distortions. The proposed approach performs better than the state-of-the-art approaches in both qualitative and quantitative measures.


Self-biased reconfigurable graphene stacks for terahertz plasmonics.
The gate-controllable complex conductivity of graphene offers unprecedented opportunities for reconfigurable plasmonics at terahertz and mid-infrared frequencies. However, the requirement of a gating electrode close to graphene and the single 'control knob' that this approach offers limits the practical implementation and performance of these devices. Here we report on graphene stacks composed of two or more graphene monolayers separated by electrically thin dielectrics and present a simple and rigorous theoretical framework for their characterization. In a first implementation, two graphene layers gate each other, thereby behaving as a controllable single equivalent layer but without any additional gating structure. Second, we show that adding an additional gate allows independent control of the complex conductivity of each layer within the stack and provides enhanced control on the stack equivalent complex conductivity. These results are very promising for the development of THz and mid-infrared plasmonic devices with enhanced performance and reconfiguration capabilities.


Genetic architecture of adaptation to novel environmental conditions in a predominantly selfing allopolyploid plant.
Genetic architecture of adaptation is traditionally studied in the context of local adaptation, viz. spatially varying conditions experienced by the species. However, anthropogenic changes in the natural environment pose a new context to this issue, that is, adaptation to an environment that is new for the species. In this study, we used crossbreeding to analyze genetic architecture of adaptation to conditions not currently experienced by the species but with high probability of encounter in the near future due to global climate change. We performed targeted interpopulation crossing using genotypes from two core and two peripheral Triticum dicoccoides populations and raised the parents and three generations of hybrids in a greenhouse under simulated desert conditions to analyze the genetic architecture of adaptation to these conditions and an effect of gene flow from plants having different origin. The hybrid (F1) fitness did not differ from that of the parents in crosses where both plants originated from the species core, but in crosses involving one parent from the species core and another one from the species periphery the fitness of F1 was consistently higher than that of the periphery-originated parent. Plant fitness in the next two generations (F2 and F3) did not differ from the F1, suggesting that effects of epistatic interactions between recombining and segregating alleles of genes contributing to fitness were minor or absent. The observed low importance of epistatic gene interactions in allopolyploid T. dicoccoides and low probability of hybrid breakdown appear to be the result of permanent fixation of heterozygosity and lack of intergenomic recombination in this species. At the same time, predominant but not complete selfing combined with an advantage of bivalent pairing of homologous chromosomes appears to maintain high genetic variability in T. dicoccoides, greatly enhancing its adaptive ability.


Tri-Ponderal Mass Index vs Body Mass Index in Estimating Body Fat During Adolescence.
Body mass index (BMI) is used to diagnose obesity in adolescents worldwide, despite evidence that weight does not scale with height squared in adolescents. To account for this, health care providers diagnose obesity using BMI percentiles for each age (BMI z scores), but this does not ensure that BMI is accurate in adolescents. To compare the accuracy of BMI vs other body fat indices of the form body mass divided by heightn in estimating body fat levels in adolescents. Cross-sectional data from the 1999 to 2006 US National Health and Nutrition Examination Survey were analyzed between September 2015 and December 2016. Dual-energy x-ray absorptiometry and anthropometric data were used to determine changes in body fat levels, body proportions, and the scaling relationships among body mass, height, and percent body fat. To assess the merits of each adiposity index, 3 criteria were used: stability with age, accuracy in estimating percent body fat, and accuracy in classifying adolescents as overweight vs normal weight. Participants included 2285 non-Hispanic white participants aged 8 to 29 years. Percent body fat varied with both age and height during adolescence, invalidating the standard weight-to-height regression as the way of finding the optimal body fat index. Because the correct regression model (percent body fat is proportional to mass divided by heightn) suggested that percent body fat scales to height with an exponent closer to 3, we therefore focused on the tri-ponderal mass index (TMI; mass divided by height cubed) as an alternative to BMI z scores. For ages 8 to 17 years, TMI yielded greater stability with age and estimated percent body fat better than BMI (R2 = 0.64 vs 0.38 in boys and R2 = 0.72 vs 0.66 in girls). Moreover, TMI misclassified adolescents as overweight vs normal weight less often than BMI z scores (TMI, 8.4%; 95% CI, 7.3%-9.5% vs BMI, 19.4%; 95% CI, 17.8%-20.0%; P < .001) and performed equally as well as updated BMI percentiles derived from the same data set (TMI, 8.4%; 95% CI, 7.3%-9.5% vs BMI, 8.0%; 95% CI, 6.9%-9.1%; P = .62). The tri-ponderal mass index estimates body fat levels more accurately than BMI in non-Hispanic white adolescents aged 8 to 17 years. Moreover, TMI diagnoses adolescents as overweight more accurately than BMI z scores and equally as well as updated BMI percentiles but is much simpler to use than either because it does not involve complicated percentiles. Taken together, it is worth considering replacing BMI z scores with TMI to estimate body fat levels in adolescents.


Validation of the new Graded Prognostic Assessment scale for brain metastases: a multicenter prospective study.
Prognostic indexes are useful to guide tailored treatment strategies for cancer patients with brain metastasis (BM). We evaluated the new Graded Prognostic Assessment (GPA) scale in a prospective validation study to compare it with two published prognostic indexes. A total of 285 newly diagnosed BM (n = 85 with synchronous BM) patients, accrued prospectively between 2000 and 2009, were included in this analysis. Mean age was 62 ± 12.0 years. The median KPS and number of BM was 70 (range, 20-100) and 3 (range, 1-50), respectively. The majority of primary tumours were lung (53%), or breast (17%) cancers. Treatment was administered to 255 (89.5%) patients. Only a minority of patients could be classified prospectively in a favourable prognostic class: GPA 3.5-4: 3.9%; recursive partitioning analysis (RPA) 1, 8.4% and Basic Score for BM (BSBM) 3, 9.1%. Mean follow-up (FU) time was 5.2 ± 4.7 months. During the period of FU, 225 (78.9%) patients died. The 6 months- and 1 year-OS was 36.9% and 17.6%, respectively. On multivariate analysis, performance status (P < 0.001), BSBM (P < 0.001), Center (P = 0.007), RPA (P = 0.02) and GPA (P = 0.03) were statistically significant for OS. The survival prediction performances' of all indexes were identical. Noteworthy, the significant OS difference observed within 3 months of diagnosis between the BSBM, RPA and GPA classes/groups was not observed after this cut-off time point. Harrell's concordance indexes C were 0.58, 0.61 and 0.58 for the GPA, BSBM and RPA, respectively. Our data suggest that the new GPA index is a valid prognostic index. In this prospective study, the prediction performance was as good as the BSBM or RPA systems. These published indexes may however have limited long term prognostication capability.


Event-related brain responses to emotional words, pictures, and faces - a cross-domain comparison.
Emotion effects in event-related brain potentials (ERPs) have previously been reported for a range of visual stimuli, including emotional words, pictures, and facial expressions. Still, little is known about the actual comparability of emotion effects across these stimulus classes. The present study aimed to fill this gap by investigating emotion effects in response to words, pictures, and facial expressions using a blocked within-subject design. Furthermore, ratings of stimulus arousal and valence were collected from an independent sample of participants. Modulations of early posterior negativity (EPN) and late positive complex (LPC) were visible for all stimulus domains, but showed clear differences, particularly in valence processing. While emotion effects were limited to positive stimuli for words, they were predominant for negative stimuli in pictures and facial expressions. These findings corroborate the notion of a positivity offset for words and a negativity bias for pictures and facial expressions, which was assumed to be caused by generally lower arousal levels of written language. Interestingly, however, these assumed differences were not confirmed by arousal ratings. Instead, words were rated as overall more positive than pictures and facial expressions. Taken together, the present results point toward systematic differences in the processing of written words and pictorial stimuli of emotional content, not only in terms of a valence bias evident in ERPs, but also concerning their emotional evaluation captured by ratings of stimulus valence and arousal.


Native bees provide insurance against ongoing honey bee losses.
One of the values of biodiversity is that it may provide 'biological insurance' for services currently rendered by domesticated species or technology. We used crop pollination as a model system, and investigated whether the loss of a domesticated pollinator (the honey bee) could be compensated for by native, wild bee species. We measured pollination provided to watermelon crops at 23 farms in New Jersey and Pennsylvania, USA, and used a simulation model to separate the pollen provided by honey bees and native bees. Simulation results predict that native bees alone provide sufficient pollination at > 90% of the farms studied. Furthermore, empirical total pollen deposition at flowers was strongly, significantly correlated with native bee visitation but not with honey bee visitation. The honey bee is currently undergoing extensive die-offs because of Colony Collapse Disorder. We predict that in our region native bees will buffer potential declines in agricultural production because of honey bee losses.


Disentangling metabolic functions of bacteria in the honey bee gut.
It is presently unclear how much individual community members contribute to the overall metabolic output of a gut microbiota. To address this question, we used the honey bee, which harbors a relatively simple and remarkably conserved gut microbiota with striking parallels to the mammalian system and importance for bee health. Using untargeted metabolomics, we profiled metabolic changes in gnotobiotic bees that were colonized with the complete microbiota reconstituted from cultured strains. We then determined the contribution of individual community members in mono-colonized bees and recapitulated our findings using in vitro cultures. Our results show that the honey bee gut microbiota utilizes a wide range of pollen-derived substrates, including flavonoids and outer pollen wall components, suggesting a key role for degradation of recalcitrant secondary plant metabolites and pollen digestion. In turn, multiple species were responsible for the accumulation of organic acids and aromatic compound degradation intermediates. Moreover, a specific gut symbiont, Bifidobacterium asteroides, stimulated the production of host hormones known to impact bee development. While we found evidence for cross-feeding interactions, approximately 80% of the identified metabolic changes were also observed in mono-colonized bees, with Lactobacilli being responsible for the largest share of the metabolic output. These results show that, despite prolonged evolutionary associations, honey bee gut bacteria can independently establish and metabolize a wide range of compounds in the gut. Our study reveals diverse bacterial functions that are likely to contribute to bee health and provide fundamental insights into how metabolic activities are partitioned within gut communities.


Clustering of Neural Activity: A Design Principle for Population Codes.
We propose that correlations among neurons are generically strong enough to organize neural activity patterns into a discrete set of clusters, which can each be viewed as a population codeword. Our reasoning starts with the analysis of retinal ganglion cell data using maximum entropy models, showing that the population is robustly in a frustrated, marginally sub-critical, or glassy, state. This leads to an argument that neural populations in many other brain areas might share this structure. Next, we use latent variable models to show that this glassy state possesses well-defined clusters of neural activity. Clusters have three appealing properties: (i) clusters exhibit error correction, i.e., they are reproducibly elicited by the same stimulus despite variability at the level of constituent neurons; (ii) clusters encode qualitatively different visual features than their constituent neurons; and (iii) clusters can be learned by downstream neural circuits in an unsupervised fashion. We hypothesize that these properties give rise to a "learnable" neural code which the cortical hierarchy uses to extract increasingly complex features without supervision or reinforcement.


Dual-function remotely-pumped Erbium-doped fiber amplifier: Loss and dispersion compensator.
An efficient Erbium-doped fiber amplifier configured in doublepass amplification scheme with chirped fiber Bragg grating as the reflector is presented in this paper. The proposed amplifier architecture is optimized and designed to work under consideration of low pump powers for remotely-pumped applications. The chirped fiber Bragg grating is used to reflect the amplified signal back to the Erbium-doped fiber and at the same time to compensate the effect of fiber dispersion. The proposed amplifier architecture is able to maintain gain of higher than 20 dB for small signals less than -23 dBm with 10 mW pump power only. The integrated function of loss and dispersion compensator in single black box is an attractive solution to be used as pre-amplifier.


Magnetic resonance imaging for lung cancer detection: experience in a population of more than 10,000 healthy individuals.
Recent refinements of lung MRI techniques have reduced the examination time and improved diagnostic sensitivity and specificity. We conducted a study to assess the feasibility of MRI for the detection of primary lung cancer in asymptomatic individuals. A retrospective chart review was performed on images of lung parenchyma, which were extracted from whole-body MRI examinations between October 2000 and December 2007. 11,766 consecutive healthy individuals (mean age, 50.4 years; 56.8% male) were scanned using one of two 1.5-T scanners (Sonata and Sonata Maestro, Siemens Medical Solutions, Erlangen, Germany). The standard protocol included a quick whole-lung survey with T2-weighted 2-dimensional half Fourier acquisition single shot turbo spin echo (HASTE) and 3-dimensional volumetric interpolated breath-hold examination (VIBE). Total examination time was less than 10 minutes, and scanning time was only 5 minutes. Prompt referrals and follow-ups were arranged in cases of suspicious lung nodules. A total of 559 individuals (4.8%) had suspicious lung nodules. A total of 49 primary lung cancers were diagnosed in 46 individuals: 41 prevalence cancers and 8 incidence cancers. The overall detection rate of primary lung cancers was 0.4%. For smokers aged 51 to 70 years, the detection rate was 1.4%. TNM stage I disease accounted for 37 (75.5%). The mean size of detected lung cancers was 1.98 cm (median, 1.5 cm; range, 0.5-8.2 cm). The most histological types were adenocarcinoma in 38 (77.6%). Rapid zero-dose MRI can be used for lung cancer detection in a healthy population.


Acting Out: Enabling Meaningful Participation Among People With Long-Term Mental Health Problems in a Music and Theater Workshop.
In this article, we explore what enables meaningful participation in a music and theater workshop from a first person's perspective of people with mental health problems. The study uses a hermeneutical-phenomenological approach. Data were collected from qualitative in-depth interviews with 12 participants in a music and theater workshop located in a Norwegian mental health hospital. Data were analyzed through thematic analysis. Two overarching themes were identified: (a) room for dignity and (b) a creative arena. This study indicates that to enable participation for people with long-term mental health problems, it is important to facilitate activities that are flexible, person centered, and resource oriented, in which participants have the possibility to participate regardless of symptoms, functional ability, or whether they are hospitalized. In addition, having professionals who believe in creative growth and offer an illness-free zone that belongs to the participants in a hospital setting is of great importance.


Galectin-1 reduces the severity of dextran sulfate sodium (DSS)-induced ulcerative colitis by suppressing inflammatory and oxidative stress response.
Ulcerative colitis is an inflammatory bowel disease that affects a large number of people around the world. Galectin-1 is a β-galactoside-binding lectin with a broad range of biological activities. The effects of galectin-1 on dextran sulfate sodium (DSS)-induced ulcerative colitis in vivo is not clear. We investigated the effect of galectin-1 on colon morphology, cell proliferation, oxidative stress, antioxidant system, and proinflammatory/antiinflammatory cytokines in a DSS-induced mouse model of ulcerative colitis. Thirty-two C57BL/6 mice were randomly assigned to one of the four groups: control, acute colitis, galectin-1, and DSS+galectin-1. Controls were treated with phosphate-buffered saline (PBS) for seven days. Acute colitis was induced by 3% DSS in drinking water administered orally for five days. Mice in galectin-1 groups were treated with 1 mg/kg recombinant human galectin-1 in PBS for seven consecutive days. Oral DSS administration resulted in acute colitis by causing histopathological changes; an increase in disease activity index (DAI), lipid peroxidation (malondialdehyde [MDA]), myeloperoxidase (MPO), and tumor necrosis factor (TNF)-α levels; a decrease in body weight, colon length, cell proliferation index, catalase, glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities, and GSH and interleukin (IL)-10 levels. The treatment with galectin-1 attenuated DSS-induced acute colitis by reducing DAI, MDA, MPO, and TNF-α levels and by increasing body weight, colon length, cell proliferation, antioxidant enzyme activity, GSH, and IL-10 levels. These findings suggest that galectin-1 has proliferative, antioxidant, antiinflammatory, and cytoprotective effects against DSS-induced ulcerative colitis in mice. Due to its antiinflammatory and antioxidant activity galectin-1 may be effective in preventing and treating ulcerative colitis.


Development of a Mobile Motion Capture (MO2CA) System for Future Military Application.
State-of-the-art three-dimensional motion analysis systems, which are utilized to predict, diagnose, and treat many musculoskeletal and neurological disorders, are expensive and space consuming. These systems have only been widely used in large research facilities because of their lack of this transportability. Since device portability is a critically important in the military, most small military hospitals are therefore deprived of these systems. The purpose of this study was to develop a mobile motion capture system, MO2CA, to automatically detect the movement of the human body. Twenty healthy young adults participated in this study. Colored tape was attached on the heel, and subjects walked on the treadmill at three different speeds: preferred, fast, and slow. Two motion capture systems were used concurrently: Qualisys (100 Hz) and MO2CA (60 Hz). Four dependent variables were: stride length, stride time, stride length variability, and stride time variability. Paired t-tests, Pearson correlation, and Bland-Altman plots were used to investigate the statistical differences between two systems. No significant differences were found for all dependent variables. Regression and Bland-Altman plots showed strong agreements between the two systems. Our MO2CA shows a potential for real-time tracking of biomechanical changes in gait, which is extremely important for military use.