Human monoclonal islet specific autoantibodies share features of islet cell and 64 kDa antibodies.
The first human monoclonal islet cell antibodies of the IgG class (MICA 1-6) obtained from an individual with Type 1 (insulin-dependent) diabetes mellitus were cytoplasmic islet cell antibodies selected by the indirect immunofluorescence test on pancreas sections. Surprisingly, they all recognized the 64 kDa autoantigen glutamate decarboxylase. In this study we investigated which typical features of cytoplasmic islet cell antibodies are represented by these monoclonals. We show by double immunofluorescence testing that MICA 1-6 stain pancreatic beta cells which is in agreement with the beta-cell specific expression of glutamate decarboxylase. In contrast an islet-reactive IgM monoclonal antibody obtained from a pre-diabetic individual stained all islet cells but lacked the tissue specificity of MICA 1-6 and must therefore be considered as a polyreactive IgM-antibody. We further demonstrate that MICA 1-6 revealed typical features of epitope sensitivity to biochemical treatment of the target tissue which has been demonstrated for islet cell antibodies, and which has been used to argue for a lipid rather than a protein nature of target antigens. Our results provide direct evidence that the epitopes recognized by the MICA are destroyed by methanol/chloroform treatment but reveal a high stability to Pronase digestion compared to proinsulin epitopes. Conformational protein epitopes in glutamate decarboxylase therefore show a sensitivity to biochemical treatment of sections such as ganglioside epitopes. MICA 1-6 share typical features of islet cell and 64 kDa antibodies and reveal that glutamate decarboxylase-reactive islet cell antibodies represent a subgroup of islet cell antibodies present in islet cell antibody-positive sera.


Predicting Greater Prairie-Chicken Lek Site Suitability to Inform Conservation Actions.
The demands of a growing human population dictates that expansion of energy infrastructure, roads, and other development frequently takes place in native rangelands. Particularly, transmission lines and roads commonly divide rural landscapes and increase fragmentation. This has direct and indirect consequences on native wildlife that can be mitigated through thoughtful planning and proactive approaches to identifying areas of high conservation priority. We used nine years (2003-2011) of Greater Prairie-Chicken (Tympanuchus cupido) lek locations totaling 870 unique leks sites in Kansas and seven geographic information system (GIS) layers describing land cover, topography, and anthropogenic structures to model habitat suitability across the state. The models obtained had low omission rates (<0.18) and high area under the curve scores (AUC >0.81), indicating high model performance and reliability of predicted habitat suitability for Greater Prairie-Chickens. We found that elevation was the most influential in predicting lek locations, contributing three times more predictive power than any other variable. However, models were improved by the addition of land cover and anthropogenic features (transmission lines, roads, and oil and gas structures). Overall, our analysis provides a hierarchal understanding of Greater Prairie-Chicken habitat suitability that is broadly based on geomorphological features followed by land cover suitability. We found that when land features and vegetation cover are suitable for Greater Prairie-Chickens, fragmentation by anthropogenic sources such as roadways and transmission lines are a concern. Therefore, it is our recommendation that future human development in Kansas avoid areas that our models identified as highly suitable for Greater Prairie-Chickens and focus development on land cover types that are of lower conservation concern.


Convergent Loss of an EDS1/PAD4 Signaling Pathway in Several Plant Lineages Reveals Coevolved Components of Plant Immunity and Drought Response.
Plant innate immunity relies on nucleotide binding leucine-rich repeat receptors (NLRs) that recognize pathogen-derived molecules and activate downstream signaling pathways. We analyzed the variation in NLR gene copy number and identified plants with a low number of NLR genes relative to sister species. We specifically focused on four plants from two distinct lineages, one monocot lineage (Alismatales) and one eudicot lineage (Lentibulariaceae). In these lineages, the loss of NLR genes coincides with loss of the well-known downstream immune signaling complex ENHANCED DISEASE SUSCEPTIBILITY 1 (EDS1)/PHYTOALEXIN DEFICIENT 4 (PAD4). We expanded our analysis across whole proteomes and found that other characterized immune genes were absent only in Lentibulariaceae and Alismatales. Additionally, we identified genes of unknown function that were convergently lost together with EDS1/PAD4 in five plant species. Gene expression analyses in Arabidopsis (Arabidopsis thaliana) and Oryza sativa revealed that several homologs of the candidates are differentially expressed during pathogen infection, drought, and abscisic acid treatment. Our analysis provides evolutionary evidence for the rewiring of plant immunity in some plant lineages, as well as the coevolution of the EDS1/PAD4 pathway and drought responses.


Introduction to machine learning for brain imaging.
Machine learning and pattern recognition algorithms have in the past years developed to become a working horse in brain imaging and the computational neurosciences, as they are instrumental for mining vast amounts of neural data of ever increasing measurement precision and detecting minuscule signals from an overwhelming noise floor. They provide the means to decode and characterize task relevant brain states and to distinguish them from non-informative brain signals. While undoubtedly this machinery has helped to gain novel biological insights, it also holds the danger of potential unintentional abuse. Ideally machine learning techniques should be usable for any non-expert, however, unfortunately they are typically not. Overfitting and other pitfalls may occur and lead to spurious and nonsensical interpretation. The goal of this review is therefore to provide an accessible and clear introduction to the strengths and also the inherent dangers of machine learning usage in the neurosciences.


Low physical activity as a key differentiating factor in the potential high-risk profile for depressive symptoms in older adults.
The identification of potential high-risk groups for depression is of importance. The purpose of the present study was to identify high-risk profiles for depressive symptoms in older individuals, with a focus on functional performance. The population-based Healthy Ageing Initiative included 2,084 community-dwelling individuals (49% women) aged 70. Explorative cluster analysis was used to group participants according to functional performance level, using measures of basic mobility skills, gait variability, and grip strength. Intercluster differences in depressive symptoms (measured by the Geriatric Depression Scale [GDS]-15), physical activity (PA; measured objectively with the ActiGraph GT3X+), and a rich set of covariates were examined. The cluster analysis yielded a seven-cluster solution. One potential high-risk cluster was identified, with overrepresentation of individuals with GDS scores >5 (15.1 vs. 2.7% expected; relative risk = 6.99, P < .001); the prevalence of depressive symptoms was significantly lower in the other clusters (all P < .01). The potential high-risk cluster had significant overrepresentations of obese individuals (39.7 vs. 17.4% expected) and those with type 2 diabetes (24.7 vs. 8.5% expected), and underrepresentation of individuals who fulfilled the World Health Organization's PA recommendations (15.6 vs. 59.1% expected; all P < .01), as well as low levels of functional performance. The present study provided a potential high-risk profile for depressive symptoms among elderly community-dwelling individuals, which included low levels functional performance combined with low levels of PA. Including PA in medical screening of the elderly may aid in identification of potential high-risk individuals for depressive symptoms.


Anti-angiogenic effect of tamoxifen combined with epirubicin in breast cancer patients.
Vascular endothelial growth factor A (VEGF-A) and vascular endothelial growth factor receptor 2 (VEGFR2) are the key factors mediating neo-vascularization. They are often coexpressed in breast cancer. Sex steroids may stimulate angiogenesis via the estrogen receptor (ER) pathway. We investigated to compare the effects of the addition of tamoxifen to epirubicin versus epirubicin alone on VEGF and VEGFR2 expression in breast cancer patients. The expression of VEGF and VEGFR2 was assessed on tissue microarray by immunohistochemistry at baseline conditions and after treatments in the case of 191 patients with T2-4 N0-1 breast cancer enrolled in a randomized trial comparing four cycles of single agent epirubicin versus epirubicin plus tamoxifen as primary systemic treatment. Epirubicin alone failed to induce changes in VEGF expression (P = 0.54), while the addition of tamoxifen to epirubicin resulted in a significant reduction in VEGF expression (P < 0.001). As a consequence, baseline VEGF had a negative prognostic role in patients who received epirubicin alone but not in patients receiving epirubicin plus tamoxifen (interaction test P < 0.05). VEGFR2 expression increased at residual tumor histology in both treatment arms, with a lesser extent in patients receiving tamoxifen plus epirubicin. Decrease in VEGFR2 expression was significantly associated with response rate (P = 0.02). The addition of tamoxifen to epirubicin resulted in a suppression of a key angiogenic pathway. These data suggest a potential synergism of these two drugs.


A model for the generation and interconversion of ER morphologies.
The peripheral endoplasmic reticulum (ER) forms different morphologies composed of tubules and sheets. Proteins such as the reticulons shape the ER by stabilizing the high membrane curvature in cross-sections of tubules and sheet edges. Here, we show that membrane curvature along the edge lines is also critical for ER shaping. We describe a theoretical model that explains virtually all observed ER morphologies. The model is based on two types of curvature-stabilizing proteins that generate either straight or negatively curved edge lines (R- and S-type proteins). Dependent on the concentrations of R- and S-type proteins, membrane morphologies can be generated that consist of tubules, sheets, sheet fenestrations, and sheet stacks with helicoidal connections. We propose that reticulons 4a/b are representatives of R-type proteins that favor tubules and outer edges of sheets. Lunapark is an example of S-type proteins that promote junctions between tubules and sheets. In a tubular ER network, lunapark stabilizes three-way junctions, i.e., small triangular sheets with concave edges. The model agrees with experimental observations and explains how curvature-stabilizing proteins determine ER morphology.


Two-dimensional intermetallic PtBi/Pt core/shell nanoplates overcome tumor hypoxia for enhanced cancer therapy.
The design of multifunctional nanoplatforms is of great importance for improving hypoxia-induced therapeutic outcomes, especially for overcoming radiotherapy (RT) tolerance. Here, two-dimensional intermetallic PtBi/Pt nanoplates (PtBi NPs) were designed as a therapeutic platform to in situ generate oxygen, and thereby overcome tumor hypoxia for boosting photothermal/radiotherapy (PTT/RT). With high X-ray attenuation coefficient, PtBi NPs exhibited outstanding radiotherapy sensitization characteristics. Moreover, the high photothermal effect of PtBi NPs could promote the catalytic activity of PtBi NPs to achieve a synergistic PTT/RT effect. PEGylated PtBi NPs (PtBi-PEG) exhibited excellent biocompatibility, prolonged blood circulation time and enhanced tumor accumulation. Finally, PtBi-PEG showed excellent trimodal contrast enhancement for infrared (IR) imaging, photoacoustic (PA) imaging and X-ray imaging, facilitating imaging-guided cancer therapy. Thus, our work highlights PtBi-PEG as a novel multifunctional theranostic nanoplatform with great potential for future multimodal imaging-guided synergistic cancer therapy.


The differential diagnosis of multiple sclerosis: classification and clinical features of relapsing and progressive neurological syndromes.
In the absence of pathognomonic clinical features or a definitive laboratory test, multiple sclerosis (MS) remains ultimately a diagnosis of exclusion. Accurate diagnosis is increasingly important with available disease modifying therapy. Unfortunately the rate of misdiagnosis remains around 5%-10%, indicating that 1 in 20 patients thought to have MS has, instead, a condition resembling MS. In this review we describe conditions that may be confused with MS because they can present as lesions disseminated in time, space, or both. Conditions often confused with MS may be inflammatory (systemic lupus erythematosus, Sjögren's syndrome, vasculitis, sarcoidosis, Behçet's disease), infectious (Lyme disease, syphilis, progressive multifocal leukoencephalopathy, HTLV-1 infection, herpes zoster), genetic (lysosomal disorders, adrenoleukodystrophy, mitochondrial disorders, CADASIL), metabolic (vitamin B12 deficiency), neoplastic (CNS lymphoma) and spinal (degenerative and vascular malformations) diseases. The key to the accurate diagnosis of MS is vigilance for atypical features, suggesting the possibility of an alternative diagnosis.


IS21-558 insertion sequences are involved in the mobility of the multiresistance gene cfr.
During a study of florfenicol-resistant porcine staphylococci from Denmark, the genes cfr and fexA were detected in the chromosomal DNA or on plasmids of Staphylococcus hyicus, Staphylococcus warneri, and Staphylococcus simulans. A novel variant of the phenicol resistance transposon Tn558 was detected on the ca. 43-kb plasmid pSCFS6 in S. warneri and S. simulans isolates. Sequence analysis of a 22,010-bp segment revealed that the new Tn558 variant harbored an additional resistance gene region integrated into the tnpC reading frame. This resistance gene region consisted of the clindamycin exporter gene lsa(B) and the gene cfr for combined resistance to phenicols, lincosamides, oxazolidinones, pleuromutilins, and streptogramin A antibiotics bracketed by IS21-558 insertion sequences orientated in the same direction. A 6-bp target site duplication was detected at the integration site within tnpC. Transpositionally active forms of the IS21-558 element, known as minicircles, were detected by PCR and suggest that this insertion sequence is involved in the mobility of the multiresistance gene cfr. Based on the knowledge of the transposition pathways of IS21-like insertion sequences and the sequence features detected, the resistance gene region of plasmid pSCFS6 is believed to have developed via IS21-558-mediated cointegrate formation. The data obtained in this study identified the multiresistance gene cfr not only in three novel host species but also in a novel genetic context whose further analysis suggested that insertion sequences of the type IS21-558 are likely to be involved in the dissemination of cfr.


Discrimination of motor imagery-induced EEG patterns in patients with complete spinal cord injury.
EEG-based discrimination between different motor imagery states has been subject of a number of studies in healthy subjects. We investigated the EEG of 15 patients with complete spinal cord injury during imagined right hand, left hand, and feet movements. In detail we studied pair-wise discrimination functions between the 3 types of motor imagery. The following classification accuracies (mean +/- SD) were obtained: left versus right hand 65.03% +/- 8.52, left hand versus feet 68.19% +/- 11.08, and right hand versus feet 65.05% +/- 9.25. In 5 out of 8 paralegic patients, the discrimination accuracy was greater than 70% but in only 1 out of 7 tetraplagic patients. The present findings provide evidence that in the majority of paraplegic patients an EEG-based BCI could achieve satisfied results. In tetraplegic patients, however, it is expected that extensive training-sessions are necessary to achieve a good BCI performance at least in some subjects.


Developing Self-Awareness in Robots via Inner Speech.
The experience of inner speech is a common one. Such a dialogue accompanies the introspection of mental life and fulfills essential roles in human behavior, such as self-restructuring, self-regulation, and re-focusing on attentional resources. Although the underpinning of inner speech is mostly investigated in psychological and philosophical fields, the research in robotics generally does not address such a form of self-aware behavior. Existing models of inner speech inspire computational tools to provide a robot with this form of self-awareness. Here, the widespread psychological models of inner speech are reviewed, and a cognitive architecture for a robot implementing such a capability is outlined in a simplified setup.


Health services utilization among South African women living with HIV and reporting sexual and substance-use risk behaviors.
HIV health services are critical in sub-Saharan African where the burden of the HIV pandemic is devastating. Existing studies suggest that HIV-infected individuals from marginalized populations who know their status do not seek health services because they are unaware of available treatment and care options, may not understand how to access services, or have poor access to and utilization of health care services. This study examined factors associated with health service utilization in a sample of poor, underserved recently diagnosed HIV-positive South African women with sexual and substance use risk behaviors. The data were collected between June 2004 and May 2008. Primary outcomes included consultation with a medical professional and utilization of any health services since learning of HIV status at 3- and 6-month follow-up assessments. The study findings suggest that denial of HIV status may be a barrier to care, leading study participants to avoid utilizing health services specific to their disease and to prefer more general medical care services. In multivariate analyses, prior use of health services, financially supporting others, and sex trading were strongly associated with health service use at follow-up assessments. The study findings suggest a reduced likelihood of health services utilization among participants who met DSM-IV criteria for drug abuse as well as participants with greater numbers of poor physical health symptoms. As an important preliminary step in examining the issue of health services utilization in sub-Saharan Africa, the findings suggest an urgent need to promote HIV prevention and early testing, to strengthen long-term HIV care services, and to increase access to services.


An MXD1-derived repressor peptide identifies noncoding mediators of MYC-driven cell proliferation.
MYC controls the transcription of large numbers of long noncoding RNAs (lncRNAs). Since MYC is a ubiquitous oncoprotein, some of these lncRNAs probably play a significant role in cancer. We applied CRISPR interference (CRISPRi) to the identification of MYC-regulated lncRNAs that are required for MYC-driven cell proliferation in the P493-6 and RAMOS human lymphoid cell lines. We identified 320 noncoding loci that play positive roles in cell growth. Transcriptional repression of any one of these lncRNAs reduces the proliferative capacity of the cells. Selected hits were validated by RT-qPCR and in CRISPRi competition assays with individual GFP-expressing sgRNA constructs. We also showed binding of MYC to the promoter of two candidate genes by chromatin immunoprecipitation. In the course of our studies, we discovered that the repressor domain SID (SIN3-interacting domain) derived from the MXD1 protein is highly effective in P493-6 and RAMOS cells in terms of the number of guides depleted in library screening and the extent of the induced transcriptional repression. In the cell lines used, SID is superior to the KRAB repressor domain, which serves routinely as a transcriptional repressor domain in CRISPRi. The SID transcriptional repressor domain is effective as a fusion to the MS2 aptamer binding protein MCP, allowing the construction of a doxycycline-regulatable CRISPRi system that allows controlled repression of targeted genes and will facilitate the functional analysis of growth-promoting lncRNAs.


OmicsVis: an interactive tool for visually analyzing metabolomics data.
When analyzing metabolomics data, cancer care researchers are searching for differences between known healthy samples and unhealthy samples. By analyzing and understanding these differences, researchers hope to identify cancer biomarkers. Due to the size and complexity of the data produced, however, analysis can still be very slow and time consuming. This is further complicated by the fact that datasets obtained will exhibit incidental differences in intensity and retention time, not related to actual chemical differences in the samples being evaluated. Additionally, automated tools to correct these errors do not always produce reliable results. This work presents a new analytics system that enables interactive comparative visualization and analytics of metabolomics data obtained by two-dimensional gas chromatography-mass spectrometry (GC × GC-MS). The key features of this system are the ability to produce visualizations of multiple GC × GC-MS data sets, and to explore those data sets interactively, allowing a user to discover differences and features in real time. The system provides statistical support in the form of difference, standard deviation, and kernel density estimation calculations to aid users in identifying meaningful differences between samples. These are combined with novel transfer functions and multiform, linked visualizations in order to provide researchers with a powerful new tool for GC × GC-MS exploration and bio-marker discovery.


A Double-Blind, Randomized, Controlled Pilot Trial of N-Acetylcysteine in Veterans With Posttraumatic Stress Disorder and Substance Use Disorders.
The antioxidant N-acetylcysteine is being increasingly investigated as a therapeutic agent in the treatment of substance use disorders (SUDs). This study explored the efficacy of N-acetylcysteine in the treatment of posttraumatic stress disorder (PTSD), which frequently co-occurs with SUD and shares impaired prefrontal cortex regulation of basal ganglia circuitry, in particular at glutamate synapses in the nucleus accumbens. Veterans with PTSD and SUD per DSM-IV criteria (N = 35) were randomly assigned to receive a double-blind, 8-week course of N-acetylcysteine (2,400 mg/d) or placebo plus cognitive-behavioral therapy for SUD (between March 2013 and April 2014). Primary outcome measures included PTSD symptoms (Clinician-Administered PTSD Scale, PTSD Checklist-Military) and craving (Visual Analog Scale). Substance use and depression were also assessed. Participants treated with N-acetylcysteine compared to placebo evidenced significant improvements in PTSD symptoms, craving, and depression (β values < -0.33; P values < .05). Substance use was low for both groups, and no significant between-group differences were observed. N-acetylcysteine was well tolerated, and retention was high. This is the first randomized controlled trial to investigate N-acetylcysteine as a pharmacologic treatment for PTSD and SUD. Although preliminary, the findings provide initial support for the use of N-acetylcysteine in combination with psychotherapy among individuals with co-occurring PTSD and SUD. ClinicalTrials.gov identifier: NCT02499029.


Treatment outcomes of uterine artery embolization and laparoscopic uterine artery ligation for uterine myoma.
In treating women with leiomyoma and who wish to preserve their uterus, laparoscopic uterine artery ligation or uterine artery embolization should be considered as possible options. This study was performed to evaluate the efficacy of laparoscopic uterine artery ligation and uterine artery embolization in treating uterine myoma. The treatment outcomes of 23 patients who underwent uterine artery embolization and 17 laparoscopic uterine artery ligation were evaluated. The uterine volume reduced 3 months after uterine artery embolization, but thereafter no significant changes were observed. On the other hand, the uterine volumes were only slightly reduced 3 months after laparoscopic uterine artery ligation, and slightly more reduced 6 months later. The average reduction in the case of laparoscopic uterine artery ligation was about 58.5%. After laparoscopic uterine artery ligation, 20% of the patients complained of vaginal spotting. Furthermore, the mechanism of volume reduction was evaluated using specimens obtained from a biopsy taken after each procedure. The results suggested that laparoscopic uterine artery ligation results mainly in physiologic cell death, that is apoptosis, whereas, the corresponding result is cell necrosis for uterine artery embolization. Uterine artery embolization and laparoscopic uterine artery ligation are both effective in relieving the symptoms caused by uterine myoma, and therefore both procedures can be used in place of hysterectomy or myomectomy.


Evaluating for impact: what type of data can assist a health promoting school approach?
There is debate within the health promoting school (HPS) movement on whether schools should monitor health behaviour outcomes as part of an evaluation or rely more on process type measures, such as changes to school policies and the physical and social environment which yield information about (in)effective implementation. The debate is often framed around ideological considerations of the role of schools and there is little empirical work on how these indicators of effective implementation can influence change at a policy and practice level in real world settings. Information has potentially powerful effects in motivating a change process, but this will vary according to the type of information and the type of organizational culture into which it is presented. The current predominant model relies on process data, policy and environmental audit monitoring and benchmarking approaches, and there is little evidence of whether this engages school communities. Theoretical assertions on the importance of monitoring data to motivate change need to be empirically tested and, in doing so, we can learn which types of data influence adoption of HPS in which types of school and policy contexts.


Anti-obesity sodium tungstate treatment triggers axonal and glial plasticity in hypothalamic feeding centers.
This study aims at exploring the effects of sodium tungstate treatment on hypothalamic plasticity, which is known to have an important role in the control of energy metabolism. Adult lean and high-fat diet-induced obese mice were orally treated with sodium tungstate. Arcuate and paraventricular nuclei and lateral hypothalamus were separated and subjected to proteomic analysis by DIGE and mass spectrometry. Immunohistochemistry and in vivo magnetic resonance imaging were also performed. Sodium tungstate treatment reduced body weight gain, food intake, and blood glucose and triglyceride levels. These effects were associated with transcriptional and functional changes in the hypothalamus. Proteomic analysis revealed that sodium tungstate modified the expression levels of proteins involved in cell morphology, axonal growth, and tissue remodeling, such as actin, CRMP2 and neurofilaments, and of proteins related to energy metabolism. Moreover, immunohistochemistry studies confirmed results for some targets and further revealed tungstate-dependent regulation of SNAP25 and HPC-1 proteins, suggesting an effect on synaptogenesis as well. Functional test for cell activity based on c-fos-positive cell counting also suggested that sodium tungstate modified hypothalamic basal activity. Finally, in vivo magnetic resonance imaging showed that tungstate treatment can affect neuronal organization in the hypothalamus. Altogether, these results suggest that sodium tungstate regulates proteins involved in axonal and glial plasticity. The fact that sodium tungstate could modulate hypothalamic plasticity and networks in adulthood makes it a possible and interesting therapeutic strategy not only for obesity management, but also for other neurodegenerative illnesses like Alzheimer's disease.


MAZ-binding G4-decoy with locked nucleic acid and twisted intercalating nucleic acid modifications suppresses KRAS in pancreatic cancer cells and delays tumor growth in mice.
KRAS mutations are primary genetic lesions leading to pancreatic cancer. The promoter of human KRAS contains a nuclease-hypersensitive element (NHE) that can fold in G4-DNA structures binding to nuclear proteins, including MAZ (myc-associated zinc-finger). Here, we report that MAZ activates KRAS transcription. To knockdown oncogenic KRAS in pancreatic cancer cells, we designed oligonucleotides that mimic one of the G-quadruplexes formed by NHE (G4-decoys). To increase their nuclease resistance, two locked nucleic acid (LNA) modifications were introduced at the 3'-end, whereas to enhance the folding and stability, two polycyclic aromatic hydrocarbon units (TINA or AMANY) were inserted internally, to cap the quadruplex. The most active G4-decoy (2998), which had two para-TINAs, strongly suppressed KRAS expression in Panc-1 cells. It also repressed their metabolic activity (IC50 = 520 nM), and it inhibited cell growth and colony formation by activating apoptosis. We finally injected 2998 and control oligonucleotides 5153, 5154 (2 nmol/mouse) intratumorally in SCID mice bearing a Panc-1 xenograft. After three treatments, 2998 reduced tumor xenograft growth by 64% compared with control and increased the Kaplan-Meier median survival time by 70%. Together, our data show that MAZ-specific G4-decoys mimicking a KRAS quadruplex are promising for pancreatic cancer therapy.


Monitoring of neuromuscular blockade at the P6 acupuncture point reduces the incidence of postoperative nausea and vomiting.
Electrical stimulation of the P6 acupuncture point reduces the incidence of postoperative nausea and vomiting (PONV). Neuromuscular blockade during general anesthesia can be monitored with electrical peripheral nerve stimulation at the wrist. The authors tested the effect of neuromuscular monitoring over the P6 acupuncture point on the reduction of PONV. In this prospective, double-blinded, randomized control trial, the authors investigated, with institutional review board approval and informed consent, 220 women undergoing elective laparoscopic surgery anesthetized with fentanyl, sevoflurane, and rocuronium. During anesthesia, neuromuscular blockade was monitored by a conventional nerve stimulator at a frequency of 1 Hz over the ulnar nerve (n = 110, control group) or over the median nerve (n = 110, P6 group) stimulating at the P6 acupuncture point at the same time. The authors evaluated the incidence of nausea and vomiting during the first 24 h. No differences in demographic and morphometric data were found between both groups. The 24-h incidence of PONV was 45% in the P6 acupuncture group versus 61% in the control group (P = 0.022). Nausea decreased from 56% in the control group to 40% in the P6 group (P = 0.022), but emesis decreased only from 28% to 23% (P = 0.439). Nausea decreased substantially during the first 6 h of the observation period (P = 0.009). Fewer subjects in the acupuncture group required ondansetron as rescue therapy (27% vs. 39%; P = 0.086). Intraoperative P6 acupuncture point stimulation with a conventional nerve stimulator during surgery significantly reduced the incidence of PONV over 24 h. The efficacy of P6 stimulation is similar to that of commonly used antiemetic drugs in the prevention of PONV.


Role of RelA and SpoT in Burkholderia pseudomallei virulence and immunity.
Burkholderia pseudomallei is a Gram-negative soil bacterium and the causative agent of melioidosis, a disease of humans and animals. It is also listed as a category B bioterrorism threat agent by the U.S. Centers for Disease Control and Prevention, and there is currently no melioidosis vaccine available. Small modified nucleotides such as the hyperphosphorylated guanosine molecules ppGpp and pppGpp play an important role as signaling molecules in prokaryotes. They mediate a global stress response under starvation conditions and have been implicated in the regulation of virulence and survival factors in many bacterial species. In this study, we created a relA spoT double mutant in B. pseudomallei strain K96243, which lacks (p)ppGpp-synthesizing enzymes, and investigated its phenotype in vitro and in vivo. The B. pseudomallei ΔrelA ΔspoT mutant displayed a defect in stationary-phase survival and intracellular replication in murine macrophages. Moreover, the mutant was attenuated in the Galleria mellonella insect model and in both acute and chronic mouse models of melioidosis. Vaccination of mice with the ΔrelA ΔspoT mutant resulted in partial protection against infection with wild-type B. pseudomallei. In summary, (p)ppGpp signaling appears to represent an essential component of the regulatory network governing virulence gene expression and stress adaptation in B. pseudomallei, and the ΔrelA ΔspoT mutant may be a promising live-attenuated vaccine candidate.


Brain mitochondrial proteome alteration driven by creatine deficiency suggests novel therapeutic venues for creatine deficiency syndromes.
Creatine (Cr) is a small metabolite with a central role in energy metabolism and mitochondrial function. Creatine deficiency syndromes are inborn errors of Cr metabolism causing Cr depletion in all body tissues and particularly in the nervous system. Patient symptoms involve intellectual disability, language and behavioral disturbances, seizures and movement disorders suggesting that brain cells are particularly sensitive to Cr depletion. Cr deficiency was found to affect metabolic activity and structural abnormalities of mitochondrial organelles; however a detailed analysis of molecular mechanisms linking Cr deficit, energy metabolism alterations and brain dysfunction is still missing. Using a proteomic approach we evaluated the proteome changes of the brain mitochondrial fraction induced by the deletion of the Cr transporter (CrT) in developing mutant mice. We found a marked alteration of the mitochondrial proteomic landscape in the brain of CrT deficient mice, with the overexpression of many proteins involved in energy metabolism and response to oxidative stress. Moreover, our data suggest possible abnormalities of dendritic spines, synaptic function and plasticity, network excitability and neuroinflammatory response. Intriguingly, the alterations occurred in coincidence with the developmental onset of neurological symptoms. Thus, cerebral mitochondrial alterations could represent an early response to Cr deficiency that could be targeted for therapeutic intervention.


The association between race- and ethnicity-related stressors and sleep: the role of rumination and anxiety sensitivity.
This study was designed to investigate the association between psychosocial factors and self-reported sleep duration and two indices of sleep quality in a racially and ethnically diverse sample of adults. We investigated the relations between both rumination and anxiety sensitivity with these self-reported sleep outcomes. We also examined rumination and anxiety sensitivity as moderators of three race- and ethnicity-related stressors: discrimination, acculturative stress, and socioeconomic status. In a cross-sectional design, we assessed 1326 adults (ages 18-48 years) selected for self-reported racial and ethnic minority status. Regression analyses were used to examine the associations between demographic, social/environmental stressors, depression severity, rumination, and anxiety sensitivity and three sleep outcomes: sleep duration, sleep quality subscale, and global sleep quality. Our findings supported the hypothesized role of rumination as an amplification factor for the influence of race- and ethnicity-related stressors on sleep duration and quality. Rumination was associated with all three sleep outcomes (sleep duration, sleep quality subscale, and global sleep quality) and was a moderator of the associations between discrimination and all 3 sleep outcomes. Anxiety sensitivity was not consistently associated with these sleep outcomes. Depression symptoms did not account for these findings. If confirmed in longitudinal study, our findings introduce a potentially important treatment target-rumination-for addressing sleep disparities in prevention or intervention models. Rumination appears to amplify the negative sleep consequences of race- and ethnicity-related stressors and is a modifiable treatment target.


Expedient treatment of a collodion baby.
Only ~270 cases of collodion babies have been reported in the literature since 1892. As the name suggests, the term "collodion baby" refers to a phenotype that can be characterized by a yellow, shiny, tight parchment-like membrane stretched over the skin. Although the collodion membrane is only an evanescent condition of the newborn, neonatal complications can occur in 45% of all collodion babies, leading to a mortality rate of ~11% in the first few weeks of life. Most children born as collodion babies will spontaneously desquamate within 2 weeks, but may be as long as 3 months. Eventually, these children develop signs of one of several types of ichthyosis, which gives the skin the appearance of "fish scales." We report a unique case of a Caucasian male that was born as a Collodion baby at the University of Kentucky Children's Hospital in Lexington, Kentucky. Although the impairment of the skin barrier function put the patient at risk for a number of complications, he improved significantly after being treated with emollients and antibiotics. In contrast to previous findings, we found that skin emollients were beneficial and did not increase the risk of infection.


Exposing public health surveillance data using existing standards.
With the growing use of information technologies, an increased volume of data is produced in Public Health Surveillance, enabling utilization of new data sources and analysis methods. Public health and research will benefit from the use of data standards promoting harmonization and data description through metadata. No data standard has yet been universally accepted for exchanging public health data. In this work, we implemented two existing standards eligible to expose public health data: Statistical Data and Metadata Exchange - Health Domain (SDMX-HD) proposed by the World Health Organization and Open Data Protocol (OData) proposed by Microsoft Corp. SDMX-HD promotes harmonization through controlled vocabulary and predefined data structure suitable for public health but requires important investment, while OData, a generic purpose standard, proposes a simple way to expose data with minimal documentation and end-user integration tools. The two solutions were implemented and are publicly available at http://sdmx.sentiweb.fr and http://odata.sentiweb.fr. These solutions show that data sharing and interoperability are already possible in Public Health Surveillance.


Predicting the mesophases of copolymer-nanoparticle composites.
The interactions between mesophase-forming copolymers and nanoscopic particles can lead to highly organized hybrid materials. The morphology of such composites depends not only on the characteristics of the copolymers, but also on the features of the nanoparticles. To explore this vast parameter space and predict the mesophases of the hybrids, we have developed a mean field theory for mixtures of soft, flexible chains and hard spheres. Applied to diblock-nanoparticle mixtures, the theory predicts ordered phases where particles and diblocks self-assemble into spatially periodic structures. The method can be applied to other copolymer-particle mixtures and can be used to design novel composite architectures.


Delayed diagnosis of critical congenital heart defects: trends and associated factors.
We aimed to examine trends in timing of diagnosis of critical congenital heart defects (CCHDs) and factors associated with delayed diagnosis (diagnosis after discharge home following delivery). We examined a population-based retrospective cohort of CCHD cases among live births identified through the Massachusetts Birth Defects Monitoring Program. Congenital heart defects were considered critical if the infant received corrective surgery, interventional catheterization, palliative care, or died as a result of the defect within 12 months of birth. Timing of initial diagnosis was classified as prenatal, postnatal before discharge home, or delayed. Demographic, perinatal, and mortality information was obtained from the Registry of Vital Records and Statistics. Prevalence ratios (PRs) were used to examine associations with delayed diagnosis. Among 460 467 live births to Massachusetts residents between 2004 and 2009, we identified 916 CCHD cases, of which 126 (13.8%) had delayed diagnosis. Rates of prenatal CCHD diagnosis increased from 44.9% in 2004 to 63.8% in 2009, whereas rates of delayed diagnosis decreased from 17.1% to 10.6% over the same time period. Among cases with delayed diagnosis, the most common defects were coarctation, pulmonary valve stenosis, and tetralogy of Fallot. Delayed diagnosis was associated with delivery outside a tertiary hospital (adjusted PR: 3.6 [95% confidence interval: 2.5-5.2]) and isolated CCHD (adjusted PR: 1.7 [95% confidence interval: 1.1-2.7]). Despite increasing prenatal diagnosis of CCHDs, delayed diagnosis still occurs in over 10% of cases. Understanding factors associated with delayed diagnosis could help to improve prenatal and postnatal screening efforts, including pulse oximetry testing.


Clustered metallothionein genes are co-regulated in rice and ectopic expression of OsMT1e-P confers multiple abiotic stress tolerance in tobacco via ROS scavenging.
Metallothioneins (MT) are low molecular weight, cysteine rich metal binding proteins, found across genera and species, but their function(s) in abiotic stress tolerance are not well documented. We have characterized a rice MT gene, OsMT1e-P, isolated from a subtractive library generated from a stressed salinity tolerant rice genotype, Pokkali. Bioinformatics analysis of the rice genome sequence revealed that this gene belongs to a multigenic family, which consists of 13 genes with 15 protein products. OsMT1e-P is located on chromosome XI, away from the majority of other type I genes that are clustered on chromosome XII. Various members of this MT gene cluster showed a tight co-regulation pattern under several abiotic stresses. Sequence analysis revealed the presence of conserved cysteine residues in OsMT1e-P protein. Salinity stress was found to regulate the transcript abundance of OsMT1e-P in a developmental and organ specific manner. Using transgenic approach, we found a positive correlation between ectopic expression of OsMT1e-P and stress tolerance. Our experiments further suggest ROS scavenging to be the possible mechanism for multiple stress tolerance conferred by OsMT1e-P. We present an overview of MTs, describing their gene structure, genome localization and expression patterns under salinity and development in rice. We have found that ectopic expression of OsMT1e-P enhances tolerance towards multiple abiotic stresses in transgenic tobacco and the resultant plants could survive and set viable seeds under saline conditions. Taken together, the experiments presented here have indicated that ectopic expression of OsMT1e-P protects against oxidative stress primarily through efficient scavenging of reactive oxygen species.


Efficacy and safety of rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation and a history of cancer: observations from ROCKET AF.
The management of anticoagulation therapy in patients with atrial fibrillation (AF) and cancer is challenging due to increased thrombotic and bleeding risks. We sought to determine the safety and efficacy of rivaroxaban in patients with AF and a history of cancer. ROCKET AF randomized 14 264 patients with AF to rivaroxaban or warfarin with a median follow-up of 1.9 years. Cox regression models were used to assess the association between cancer history and clinical outcomes, and the relative treatment effect of rivaroxaban vs. warfarin in these patients. A total of 640 patients enrolled in ROCKET AF had a history of cancer, with the most common types being prostate (28.6%), colorectal (16.1%), and breast (14.7%) cancer. Patients with a history of cancer were older, more frequently male, more likely to have prior vitamin K antagonist (VKA) use and had higher rates of overall bleeding [hazard ratio (HR) 1.30, 95% confidence interval (CI) 1.16-1.47; P < 0.0001] and non-cardiovascular death (HR 1.47, 95% CI 1.04-2.07; P = 0.031) compared with those with no cancer history. There were no significant associations between cancer history and stroke, venous thromboembolism, or myocardial infarction. The relative efficacy of rivaroxaban vs. warfarin for prevention of stroke/systemic embolism was similar in those with and without a history of cancer (interaction P-value = 0.21). In ROCKET AF, a history of cancer was associated with a higher risk of bleeding and non-cardiovascular death, but not ischaemic events. The relative efficacy and safety of rivaroxaban compared with warfarin were not significantly different in patients with and without a history of cancer. The results of this study are exploratory and should be taken in context of the study population, which may not be generalizable to those with advanced malignancy. Further investigation is needed to understand optimal anticoagulation strategies in patients with AF and cancer.Clinical trial registration: ClinicalTrials.gov: NCT00403767.


Identification of ovarian cancer symptoms in health insurance claims data.
Women with ovarian cancer have reported abdominal/pelvic pain, bloating, difficulty eating or feeling full quickly, and urinary frequency/urgency prior to diagnosis. We explored these findings in a general population using a dataset of insured women aged 40-64 and investigated the potential effectiveness of a routine review of claims data as a prescreen to identify women at high risk for ovarian cancer. Data from a large Washington State health insurer were merged with the Seattle-Puget Sound Surveillance, Epidemiology and End Results (SEER) cancer registry for 2000-2004. We estimated the prevalence of symptoms in the 36 months prior to diagnosis for early and late-stage ovarian cancer cases and for two comparison groups. The potential performance of a passive screener that would flag women with two or more visits for any of the symptoms in the previous 2-month period was examined. Of the 223,903 insured women, 161 had incident cases of ovarian cancer. Both early and late-stage patients had a higher prevalence of abdominal/pelvic pain and bloating than the comparison groups, primarily in the 3 months before diagnosis. The passive screener had a sensitivity of 0.31 and specificity of 0.83 and usually identified women right before diagnosis. Assuming an average cost of $500 per false positive, the screener would be considered cost-effective if the true positives had an average increase of 8.5 years of life expectancy. These results support previous findings that ovarian cancer symptoms were reported in health insurance claims and were more prevalent before diagnosis, but the symptoms may occur too close to the diagnosis date to provide useful diagnostic information. The passive screening approach should be reevaluated in the future using electronic medical records; if found to be effective, the method may be potentially useful for other incident diseases.


Dating the time interval from meconium passage to birth.
The gross and microscopic effects of exposing placenta and umbilical cord to meconium were studied in vitro. Gross staining begins with one hour and is a surface phenomenon proportional to length of exposure and meconium concentration. Pigment penetration into the membranes with subsequent uptake by macrophages is dependent primarily on exposure length. Eight of 11 placentas exposed to various meconium solutions were found to have meconium pigment-laden macrophages in the amnion after one hour. These were seen in the chorion somewhat later. Although only three of 11 placentas showed chorionic pigmented macrophages at one hour, 12 of 12 exhibited this finding after three hours. Amniotic epithelial degeneration also showed a time correlation. These findings, especially the microscopic changes described, permit more accurate determination of the defecation-to-birth interval.


A minimal gene set for cellular life derived by comparison of complete bacterial genomes.
The recently sequenced genome of the parasitic bacterium Mycoplasma genitalium contains only 468 identified protein-coding genes that have been dubbed a minimal gene complement [Fraser, C.M., Gocayne, J.D., White, O., Adams, M.D., Clayton, R.A., et al. (1995) Science 270, 397-403]. Although the M. genitalium gene complement is indeed the smallest among known cellular life forms, there is no evidence that it is the minimal self-sufficient gene set. To derive such a set, we compared the 468 predicted M. genitalium protein sequences with the 1703 protein sequences encoded by the other completely sequenced small bacterial genome, that of Haemophilus influenzae. M. genitalium and H. influenzae belong to two ancient bacterial lineages, i.e., Gram-positive and Gram-negative bacteria, respectively. Therefore, the genes that are conserved in these two bacteria are almost certainly essential for cellular function. It is this category of genes that is most likely to approximate the minimal gene set. We found that 240 M. genitalium genes have orthologs among the genes of H. influenzae. This collection of genes falls short of comprising the minimal set as some enzymes responsible for intermediate steps in essential pathways are missing. The apparent reason for this is the phenomenon that we call nonorthologous gene displacement when the same function is fulfilled by nonorthologous proteins in two organisms. We identified 22 nonorthologous displacements and supplemented the set of orthologs with the respective M. genitalium genes. After examining the resulting list of 262 genes for possible functional redundancy and for the presence of apparently parasite-specific genes, 6 genes were removed. We suggest that the remaining 256 genes are close to the minimal gene set that is necessary and sufficient to sustain the existence of a modern-type cell. Most of the proteins encoded by the genes from the minimal set have eukaryotic or archaeal homologs but seven key proteins of DNA replication do not. We speculate that the last common ancestor of the three primary kingdoms had an RNA genome. Possibilities are explored to further reduce the minimal set to model a primitive cell that might have existed at a very early stage of life evolution.


Epigenetic effects of polymorphic Y chromosomes modulate chromatin components, immune response, and sexual conflict.
Genetic conflicts between sexes and generations provide a foundation for understanding the functional evolution of sex chromosomes and sexually dimorphic phenotypes. Y chromosomes of Drosophila contain multi-megabase stretches of satellite DNA repeats and a handful of protein-coding genes that are monomorphic within species. Nevertheless, polymorphic variation in heterochromatic Y chromosomes of Drosophila result in genome-wide gene expression variation. Here we show that such naturally occurring Y-linked regulatory variation (YRV) can be detected in somatic tissues and contributes to the epigenetic balance of heterochromatin/euchromatin at three distinct loci showing position-effect variegation (PEV). Moreover, polymorphic Y chromosomes differentially affect the expression of thousands of genes in XXY female genotypes in which Y-linked protein-coding genes are not transcribed. The data show a disproportionate influence of YRV on the variable expression of genes whose protein products localize to the nucleus, have nucleic-acid binding activity, and are involved in transcription, chromosome organization, and chromatin assembly. These include key components such as HP1, Trithorax-like (GAGA factor), Su(var)3-9, Brahma, MCM2, ORC2, and inner centromere protein. Furthermore, mitochondria-related genes, immune response genes, and transposable elements are also disproportionally affected by Y chromosome polymorphism. These functional clusterings may arise as a consequence of the involvement of Y-linked heterochromatin in the origin and resolution of genetic conflicts between males and females. Taken together, our results indicate that Y chromosome heterochromatin serves as a major source of epigenetic variation in natural populations that interacts with chromatin components to modulate the expression of biologically relevant phenotypic variation.


Cervical and spinopelvic parameters can predict patient reported outcomes following cervical deformity surgery.
Recent studies have evaluated the correlation of health-related quality of life (HRQL) scores with radiographic parameters. This relationship may provide insight into the connection of patient-reported disability and disease burden caused by cervical diagnoses. To evaluate the association between spinopelvic sagittal parameters and HRQLs in patients with primary cervical diagnoses. Patients ≥18 years meeting criteria for primary cervical diagnoses. Cervical radiographic parameters assessed cervical sagittal vertical axis, TS-CL, chin-to-brow vertical angle, C2-T3, CL, C2 Slope, McGregor's slope. Global radiographic alignment parameters assessed PT, SVA, PI-LL, T1 Slope. Pearson correlations were run for all combinations at baseline (BL) and 1 year (1Y) for continuous BL and 1Y modified Japanese Orthopaedic Association scale (mJOA) scores, as well as decline or improvement in those HRQLs at 1Y. Multiple linear regression models were constructed to investigate BL and 1Y alignment parameters as independent variables. Ninety patients included 55.6 ± 9.6 years, 52% female, 30.7 ± 7kg/m2. By approach, 14.3% of patients underwent procedures by anterior approach, 56% posterior, and 30% had combined approaches. Average anterior levels fused: 3.6, posterior: 4.8, and mean total number of levels fused: 4.5. Mean operative time for the cohort was 902.5 minutes with an average estimated blood loss of 830 ccs. The mean BL neck disability index (NDI) score was 56.5 and a mJOA of 12.81. While BL NDI score correlated with gender (P = 0.050), it did not correlate with BL global or cervical radiographic factors. An increased NDI score at 1Y postoperatively correlated with BL body mass index (P = 0.026). A decreased NDI score was associated with 1Y T12-S1 angle (P = 0.009) and 1Y T10 L2 angle (P = 0.013). Overall, BL mJOA score correlated with the BL radiographic factors of T1 slope (P = 0.005), cervical lordosis (P = 0.001), C2-T3 (P = 0.008), C2 sacral slope (P = 0.050), SVA (P = 0.010), and CL Apex (P = 0.043), as well as gender (P = 0.050). Linear regression modeling for the prior independent variables found a significance of P = 0.046 and an R2 of 0.367. Year 1 mJOA scores correlated with 1Y values for maximum kyphosis (P = 0.043) and TS-CL (P = 0.010). At 1Y, a smaller mJOA score correlated with BL S1 sacral slope (P = 0.014), pelvic incidence (P = 0.009), L1-S1 (P = 0.012), T12-S1 (P = 0.008). The linear regression model for those 4 variables demonstrated an R2 of 0.169 and a P = 0.005. An increased mJOA score correlated with PI-LL difference at 1Y (P = 0.012), L1-S1 difference (P = 0.036), T12-S1 difference (0.006), maximum lordosis (P = 0.026), T9-PA difference (P = 0.010), and difference of T4-PA (P = 0.008). While the impact of preoperative sagittal and cervical parameters on mJOA was strong, the BL radiographic factors did not impact NDI scores. PostOp HRQL was significantly associated with sagittal parameters for mJOA (both worsening and improvement) and NDI scores (improvement). When cervical surgery has been indicated, radiographic alignment is important for postoperative HRQL.


Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study.
Large numbers of hormone replacement therapies (HRTs) are available for the treatment of menopausal symptoms. It is still unclear whether some are more deleterious than others regarding breast cancer risk. The goal of this study was to assess and compare the association between different HRTs and breast cancer risk, using data from the French E3N cohort study. Invasive breast cancer cases were identified through biennial self-administered questionnaires completed from 1990 to 2002. During follow-up (mean duration 8.1 postmenopausal years), 2,354 cases of invasive breast cancer occurred among 80,377 postmenopausal women. Compared with HRT never-use, use of estrogen alone was associated with a significant 1.29-fold increased risk (95% confidence interval 1.02-1.65). The association of estrogen-progestagen combinations with breast cancer risk varied significantly according to the type of progestagen: the relative risk was 1.00 (0.83-1.22) for estrogen-progesterone, 1.16 (0.94-1.43) for estrogen-dydrogesterone, and 1.69 (1.50-1.91) for estrogen combined with other progestagens. This latter category involves progestins with different physiologic activities (androgenic, nonandrogenic, antiandrogenic), but their associations with breast cancer risk did not differ significantly from one another. This study found no evidence of an association with risk according to the route of estrogen administration (oral or transdermal/percutaneous). These findings suggest that the choice of the progestagen component in combined HRT is of importance regarding breast cancer risk; it could be preferable to use progesterone or dydrogesterone.


Chemoresistance induces enhanced adhesion and transendothelial penetration of neuroblastoma cells by down-regulating NCAM surface expression.
Drug resistance to chemotherapy is often associated with increased malignancy in neuroblastoma (NB). One explanation for the link between resistance and malignancy might be that resistance facilitates cancer progression and invasion. To investigate this hypothesis, adhesion, transendothelial penetration and NCAM (CD56) adhesion receptor expression of drug-resistant versus drug-sensitive NB tumor cells were evaluated. Acquired drug resistance was mimicked by exposing parental UKF-NB-2, UKF-NB-3 or IMR-32 tumor cells to increasing concentrations of vincristine- (VCR) or doxorubicin (DOX) to establish the resistant tumor cell sublines UKF-NB-2VCR, UKF-NB-2DOX, UKF-NB-3VCR, UKF-NB-3DOX, IMR-32VCR and IMR-32DOX. Additionally, the malignant behaviour of UKF-NB-4, which already possessed the intrinsic multidrug resistance (MDR) phenotype, was analyzed. UKF-NB-4 exposed to VCR or DOX were designated UKF-NB-4VCR or UKF-NB-4DOX. Combined phase contrast - reflection interference contrast microscopy was used to separately evaluate NB cell adhesion and penetration. NCAM was analyzed by flow cytometry, western blot and RT-PCR. VCR and DOX resistant tumor sublines showed enhanced adhesion and penetration capacity, compared to their drug naïve controls. Strongest effects were seen with UKF-NB-2VCR, UKF-NB-3VCR and IMR-32DOX. DOX or VCR treatment also evoked increased invasive behaviour of UKF-NB-4. The process of accelerated tumor invasion was accompanied by decreased NCAM surface and protein expression, and down-regulation of NCAM coding mRNA. Transfection of UKF-NB-4VCR cells with NCAM cDNA led to a significant receptor up-regulation, paralleled by diminished adhesion to an endothelial cell monolayer. It is concluded that NB cells resistant to anticancer drugs acquire increased invasive capacity relative to non-resistant parental cells, and that enhanced invasion is caused by strong down-regulation of NCAM adhesion receptors.


Italian version of the Assessment of Interprofessional Team Collaboration Scale II (I-AITCS II): a multiphase study of validity and reliability amongst healthcare providers.
To develop and validate an Italian version of the Assessment of Interprofessional Team Collaboration Scale II (I-AITCS II). A multiphase validation study was conducted. The first phase was the AITCS-II translation from English into Italian to develop the first version of I-AITCS II for practitioners. The second phase was the study of I-AITCS II face and content validity, and the third phase was a cross-sectional data collection to provide evidence of construct validity using the psychometrics testing and the reliability assessment through the internal consistency study. The agreement for the forward-translation among researchers was high. The face and content validity were satisfactory. The underlying constructs of I-AITCS II were partnership, cooperation and coordination. Internal consistency was good for both scale and domains level. There were significant differences related to partnership in the comparison between settings. I-AITCS II showed evidence of validity and reliability. It will be useful to gather data to address programs aimed to enhance interprofessional team collaboration within the Italian healthcare contexts, and it could be used for cross-national researches.


Role of phenolic compounds in nitric oxide synthase activity in colon and breast adenocarcinoma.
Cancer chemopreventive agents are designed to reduce the incidence of tumorigenesis by intervening at one or more stages of carcinogenesis. This study aimed to determine the effects of resveratrol (RES) and tannic acid (TA), which are chemopreventive agents, on the nitric oxide synthase (NOS) levels that are effective for development of cancer in colon and breast cancer cell lines. The CaCo-2 (human colon carcinoma cell line) and MCF-7 (Michigan Cancer Foundation-7; human breast adenocarcinoma cell line) cells were grown in the laboratory. RES and TA were used to treat CaCo-2 and MCF-7 cells. Nitric Oxide Synthase Assay Kit was used to determine the NOS enzyme activity of CaCo-2 and MCF-7. Statistical differences between control and RES- and TA-treated cells were calculated using the Student's t-test for double comparison. It was observed that NO activity was generally decreased in CaCo-2 and MCF-7 cells, in which RES and TA were applied. Results suggest that the phenolic compounds RES and TA have different effects on NOS enzyme activity of the colon and breast cancer cells.


Differential expression of KCNQ4 in inner hair cells and sensory neurons is the basis of progressive high-frequency hearing loss.
Human KCNQ4 mutations known as DFNA2 cause non-syndromic, autosomal-dominant, progressive high-frequency hearing loss in which the cellular and molecular basis is unclear. We provide immunofluorescence data showing that Kcnq4 expression in the adult cochlea has both longitudinal (base to apex) and radial (inner to outer hair cells) gradients. The most intense labeling is in outer hair cells at the apex and in inner hair cells as well as spiral ganglion neurons at the base. Spatiotemporal expression studies show increasing intensity of KCNQ4 protein labeling from postnatal day 21 (P21) to P120 mice that is most apparent in inner hair cells of the middle turn. We have identified four alternative splice variants of Kcnq4 in mice. The alternative use of exons 9-11 produces three transcript variants (v1-v3), whereas the fourth variant (v4) skips all three exons; all variants have the same amino acid sequence at the C termini. Both reverse transcription-PCR and quantitative PCR analyses demonstrate that these variants have differential expression patterns along the length of the mouse organ of Corti and spiral ganglion neurons. Our expression data suggest that the primary defect leading to high-frequency loss in DFNA2 patients may be attributable to high levels of the dysfunctional Kcnq4_v3 variant in the spiral ganglion and inner hair cells in the basal hook region. Progressive hearing loss associated with aging may result from an increasing mutational load expansion toward the apex in inner hair cells and spiral ganglion neurons.


A set of high quality colour images with Spanish norms for seven relevant psycholinguistic variables: the Nombela naming test.
This paper presents a new corpus of 140 high quality colour images belonging to 14 subcategories and covering a range of naming difficulty. One hundred and six Spanish speakers named the items and provided data for several psycholinguistic variables: age of acquisition, familiarity, manipulability, name agreement, typicality and visual complexity. Furthermore, we also present lexical frequency data derived internet search hits. Apart from the large number of variables evaluated, these stimuli present an important advantage with respect to other comparable image corpora in so far as naming performance in healthy individuals is less prone to ceiling effect problems. Reliability and validity indexes showed that our items display similar psycholinguistic characteristics to those of other corpora. In sum, this set of ecologically valid stimuli provides a useful tool for scientists engaged in cognitive and neuroscience-based research.


The conserved microRNA miR-8-3p coordinates the expression of V-ATPase subunits to regulate ecdysone biosynthesis for Drosophila metamorphosis.
The steroid hormone ecdysone is the central regulator of insect metamorphosis, during which a growing, immature larva is remodeled, through pupal stages, to a reproductive adult. However, the underlying mechanisms of ecdysone-mediated metamorphosis remain to be fully elucidated. Here, we identified metamorphosis-associated microRNAs (miRNAs) and their potential targets by cross-linking immunoprecipitation coupled with deep sequencing of endogenous Argonaute 1 protein in Drosophila. Interestingly, miR-8-3p targeted five Vha genes encoding distinct subunits of vacuolar H+ -ATPase (V-ATPase), which has a vital role in the organellar acidification. The expression of ecdysone-responsive miR-8-3p is normally downregulated during Drosophila metamorphosis, but temporary overexpression of miR-8-3p in the whole body at the end of larval development led to defects in metamorphosis and survival, hallmarks of aberrant ecdysone signaling. In addition, miR-8-3p was expressed in the prothoracic gland (PG), which produces and releases ecdysone in response to prothoracicotropic hormone (PTTH). Notably, overexpression of miR-8-3p or knockdown of its Vha targets in the PG resulted in larger than normal, ecdysone-deficient larvae that failed to develop into the pupal stage but could be rescued by ecdysone feeding. Moreover, these animals showed defective PTTH signaling with a concomitant decrease in the expression of ecdysone biosynthetic genes. We also demonstrated that the regulatory network between the conserved miR-8-3p/miR-200 family and V-ATPase was functional in human cells. Consequently, our data indicate that the coordinated regulation of V-ATPase subunits by miR-8-3p is involved in Drosophila metamorphosis by controlling the ecdysone biosynthesis.


Hidden magnetic order in plutonium dioxide nuclear fuel.
A thorough understanding of the chemistry of PuO2 is critical to the design of next-generation nuclear fuels and the long-term storage of nuclear materials. Despite over 75 years of study, the ground-state magnetic structure of PuO2 remains a matter of much debate. Experimental studies loosely indicate a diamagnetic (DM) ground-state, whereas theoretical methods have proposed either a collinear ferromagnetic (FM) or anti-ferromagnetic (AFM) ground-state, both of which would be expected to cause a distortion from the reported Fm3[combining macron]m symmetry. In this work, we have used accurate calculations based on the density functional theory (DFT) to systematically investigate the magnetic structure of PuO2 to resolve this controversy. We have explicitly considered electron-correlation, spin-orbit interaction and noncollinear magnetic contributions to identify a hereto unknown longitudinal 3k AFM ground-state that retains Fm3[combining macron]m crystal symmetry. Given the broad interest in plutonium materials and the inherent experimental difficulties of handling this compound, the results presented in this paper have considerable implications for future computational studies relating to PuO2 and related actinide structures. As the crystal structure is coupled by spin-orbit interactions to the magnetic state, it is imperative to consider relativity when creating computational models.


Estimating recharge rates with analytic element models and parameter estimation.
Quantifying the spatial and temporal distribution of recharge is usually a prerequisite for effective ground water flow modeling. In this study, an analytic element (AE) code (GFLOW) was used with a nonlinear parameter estimation code (UCODE) to quantify the spatial and temporal distribution of recharge using measured base flows as calibration targets. The ease and flexibility of AE model construction and evaluation make this approach well suited for recharge estimation. An AE flow model of an undeveloped watershed in northern Wisconsin was optimized to match median annual base flows at four stream gages for 1996 to 2000 to demonstrate the approach. Initial optimizations that assumed a constant distributed recharge rate provided good matches (within 5%) to most of the annual base flow estimates, but discrepancies of >12% at certain gages suggested that a single value of recharge for the entire watershed is inappropriate. Subsequent optimizations that allowed for spatially distributed recharge zones based on the distribution of vegetation types improved the fit and confirmed that vegetation can influence spatial recharge variability in this watershed. Temporally, the annual recharge values varied >2.5-fold between 1996 and 2000 during which there was an observed 1.7-fold difference in annual precipitation, underscoring the influence of nonclimatic factors on interannual recharge variability for regional flow modeling. The final recharge values compared favorably with more labor-intensive field measurements of recharge and results from studies, supporting the utility of using linked AE-parameter estimation codes for recharge estimation.


A Qualitative Exploration of the Mental Health and Psychosocial Contexts of HIV-Positive Adolescents in Tanzania.
Although 85% of HIV-positive adolescents reside in sub-Saharan Africa, little is known about the psychosocial and mental health factors affecting their daily well-being. Identifying these contextual variables is key to development of culturally appropriate and effective interventions for this understudied and high-risk population. The purpose of this study was to identify salient psychosocial and mental health challenges confronted by HIV-positive youth in a resource-poor Tanzanian setting. A total of 24 qualitative interviews were conducted with a convenience sample of adolescents aged 12-24 receiving outpatient HIV care at a medical center in Moshi, Tanzania. All interviews were audio-recorded, transcribed, and coded using thematic analysis. Psychosocial challenges identified included loss of one or more parents, chronic domestic abuse, financial stressors restricting access to medical care and education, and high levels of internalized and community stigma among peers and other social contacts. Over half of youth (56%) reported difficulties coming to terms with their HIV diagnosis and espoused related feelings of self-blame. These findings highlight the urgent need to develop culturally proficient programs aimed at helping adolescents cope with these manifold challenges. Results from this study guided the development of Sauti ya Vijana (The Voice of Youth), a 10-session group mental health intervention designed to address the psychosocial and mental health needs of HIV-positive Tanzanian youth.


Economic evaluation of Viaflex with vial adapter in a unit-dose drug distribution system.
The cost of parenteral admixtures has an important impact on the hospital budget. Recently, a Viaflex with vial adapter (named 'minibag plus' in some countries) has been commercialized in order to facilitate parenteral admixture preparation. In the present study a preparation using Viaflex with a vial adapter has been economically compared with a preparation with a traditional Viaflex (without adapter) in a centralized unit or in nursing wards in a unit-dose drug distribution system. A cost-analysis was conducted from the hospital point of view. Direct costs were considered: these included supplies and human resources. Differences in the whole process between the two types of Viaflex were analysed. The process included: purchasing, reception, storage, medical order record, preparation in the Pharmacy Service (PS), delivery from the PS to the nursing unit, preparation by the nurse, return of unused material to the PS. Human resource costs were estimated by time counting and multiplying by the average salary. To estimate wasted material, drug and supplies delivered from the PS and returned to the PS were counted during 26 days. With the new Viaflex costs are reduced by 30% in comparison with drug dilution using the traditional Viaflex in a centralized unit of the PS, and by 13.4% in comparison with preparation with the traditional Viaflex in the nursing ward. In addition it can be estimated that contamination risk with the new Viaflex is lower than preparation in the nursing ward with the traditional Viaflex. Therefore, owing to its lower cost we recommend the use of Viaflex with vial adapter for drug dilution for those vials that are compatible with the system.


Dark matter maps reveal cosmic scaffolding.
Ordinary baryonic particles (such as protons and neutrons) account for only one-sixth of the total matter in the Universe. The remainder is a mysterious 'dark matter' component, which does not interact via electromagnetism and thus neither emits nor reflects light. As dark matter cannot be seen directly using traditional observations, very little is currently known about its properties. It does interact via gravity, and is most effectively probed through gravitational lensing: the deflection of light from distant galaxies by the gravitational attraction of foreground mass concentrations. This is a purely geometrical effect that is free of astrophysical assumptions and sensitive to all matter--whether baryonic or dark. Here we show high-fidelity maps of the large-scale distribution of dark matter, resolved in both angle and depth. We find a loose network of filaments, growing over time, which intersect in massive structures at the locations of clusters of galaxies. Our results are consistent with predictions of gravitationally induced structure formation, in which the initial, smooth distribution of dark matter collapses into filaments then into clusters, forming a gravitational scaffold into which gas can accumulate, and stars can be built.


RAW 264.7 co-cultured with ultra-high molecular weight polyethylene particles spontaneously differentiate into osteoclasts: an in vitro model of periprosthetic osteolysis.
Wear-particle osteolysis affects prosthesis survival leading to implant loosening up to 70% of revisions. Therapeutic strategies are increasing, however alternative testing methods to experimentally evaluate such treatments are lacking. The aim of this study was to reproduce an in vitro osteolysis model recapitulating the events that, starting from the exposure of macrophages to polyethylene, lead to the establishment of osteoclastogenesis and inflammation. Responses to polyethylene, at 3 and 7 days, in a macrophage cell line, RAW 264.7, were determined by DNA quantification, immunofluorescence, pit assay, gene expression, cytokine production and NF-kB activation. Results showed that 3 days exposure to particles could induce a significant production of Tumor Necrosis Factor alpha (p < 0.0005) and Prostaglandin E2 (p < 0.005) compared to controls. Particles also induced macrophages to spontaneously differentiate into mature and active osteoclasts, in terms of identification of multinucleated cells by Phalloidin staining and by the analysis of osteoclast-specific gene markers. In particular, at 3 days polyethylene induced a significant up-regulation of Nuclear Factor of Activated T-cells, cytoplasmic 1, Receptor Activator of Nuclear factor Kappa-B and Receptor Activator of Nuclear Factor Kappa-B Ligand genes (p < 0.0005) compared to controls. At protein level, the particles induced a significant increase of Receptor Activator of Nuclear Factor Kappa-B Ligand at day 7 over controls (p < 0.0005). Osteoclasts were capable to resorb bone even in absence of differentiating factors. The possible mechanism, beside spontaneous osteoclastogenesis mediated by wear debris, was identified in an autocrine up-regulation of Receptor activator of nuclear factor kappa-B ligand gene expression and protein synthesis. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 510-520, 2017.


Surgeon-Specific Traction Time During Hip Arthroscopy for Primary Labral Repair Can Continue to Decrease After a Substantial Number of Surgeries.
The purpose of this study was to evaluate the total traction time and traction time as a function of anchors placed (TTAP) for primary labral repair in patients undergoing hip arthroscopy by a single surgeon. Patients were included if they received a primary labral repair with or without acetabuloplasty, chondroplasty, or ligamentum teres debridement as part of the treatment for femoroacetabular impingement (FAI). Patients were excluded if they had a previous ipsilateral hip surgery, prior hip conditions, Tönnis grade >1, open procedures, microfracture, ligamentum teres reconstruction, or labral reconstruction. TTAP was calculated by dividing total traction time by the number of anchors placed. 2,350 hips met the inclusion criteria. The mean age and BMI in this cohort were 34.22 years and 25.72 kg/m2, respectively. A total traction time of 60 minutes was first achieved after 268 cases. Mean overall total traction time was 58.16 minutes (95% CI [57.35, 58.97]) and mean TTAP was 16.24 minutes (95% CI [15.93,16.55]) after 2,350 cases. Total traction time plateaued after 374 cases at 55.92 minutes, while TTAP plateaued after 487 cases at 14.93 minutes. Surgeons who introduce hip arthroscopy into their practice can expect to see improvements in traction time during the first 500 surgeries performed, as total traction time plateaued after 374 cases and TTAP plateaued after 487 cases. IV: case series.


Fano-resonant asymmetric metamaterials for ultrasensitive spectroscopy and identification of molecular monolayers.
Engineered optical metamaterials present a unique platform for biosensing applications owing to their ability to confine light to nanoscale regions and to their spectral selectivity. Infrared plasmonic metamaterials are especially attractive because their resonant response can be accurately tuned to that of the vibrational modes of the target biomolecules. Here we introduce an infrared plasmonic surface based on a Fano-resonant asymmetric metamaterial exhibiting sharp resonances caused by the interference between subradiant and superradiant plasmonic resonances. Owing to the metamaterial's asymmetry, the frequency of the subradiant resonance can be precisely determined and matched to the molecule's vibrational fingerprints. A multipixel array of Fano-resonant asymmetric metamaterials is used as a platform for multispectral biosensing of nanometre-scale monolayers of recognition proteins and their surface orientation, as well as for detecting chemical binding of target antibodies to recognition proteins.


Relationship among achievement goal orientations and multidimensional situational motivation in physical education.
Contemporary research suggests that task and ego achievement goal orientations affect students' intrinsic motivation in physical education. This research has assessed intrinsic motivation as a unidimensional contruct, however, which is inconsistent with the more contemporary postulates of self-determination theory (Deci & Ryan, 1985, 1991) which states that intrinsic motivation is only one type of motivation. To date, research has not addressed whether different types of motivation at the situational level are influenced by the proneness to adopt task or ego involvement. To examine the relationship between achievement goal orientations and multidimensional situational motivation in PE. Middle school children (182 male, 136 female; M age = 13.2 years). Responded to questionnaires assessing their dispositional goal orientation (POSQ; Roberts, Treasure, & Balague, 1998) and situational motivation (SIMS; Guay, Vallerand, & Blanchard, 2000) in PE. Task orientation was found to be positively associated with more self-determined types of situational motivation. Ego orientation was weakly related to less self-determined motivation. An extreme group split was conducted to create four goal groups and goal profile analyses conducted. A significant MANOVA was followed by univariate analyses, post hoc comparisons, and calculated effect sizes, which revealed that groups high in task orientation reported more motivationally adaptive responses than groups low in task orientation. The results suggest that a high level of task orientation singularly or in combination with ego orientation fosters self-determined situational motivation in the context of PE.


Identified postnatal mesolimbic dopamine neurons in culture: morphology and electrophysiology.
To examine the intrinsic properties of postnatal mesolimbic dopamine (DA) neurons, we dissociated the ventral tegmental area (VTA) from postnatal rats, enriched for DA neurons by microdissection or gradient purification, and grew the cells in culture. In these cultures, up to 50% of neurons were dopaminergic. DA neurons resembled their in vivo counterparts in soma shapes, and in showing two levels of tyrosine hydroxylase (TH) expression, axodendritic differentiation, two sizes of synaptic vesicles, nest-like synaptic arrangements with non-DA cells, and synaptic specializations. Electrophysiologically, however, they could not be distinguished from non-DA cells, which could be consistent with heterogeneity in cell properties. To examine a functional subset of VTA DA neurons, we retrogradely labeled VTA neurons projecting to the nucleus accumbens. These mesoaccumbens neurons were 86% TH positive, 56% cholecystokinin positive, and 0% neurotensin positive; they also displayed the soma shapes characteristic of DA neurons more generally and two levels of TH expression. Like their in vivo counterparts, mesoaccumbens cells generally fired single broad spikes that were triggered by slow depolarizations and had robust spike afterhyperpolarizations, low- and high-threshold Ca2+ spikes, rapid accommodation of firing, time-dependent anomalous rectification, and hyperpolarizing autoreceptor responses. Strikingly, the expression of these active properties did not change with time in culture. Mesoaccumbens DA cells could be identified by a distinctive subset of properties that made up an electrophysiological signature; however, unlike their in vivo counterparts, they were less often spontaneously active and never fired in bursts. These results suggest that most DA cell properties are intrinsic to the cells, including a significant heterogeneity that is maintained in postnatal culture; their level and mode of activity, however, appear to require afferent input. Culturing identified postnatal VTA DA neurons now makes possible examination of the impact of their individual properties on synaptic function.


Experience in Transitioning From Parenteral Prostacyclins to Selexipag in Pulmonary Arterial Hypertension.
Parenteral prostacyclin therapies remain first-line therapy for patients with pulmonary arterial hypertension (PAH) with class IV symptoms. In selected patients who have been clinically stabilized, switching to selexipag, a chemically distinct prostacyclin receptor agonist, may alleviate risks associated with long-term parenteral therapy. We report our experience with transition of patients from parenteral prostacyclin therapy to selexipag. From January 2016 to July 2017, patients with PAH at the Duke University Pulmonary Vascular Disease Center with functional class II symptoms on stable parenteral prostacyclin therapy were offered the opportunity to transition to selexipag. A standardized protocol was developed to guide titration of therapies. Patients underwent pre- and post-transition assessments of hemodynamics, echocardiography, laboratory biomarkers, and functional status. We studied 14 patients with PAH (11 women; median age 53 years) in total. Overall, 13 patients tolerated the switch to selexipag and remained on the drug at study completion, and 1 patient passed away due to progressive liver failure. Surrogate markers including NT-proBNP, 6MWD, RV function, and TAPSE, and right heart catheterization hemodynamics were similar before and after transition. The transition from parenteral prostanoid therapy to oral selexipag was overall well-tolerated in patients with stable PAH and functional class II symptoms. Finally, doses of selexipag up to 3200 μg twice daily were well-tolerated in patients who had been treated with prior parenteral prostacyclins.


[The Galenic content of Isaac Beeckman's medical ideas (1617-1629)].
The Journal tenu par Isaac Beeckman de 1604 à 1634 has been studied in the history of the seventeenth-century scientific revolution following the theme of Isaac Beeckman's physical mathematical mechanistic view, his proto-molecular theory and his atomistic Lucretian influence. This article goes deeper into the medical ideas of the Journal: how Isaac Beeckman (1588-1637) settles the structure of living matter according to his intensive reading of Galen. It develops a different analysis from the traditionally triumphalist approach in the history of science, focused on the victory of Cartesian mechanism, particularly in the history of medicine taking up Galenism very briefly because of its obsolete physiology. The Galenic corpus inside Isaac Beeckman's Journal consists of the many commentaries of Galen which Beeckman has put down in writing since 1616 until 1627, after when the passages linked to Galen became fewer. Isaac Beeckman's study of Galenic medicine is analyzed according to three approaches: the teleological dimension of Galenism showing up the organic conception of human body corresponding to the divine Providence and consistent with Beeckman's Calvinist belief, the physiologic angle of Galenism, based on natural faculties, stressing the purely speculative aspect of Beeckman's commentaries, while the pathologic and therapeutic angle supports the Hippocratic humourism influence.


Dynamic density functional theory of protein adsorption on polymer-coated nanoparticles.
We present a theoretical model for the description of the adsorption kinetics of globular proteins onto charged core-shell microgel particles based on Dynamic Density Functional Theory (DDFT). This model builds on a previous description of protein adsorption thermodynamics [Yigit et al., Langmuir, 2012, 28], shown to well interpret the available calorimetric experimental data of binding isotherms. In practice, a spatially-dependent free-energy functional including the same physical interactions is built, and used to study the kinetics via a generalised diffusion equation. To test this model, we apply it to the case study of lysozyme adsorption on PNIPAM coated nanoparticles, and show that the dynamics obtained within DDFT is consistent with that extrapolated from experiments. We also perform a systematic study of the effect of various parameters in our model, and investigate the loading dynamics as a function of proteins' valence and hydrophobic adsorption energy, as well as their concentration and that of the nanoparticles. Although we concentrated here on the case of adsorption for a single protein type, the model's generality allows to study multi-component system, providing a reliable instrument for future studies of competitive and cooperative adsorption effects often encountered in protein adsorption experiments.


A simple statistical test of taxonomic or functional homogeneity using replicated microbiome sequencing samples.
One important question in microbiome analysis is how to assess the homogeneity of the microbial composition in a given environment, with respect to a given analysis method. Do different microbial samples taken from the same environment follow the same taxonomic distribution of organisms, or the same distribution of functions? Here we provide a non-parametric statistical "triangulation test" to address this type of question. The test requires that multiple replicates are available for each of the biological samples, and it is based on three-way computational comparisons of samples. To illustrate the application of the test, we collected three biological samples taken from different locations in one piece of human stool, each represented by three replicates, and analyzed them using MEGAN. (Despite its name, the triangulation test does not require that the number of biological samples or replicates be three.) The triangulation test rejects the null hypothesis that the three biological samples exhibit the same distribution of taxa or function (error probability ≤0.05), indicating that the microbial composition of the investigated human stool is not homogenous on a macroscopic scale, suggesting that pooling material from multiple locations is a reasonable practice. We provide an implementation of the test in our open source program MEGAN Community Edition.


Are melanized feather barbs stronger?
Melanin has been associated with increased resistance to abrasion, decreased wear and lowered barb breakage in feathers. But, this association was inferred without considering barb position along the rachis as a potentially confounding variable. We examined the cross-sectional area, breaking force, breaking stress, breaking strain and toughness of melanized and unmelanized barbs along the entire rachis of a primary feather from an osprey (Pandion haliaetus). Although breaking force was higher for melanized barbs, breaking stress (force divided by cross-sectional area) was greater for unmelanized barbs. But when position was considered, all mechanical differences between melanized and unmelanized barbs disappeared. Barb breaking stress, breaking strain and toughness decreased, and breaking stiffness increased, distally along the rachis. These proximal-distal material property changes are small and seem unlikely to affect flight performance of barbs. Our observations of barb bending, breaking and morphology, however, lead us to propose a design principle for barbs. We propose that, by being thicker-walled dorso-ventrally, the barb's flexural stiffness is increased during flight; but, by allowing for twisting when loaded with dangerously high forces, barbs firstly avoid failure by bending and secondly avoid complete failure by buckling rather than rupturing.


Clinical and pathologic correlation of 84 mucinous cystic neoplasms of the pancreas: can one reliably differentiate benign from malignant (or premalignant) neoplasms?
To determine whether the long-term behavior of cystic mucinous neoplasms of the pancreas could be predicted using a novel, precisely defined classification of benign mucinous cystadenomas, noninvasive proliferative cystic mucinous neoplasms, and invasive mucinous cystadenocarcinomas. The primary interest was to obtain long-term follow-up after complete resection to determine the recurrence rates based on this objective classification. Current understanding is that all cystic mucinous neoplasms of the pancreas are potentially malignant and that mucinous cystadenomas, when completely removed, are biologically benign. Cystadenocarcinomas are thought to be less aggressively malignant than ordinary ductal adenocarcinoma, but reported recurrence rates vary widely and are unpredictable. All patients who underwent "curative" resection for cystic mucinous neoplasms at Mayo Clinic Rochester from 1940 to 1997 were identified. All available pathology slides, gross specimens, and clinical records were reviewed, eliminating patients with inadequate documentation. Neoplasms were reclassified as mucinous cystadenomas, noninvasive proliferative mucinous cystic neoplasms, or invasive cystadenocarcinomas based on specific histologic criteria. Of 84 patients (70 women, 14 men) with cystic mucinous neoplasms of the pancreas, 54 were classified as cystadenomas, 23 as noninvasive proliferative cystic mucinous neoplasms, and only 7 as cystadenocarcinomas. Recurrent disease developed in none of the 77 patients without invasion, but 5 of the 6 patients surviving resection for cystadenocarcinomas died of recurrent cystadenocarcinoma within 5 years. When the neoplasm is completely resected and subjected to adequate histopathologic examination based on these objective criteria, absence of tissue invasion predicts a curative operation and detailed follow-up may be unnecessary. In contrast, a histologic diagnosis of invasive cystadenocarcinoma portends a dismal prognosis, similar to that of typical ductal adenocarcinoma of the pancreas.


Roundtable on Urban Living Environment Research (RULER).
For 18 months in 2009-2010, the Rockefeller Foundation provided support to establish the Roundtable on Urban Living Environment Research (RULER). Composed of leading experts in population health measurement from a variety of disciplines, sectors, and continents, RULER met for the purpose of reviewing existing methods of measurement for urban health in the context of recent reports from UN agencies on health inequities in urban settings. The audience for this report was identified as international, national, and local governing bodies; civil society; and donor agencies. The goal of the report was to identify gaps in measurement that must be filled in order to assess and evaluate population health in urban settings, especially in informal settlements (or slums) in low- and middle-income countries. Care must be taken to integrate recommendations with existing platforms (e.g., Health Metrics Network, the Institute for Health Metrics and Evaluation) that could incorporate, mature, and sustain efforts to address these gaps and promote effective data for healthy urban management. RULER noted that these existing platforms focus primarily on health outcomes and systems, mainly at the national level. Although substantial reviews of health outcomes and health service measures had been conducted elsewhere, such reviews covered these in an aggregate and perhaps misleading way. For example, some spatial aspects of health inequities, such as those pointed to in the 2008 report from the WHO's Commission on the Social Determinants of Health, received limited attention. If RULER were to focus on health inequities in the urban environment, access to disaggregated data was a priority. RULER observed that some urban health metrics were already available, if not always appreciated and utilized in ongoing efforts (e.g., census data with granular data on households, water, and sanitation but with little attention paid to the spatial dimensions of these data). Other less obvious elements had not exploited the gains realized in spatial measurement technology and techniques (e.g., defining geographic and social urban informal settlement boundaries, classification of population-based amenities and hazards, and innovative spatial measurement of local governance for health). In summary, the RULER team identified three major areas for enhancing measurement to motivate action for urban health-namely, disaggregation of geographic areas for intra-urban risk assessment and action, measures for both social environment and governance, and measures for a better understanding of the implications of the physical (e.g., climate) and built environment for health. The challenge of addressing these elements in resource-poor settings was acknowledged, as was the intensely political nature of urban health metrics. The RULER team went further to identify existing global health metrics structures that could serve as platforms for more granular metrics specific for urban settings.


Chronic hypoxia decreases heterogeneity of pulmonary blood flow distribution in rats.
Pulmonary blood flow (PBF) distribution was studied in 15 chronically hypoxic rats (3 weeks, 10% O2 in N2) breathing 10% O2 (chronic hypoxia, CHx) and after 30 min of breathing air (acute normoxia, ANx). Controls were 15 normoxic littermates (normoxia, Nx) breathing air. Nonradioactive microspheres were infused into the inferior vena cava in the conscious resting state. The lungs were cut into 28 samples, and relative scatter of specific PBF was calculated as (sample activity/sample dry weight)/(total activity/total lung dry weight). In Nx, PBF had a small but significant preferential distribution to the hilar, central regions, with lower blood flow to the peripheral regions (central-to-peripheral pattern). In CHx, however, there was no significant difference between blood flows to the central, middle and peripheral regions of the lung. ANx resulted in no change in PBF distribution. The results indicate that CHx attenuates the central-to-peripheral gradient of PBF distribution, probably due to vascular structural remodeling developed in CHx.