Bayesian Filtering with Multiple Internal Models: Toward a Theory of Social Intelligence.
To exhibit social intelligence, animals have to recognize whom they are communicating with. One way to make this inference is to select among internal generative models of each conspecific who may be encountered. However, these models also have to be learned via some form of Bayesian belief updating. This induces an interesting problem: When receiving sensory input generated by a particular conspecific, how does an animal know which internal model to update? We consider a theoretical and neurobiologically plausible solution that enables inference and learning of the processes that generate sensory inputs (e.g., listening and understanding) and reproduction of those inputs (e.g., talking or singing), under multiple generative models. This is based on recent advances in theoretical neurobiology-namely, active inference and post hoc (online) Bayesian model selection. In brief, this scheme fits sensory inputs under each generative model. Model parameters are then updated in proportion to the probability that each model could have generated the input (i.e., model evidence). The proposed scheme is demonstrated using a series of (real zebra finch) birdsongs, where each song is generated by several different birds. The scheme is implemented using physiologically plausible models of birdsong production. We show that generalized Bayesian filtering, combined with model selection, leads to successful learning across generative models, each possessing different parameters. These results highlight the utility of having multiple internal models when making inferences in social environments with multiple sources of sensory information.


Characteristics of a foot-and-mouth disease virus with a partial VP1 G-H loop deletion in experimentally infected cattle.
Previous work in cattle illustrated the protective efficacy and negative marker potential of a A serotype foot-and-mouth disease virus (FMDV) vaccine prepared from a virus lacking a significant portion of the VP1 G-H loop (termed A(-)). Since this deletion also includes the arginine-glycine-aspartate (RGD) motif required for virus attachment to the host cell in vivo, it was hypothesised that this virus would be attentuated in naturally susceptible animals. The A(-) virus was passaged three times in cattle via needle inoculation of virus suspension delivered into the intradermal space of the tongue (intradermolingual: IDL). Included in the study were three direct contact cattle, two of which were used for the third cattle passage (by inoculation) after direct contact exposure for three days. Cattle were monitored for clinical signs and samples were collected for sequencing as well as antibody and viral genome detection by ELISA and qRT-PCR. Following needle inoculation with the A(-) virus, naïve cattle developed typical clinical signs of FMDV infection, diagnostic assays also provided positive serological and virological results. However, the contact cattle did not develop clinical signs or generate serological or virological markers indicative of FMDV infection even when the cattle were subsequently needle inoculated with 10(5) TCID50 A(-) FMDV delivered IDL following three days of direct contact exposure. The results suggest that the A(-) virus is not attentuated in cattle when inoculated IDL. This virus could be useful as a tool to understand further the natural pathogenesis, receptor usage and internalisation pathways of FMDV.


Brain activity in valuation regions while thinking about the future predicts individual discount rates.
People vary widely in how much they discount delayed rewards, yet little is known about the sources of these differences. Here we demonstrate that neural activity in ventromedial prefrontal cortex (VMPFC) and ventral striatum (VS) when human subjects are asked to merely think about the future--specifically, to judge the subjective length of future time intervals--predicts delay discounting. High discounters showed lower activity for longer time delays, while low discounters showed the opposite pattern. Our results demonstrate that the correlation between VMPFC and VS activity and discounting occurs even in the absence of choices about future rewards, and does not depend on a person explicitly evaluating future outcomes or judging their self-relevance. This suggests a link between discounting and basic processes involved in thinking about the future, such as temporal perception. Our results also suggest that reducing impatience requires not suppression of VMPFC and VS activity altogether, but rather modulation of how these regions respond to the present versus the future.


Network frailty and the geometry of herd immunity.
The spread of infectious disease through communities depends fundamentally on the underlying patterns of contacts between individuals. Generally, the more contacts one individual has, the more vulnerable they are to infection during an epidemic. Thus, outbreaks disproportionately impact the most highly connected demographics. Epidemics can then lead, through immunization or removal of individuals, to sparser networks that are more resistant to future transmission of a given disease. Using several classes of contact networks-Poisson, scale-free and small-world-we characterize the structural evolution of a network due to an epidemic in terms of frailty (the degree to which highly connected individuals are more vulnerable to infection) and interference (the extent to which the epidemic cuts off connectivity among the susceptible population that remains following an epidemic). The evolution of the susceptible network over the course of an epidemic differs among the classes of networks; frailty, relative to interference, accounts for an increasing component of network evolution on networks with greater variance in contacts. The result is that immunization due to prior epidemics can provide greater community protection than random vaccination on networks with heterogeneous contact patterns, while the reverse is true for highly structured populations.


The balanced lethal system of crested newts: a ghost of sex chromosomes past?
Balanced lethal systems are more than biological curiosities: as theory predicts, they should quickly be eliminated through the joint forces of recombination and selection. That such systems might become fixed in natural populations poses a challenge to evolutionary theory. Here we address the case of a balanced lethal system fixed in crested newts and related species, which makes 50% of offspring die early in development. All adults are heteromorphic for chromosome pair 1. The two homologues (1A and 1B) have different recessive deleterious alleles fixed on a nonrecombining segment, so that heterozygotes are viable, while homozygotes are lethal. Given such a strong segregation load, how could autosomes stop recombining? We propose a role for a sex-chromosome turnover from pair 1 (putative ancestral sex chromosome) to pair 4 (currently active sex chromosome). Accordingly, 1A and 1B represent two variants (Y(A) and Y(B)) of the Y chromosome from an ancestral male-heterogametic system. We formalize a scenario in which turnovers are driven by sex ratio selection stemming from gene-environment interactions on sex determination. Individual-based simulations show that a balanced lethal system can be fixed with significant likelihood, provided the masculinizing allele on chromosome 4 appears after the elimination of the feminizing allele on chromosome 1. Our study illustrates how strikingly maladaptive traits might evolve through natural selection.


Computer-based cognitive training for older adults: Determinants of adherence.
The possibilities of computer-based cognitive training (CCT) in postponing the onset of dementia are currently unclear, but promising. Our aim is to investigate older adults´ adherence to a long-term CCT program, and which participant characteristics are associated with adherence to the CCT. This study was part of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). Participants were 60-77-year-old individuals with increased dementia risk, recruited from previous population-based studies. The participants included in this study (n = 631) had been randomized to receive a multi-domain lifestyle intervention, including CCT. The measure of adherence was the number of completed CCT sessions (max = 144) as continuous measure. Due to a substantial proportion of participants with 0 sessions, the zero inflated negative binomial regression analyses were used to enable assessment of both predictors of starting the training and predictors of completing a higher number of training sessions. Several cognitive, demographic, lifestyle, and health-related variables were examined as potential predictors of adherence to CCT. Altogether, 63% of the participants participated in the CCT at least once, 20% completed at least half of the training, and 12% completed all sessions. Previous experience with computers, being married or cohabiting, better memory performance, and positive expectations toward the study predicted greater odds for starting CCT. Previous computer use was the only factor associated with a greater number of training sessions completed. Our study shows that there is a large variation in adherence to a long-lasting CCT among older adults with an increased risk of dementia. The results indicate that encouraging computer use, and taking into account the level of cognitive functioning, may help boost adherence to CCT.


Sphingosine 1-phosphate, lysophosphatidic acid and growth factor signaling and termination.
Sphingosine 1 phosphate (S1P) and lysophosphatidic acid (LPA) are bioactive lipid phosphates that bind to cell surface G-protein coupled receptors (GPCR) and, in addition, exhibit intracellular actions. We have summarised herein, an important functional interaction between lipid phosphate GPCR and receptor tyrosine kinases (RTK) that enables growth factors to spatially regulate effectors, thereby governing the nature of the biological response. For instance, we describe how the formation of functional complexes between the S1P(1) receptor and PDGFbeta receptor may effectively re-programme platelet-derived growth factor from a mitogenic to a migratory stimulus. This is achieved by integration of RTK- and GPCR-specific signals that results in spatial regulation of a cytoplasmic retained pool of extracellular signal regulated kinase-1/2 linked to myosin light chain kinase, myosin light chain phosphorylation and migration. We therefore suggest that the lipid phosphate receptor is a major determinant in regulating growth factor-dependent biology. Growth factors can also increase S1P inside cells, and we discuss the concept of spatial/temporal aspects of compartmentalised intracellular signaling of S1P in relation to defined interactions between, for instance, sphingosine kinase, phospholipase D1 and lipid phosphate phosphatases and regulation of cell survival.


Short-term variability of dissolved trace element concentrations in the Marne and Seine rivers near Paris.
The concentrations of dissolved trace elements (Li, B, Mn, Cu, As, Rb, Sr, Mo, Cd, Ba, Pb) in the Marne and Seine rivers in the Paris urban area were monitored over a 2-year period. The resulting data indicated moderate contamination of waters by the most toxic elements (Cu, As, Cd and Pb). The River Marne upstream and the River Seine downstream of the city of Paris displayed similar concentrations. However higher fluxes of trace elements were observed in the Seine than in the Marne due to their different discharges. Li, B, Rb, Sr and Ba concentrations were correlated with river discharge and concentrations were higher during high river flow. This was interpreted as a dilution by discharge from a major natural or anthropogenic source. Mn, Cu, Mo, Cd and Pb concentrations were not correlated with discharge. Dissolved Mn, Cu and Cd increased rapidly in summer, whereas the concentration of Mo decreased. These variations were attributed to redox processes. During summer when the dissolved oxygen concentrations decrease, Mn, Cu, Cd and Pb are released into solution whereas Mo is immobilised. Like metals, variations in arsenic contents were not linked with discharge. Its similarity with phosphate distribution suggests similar controls involving phytoplankton uptake and release from sediments through organic matter mineralization.


Ferulic Acid, an Angelica sinensis-Derived Polyphenol, Slows the Progression of Membranous Nephropathy in a Mouse Model.
Membranous nephropathy (MN) is a leading cause of adult nephrotic syndrome but lacks adequate treatment. Different extracts of Angelica sinensis (AS) and one of its active compounds, ferulic acid (FA), were used to evaluate the therapeutic effects in a MN mouse model. The MN model was grouped into three subgroups: no treatment (N-T), treatment at induction of MN (Pre-T), and treatment after full-blown MN (Post-T). The results showed that the methanol (ME) layer of AS extract exhibited a therapeutic effect on MN-induced proteinuria. The ME layer-enriched compound, FA, improved the hypoalbuminemia, hyperlipidemia, and proteinuria in both Pre-T and Post-T groups. Ferulic acid also reduced the formation of oxidative protein products and increased the synthesis of antioxidant enzymes in groups Pre-T and Post-T. Regarding angiogenesis factors, the antiangiogenic factors in renal glomeruli were increased in group N-T, but, after FA treatment, only one of the antiangiogenic factors, thrombospondin-1, showed a significant decrease. Furthermore, the expression of Th2 predominant showed significant decrease in both Pre-T and Post-T groups when compared to that of N-T group. In summary, FA retarded the progression of MN, and the mechanisms involved the regulation of oxidative stresses, angiogenic and antiangiogenic factors, and attenuation of Th2 response.


Communication challenges of HPV vaccination.
The UK has introduced a national human papillomavirus (HPV) immunisation programme for girls aged 12-13 from autumn 2008. Previous research has explored public understanding of the causes of cervical cancer and found little awareness of the role of HPV. To explore GPs' and practice nurses' views of HPV vaccination, prior to implementation of the national immunisation programme, with a focus on their role and anticipated difficulties. Qualitative semi-structured interviews were conducted with 17 GPs and practice nurses from practices in Hampshire and Wiltshire, in March 2008. The prevailing theme of new communication challenges was identified and these were connected to the activities of (i) explaining, (ii) consenting and (iii) managing conflicts between parents and their children with respect to vaccination decisions. The importance of decisions being fully informed was emphasized and concern was expressed about the adequacy of the information provided to girls and their parents in schools. Whether consent would be granted by the parent or by the child and how potential disagreements should be managed remained ambiguous. Participants considered it appropriate to offer the vaccine without parental consent if other criteria, such as an assessment of competency, were met. Success of the national immunization programme will depend on overcoming the challenges of providing explanations to ensure that individuals understand the potential benefits of HPV vaccination. Primary care can play an important role, but this study suggests there are fundamental issues that need further clarification.


Relationship of airborne microorganisms with the lung function and leucocyte levels of workers with a history of humidifier fever.
An influenza-like illness appeared recently among workers in a plant processing synthetic yarn. A humidifier, a cold-water spraying system, was the suspected cause. Lung function changes over the day and week and changes in blood leucocytes were studied among the workers from the suspected department and two reference populations. Exposure to colony-forming units of bacteria and fungi and to endotoxins was also monitored. The workers from the suspected department had statistically significantly lower lung functions on the first workday of the week than the referents. Their blood leucocytes were also raised statistically significantly. The exposure to fungi, bacteria, and endotoxins differed significantly between the various departments, but the measured levels were low. It was concluded that the observed effects were suggestive of a "Monday morning fever" type of reaction and that adverse effects occurred at exposure levels lower than those found to date in the literature.


Hepatitis C virus-induced cryoglobulinemia.
In this review we discuss the clinical manifestations, pathogenesis, and treatment of hepatitis C virus (HCV)-related cryoglobulinemia. HCV is a major cause of liver-related morbidity and is increasingly recognized as an instigator of B-cell lymphoproliferative disorders such as mixed cryoglobulinemia and non-Hodgkin lymphoma. Cryoglobulinemia is characterized by the clonal expansion of rheumatoid factor-expressing B cells in the liver, lymph nodes, and peripheral blood, resulting in the presence of cryoglobulins in the circulation. Cryoglobulins are cold-insoluble immune complexes containing rheumatoid factor, polyclonal IgG, and HCV RNA that precipitate and deposit on vascular endothelium, causing vasculitis in organs such as the skin, kidneys, and peripheral nerves. A subset of patients develops a low-grade lymphoma composed of B cells that are immunophenotypically similar to the expanded B cells seen in cryoglobulinemia. HCV-related B-cell lymphoproliferative disorders likely comprise a spectrum of disease, ranging from asymptomatic clonal B-cell expansions to pathogenic cryoglobulinemia and lymphoma. It is unclear how B cells become dysregulated during the course of chronic HCV infection, and continued patient-centered research is necessary to elucidate the pathogenesis of HCV-related B-cell dysregulation.


SPINK1 Status in Colorectal Cancer, Impact on Proliferation, and Role in Colitis-Associated Cancer.
Colorectal cancer is a major cause of deaths due to cancer; therefore, research into its etiology is urgently needed. Although it is clear that chronic inflammation is a risk factor for colorectal cancer, the details remain uncertain. Serine protease inhibitor, Kazal type 1 (SPINK1) is mainly produced in pancreatic acinar cells. However, SPINK1 is expressed in various cancers and in inflammatory states, such as colon cancer and inflammatory bowel disease. There are structural similarities between SPINK1 and epidermal growth factor (EGF). Hence, it was hypothesized that SPINK1 functions as a growth factor for tissue repair in inflammatory states, and if prolonged, acts as a promoter for cell proliferation in cancerous tissues. Here, immunohistochemical staining for SPINK1 was observed in a high percentage of colorectal cancer patient specimens and SPINK1 induced proliferation of human colon cancer cell lines. To clarify its role in colon cancer in vivo, a mouse model exposed to the colon carcinogen azoxymethane and nongenotoxic carcinogen dextran sodium sulfate revealed that Spink3 (mouse homolog of SPINK1) is overexpressed in cancerous tissues. In Spink3 heterozygous mice, tumor multiplicity and tumor volume were significantly decreased compared with wild-type mice. These results suggest that SPINK1/Spink3 stimulates the proliferation of colon cancer cells and is involved in colorectal cancer progression. Evidence suggests that SPINK1 is an important growth factor that connects chronic inflammation and cancer.


Eye movements and optical flow.
Translation of an observer through a static environment generates a pattern of optical flow that specifies the direction of self-motion, but the retinal flow pattern is confounded by pursuit eye movements. How does the visual system decompose the translational and rotational components of flow to determine heading? It is shown that observers can perceive their direction of self-motion during stationary fixations and pursuit eye movements and with displays that simulate the optical effects of eye movements. Results indicate that the visual system can perform the decomposition with both continuous and discontinuous fields on the basis of flow-field information alone but requires a three-dimensional environmental structure to do so. The findings are inconsistent with general computational models and theories based on the maximum of divergence, oculomotor signals, or multiple fixations but are consistent with the theory of reliance on differential motion produced by environmental variation in depth.


Exercise intensity effects on total sweat electrolyte losses and regional vs. whole-body sweat [Na+], [Cl-], and [K+].
To quantify total sweat electrolyte losses at two relative exercise intensities and determine the effect of workload on the relation between regional (REG) and whole body (WB) sweat electrolyte concentrations. Eleven recreational athletes (7 men, 4 women; 71.5 ± 8.4 kg) completed two randomized trials cycling (30 °C, 44% rh) for 90 min at 45% (LOW) and 65% (MOD) of VO2max in a plastic isolation chamber to determine WB sweat [Na+] and [Cl-] using the washdown technique. REG sweat [Na+] and [Cl-] were measured at 11 REG sites using absorbent patches. Total sweat electrolyte losses were the product of WB sweat loss (WBSL) and WB sweat electrolyte concentrations. WBSL (0.86 ± 0.15 vs. 1.27 ± 0.24 L), WB sweat [Na+] (32.6 ± 14.3 vs. 52.7 ± 14.6 mmol/L), WB sweat [Cl-] (29.8 ± 13.6 vs. 52.5 ± 15.6 mmol/L), total sweat Na+ loss (659 ± 340 vs. 1565 ± 590 mg), and total sweat Cl- loss (931 ± 494 vs. 2378 ± 853 mg) increased significantly (p < 0.05) from LOW to MOD. REG sweat [Na+] and [Cl-] increased from LOW to MOD at all sites except thigh and calf. Intensity had a significant effect on the regression model predicting WB from REG at the ventral wrist, lower back, thigh, and calf for sweat [Na+] and [Cl-]. Total sweat Na+ and Cl- losses increased by ~ 150% with increased exercise intensity. Regression equations can be used to predict WB sweat [Na+] and [Cl-] from some REG sites (e.g., dorsal forearm) irrespective of intensity (between 45 and 65% VO2max), but other sites (especially ventral wrist, lower back, thigh, and calf) require separate prediction equations accounting for workload.


Overlooked mountain rock pools in deserts are critical local hotspots of biodiversity.
The world is undergoing exceptional biodiversity loss. Most conservation efforts target biodiversity hotspots at large scales. Such approach overlooks small-sized local hotspots, which may be rich in endemic and highly threatened species. We explore the importance of mountain rock pools (gueltas) as local biodiversity hotspots in the Sahara-Sahel. Specifically, we considered how many vertebrates (total and endemics) use gueltas, what factors predict species richness, and which gueltas are of most priority for conservation. We expected to provide management recommendations, improve local biodiversity conservation, and simultaneously contribute with a framework for future enhancement of local communities' economy. The identification of local hotspots of biodiversity is important for revaluating global conservation priorities. We quantified the number of vertebrate species from each taxonomic group and endemics present in 69 gueltas in Mauritania, then compared these with species present in a surrounding area and recorded in the country. We evaluated the predictors of species number's present in each guelta through a multiple regression model. We ranked gueltas by their priority for conservation taking into account the percentage of endemics and threats to each guelta. Within a mere aggregate extent of 43 ha, gueltas hold about 32% and 78% of the total taxa analysed and endemics of Mauritania, respectively. The number of species present in each guelta increased with the primary productivity and area of gueltas and occurrence of permanent water. Droughts and human activities threaten gueltas, while 64% of them are currently unprotected. Gueltas are crucial for local biodiversity conservation and human activities. They require urgent management plans in Mauritania's mountains. They could provide refugia under climate change being important for long-term conservation of Sahara-Sahel biodiversity. Given their disproportional importance in relation to their size, they are local hotspots of biodiversity deserving global attention.


Doppler radar fall activity detection using the wavelet transform.
We propose in this paper the use of Wavelet transform (WT) to detect human falls using a ceiling mounted Doppler range control radar. The radar senses any motions from falls as well as nonfalls due to the Doppler effect. The WT is very effective in distinguishing the falls from other activities, making it a promising technique for radar fall detection in nonobtrusive inhome elder care applications. The proposed radar fall detector consists of two stages. The prescreen stage uses the coefficients of wavelet decomposition at a given scale to identify the time locations in which fall activities may have occurred. The classification stage extracts the time-frequency content from the wavelet coefficients at many scales to form a feature vector for fall versus nonfall classification. The selection of different wavelet functions is examined to achieve better performance. Experimental results using the data from the laboratory and real inhome environments validate the promising and robust performance of the proposed detector.


Statistics in medical journals: some recent trends.
I review some areas of medical statistics that have gained prominence over the last 5-10 years: meta-analysis, evidence-based medicine, and cluster randomized trials. I then consider several issues relating to data analysis and interpretation, many relating to the use and misuse of hypothesis testing, drawing on recent reviews of the use of statistics in medical journals. I also consider developments in the reporting of research in medical journals.


Teaching productive sign modifications to children with intellectual disabilities.
Research suggests that few children who are reliant on manual sign for expressive communication progress beyond a basic level of sign combinations. However, they may be capable of expressing complex meanings by changing the form of their signs. This study investigated whether children with intellectual disabilities could be taught productive use of modified signs. Eight children participated in a matrix-based intervention program to teach sign modifications that were contrastive, generalized, and consistent. Results indicated that modified signs could be systematically taught. There was also evidence to suggest that the children were beginning to use modified signs productively. However, it is suggested that their patterns of use were more characteristic of a gestural than a linguistic system.


Tumor antigen acrosin binding protein normalizes mitotic spindle function to promote cancer cell proliferation.
Cancer cells manage to divide in the context of gross chromosomal abnormalities. These abnormalities can promote bypass of normal restraints on cell proliferation but at a cost of mitotic vulnerabilities that can be attacked by chemotherapy. Determining how cancer cells balance these issues may permit chemotherapeutic sensitivity to be leveraged more efficiently. From a pan-genomic small interfering RNA screen for modifiers of chemoresponsiveness, we identified the tumor antigen acrosin binding protein (ACRBP)/OY-TES-1 as a specifier of paclitaxel resistance. ACRBP expression is normally restricted to the testes but is detected in a wide variety of cancers, including most ovarian cancers. We found that ACRBP is both necessary and sufficient for paclitaxel resistance in ovarian cancer cell lines and ovarian tumor explants. Moreover, high ACRBP expression correlated with reduced survival time and faster relapse among ovarian cancer patients. We identified the mitotic spindle protein NuMA as an ACRBP-interacting protein that could account for the effects of ACRBP on paclitaxel sensitivity. In cancer cells, ACRBP restricted a NuMA-dependent abrogation of a mitotic spindle assembly that is otherwise pathologic. As a consequence, ACRBP depletion resulted in mitotic errors and reduced proliferative fitness that could be rescued by NuMA codepletion. We propose that the codependent relationship of ACRBP and NuMA in cancer cells reflects their passage through a selection bottleneck during tumor evolution, one which requires the acquisition of traits that normalize mitotic perturbations that originally drove the plasticity of a preneoplastic genome. The molecular definition of such traits as defined by the ACRBP-NuMA complex may represent conceptually ideal intervention targets based on the wide therapeutic windows they may offer.


Heart failure modulates electropharmacological characteristics of sinoatrial nodes.
The impact of heart failure (HF) on sinoatrial node (SAN) channel regulation and electropharmacological responses has remained elusive. The present study aimed to investigate the effects of HF on the electrical activity of SANs with and without pharmacological interventions. Action potentials (APs) were recorded in isolated SANs from normal rabbits (control) and those with HF (rapid ventricular pacing for 4 weeks) prior to and after administration of a funny current blocker (ivabradine; 0.1, 0.3, 3 or 10 µM), a calmodulin kinase II inhibitor (KN-93; 0.3 or 3 µM), a sarcoplasmic reticulum Ca2+ release inhibitor (ryanodine; 0.3 or 3 µM), a sodium current inhibitor (tetrodotoxin; 1, 3 or 10 µM) and a late sodium current inhibitor (ranolazine; 10 µM). Western blot analysis was used to investigate the protein expression in SANs from normal rabbits and those with HF. Control SANs had a higher beating rate than SANs from rabbits with HF (2.3±0.1 vs. 1.5±0.1 Hz; P<0.001). Similarly, ivabradine (10 µM), KN-93 (3 µM), ranolazine (10 µM) and ryanodine (3 µM) decreased the beating rates of SANs in the control (n=6) and HF (n=6) groups. Ivabradine treatment resulted in a higher incidence of AP block in HF vs. control SANs (66.7 vs. 0%; P<0.05). Tetrodotoxin (1, 3 or 10 µM) decreased the beating rate to a higher extent in SANs from rabbits with HF than in those from control rabbits and induced a higher incidence of AP block (66.7 vs. 0%; P<0.05). Furthermore, SANs from rabbits with HF had higher protein levels of phospholamban (PLB) and lower levels of hyperpolarization-activated cyclic nucleotide-gated potassium channel 4, ryanodine receptor and phosphorylated PLB than control SANs. In conclusion, HF modulates electropharmacological responses in the SAN by channel regulation, which may result in SAN dysfunction.


Dysregulation of soluble epoxide hydrolase and lipidomic profiles in anorexia nervosa.
Individuals with anorexia nervosa (AN) restrict eating and become emaciated. They tend to have an aversion to foods rich in fat. Because epoxide hydrolase 2 (EPHX2) was identified as a novel AN susceptibility gene, and because its protein product, soluble epoxide hydrolase (sEH), converts bioactive epoxides of polyunsaturated fatty acid (PUFA) to the corresponding diols, lipidomic and metabolomic targets of EPHX2 were assessed to evaluate the biological functions of EPHX2 and their role in AN. Epoxide substrates of sEH and associated oxylipins were measured in ill AN, recovered AN and gender- and race-matched controls. PUFA and oxylipin markers were tested as potential biomarkers for AN. Oxylipin ratios were calculated as proxy markers of in vivo sEH activity. Several free- and total PUFAs were associated with AN diagnosis and with AN recovery. AN displayed elevated n-3 PUFAs and may differ from controls in PUFA elongation and desaturation processes. Cytochrome P450 pathway oxylipins from arachidonic acid, linoleic acid, alpha-linolenic acid and docosahexaenoic acid PUFAs are associated with AN diagnosis. The diol:epoxide ratios suggest the sEH activity is higher in AN compared with controls. Multivariate analysis illustrates normalization of lipidomic profiles in recovered ANs. EPHX2 influences AN risk through in vivo interaction with dietary PUFAs. PUFA composition and concentrations as well as sEH activity may contribute to the pathogenesis and prognosis of AN. Our data support the involvement of EPHX2-associated lipidomic and oxylipin dysregulations in AN, and reveal their potential as biomarkers to assess responsiveness to future intervention or treatment.


Tocilizumab in Large Vessel Vasculitis - Different Routes of Administration.
Tocilizumab is increasingly used in the treatment of large vessel vasculitis with recent approval for giant cell arteritis. To determine the efficacy and safety of tocilizumab in large vessel vasculitis in a real-life setting using different routes of administration. Retrospective analysis of consecutive patients at a tertiary rheumatology department who received tocilizumab for large vessel vasculitis. A total of 11 patients were treated with tocilizumab (8 giant cell arteritis, 2 large vessel vasculitis associated with rheumatoid arthritis, 1 Takayasu arteritis) after a median of 2 other steroid-sparing agents (range 1-4). Of these, 9 received tocilizumab as salvage therapy for active vasculitis and 2 due to the toxicity of their former steroid-sparing medication. After a mean follow-up of 23 months 7 patients were in remission as to vasculitis under a mean prednisolone dose of 1.7 ± 1.5 mg; one patient relapsed after long term remission having discontinued tocilizumab for elective surgery; one patient stopped tocilizumab after attributable infectious complications, and two patients died: one due to complications of vascular surgery, probably not attributable to tocilizumab; and the other due to sepsis secondary to sigmoiditis. Only 3 relapses occurred under continuous tocilizumab treatment. In all these 3 cases, renewed remission could be achieved by switching from subcutaneous (162 mg qw) to intravenous tocilizumab (8mg/kg q4w). Tocilizumab is efficacious in patients with large vessel vasculitis in a real-life situation. Safety appears to be acceptable, but infectious complications have to be considered. Intravenous tocilizumab may be used in patients who relapse under subcutaneous application.


Relative importance of competition and plant-soil feedback, their synergy, context dependency and implications for coexistence.
Plants interact simultaneously with each other and with soil biota, yet the relative importance of competition vs. plant-soil feedback (PSF) on plant performance is poorly understood. Using a meta-analysis of 38 published studies and 150 plant species, we show that effects of interspecific competition (either growing plants with a competitor or singly, or comparing inter- vs. intraspecific competition) and PSF (comparing home vs. away soil, live vs. sterile soil, or control vs. fungicide-treated soil) depended on treatments but were predominantly negative, broadly comparable in magnitude, and additive or synergistic. Stronger competitors experienced more negative PSF than weaker competitors when controlling for density (inter- to intraspecific competition), suggesting that PSF could prevent competitive dominance and promote coexistence. When competition was measured against plants growing singly, the strength of competition overwhelmed PSF, indicating that the relative importance of PSF may depend not only on neighbour identity but also density. We evaluate how competition and PSFs might interact across resource gradients; PSF will likely strengthen competitive interactions in high resource environments and enhance facilitative interactions in low-resource environments. Finally, we provide a framework for filling key knowledge gaps and advancing our understanding of how these biotic interactions influence community structure.


The In Vitro and In Vivo Activity of the Microtubule Disruptor STX140 Is Mediated by Hif-1 Alpha and CAIX Expression.
Tumor neo-angiogenesis is regulated, in part, by the hypoxia-inducible gene HIF1. Evidence suggests HIF1 associates with polymerized microtubules and traffics to the nucleus. This study investigated the role of HIF1 in mediating the antitumor activity of two steroid-based sulfamate ester microtubule disruptors, STX140 and STX243, in vitro and in vivo. The effects of STX140, STX243 and the parental compound 2-methoxyestradiol (STX66) on HIF1α and HIF2α protein expression were assessed in vitro in MCF-7 and MDA-MB-231 cells cultured under hypoxia. More pertinently, their effects were examined on HIF1-regulated genes in vivo in mice bearing MCF-7 or MDA-MB-231 tumors. The level of mRNA expression of vascular endothelial growth factor (VEGF), glucose transporter 1 (GLUTI), phosphoglycerate kinase (PGK), ATP-binding cassette sub-family B member 1 (ABCB1) and carbonic anhydrase IX (CAIX) was quantified by Real-time Polymerase Chain Reaction (RT-PCR). Despite inhibiting nuclear HIF1α protein accumulation under hypoxia in vitro, STX140 and STX243 did not significantly regulate the expression of four out of five HIF1α-regulated genes in vitro and in vivo. Only CAIX mRNA expression was down-regulated both in vitro and in vivo. Immunoblot analysis showed that STX140 and STX243 reduced CAIX protein expression in vitro. These compounds had no effect on HIF2α translocation. The potential for inhibition of CAIX by STX140 and STX243 was examined by docking the ligands to the active site in comparison with a known sulfamate-based inhibitor. Microtubule disruption and antitumor activity of STX140 and STX243 is most likely HIF1-independent and may, at least in part, be mediated by inhibition of CAIX expression and activity.


Ensuring effective implementation of the post-2020 global biodiversity targets.
Biodiversity underpins the fundamental elements for human well-being including food security, human health and access to clean water. In 2010, the Aichi Targets were adopted by world leaders to address the crisis of biodiversity loss. Despite conservation efforts, none of the Aichi Targets have been fully met. However, comprehensive analysis of the reasons for failure in terms of implementation mechanisms is, to date, rare and limited in scope. Here, we demonstrate that most parties did not set effective national targets in accordance with the Aichi Targets, and investments, knowledge and accountability for biodiversity conservation have been inadequate to enable effective implementation. We recommend that the new global targets under the post-2020 Global Biodiversity Framework should be adopted by parties as the minimum national targets to achieve the 2050 Vision. We propose that financial resources for biodiversity conservation are substantially increased through a variety of sources, including the deployment of new economic instruments such as payments for ecosystem services. In addition, science-policy interfaces at all levels need to be strengthened to integrate scientific, Indigenous and local knowledge to support decision-making. We suggest that a compliance and accountability mechanism, based on monitoring systems, is created to provide transparent and credible review of parties' implementation of the new global targets.


Interaction of the retinoblastoma protein (pRb) with the catalytic subunit of DNA polymerase delta (p125).
The retinoblastoma gene product (pRb) interacts with many cellular proteins to function in the control of cell division, differentiation, and apoptosis. Several pRb binding proteins complex with pRb through an amino acid sequence called the LXCXE motif. The catalytic subunit of DNA polymerase delta (p125) contains a LXCXE motif. To further study the biochemical function of this polymerase, we sought to determine if p125 interacts with pRb. Experiments using GST-pRb fusion proteins showed that p125 from breast epithelial (MCF10A) cell extracts associates with pRb. In addition, GST-p125 fusion proteins bound pRb from the same cell extracts. The pRb that associated with GST-p125 was largely unphosphorylated. Coimmunoprecipitation experiments using cell cycle synchronized cells revealed that p125 and pRb form a complex predominantly during G1 phase, the phase during which pRb is mostly unphosphorylated. In vitro phosphorylation of GST-pRb by the cyclin dependent kinases reduced the ability of p125 to associate with GST-pRh. Addition of the LXCXE containing protein SV40 large T antigen to GST-pRb blocks the ability of p125 to associate with pRb, suggesting that it may be through a LXCXE sequence by which p125 interacts with pRb. Finally, in vitro polymerase assays demonstrate that GST-pRb fusion protein stimulates DNA polymerase delta activity.


Where The Money Goes: The Evolving Expenses Of The US Health Care System.
National health care expenditures constitute revenue to the health care system. However, little is known about how this revenue is distributed across sectors. This article calculates revenues and detailed expenditures for physicians' offices, hospitals, and outpatient care centers in 1997, 2002, 2007, and 2012, using a range of Census Bureau and Bureau of Labor Statistics sources. Between 1997 and 2012, spending on these three sectors rose by $580 billion, and employment rose by 1.7 million people. Just under half of all 2012 revenues were spent on labor compensation. The labor compensation share of spending declined slightly; within these sectors, the share of compensation paid to physicians and nurses increased. Although employment of nonprofessional labor grew during the study period, this group did not account for much of the sector's increased spending. The plurality of the 1997-2012 spending increase went to producers of purchased materials and services, which now account for more than one-third of payments.


Chlamydomonas flagellar mutants lacking radial spokes and central tubules. Structure, composition, and function of specific axonemal components.
The fine structure, protein composition, and roles in flagellar movement of specific axonemal components were studied in wild-type Chlamydomonas and paralyzed mutants pf-14, pf-15A, and pf-19. Electron microscope examination of the isolated axoneme of pf-14 showed that it lacks the radial spokes but is otherwise structurally normal. Comparison of isolated axonemes of wild type and pf-14 by sodium dodecyl sulfate-acrylamide gel electrophoresis indicated that the mutant is missing a protein of 118,000 mol wt; this protein is apparently a major component of the spokes. Pf-15A and pf-19 lack the central tubules and sheath; axonemes of these mutants are missing three high molecular weight proteins which are probably components of the central tubule-central sheath complex. Under conditions where wild-type axonemes reactivated, axonemes of the three mutants remained intact but did not form bends. However, mutant and wild-type axonemes underwent identical adenosine triphosphate-induced disintegration after treatment with trypsin; the dynein arms of the mutants are therefore capable of generating interdoublet shearing forces. These findings indicated that both the radial spokes and the central tubule-central sheath complex are essential for conversion of interdoublet sliding into axonemal bending. Moreover, because axonemes of pf-14 remained intact under reactivating conditions, the nexin links alone are sufficient to limit the amount of interdoublet sliding that occurs. The axial periodicities of the central sheath, dynein arms, radial spokes, and nexin links of Chlamydomonas were determined by electron microscopy using the lattice-spacing of crystalline catalase as an internal standard. Some new ultrastructural details of the components are described.


Detecting quantum coherence of Bose gases in optical lattices by scattering light intensity in cavity.
We propose a new method of detecting quantum coherence of a Bose gas trapped in a one-dimensional optical lattice by measuring the light intensity from Raman scattering in cavity. After pump and displacement process, the intensity or amplitude of scattering light is different for different quantum states of a Bose gas, such as superfluid and Mott-Insulator states. This method can also be useful to detect quantum states of atoms with two components in an optical lattice.


Tinkering with constraints in the evolution of the vertebrate limb anterior-posterior polarity.
Genes belonging to both HoxA and HoxD clusters are required for proper vertebrate limb development. Mice lacking all, or parts of, Hoxa and Hoxd functions in forelimbs, as well as mice with a gain of function of these genes in the early limb bud, have helped us to understand functional and regulatory issues associated with these genes, such that, for example, the tight mechanistic interdependency that exists between the production of the limb and its anterior to posterior (AP) polarity. Our studies suggest that the evolutionary recruitment of Hox gene function into growing appendages was crucial to implement hedgehog signalling, subsequently leading to the distal extension of tetrapod appendages, with an already built-in AP polarity. We propose that this process results from the evolutionary co-option, in the developing limbs, of a particular regulatory mechanism (collinearity), which is necessary to pattern the developing trunk. This major regulatory constraint imposed a polarity to our limbs as the most parsimonious solution to grow appendages.


Tracheal decannulation protocol in patients affected by traumatic brain injury.
Introduction The frequency of tracheostomy in patients with traumatic brain injury (TBI) contrasts with the lack of objective criteria for its management. The study arose from the need for a protocol in the decision to remove the tracheal tube. Objective To evaluate the applicability of a protocol for tracheal decannulation. Methods A prospective study with 20 patients, ranging between 21 and 85 years of age (average 33.55), 4 of whom were women (20%) and 16 were men (80%). All patients had been diagnosed by a neurologist as having TBI, and the anatomical region of the lesion was known. Patients were evaluated following criteria for tracheal decannulation through a clinical evaluation protocol developed by the authors. Results Decannulation was performed in 12 (60%) patients. Fourteen (70%) had a score greater than 8 on the Glasgow Coma Scale and only 2 (14%) of these were not able to undergo decannulation. Twelve (60%) patients maintained the breathing pattern with occlusion of the tube and were successfully decannulated. Of the 20 patients evaluated, 11 (55%) showed no signs suggestive of tracheal aspiration, and of these, 9 (82%) began training on occlusion of the cannula. The protocol was relevant to establish the beginning of the decannulation process. The clinical assessment should focus on the patient's condition to achieve early tracheal decannulation. Conclusion This study allowed, with the protocol, to establish six criteria for tracheal decannulation: level of consciousness, respiration, tracheal secretion, phonation, swallowing, and coughing.


Inequalities in utilization of maternal and child health services in Ethiopia: the role of primary health care.
Health systems aim to narrow inequality in access to health care across socioeconomic groups and area of residency. However, in low-income countries, studies are lacking that systematically monitor and evaluate health programs with regard to their effect on specific inequalities. We aimed to measure changes in inequality in access to maternal and child health (MCH) interventions and the effect of Primary Health Care (PHC) facilities expansion on the inequality in access to care in Ethiopia. The Demographic and Health Survey datasets from Ethiopia (2005 and 2011) were used. We calculated changes in utilization of MCH interventions and child morbidity. Concentration and horizontal inequity indices were estimated. Decomposition analysis was used to calculate the contribution of each determinant to the concentration index. Between 2005 and 2011, improvements in aggregate coverage have been observed for MCH interventions in Ethiopia. Wealth-related inequality has remained persistently high in all surveys. Socioeconomic factors were the main predictors of differences in maternal and child health services utilization and child health outcome. Utilization of primary care facilities for selected maternal and child health interventions have shown marked pro-poor improvement over the period 2005-2011. Our findings suggest that expansion of PHC facilities in Ethiopia might have an important role in narrowing the urban-rural and rich-poor gaps in health service utilization for selected MCH interventions.


Atrial Fibrillation Dynamics and Ionic Block Effects in Six Heterogeneous Human 3D Virtual Atria with Distinct Repolarization Dynamics.
Atrial fibrillation (AF) usually manifests as reentrant circuits propagating through the whole atria creating chaotic activation patterns. Little is yet known about how differences in electrophysiological and ionic properties between patients modulate reentrant patterns in AF. The goal of this study is to quantify how variability in action potential duration (APD) at different stages of repolarization determines AF dynamics and their modulation by ionic block using a set of virtual whole-atria human models. Six human whole-atria models are constructed based on the same anatomical structure and fiber orientation, but with different electrophysiological phenotypes. Membrane kinetics for each whole-atria model are selected with distinct APD characteristics at 20, 50, and 90% repolarization, from an experimentally calibrated population of human atrial action potential models, including AF remodeling and acetylcholine parasympathetic effects. Our simulations show that in all whole-atria models, reentrant circuits tend to organize around the pulmonary veins and the right atrial appendage, thus leading to higher dominant frequency (DF) and more organized activation in the left atrium than in the right atrium. Differences in APD in all phases of repolarization (not only APD90) yielded quantitative differences in fibrillation patterns with long APD associated with slower and more regular dynamics. Long APD50 and APD20 were associated with increased interatrial conduction block and interatrial differences in DF and organization index, creating reentry instability and self-termination in some cases. Specific inhibitions of IK1, INaK, or INa reduce DF and organization of the arrhythmia by enlarging wave meandering, reducing the number of secondary wavelets, and promoting interatrial block in all six virtual patients, especially for the phenotypes with short APD at 20, 50, and/or 90% repolarization. This suggests that therapies aiming at prolonging the early phase of repolarization might constitute effective antiarrhythmic strategies for the pharmacological management of AF. In summary, simulations report significant differences in atrial fibrillatory dynamics resulting from differences in APD at all phases of repolarization.


Genetic diversity of Desmanthus sp accessions using ISSR markers and morphological traits.
Desmanthus is a genus of forage legumes with high nutritional value, productive potential, and ability to obtain nitrogen in association with diazotrophic bacteria. The use of accurate techniques for genotype identification and characterization is essential for breeding programs. Morphological markers are widely used to know the genetic diversity and the molecular markers are fundamental in these studies. We investigated the genetic diversity among Desmanthus sp genotypes in Pernambuco (Brazilian Northeast State), using morphological traits and ISSR markers. Morphological and molecular characterizations were performed in 18 and 26 accessions, respectively, in plants belonging to the germplasm bank of forage legumes of Universidade Federal Rural de Pernambuco (UFRPE), Academic Unit of Serra Talhada, PE, Brazil. Eight ISSR primers were selected, and 95 loci were generated, with polymorphism of 95.79%. The allele number observed was 1.958, where the effective number was 1.359, and the Nei diversity genetic index was 0.226. About the morphological markers, seed number was the variable that most contributed to the genetic divergence. A large amount of genetic diversity was observed among Desmanthus species, occurring spontaneously in Pernambuco, Brazil. Thus, the variability found in morphological and ISSR markers is importance for the improvement of Desmanthus spp. Our findings showed that 17L, 27L, 25F, 22F, 19S, 13Au, and 28G accessions could be used in breeding programs to explore the maximum genetic divergence.


A sampling design for a sentinel general practitioner network.
To construct a design for probabilistic sampling of reporting physicians in sentinel networks. We performed a multi-stage sample selection study. Data on primary care physicians and their patients were obtained from the Madrid Health Institute for 2005. The geographical unit of reference was the basic health area. A factorial analysis was performed on the basis of demographic, socio-cultural and socio-occupational variables. A cluster analysis was conducted to group the 247 basic health areas into homogeneous strata, which were then tested using a discriminant analysis. The general practitioners and pediatricians needed in each stratum were selected by simple random sampling. The representativeness of the population monitored by the selected physicians was studied with respect to the population of Madrid. Factorial analysis yielded five factors. Using these, 14 strata were obtained, which were shown to be homogeneous and mutually different by discriminant analysis. The minimum population that needed to be monitored consisted of 146,946 adults and 24,518 children, proportionally distributed among the respective strata. Eighty-eight general practitioners and 32 pediatricians were selected, who respectively covered populations of 154,610 and 31,336 persons representative of the general population. Obtaining samples through suitable designs improves the accuracy of the information gathered by health sentinel networks in epidemiologic surveillance. Ensuring the representativeness of the study population vis-à-vis the general population is essential; cluster analysis and simple random sampling are methods that meet this need. Selecting physicians by means of probabilistic methods enables the accuracy of estimates to be ascertained.


Low-voltage back-gated atmospheric pressure chemical vapor deposition based graphene-striped channel transistor with high-κ dielectric showing room-temperature mobility > 11,000 cm(2)/V·s.
Utilization of graphene may help realize innovative low-power replacements for III-V materials based high electron mobility transistors while extending operational frequencies closer to the THz regime for superior wireless communications, imaging, and other novel applications. Device architectures explored to date suffer a fundamental performance roadblock due to lack of compatible deposition techniques for nanometer-scale dielectrics required to efficiently modulate graphene transconductance (gm) while maintaining low gate capacitance-voltage product (CgsVgs). Here we show integration of a scaled (10 nm) high-κ gate dielectric aluminum oxide (Al2O3) with an atmospheric pressure chemical vapor deposition (APCVD)-derived graphene channel composed of multiple 0.25 μm stripes to repeatedly realize room-temperature mobility of 11,000 cm(2)/V·s or higher. This high performance is attributed to the APCVD graphene growth quality, excellent interfacial properties of the gate dielectric, conductivity enhancement in the graphene stripes due to low tox/Wgraphene ratio, and scaled high-κ dielectric gate modulation of carrier density allowing full actuation of the device with only ±1 V applied bias. The superior drive current and conductance at Vdd = 1 V compared to other top-gated devices requiring undesirable seed (such as aluminum and poly vinyl alcohol)-assisted dielectric deposition, bottom gate devices requiring excessive gate voltage for actuation, or monolithic (nonstriped) channels suggest that this facile transistor structure provides critical insight toward future device design and process integration to maximize CVD-based graphene transistor performance.


The pleiotropic effects of TNFα in breast cancer subtypes is regulated by TNFAIP3/A20.
TNFα is a pleiotropic cytokine which fuels tumor cell growth, invasion, and metastasis in some malignancies, while in others it induces cytotoxic cell death. However, the molecular mechanism by which TNFα exerts its diverse effects on breast cancer subtypes remains elusive. Using in vitro assays and mouse xenografts, we show here that TNFα contributes to the aggressive properties of triple negative breast cancer (TNBC) cell lines via upregulation of TNFAIP3(A20). In a striking contrast, TNFα induces a potent cytotoxic cell death in luminal (ER+) breast cancer cell lines which fail to upregulate A20 expression. Overexpression of A20 not only protects luminal breast cancer cell lines from TNFα-induced cell death via inducing HSP70-mediated anti-apoptotic pathway but also promotes a robust EMT/CSC phenotype by activating the pStat3-mediated inflammatory signaling. Furthermore, A20 overexpression in luminal breast cancer cells induces aggressive metastatic properties in mouse xenografts via generating a permissive inflammatory microenvironment constituted by granulocytic-MDSCs. Collectively, our results reveal a mechanism by which A20 mediates pleiotropic effects of TNFα playing role in aggressive behaviors of TNBC subtype while its deficiency results in TNFα-induced apoptotic cell death in luminal breast cancer subtype.


Secondary structure of the C-terminal domain of the tyrosyl-transfer RNA synthetase from Bacillus stearothermophilus: a novel type of anticodon binding domain?
The tyrosyl-tRNA synthetase catalyzes the activation of tyrosine and its coupling to the cognate tRNA. The enzyme is made of two domains: an N-terminal catalytic domain and a C-terminal domain that is necessary for tRNA binding and for which it was not possible to determine the structure by X-ray crystallography. We determined the secondary structure of the C-terminal domain of the tyrosyl-tRNA synthetase from Bacillus stearothermophilus by nuclear magnetic resonance methods and found that it is of the alpha+beta type. Its arrangement differs from those of the other anticodon binding domains whose structure is known. We also found that the isolated C-terminal domain behaves as a folded globular protein, and we suggest the presence of a flexible linker between the two domains.


Combining de novo and reference-guided assembly with scaffold_builder.
Genome sequencing has become routine, however genome assembly still remains a challenge despite the computational advances in the last decade. In particular, the abundance of repeat elements in genomes makes it difficult to assemble them into a single complete sequence. Identical repeats shorter than the average read length can generally be assembled without issue. However, longer repeats such as ribosomal RNA operons cannot be accurately assembled using existing tools. The application Scaffold_builder was designed to generate scaffolds - super contigs of sequences joined by N-bases - based on the similarity to a closely related reference sequence. This is independent of mate-pair information and can be used complementarily for genome assembly, e.g. when mate-pairs are not available or have already been exploited. Scaffold_builder was evaluated using simulated pyrosequencing reads of the bacterial genomes Escherichia coli 042, Lactobacillus salivarius UCC118 and Salmonella enterica subsp. enterica serovar Typhi str. P-stx-12. Moreover, we sequenced two genomes from Salmonella enterica serovar Typhimurium LT2 G455 and Salmonella enterica serovar Typhimurium SDT1291 and show that Scaffold_builder decreases the number of contig sequences by 53% while more than doubling their average length. Scaffold_builder is written in Python and is available at http://edwards.sdsu.edu/scaffold_builder. A web-based implementation is additionally provided to allow users to submit a reference genome and a set of contigs to be scaffolded.


SiR-Hoechst is a far-red DNA stain for live-cell nanoscopy.
Cell-permeable DNA stains are popular markers in live-cell imaging. Currently used DNA stains for live-cell imaging are either toxic, require illumination with blue light or are not compatible with super-resolution microscopy, thereby limiting their utility. Here we describe a far-red DNA stain, SiR-Hoechst, which displays minimal toxicity, is applicable in different cell types and tissues, and is compatible with super-resolution microscopy. The combination of these properties makes this probe a powerful tool for live-cell imaging.


Mate choice for major histocompatibility complex complementarity in a strictly monogamous bird, the grey partridge (Perdix perdix).
Sexual selection has been hypothesised as favouring mate choice resulting in production of viable offspring with genotypes providing high pathogen resistance. Specific pathogen recognition is mediated by genes of the major histocompatibility complex (MHC) encoding proteins fundamental for adaptive immune response in jawed vertebrates. MHC genes may also play a role in odour-based individual recognition and mate choice, aimed at avoiding inbreeding. MHC genes are known to be involved in mate choice in a number of species, with 'good genes' (absolute criteria) and 'complementary genes' (self-referential criteria) being used to explain MHC-based mating. Here, we focus on the effect of morphological traits and variation and genetic similarity between individuals in MHC class IIB (MHCIIB) exon 2 on mating in a free-living population of a monogamous bird, the grey partridge. We found no evidence for absolute mate choice criteria as regards grey partridge MHCIIB genotypes, i.e., number and occurrence of amino acid variants, though red chroma of the spot behind eyes was positively associated with male pairing success. On the other hand, mate choice at MHCIIB was based on relative criteria as females preferentially paired with more dissimilar males having a lower number of shared amino acid variants. This observation supports the 'inbreeding avoidance' and 'complementary genes' hypotheses. Our study provides one of the first pieces of evidence for MHC-based mate choice for genetic complementarity in a strictly monogamous bird. The statistical approach employed can be recommended for testing mating preferences in cases where availability of potential mates (recorded with an appropriate method such as radio-tracking) shows considerable temporal variation. Additional genetic analyses using neutral markers may detect whether MHC-based mate choice for complementarity emerges as a by-product of general inbreeding avoidance in grey partridges.


An organic sensitizer with a fused dithienothiophene unit for efficient and stable dye-sensitized solar cells.
We report a high molar extinction coefficient organic sensitizer for high efficiency dye-sensitized solar cells. In combination with a solvent-free ionic liquid electrolyte, we have demonstrated a approximately 7% cell showing an excellent stability measured under the thermal and light soaking dual stress. This is expected to have an important practical consequence on the production of flexible, low-cost, and lightweight DSC based on plastic matrix.


Statin prescription in men and women at cardiovascular risk: to whom and when?
To review the recent evidence of the effectiveness of statin therapy in the primary prevention of cardiovascular disease in men and women without established cardiovascular disease (CVD). The use of statins in patients without established CVD has important public health implications. Until recently, research has provided ambiguous answers and the reliability of treatment in older people (>65 years), women, and patients with diabetes has remained uncertain, mainly because of a lack of data or inconsistent findings within these clinically defined groups. The Justification for the use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) demonstrated a significant benefit of rosuvastatin in low-risk patients with no apparent vascular disease, low-density lipoprotein levels of less than 3.4 mmol/l, and elevated high sensitivity C-reactive protein. The latest meta-analysis of statins in 70 000 patients without established CVD confirmed the overall benefit of statins in these low-risk patients and found no significant heterogeneity of the treatment effect in the clinically defined subgroups of elderly (>65 years), women, and patients with diabetes. The use of statins in low-risk patients without CVD remains a matter of intense debate, even following the latest findings from the JUPITER. Statins reduce cardiovascular risk and mortality in this patient category. However, the overall absolute risk reductions and cost-effectiveness of long-term statin prescription should be kept in mind before prescribing statins to relatively healthy individuals. The exact threshold of baseline risk of CVD has not been determined yet and is a challenge for emerging treatment guidelines in primary prevention.


Algorithm for the early diagnosis and treatment of patients with cross reactive immunologic material-negative classic infantile pompe disease: a step towards improving the efficacy of ERT.
Although enzyme replacement therapy (ERT) is a highly effective therapy, CRIM-negative (CN) infantile Pompe disease (IPD) patients typically mount a strong immune response which abrogates the efficacy of ERT, resulting in clinical decline and death. This study was designed to demonstrate that immune tolerance induction (ITI) prevents or diminishes the development of antibody titers, resulting in a better clinical outcome compared to CN IPD patients treated with ERT monotherapy. We evaluated the safety, efficacy and feasibility of a clinical algorithm designed to accurately identify CN IPD patients and minimize delays between CRIM status determination and initiation of an ITI regimen (combination of rituximab, methotrexate and IVIG) concurrent with ERT. Clinical and laboratory data including measures of efficacy analysis for response to ERT were analyzed and compared to CN IPD patients treated with ERT monotherapy. Seven CN IPD patients were identified and started on the ITI regimen concurrent with ERT. Median time from diagnosis of CN status to commencement of ERT and ITI was 0.5 months (range: 0.1-1.6 months). At baseline, all patients had significant cardiomyopathy and all but one required respiratory support. The ITI regimen was safely tolerated in all seven cases. Four patients never seroconverted and remained antibody-free. One patient died from respiratory failure. Two patients required another course of the ITI regimen. In addition to their clinical improvement, the antibody titers observed in these patients were much lower than those seen in ERT monotherapy treated CN patients. The ITI regimen appears safe and efficacious and holds promise in altering the natural history of CN IPD by increasing ERT efficacy. An algorithm such as this substantiates the benefits of accelerated diagnosis and management of CN IPD patients, thus, further supporting the importance of early identification and treatment initiation with newborn screening for IPD.


Trans-foraminal versus posterior lumbar interbody fusion: comparison of surgical morbidity.
Posterior lumbar interbody fusion (PLIF) and trans-foraminal lumbar interbody fusion (TLIF) are both accepted surgical approaches for spinal fusion in spondylolisthesis and degenerative disc disease. The unilateral approach of TLIF may minimize the risk of iatrogenic durotomy and nerve root injury; however, there is no definitive evidence to support either approach. We review our experience with TLIF versus PLIF to compare operative complications. We retrospectively reviewed 119 consecutive cases of PLIF or TLIF performed for degenerative disc disease or spondylolithesis at a single institution over 5 years and examined the incidences of operative complications and outcomes. PLIF was performed in 76 (63%) patients and TLIF in 43 (37%). Patients were 48 ± 13 years old and presented with mechanical back pain [109 (92%)], radicular pain [95 (80%)], and radicular motor weakness [10 (8%)]. Patients undergoing PLIF and TLIF had similar baseline demographic, clinical, and radiographic characteristics. PLIF was associated with a higher incidence of post-operative iatrogenic nerve root dysfunction [6 (7.8%) versus 1 (2%)] and durotomy [13 (17%) versus 4 (9%)]; however, these differences did not reach statistical significance. All cases of nerve root injury were transient and resolved by the third month post-operatively. Estimated operative blood loss, length of hospitalization, and other peri-operative indices were similar between cohorts. By 12 months, evidence of pseudoarthrosis was present in 2 (2.6%) and 2 (4.6%) patients with PLIF or TLIF, respectively. There was a similar incidence of improvement in radicular pain (88% versus 79%) and low back pain (74% versus 80%) between TLIF and PLIF. In our experience with surgical management of degenerative disc disease and spondylolesthesis, PLIF versus TLIF was associated with a trend toward a higher incidence of nerve root injury and durotomy. However, iatrogenic nerve root dysfunction was transient in all cases and 12-month pseudoarthrosis rates were similar between cohorts. Similar to previous clinical studies, the incidence of neurological complications and durotomy increases when an interbody fusion is performed through a posterior approach compared to non-interbody fusion techniques. However, the fusion rates with the interbody technique are also enhanced. TLIF and PLIF should only be considered when the goals of surgery cannot be addressed with decompression and traditional posterolateral fusion.


De novo ITPR1 variants are a recurrent cause of early-onset ataxia, acting via loss of channel function.
We explored the clinico-genetic basis of spinocerebellar ataxia 29 (SCA29) by determining the frequency, phenotype, and functional impact of ITPR1 missense variants associated with early-onset ataxia (EOA). Three hundred thirty one patients from a European EOA target cohort (n = 120), US-American EOA validation cohort (n = 72), and early-onset epileptic encephalopathy (EOEE) control cohort (n = 139) were screened for de novo ITPR1 variants. The target cohort was also screened for inherited ITPR1 variants. The variants' functional impact was determined by IP3-induced Ca2+ release in HEK293 cells. 3/120 patients (2.5%) from the target cohort and 4/72 patients (5.5%) from the validation cohort, but none from the EOEE control cohort, carried de novo ITPR1 variants. However, most ITPR1 variants (7/10 = 70%) in the target cohort were inherited from a healthy parent, with 3/6 patients carrying disease-causing variants in other genes. This suggests limited or no phenotypic impact of many ITPR1 missense variants, even if ultra-rare and well-conserved. While common bioinformatics tools did not discriminate de novo from other ITPR1 variants, functional characterization demonstrated reduced IP3-induced Ca2+ release for all de novo variants, including the recurrent c.805C>T (p.(R269W)) variant. In sum, these findings show that de novo ITPR1 missense variants are a recurrent cause of EOA (SCA29) across independent cohorts, acting via loss of IP3 channel function. Inherited ITPR1 variants are also enriched in EOA, but often without strong impact, albeit rare and well-conserved. Functional studies allow identifying ITPR1 variants with large impact, likely disease-causing. Such functional confirmation is warranted for inherited ITPR1 variants before making a SCA29 diagnosis.


Southern Right Whale (Eubalaena australis) Reproductive Success is Influenced by Krill (Euphausia superba) Density and Climate.
The reproductive success of southern right whale (Eubalaena australis) depends on body condition and, therefore, on foraging success. This, in turn, might be affected by climatically driven change in the abundance of the species main prey, krill (Euphausia superba), on the feeding grounds. Annual data on southern right whale number of calves were obtained from aerial surveys carried out between 1997 and 2013 in southern Brazil, where the species concentrate during their breeding season. The number of calves recorded each year varied from 7 to 43 ( = 21.11 ± 11.88). Using cross-correlation analysis we examined the response of the species to climate anomalies and krill densities. Significant correlations were found with krill densities (r = 0.69, p = 0.002, lag 0 years), Oceanic Niño Index (r = -0.65, p = 0.03, lag 6 years), Antarctic Oscillation (r = 0.76, p = 0.01, lag 7 years) and Antarctic sea ice area (r = -0.68, p = 0.002, lag 0 years). Our results suggest that global climate indices influence southern right whale breeding success in southern Brazil by determining variation in food (krill) availability for the species. Therefore, increased frequency of years with reduced krill abundance, due to global warming, is likely to reduce the current rate of recovery of southern right whales from historical overexploitation.


Phase I trial of weekly paclitaxel in advanced lung cancer.
We conducted a phase I study in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC) to determine the maximum-tolerated dose (MTD) of paclitaxel using an extended weekly schedule. Patients with stage IIIB/IV NSCLC were treated with paclitaxel administered weekly over 3 hours for 6 weeks of an 8-week cycle. Doses were modified for granulocyte counts less than 1,800/microL or neurotoxicity greater than grade I. Groups of three patients were entered at each dose level. The dose was escalated to the next level if less than 50% of patients developed unacceptable toxicity and received more than 80% of the intended first-cycle dose. Twenty-six patients were entered through six dose levels (100, 125, 135, 150, 175, and 200 mg/m2/wk). Four of six patients at the 175-mg/m2 dose level and only one of six patients at the 200-mg/m2 level received all scheduled doses of paclitaxel during cycle 1. Neutropenia was dose-limiting. Fourteen patients were treated with subsequent cycles of paclitaxel. Grade II to III neuropathy developed in five of 24 patients. It occurred more commonly with greater duration of therapy, but improved following dose reduction. Nine of 26 (35% +/- 10%) patients demonstrated an objective response. The MTD of paclitaxel using a weekly schedule is 175 mg/m2/wk for 6 of 8 weeks. Neutropenia limits dosing acutely, but neuropathy is limiting with sustained therapy. This schedule of paclitaxel results in a twofold to threefold increase in dose-intensity with less toxicity than anticipated from conventional dosing. Further evaluation of this schedule is warranted to assess efficacy and toxicity of prolonged administration.


Intraoperative confocal laser endomicroscopy for interpretation of a sellar hemangioblastoma: illustrative case.
Intraoperative frozen sections play a critical role in surgical strategy because of their ability to provide rapid histopathological information. In cases in which intraoperative biopsy carries a significant risk of bleeding, intraoperative confocal laser endomicroscopy (CLE) can assist in decision-making. The authors present a rare case of a large sellar hemangioblastoma. Preoperative radiographic imaging and normal pituitary function suggested a differential diagnosis that included hemangioblastoma. The patient underwent partial preoperative embolization and a right-sided pterional craniotomy for resection of the lesion. Gross intraoperative examination revealed a highly vascular sellar lesion requiring circumferential dissection to minimize blood loss. The serious vascularity precluded intraoperative frozen section analysis, and CLE imaging was performed. CLE imaging provided excellent visualization of the remarkable vascular structure and characteristic histoarchitecture with microvasculature, intracytoplasmic vacuoles, and atypical cells consistent with hemangioblastoma. Resection and decompression of the chiasm was accomplished, and the patient was discharged with improved vision. The final histopathological diagnosis was hemangioblastoma. When the benefits of obtaining intraoperative frozen sections greatly outweigh the associated risks, CLE imaging can aid in decision-making. CLE imaging offers real-time, on-the-fly evaluation of intraoperative tissue without the need to biopsy a vascular lesion.


GSK-3 promotes conditional association of CREB and its coactivators with MEIS1 to facilitate HOX-mediated transcription and oncogenesis.
Acute leukemias induced by MLL chimeric oncoproteins are among the subset of cancers distinguished by a paradoxical dependence on GSK-3 kinase activity for sustained proliferation. We demonstrate here that GSK-3 maintains the MLL leukemia stem cell transcriptional program by promoting the conditional association of CREB and its coactivators TORC and CBP with homedomain protein MEIS1, a critical component of the MLL-subordinate program, which in turn facilitates HOX-mediated transcription and transformation. This mechanism also applies to hematopoietic cells transformed by other HOX genes, including CDX2, which is highly expressed in a majority of acute myeloid leukemias, thus providing a molecular approach based on GSK-3 inhibitory strategies to target HOX-associated transcription in a broad spectrum of leukemias.


Important prognostic factors in leiomyosarcoma survival: a National Cancer Database (NCDB) analysis.
Leiomyosarcoma (LMS) is an aggressive, malignant mesenchymal tumor with characteristic smooth muscle lineage accounting for 10-20% of all soft tissue tumors. The goal of this study is to determine the impact of prognostic factors on leiomyosarcoma survival irrespective of primary anatomical site. There were a total of 7154 patients with primary leiomyosarcoma identified and analyzed from the National Cancer Database. Descriptive statistics, median survival, and 5- and 10-year survival probabilities were calculated along with a Cox proportional hazard model to determine independent prognostic factors. In this study, females comprised 68.3% of the cohort with a median age of 58 years. The most common primary anatomical sites were the extremities followed by female reproductive organs, abdomen, pelvis, thorax or lung, and head or neck. Tumors localized in the female reproductive organs had the worst survival (5-year survival probability: 45.3%), while tumors localized in the extremities had the best survival outcomes (5-year survival probability: 73.4%). Surgery with adjuvant radiation yielded better outcomes compared to surgery alone (HR 0.82, 95% CI 0.74-0.91). Microscopic and macroscopic margins resulted in a 32% and a 134% increased risk in mortality, respectively, when compared to negative surgical margins (p < 0.0001). This study showed a significantly higher risk of mortality associated with older patients, tumors localized to the female reproductive organs, African American patients, higher tumor stage, increased Charlson/Deyo scores, tumors treated with surgery alone without adjuvant radiation, and tumors with positive microscopic, macroscopic, or indeterminate surgical margins.


Nanoscale imaging of fundamental li battery chemistry: solid-electrolyte interphase formation and preferential growth of lithium metal nanoclusters.
The performance characteristics of Li-ion batteries are intrinsically linked to evolving nanoscale interfacial electrochemical reactions. To probe the mechanisms of solid electrolyte interphase (SEI) formation and to track Li nucleation and growth mechanisms from a standard organic battery electrolyte (LiPF6 in EC:DMC), we used in situ electrochemical scanning transmission electron microscopy (ec-S/TEM) to perform controlled electrochemical potential sweep measurements while simultaneously imaging site-specific structures resulting from electrochemical reactions. A combined quantitative electrochemical measurement and STEM imaging approach is used to demonstrate that chemically sensitive annular dark field STEM imaging can be used to estimate the density of the evolving SEI and to identify Li-containing phases formed in the liquid cell. We report that the SEI is approximately twice as dense as the electrolyte as determined from imaging and electron scattering theory. We also observe site-specific locations where Li nucleates and grows on the surface and edge of the glassy carbon electrode. Lastly, this report demonstrates the investigative power of quantitative nanoscale imaging combined with electrochemical measurements for studying fluid-solid interfaces and their evolving chemistries.


Resonance lineshapes in two-dimensional Fourier transform spectroscopy.
We derive an analytical form for resonance lineshapes in two-dimensional (2D) Fourier transform spectroscopy. Our starting point is the solution of the optical Bloch equations for a two-level system in the 2D time domain. Application of the projection-slice theorem of 2D Fourier transforms reveals the form of diagonal and cross-diagonal slices in the 2D frequency data for arbitrary inhomogeneity. The results are applied in quantitative measurements of homogeneous and inhomogeneous broadening of multiple resonances in experimental data.


Pyrrolidinium fullerene induces apoptosis by activation of procaspase-9 via suppression of Akt in primary effusion lymphoma.
Primary effusion lymphoma (PEL) is a subtype of non-Hodgkin's B-cell lymphoma and is an aggressive neoplasm caused by Kaposi's sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients. In general, PEL cells are derived from post-germinal center B-cells and are infected with KSHV. To evaluate potential novel anti-tumor compounds against KSHV-associated PEL, seven water-soluble fullerene derivatives were evaluated as potential drug candidates for the treatment of PEL. Herein, we discovered a pyrrolidinium fullerene derivative, 1,1,1',1'-tetramethyl [60]fullerenodipyrrolidinium diiodide, which induced apoptosis of PEL cells via a novel mechanism, the caspase-9 activation by suppressing the caspase-9 phosphorylation, causing caspase-9 inactivation. Pyrrolidinium fullerene treatment reduced significantly the viability of PEL cells compared with KSHV-uninfected lymphoma cells, and induced the apoptosis of PEL cells by activating caspase-9 via procaspase-9 cleavage. Pyrrolidinium fullerene additionally reduced the Ser473 phosphorylation of Akt and Ser196 of procaspase-9. Ser473-phosphorylated Akt (i.e., activated Akt) phosphorylates Ser196 in procaspase-9, causing inactivation of procaspase-9. We also demonstrated that Akt inhibitors suppressed the proliferation of PEL cells compared with KSHV-uninfected cells. Our data therefore suggest that Akt activation is essential for cell survival in PEL and a pyrrolidinium fullerene derivative induced apoptosis by activating caspase-9 via suppression of Akt in PEL cells. In addition, we evaluated whether pyrrolidinium fullerene in combination with the HSP90 inhibitor (geldanamycin; GA) or valproate, potentiated the cytotoxic effects on PEL cells. Compared to treatment with pyrrolidinium fullerene alone, the addition of low-concentration GA or valproate enhanced the cytotoxic activity of pyrrolidinium fullerene. These results indicate that pyrrolidinium fullerene could be used as a novel therapy for the treatment of PEL.


Fossilization of soft tissue in the laboratory.
Some of the most remarkable fossils preserve cellular details of soft tissues. In many of these, the tissues have been replaced by calcium phosphate. This process has been assumed to require elevated concentrations of phosphate in sediment pore waters. In decay experiments modern shrimps became partially mineralized in amorphous calcium phosphate, preserving cellular details of muscle tissue, particularly in a system closed to oxygen. The source for the formation of calcium phosphate was the shrimp itself. Mineralization, which was accompanied by a drop in pH, commenced within 2 weeks and increased in extent for at least 4 to 8 weeks. This mechanism halts the normal loss of detail of soft-tissue morphology before fossilization. Similar closed conditions would prevail where organisms are rapidly overgrown by microbial mats.


The Dorsal Column Lesion Model of Spinal Cord Injury and Its Use in Deciphering the Neuron-Intrinsic Injury Response.
The neuron-intrinsic response to axonal injury differs markedly between neurons of the peripheral and central nervous system. Following a peripheral lesion, a robust axonal growth program is initiated, whereas neurons of the central nervous system do not mount an effective regenerative response. Increasing the neuron-intrinsic regenerative response would therefore be one way to promote axonal regeneration in the injured central nervous system. The large-diameter sensory neurons located in the dorsal root ganglia are pseudo-unipolar neurons that project one axon branch into the spinal cord, and, via the dorsal column to the brain stem, and a peripheral process to the muscles and skin. Dorsal root ganglion neurons are ideally suited to study the neuron-intrinsic injury response because they exhibit a successful growth response following peripheral axotomy, while they fail to do so after a lesion of the central branch in the dorsal column. The dorsal column injury model allows the neuron-intrinsic regeneration response to be studied in the context of a spinal cord injury. Here we will discuss the advantages and disadvantages of this model. We describe the surgical methods used to implement a lesion of the ascending fibers, the anatomy of the sensory afferent pathways and anatomical, electrophysiological, and behavioral techniques to quantify regeneration and functional recovery. Subsequently we review the results of experimental interventions in the dorsal column lesion model, with an emphasis on the molecular mechanisms that govern the neuron-intrinsic injury response and manipulations of these after central axotomy. Finally, we highlight a number of recent advances that will have an impact on the design of future studies in this spinal cord injury model, including the continued development of adeno-associated viral vectors likely to improve the genetic manipulation of dorsal root ganglion neurons and the use of tissue clearing techniques enabling 3D reconstruction of regenerating axon tracts. © 2018 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 00: 000-000, 2018.


The changing role of palliative care in the ICU.
Palliative care is an interprofessional specialty as well as an approach to care by all clinicians caring for patients with serious and complex illness. Unlike hospice, palliative care is based not on prognosis but on need and is an essential component of comprehensive care for critically ill patients from the time of ICU admission. In this clinically focused article, we review evidence of opportunities to improve palliative care for critically ill adults, summarize strategies for ICU palliative care improvement, and identify resources to support implementation. We searched the MEDLINE database from inception through January 2014. We also searched the Reference Library of The Improving Palliative Care in the ICU Project website sponsored by the National Institutes of Health and the Center to Advance Palliative Care, which is updated monthly. We hand-searched reference lists and author files. Selected studies included all English-language articles concerning adult patients using the search terms 'intensive care' or 'critical care' with 'palliative care,' 'supportive care,' 'end-of-life care,' or 'ethics.' : After examination of peer-reviewed original scientific articles, consensus statements, guidelines, and reviews resulting from our literature search, we made final selections based on author consensus. Existing evidence is organized to address: 1) opportunities to alleviate physical and emotional symptoms, improve communication, and provide support for patients and families; 2) models and specific interventions for improving ICU palliative care; 3) available resources for ICU palliative care improvement; and 4) ongoing challenges and targets for future research. Key domains of ICU palliative care have been defined and operationalized as measures of quality. There is increasing recognition that effective integration of palliative care during acute and chronic critical illness may help patients and families face challenges after discharge from intensive care. Palliative care is increasingly accepted as an essential component of comprehensive care for critically ill patients, regardless of diagnosis or prognosis. A variety of strategies to improve ICU palliative care appear to be effective, and resources including technical assistance and tools are available to support improvement efforts. As the longer-term impact of intensive care on those surviving acute critical illness is increasingly documented, palliative care can help prepare and support patients and families for challenges after ICU discharge. Further research is needed to inform efforts to integrate palliative care with intensive care more effectively and efficiently in and after the ICU and to document improvement using valid and responsive outcome measures.


Risk perception for developing diabetes: comparative risk judgments of physicians.
To assess personal risk perceptions for developing diabetes among practicing physicians. Little is known about comparative risk perceptions concerning diabetes among medical experts. We administered the new Risk Perception Survey for Developing Diabetes to 535 nondiabetic physicians. The participants were 86% male, had a mean age of 49 years, and were 66% white and 24% Asian. Almost 37% were considered at higher risk for developing diabetes based on self-reported risk factors. Over 91% of respondents were either internal medicine or family medicine physicians. Of the four subscales, Comparative Disease Risk and Environmental Risk indicated moderate risk perceptions, whereas Personal Control scores indicated a robust sense of control over developing diabetes. Optimistic Bias scores showed a tendency toward participants' being optimistic that they were less likely to develop diabetes. Based on self-reported risk factor categories, a comparison of scores between physicians at higher risk (n = 196) and those at lower risk (n = 313) for developing diabetes showed greater comparative disease risk perception among the higher risk physicians (P < 0.01), as well as greater perception of diabetes risk (P < 0.001). Nearly 50% of higher risk physicians, however, reported an optimistic bias that they were less likely to develop diabetes than other people of their same age and sex. Women (n = 75) reported greater perception of environmental risks than men (P < 0.001). Asian respondents (n = 126) reported greater perception of environmental risk (P < 0.001) and greater worry about developing diabetes (P < 0.0001) than white respondents (n = 355). Regression analyses showed that scores for nondiabetes comparative disease risks (0.39) and level of optimistic bias (0.31) were predictive of diabetes risk perception (P < 0.0001). The data gathered on physicians' perception of their personal risk for developing diabetes and other comparative risk judgments provided an expert comparison for future analyses of at-risk or lay individuals' perceptions of diabetes risk. Effective communication of diabetes risk among physicians, patients, and the general public relies on knowledge of and sensitivity to group differences in these perceptions.


Microtubule-dependent nuclear-cytoplasmic shuttling of Runx2.
RUNX/AML transcription factors are critical regulators of cell growth and differentiation in multiple lineages and have been linked to human cancers including acute myelogenous leukemia (RUNX1), as well as breast (RUNX2) and gastric cancers (RUNX3). RUNX proteins are targeted to gene regulatory micro-environments within the nucleus via a specific subnuclear targeting signal. However, the dynamics of RUNX distribution and compartmentalization between the cytoplasm and nucleus is minimally understood. Here we show by immunofluorescence microscopy that RUNX2 relocates from the nucleus to the cytoplasm when microtubules are stabilized by the chemotherapeutic agent taxol. The taxol-dependent cytoplasmic accumulation of RUNX2 is inhibited by leptomycin B, which blocks CRM-1 dependent nuclear export, and is not affected by the protein synthesis inhibitor cycloheximide. Using biochemical assays, we show that endogenous RUNX2 associates with stabilized microtubules in a concentration-dependent manner and that the RUNX2 amino terminus mediates the microtubule association. In soluble fractions of cells, RUNX2 co-immunoprecipitates alpha tubulin suggesting that microtubule binding involves the alpha/beta tubulin subunits. We conclude that RUNX2 associates with microtubules and shuttles between the nucleus and the cytoplasm. We propose that nuclear-cytoplasmic shuttling of RUNX2 may modulate its transcriptional activity, as well as its ability to interface with signal transduction pathways that are integrated at RUNX2 containing subnuclear sites. It is possible that taxol-induced acute depletion of the nuclear levels of RUNX2 and/or other cell growth regulatory factors may represent an alternative pathway by which taxol exerts its biological effects during cancer chemotherapies.


Appropriate wastewater treatment systems for developing countries: criteria and indictor assessment in Thailand.
This paper presents a comprehensive approach with factors to select appropriate wastewater treatment systems in developing countries in general and Thailand in particular. Instead of focusing merely on the technical dimensions, the study integrates the social, economic, and environmental concerns to develop a set of criteria and indicators (C&I) useful for evaluating appropriate system alternatives. The paper identifies seven elements crucial for technical selection: reliability, simplicity, efficiency, land requirement, affordability, social acceptability, and sustainability. Variables are organized into three hierarchical elements, namely: principles, criteria, and indicators. The study utilizes a mail survey to obtain information from Thai experts-academicians, practitioners, and government officials-to evaluate the C&I list. Responses were received from 33 experts on two multi-criteria analysis inquiries-ranking and rating-to obtain evaluative judgments. Results show that reliability, affordability, and efficiency are among the most important elements, followed by sustainability and social acceptability. Land requirement and simplicity are low in priority with relatively inferior weighting. A number of criteria are then developed to match the contextual environment of each particular condition. A total of 14 criteria are identified which comprised 64 indicators. Unimportant criteria and indicators are discarded after careful consideration, since some of the indicators are local or site specific.


The relation of mean platelet volume with microalbuminuria and glomerular filtration rate in obese individuals without other metabolic risk factors: the role of platelets on renal functions.
Mean platelet volume (MPV) is an indirect indicator of platelet activity that plays a major role in the pathogenesis of endothelial injury. Obese individuals have higher microalbuminuria which is the initial step of renal endothelial injury. We aimed to analyze the relation of microalbuminuria and MPV in obese individuals without metabolic risk factors. A total of 290 obese individuals (body mass index (BMI)>30 kg/m2) without an accompanying chronic disorder, and 204 nonobese healthy subjects were enrolled into the study. All participants underwent physical examination. Biochemical, hemogram, and hormonal parameters along with urine albumin analysis were performed. Glomerular filtration rate (GFR) was measured by Cockcroft-Gault (GFRC&G), modification of diet in renal disease (MDRD). The BMI was calculated as weight/height2 (kg/m2). Logistic regression analysis was used to analyze relation of variables. The patient group consisted of 171 (59%) female (mean age: 37.15±8.05 years) and 119 (41%) male (mean age 38.98±10.68 years) obese individuals. 130 (63.7%) age matched female (mean age 36.18±8.26 years) and 74 (36.3%) age matched male (mean age 36.49±10.25 years) controls were assigned to the control group. There was a significant difference between groups with regard to BMI, spot microalbuminuria, spot urine microalbuminuria/creatinine ratio but not with to MPV and spot urine creatinine (p: 0.01, 0.004, 0.002; respectively). GFR measured by MDRD and Cockcroft-Gault formula were significantly higher in the obese group (p<0.001 for both). Correlation analysis revealed a significant correlation between BMI and spot urine microalbuminuria, spot urine microalbuminuria/creatinine ratio, GFR (Cockcroft-Gault Formula), Homeostasis Model Assessment of Insulin resistance (HOMA-IR), insulin, C-peptide, diastolic blood pressure, glucose, uric acid, total cholesterol, low density lipoprotein (LDL)-cholesterol, c-reactive protein (CRP), thyroid stimulating hormone (TSH), leukocyte count, platelet count. MPV was inversely and significantly correlated with spot urine creatinine, systolic blood pressure, triglyceride, C-peptide, and platelet count. Mean urea, creatinine, uric acid, triglyceride, total cholesterol, LDL-cholesterol, insulin, C-peptide, HOMA-IR were significantly higher in obese male individuals while obese female individuals had higher levels of mean high density lipoprotein (HDL), CRP, TSH, platelet count, spot urine microalbumin/creatinine rate, and GFR measured by MDRD. Obese individuals have higher microalbuminuria and nonsignificantly elevated MPV, however, urine albumin loss is independent of MPV.