The Canine Frustration Questionnaire-Development of a New Psychometric Tool for Measuring Frustration in Domestic Dogs (Canis familiaris).
Introduction: Psychometric tools have been developed for the assessment of behavioral and affective traits in non-human animals. Frustration can be defined as an emotional reaction experienced after a given expectation is violated. Frustration is a negative emotional state and whilst it probably plays a key role in certain behavior problems in dogs (e.g., aggressive behaviors), there appears to have been little attempt to scale this affective tendency. Therefore, the aim of the current study was to develop a tool to assess frustration tendencies in dogs. Materials and Methods: An online owner survey was developed. Items covered demographics, the training/behavioral history of the dog, and 33 frustration related items scored using a 5-point Likert scale. The questionnaire was disseminated via on-line channels over a 5-month period. Two thousand three hundred forty-eight respondents completed the questionnaire. Of these, 273 respondents completed it a second time 6 weeks later, and a separate 276 respondents completed it a second time 1 year later. Additionally, 92 paired responses were collected where two carers completed the questionnaire independently about the same dog. Intra- and inter-rater reliabilities were assessed prior to structuring the items using principal component analysis (PCA) with a Varimax rotation. Items were retained if they loaded > 0.4 on at least one of the components extracted using the Kaiser criterion. Results: Twenty-two items were deemed to be reliable enough to be used in the PCA and 21 items loaded on a biologically meaningful 5-principal component solution. There was a significant positive correlation between each principal component and the owners' general perception of their dogs' frustration tendencies, alongside other expected correlates. Conclusion: This is the first reliable psychometric tool for the assessment of frustration in dogs-the Canine Frustration Questionnaire (CFQ). Further validation with behavioral tests and physiological measures is ongoing.


Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment.
In Parkinson's disease (PD), α-synuclein (αS) pathologically impacts the brain, a highly lipid-rich organ. We investigated how alterations in αS or lipid/fatty acid homeostasis affect each other. Lipidomic profiling of human αS-expressing yeast revealed increases in oleic acid (OA, 18:1), diglycerides, and triglycerides. These findings were recapitulated in rodent and human neuronal models of αS dyshomeostasis (overexpression; patient-derived triplication or E46K mutation; E46K mice). Preventing lipid droplet formation or augmenting OA increased αS yeast toxicity; suppressing the OA-generating enzyme stearoyl-CoA-desaturase (SCD) was protective. Genetic or pharmacological SCD inhibition ameliorated toxicity in αS-overexpressing rat neurons. In a C. elegans model, SCD knockout prevented αS-induced dopaminergic degeneration. Conversely, we observed detrimental effects of OA on αS homeostasis: in human neural cells, excess OA caused αS inclusion formation, which was reversed by SCD inhibition. Thus, monounsaturated fatty acid metabolism is pivotal for αS-induced neurotoxicity, and inhibiting SCD represents a novel PD therapeutic approach.


Wearable Urban Mobility Assistive Device for Visually Impaired Pedestrians Using a Smartphone and a Tactile-Foot Interface.
This paper reports on the progress of a wearable assistive technology (AT) device designed to enhance the independent, safe, and efficient mobility of blind and visually impaired pedestrians in outdoor environments. Such device exploits the smartphone's positioning and computing capabilities to locate and guide users along urban settings. The necessary navigation instructions to reach a destination are encoded as vibrating patterns which are conveyed to the user via a foot-placed tactile interface. To determine the performance of the proposed AT device, two user experiments were conducted. The first one requested a group of 20 voluntary normally sighted subjects to recognize the feedback provided by the tactile-foot interface. The results showed recognition rates over 93%. The second experiment involved two blind voluntary subjects which were assisted to find target destinations along public urban pathways. Results show that the subjects successfully accomplished the task and suggest that blind and visually impaired pedestrians might find the AT device and its concept approach useful, friendly, fast to master, and easy to use.


Spatial risk assessments based on vector-borne disease epidemiologic data: importance of scale for West Nile virus disease in Colorado.
We used epidemiologic data for human West Nile virus (WNV) disease in Colorado from 2003 and 2007 to determine 1) the degree to which estimates of vector-borne disease occurrence is influenced by spatial scale of data aggregation (county versus census tract), and 2) the extent of concordance between spatial risk patterns based on case counts versus incidence. Statistical analyses showed that county, compared with census tract, accounted for approximately 50% of the overall variance in WNV disease incidence, and approximately 33% for the subset of cases classified as West Nile neuroinvasive disease. These findings indicate that sub-county scale presentation provides valuable risk information for stakeholders. There was high concordance between spatial patterns of WNV disease incidence and case counts for census tract (83%) but not for county (50%) or zip code (31%). We discuss how these findings impact on practices to develop spatial epidemiologic data for vector-borne diseases and present data to stakeholders.


Enhanced Molecular Spin-Photon Coupling at Superconducting Nanoconstrictions.
We combine top-down and bottom-up nanolithography to optimize the coupling of small molecular spin ensembles to 1.4 GHz on-chip superconducting resonators. Nanoscopic constrictions, fabricated with a focused ion beam at the central transmission line, locally concentrate the microwave magnetic field. Drops of free-radical molecules have been deposited from solution onto the circuits. For the smallest ones, the molecules were delivered at the relevant circuit areas by means of an atomic force microscope. The number of spins Neff effectively coupled to each device was accurately determined combining Scanning Electron and Atomic Force Microscopies. The collective spin-photon coupling constant has been determined for samples with Neff ranging between 2 × 106 and 1012 spins, and for temperatures down to 44 mK. The results show the well-known collective enhancement of the coupling proportional to the square root of Neff. The average coupling of individual spins is enhanced by more than 4 orders of magnitude (from 4 mHz up to above 180 Hz), when the transmission line width is reduced from 400 μm down to 42 nm, and reaches maximum values near 1 kHz for molecules located on the smallest nanoconstrictions.


cDNA and derived amino acid sequence of ethanol-inducible rabbit liver cytochrome P-450 isozyme 3a (P-450ALC).
Administration of ethanol to rabbits is known to induce a unique liver microsomal cytochrome P-450, termed isozyme 3a or P-450ALC, which is responsible for the increased oxidation of ethanol and other alcohols and the activation of toxic or carcinogenic compounds such as acetaminophen and N-nitrosodimethylamine. To further characterize this cytochrome P-450 we have identified cDNA clones to isozyme 3a by immunoscreening, DNA hybridization, and hybridization-selection. The cDNA sequence determined from two overlapping clones contains an open reading frame of 1416 nucleotides, and the first 25 amino acids of this reading frame correspond to residues 21-45 of cytochrome P-450 3a. The complete polypeptide, including residues 1 to 20, contains 492 amino acids and has a molecular weight of 56,820. Cytochrome P-450 3a is approximately 55% identical in sequence to P-450 isozymes 1 and 3b and 48% identical to isozyme 2. Hybridization of clone p3a-2 to electrophoretically fractionated rabbit liver poly(A)+ RNA revealed multiple bands, but, with a probe derived from the 3' nontranslated portion of this cDNA, only a 1.9-kilobase band was observed. Treatment of rabbits with imidazole, which increases the content of isozyme 3a, resulted in a transient increase in form 3a mRNA, but this was judged to be insufficient to account for the known 4.5-fold increase in form 3a protein. Genomic DNA analysis indicated that the cytochrome P-450 3a gene does not belong to a large subfamily.


The Clinicopathologic Features and Treatment of 607 Hindgut Neuroendocrine Tumor (NET) Patients at a Single Institution.
The clinicopathologic features of hindgut neuroendocrine tumor (NET) as well as the treatment outcomes are not well known. There are currently no published data on treatment outcomes for patients with metastatic hindgut NET. The aim of this study was to conduct a comprehensive analysis of clinicopathologic features, treatments and survival in hindgut NET patients. Among patients who were pathologically diagnosed with hindgut NET at Samsung Medical Center between March 2001 and February 2015, 607 were analyzed in this study. Hindgut NETs were defined as NETs that originated from the transverse and distal colon, rectum, and anus. Primary sites included 81 colon (13.3%) and 526 rectum (86.7%). According to the WHO classification, 578 patients (95.2%) had grade 1 NETs, 17 (2.8%) grade 2 NETs, and 12 (2.0%) had neuroendocrine carcinoma (NEC). Forty-two patients (6.9%) had extensive disease, while the majority (93.1%, 565 patients) only exhibited localized disease. The 5- and 10-year survival rates of 565 localized NET patients were 98.1% and 95.3%, respectively. The median OS in 42 patients with extensive disease was 24.8 months (95% CI, 10.7-38.8). Among 565 patients with localized disease, the majority (484 patients, 85.7%) were treated with endoscopic procedure by gastroenterologists. For 42 patients with extensive disease, 17 patients were managed by supportive care, 3 by concurrent chemoradiotherapy (CCRT), and 22 by systemic therapy. Among these 22 patients, 12 patients received only first-line therapy, 8 had second-line, and only 2 patients had third-line therapy. As first-line chemotherapy, the most commonly used regimens were etoposide plus cisplatin (N = 7) and long acting octreotide (N = 7). During treatment courses, the most commonly used regimen was long-acting octreotide. The median OS in 22 metastatic NET patients receiving systemic therapy was 19.3 months (95% CI, 3.2-35.3). Multivariate analysis in all 607 hindgut NETs patients suggested that the extent and the primary site of disease were significant independent prognostic factors for long term survival. This analysis provides useful information about the clinicopathologic features, treatments and survival outcomes for hindgut NET patients.


The epidemic volatility index, a novel early warning tool for identifying new waves in an epidemic.
Early warning tools are crucial for the timely application of intervention strategies and the mitigation of the adverse health, social and economic effects associated with outbreaks of epidemic potential such as COVID-19. This paper introduces, the Epidemic Volatility Index (EVI), a new, conceptually simple, early warning tool for oncoming epidemic waves. EVI is based on the volatility of newly reported cases per unit of time, ideally per day, and issues an early warning when the volatility change rate exceeds a threshold. Data on the daily confirmed cases of COVID-19 are used to demonstrate the use of EVI. Results from the COVID-19 epidemic in Italy and New York State are presented here, based on the number of confirmed cases of COVID-19, from January 22, 2020, until April 13, 2021. Live daily updated predictions for all world countries and each of the United States of America are publicly available online. For Italy, the overall sensitivity for EVI was 0.82 (95% Confidence Intervals: 0.75; 0.89) and the specificity was 0.91 (0.88; 0.94). For New York, the corresponding values were 0.55 (0.47; 0.64) and 0.88 (0.84; 0.91). Consecutive issuance of early warnings is a strong indicator of main epidemic waves in any country or state. EVI's application to data from the current COVID-19 pandemic revealed a consistent and stable performance in terms of detecting new waves. The application of EVI to other epidemics and syndromic surveillance tasks in combination with existing early warning systems will enhance our ability to act swiftly and thereby enhance containment of outbreaks.


The DNA-PK Inhibitor VX-984 Enhances the Radiosensitivity of Glioblastoma Cells Grown In Vitro and as Orthotopic Xenografts.
Radiotherapy is a primary treatment modality for glioblastomas (GBM). Because DNA-PKcs is a critical factor in the repair of radiation-induced double strand breaks (DSB), this study evaluated the potential of VX-984, a new DNA-PKcs inhibitor, to enhance the radiosensitivity of GBM cells. Treatment of the established GBM cell line U251 and the GBM stem-like cell (GSC) line NSC11 with VX-984 under in vitro conditions resulted in a concentration-dependent inhibition of radiation-induced DNA-PKcs phosphorylation. In a similar concentration-dependent manner, VX-984 treatment enhanced the radiosensitivity of each GBM cell line as defined by clonogenic analysis. As determined by γH2AX expression and neutral comet analyses, VX-984 inhibited the repair of radiation-induced DNA double-strand break in U251 and NSC11 GBM cells, suggesting that the VX-984-induced radiosensitization is mediated by an inhibition of DNA repair. Extending these results to an in vivo model, treatment of mice with VX-984 inhibited radiation-induced DNA-PKcs phosphorylation in orthotopic brain tumor xenografts, indicating that this compound crosses the blood-brain tumor barrier at sufficient concentrations. For mice bearing U251 or NSC11 brain tumors, VX-984 treatment alone had no significant effect on overall survival; radiation alone increased survival. The survival of mice receiving the combination protocol was significantly increased as compared with control and as compared with radiation alone. These results indicate that VX-984 enhances the radiosensitivity of brain tumor xenografts and suggest that it may be of benefit in the therapeutic management of GBM. Mol Cancer Ther; 17(6); 1207-16. ©2018 AACR.


Investigation of a sudden malaria outbreak in the isolated Amazonian village of Saul, French Guiana, January-April 2009.
Malaria is endemic in French Guiana. Plasmodium falciparum and Plasmodium vivax are the predominant species responsible and Anopheles darlingi is described as the major vector. In mid-August 2008, an increase in malaria incidence was observed in Saül. A retrospective cohort survey was performed. In vitro susceptibility profiles to antimalarials were determined on P. falciparum isolates. Collections of mosquitoes were organized. The malaria attack rate reached 70.6/100. The risk of malaria increased for people between 40 and 49 years of age, living in a house not subjected to a recent indoor residual insecticide spraying or staying overnight in the surrounding forest. All isolates were susceptible. Anopheles darlingi females and larvae were collected in the village suggesting a local transmission. Our results strongly support a role of illegal mining activities in the emergence of new foci of malaria. Therefore, public health authorities should define policies to fight malaria at a transborder level.


Repeat polymorphisms in the low-complexity regions of Plasmodium falciparum ABC transporters and associations with in vitro antimalarial responses.
The Plasmodium falciparum genome is rich in regions of low amino acid complexity which evolve with few constraints on size. To explore the extent of diversity in these loci, we sequenced repeat regions in pfmdr1, pfmdr5, pfmdr6, pfmrp2, and the antigenic locus pfmsp8 in laboratory and cultured-adapted clinical isolates. We further assessed associations between the repeats and parasite in vitro responses to 7 antimalarials to determine possible adaptive roles of these repeats in drug tolerance. Our results show extensive repeat variations in the reference and clinical isolates in all loci. We also observed a modest increase in dihydroartemisinin activity in parasites harboring the pfmdr1 sequence profile 7-2-10 (reflecting the number of asparagine repeats, number of aspartate repeats, and number of asparagine repeats in the final series of the gene product) (P = 0.0321) and reduced sensitivity to chloroquine, mefloquine, quinine, and dihydroartemisinin in those with the 7-2-11 profile (P = 0.0051, 0.0068, 0.0011, and 0.0052, respectively). Interestingly, we noted an inverse association between two drugs whereby isolates with 6 asparagine repeats encoded by pfmdr6 were significantly more susceptible to piperaquine than those with 8 (P = 0.0057). Against lumefantrine, those with 8 repeats were, however, more sensitive (P = 0.0144). In pfmrp2, the 7-DNNNTS/NNNNTS (number of DNNNTS or NNNNTS motifs; underlining indicates dimorphism) repeat group was significantly associated with a higher lumefantrine 50% inhibitory concentration (IC50) (P = 0.008) than in those without. No associations were observed with pfmsp8. These results hint at the probable utility of some repeat conformations as markers of in vitro antimalarial response; hence, biochemical functional studies to ascertain their role in P. falciparum are required.


Visualizing late insect embryogenesis: extraembryonic and mesodermal enhancer trap expression in the beetle Tribolium castaneum.
The beetle Tribolium castaneum has increasingly become a powerful model for comparative research on insect development. One recent resource is a collection of piggyBac transposon-based enhancer trap lines. Here, we provide a detailed analysis of three selected lines and demonstrate their value for investigations in the second half of embryogenesis, which has thus far lagged behind research on early stages. Two lines, G12424 and KT650, show enhanced green fluorescent protein (EGFP) expression throughout the extraembryonic serosal tissue and in a few discrete embryonic domains. Intriguingly, both lines show for the first time a degree of regionalization within the mature serosa. However, their expression profiles illuminate distinct aspects of serosal biology: G12424 tracks the tissue's rapid maturation while KT650 expression likely reflects ongoing physiological processes. The third line, G04609, is stably expressed in mesodermal domains, including segmental muscles and the heart. Genomic mapping followed by in situ hybridization for genes near to the G04609 insertion site suggests that the transposon has trapped enhancer information for the Tribolium orthologue of midline (Tc-mid). Altogether, our analyses provide the first live imaging, long-term characterizations of enhancer traps from this collection. We show that EGFP expression is readily detected, including in heterozygote crosses that permit the simultaneous visualization of multiple tissue types. The tissue specificity provides live, endogenous marker gene expression at key developmental stages that are inaccessible for whole mount staining. Furthermore, the nonlocalized EGFP in these lines illuminates both the nucleus and cytoplasm, providing cellular resolution for morphogenesis research on processes such as dorsal closure and heart formation. In future work, identification of regulatory regions driving these enhancer traps will deepen our understanding of late developmental control, including in the extraembryonic domain, which is a hallmark of insect development but which is not yet well understood.


Peptidomic approaches to study proteolytic activity.
Peptidomics, the analysis of the peptide content of cells or tissues, can be used to study proteases in several ways. First, nearly all of the peptides detected in cells and tissues are proteolytic fragments of proteins. Analysis of the peptides therefore provides information regarding the proteolytic activities that occurred to generate the observed peptides. The use of quantitative peptidomic approaches allows the comparison of relative peptide levels in two or more different samples, which enables studies examining the consequences of increasing proteolytic activity (by enzyme activation or overexpression) or reducing proteolytic activity (by inhibition, knock down, or knock out). Quantitative peptidomics can also be used to directly test the cleavage specificity of purified proteases. For this, peptides are purified from the tissue or cell line of interest, incubated in the presence of various amounts of protease or in the absence of protease, and then analyzed by the quantitative peptidomics approach. This reveals which peptides are preferred substrates, which are products, and which are not cleaved. Collectively, these studies complement conventional approaches to study proteolytic activity and allow for a more complete understanding of an enzyme's substrate specificity. This unit describes the use of quantitative peptidomics in the analysis of the biological peptidome as well as in the in vitro analysis of peptidase activity.


Effects of manipulated herbivore inputs on nutrient flux and decomposition in a tropical rainforest in Puerto Rico.
Forest canopy herbivores are known to increase rates of nutrient fluxes to the forest floor in a number of temperate and boreal forests, but few studies have measured effects of herbivore-enhanced nutrient fluxes in tropical forests. We simulated herbivore-induced fluxes in a tropical rainforest in Puerto Rico by augmenting greenfall (fresh foliage fragments), frassfall (insect feces), and throughfall (precipitation enriched with foliar leachates) in replicated experimental plots on the forest floor. Background rates of greenfall and frassfall were measured monthly using litterfall collectors and augmented by adding 10× greenfall or 10× frassfall to designated plots. Throughfall fluxes of NH(4), NO(3) and PO(4) (but not water) were doubled in treatment plots, based on published rates of fluxes of these nutrients in throughfall. Control plots received only background flux rates for these compounds but the same minimum amount of distilled water. We evaluated treatment effects as changes in flux rates for NO(3), NH(4) and PO(4), measured as decomposition rate of leaf litter in litterbags and as adsorption in ion-exchange resin bags at the litter-soil interface. Frass addition significantly increased NO(3) and NH(4) fluxes, and frass and throughfall additions significantly reduced decay rate, compared to controls. Reduced decay rate suggests that nitrogen flux was sufficient to inhibit microbial decomposition activity. Our treatments represented fluxes expected from low-moderate herbivore outbreaks and demonstrated that herbivores, at these outbreak levels, increase ecosystem-level N and P fluxes by >30% in this tropical rainforest.


CD147 Promotes Tumor Lymphangiogenesis in Melanoma via PROX-1.
Malignant melanoma is one of the most aggressive skin cancers and is characterized by early lymph node metastasis and the capacity to develop resistance to therapies. Hence, understanding the regulation of lymphangiogenesis through mechanisms contributing to lymphatic vessel formation represents a treatment strategy for metastatic cancer. We have previously shown that CD147, a transmembrane glycoprotein overexpressed in melanoma, regulates the angiogenic process in endothelial cells. In this study, we show a correlation between high CD147 expression levels and the number of lymphatic vessels expressing LYVE-1, Podoplanin, and VEGFR-3 in human melanoma lymph nodes. CD147 upregulates in vitro lymphangiogenesis and its related mediators through the PROX-1 transcription factor. In vivo studies in a melanoma model confirmed that CD147 is involved in metastasis through a similar mechanism as in vitro. This study, demonstrating the paracrine role of CD147 in the lymphangiogenesis process, suggests that CD147 could be a promising target for the inhibition of melanoma-associated lymphangiogenesis.


Transitions of care in heart failure: a scientific statement from the American Heart Association.
In patients with heart failure (HF), use of 30-day rehospitalization as a healthcare metric and increased pressure to provide value-based care compel healthcare providers to improve efficiency and to use an integrated care approach. Transition programs are being used to achieve goals. Transition of care in the context of HF management refers to individual interventions and programs with multiple activities that are designed to improve shifts or transitions from one setting to the next, most often from hospital to home. As transitional care programs become the new normal for patients with chronic HF, it is important to understand the current state of the science of transitional care, as discussed in the available research literature. Of transitional care reports, there was much heterogeneity in research designs, methods, study aims, and program targets, or they were not well described. Often, programs used bundled interventions, making it difficult to discuss the efficiency and effectiveness of specific interventions. Thus, further HF transition care research is needed to ensure best practices related to economically and clinically effective and feasible transition interventions that can be broadly applicable. This statement provides an overview of the complexity of HF management and includes patient, hospital, and healthcare provider barriers to understanding end points that best reflect clinical benefits and to achieving optimal clinical outcomes. The statement describes transitional care interventions and outcomes and discusses implications and recommendations for research and clinical practice to enhance patient-centered outcomes.


Antimicrobial resistance trends in blood culture positive Salmonella Typhi isolates from Pondicherry, India, 2005-2009.
Typhoid fever is caused by Salmonella enterica serovar Typhi, a major public health concern in developing countries. Recently, there has been an upsurge in the occurrence of bacterial isolates that are resistant to ciprofloxacin, and the emergence of broad spectrum β-lactamases in typhoidal salmonellae constitutes a new challenge for the clinician. A total of 337 blood culture isolates of S. Typhi, isolated from Pondicherry, India, between January 2005 and December 2009, were investigated using phenotypic, molecular and serological methods. Of the 337 isolates, 74 (22%) were found to be multidrug resistant (MDR) and 264 (78%) nalidixic acid resistant (NAR). Isolates with reduced susceptibility to ciprofloxacin possessed single mutations in the gyrA gene. A high rate of resistance (8%) was found to ciprofloxacin. All isolates with a ciprofloxacin MIC ≥ 4 mg/L possessed both double mutations in the QRDR of the gyrA gene and a single mutation in the parC gene. Active efflux pump mechanisms were also found to be involved in ciprofloxacin resistance. Finally, a large number of PFGE patterns (non-clonal genotypes) were observed among the S. Typhi isolates. In conclusion, a high rate of ciprofloxacin resistance was observed in comparison to other endemic areas in blood culture isolates of S. Typhi from Pondicherry, India, with steadily increasing NAR but decreasing MDR isolations over the study period. This is most likely to be due to an increased use of ciprofloxacin as a first-line drug of choice over more traditional antimicrobial agents for the treatment of typhoid fever.


A Micro-Polyethylene Glycol Precipitation Assay as a Relative Solubility Screening Tool for Monoclonal Antibody Design and Formulation Development.
Adequate protein solubility is an important prerequisite for development, manufacture, and administration of biotherapeutic drug candidates, especially for high-concentration protein formulations. A previously established method for determining the relative apparent solubility (thermodynamic activity) of proteins using polyethylene glycol (PEG) precipitation is adapted for screening and comparing monoclonal antibody (mAb) candidates where only limited quantities (≤1 mg) are available. This micro-PEG assay is used to evaluate various broadly neutralizing mAb candidates to HIV-1 viral spike (gp120 and gp41 glycoproteins). Using ∼1 mg of VRC01-WT mAb per assay, the precision of the micro-PEG assay was established. A series of 7 different broadly neutralizing mAbs to the HIV-1 viral spike proteins were compared by curve shape (%PEG vs. protein concentration), %PEGmidpoint determinations, and extrapolated apparent solubility values. Numerous formulation conditions were then evaluated for their relative effects on the VRC01-WT mAb. The PEGmidpt and apparent solubility values of VRC01-WT mAb decreased as the solution pH increased and increased as NaCl and arginine were added. A final optimization of the micro-PEG assay established that amounts as low as 0.1-0.2 mg can be used. Thus, the micro-PEG assay has significant potential as a relative solubility screening tool during candidate selection and early formulation development.


beta-Synuclein inhibits alpha-synuclein aggregation: a possible role as an anti-parkinsonian factor.
We characterized beta-synuclein, the non-amyloidogenic homolog of alpha-synuclein, as an inhibitor of aggregation of alpha-synuclein, a molecule implicated in Parkinson's disease. For this, doubly transgenic mice expressing human (h) alpha- and beta-synuclein were generated. In doubly transgenic mice, beta-synuclein ameliorated motor deficits, neurodegenerative alterations, and neuronal alpha-synuclein accumulation seen in halpha-synuclein transgenic mice. Similarly, cell lines transfected with beta-synuclein were resistant to alpha-synuclein accumulation. halpha-synuclein was coimmunoprecipitated with hbeta-synuclein in the brains of doubly transgenic mice and in the double-transfected cell lines. Our results raise the possibility that beta-synuclein might be a natural negative regulator of alpha-synuclein aggregation and that a similar class of endogenous factors might regulate the aggregation state of other molecules involved in neurodegeneration. Such an anti-amyloidogenic property of beta-synuclein might also provide a novel strategy for the treatment of neurodegenerative disorders.


Am I who I say I am? Unobtrusive self-representation and personality recognition on Facebook.
Across social media platforms users (sub)consciously represent themselves in a way which is appropriate for their intended audience. This has unknown impacts on studies with unobtrusive designs based on digital (social) platforms, and studies of contemporary social phenomena in online settings. A lack of appropriate methods to identify, control for, and mitigate the effects of self-representation, the propensity to express socially responding characteristics or self-censorship in digital settings, hinders the ability of researchers to confidently interpret and generalize their findings. This article proposes applying boosted regression modelling to fill this research gap. A case study of paid Amazon Mechanical Turk workers (n = 509) is presented where workers completed psychometric surveys and provided anonymized access to their Facebook timelines. Our research finds indicators of self-representation on Facebook, facilitating suggestions for its mitigation. We validate the use of LIWC for Facebook personality studies, as well as find discrepancies with extant literature about the use of LIWC-only approaches in unobtrusive designs. Using survey data and LIWC sentiment categories as predictors, the boosted regression model classified the Five Factor personality model with an average accuracy of 74.6%. The contribution of this work is an accurate prediction of psychometric information based on short, informal text.


Dendrimer pharmacokinetics: the effect of size, structure and surface characteristics on ADME properties.
Dendrimers show increasing promise as drug-delivery vectors and can be generated with a wide range of scaffold structures, sizes and surface functionalities. To this point, the majority of studies of dendrimer-based drug-delivery systems have detailed pharmacodynamic outcomes, or have followed the pharmacokinetics of a solubilized or conjugated drug. By contrast, detailed commentary on the in vivo fate of the dendrimer carrier is less evident, even though the pharmacokinetics of the carrier will likely dictate both pharmacodynamic and toxicokinetic outcomes. In the current article, the influence of size, structure and surface functionality on the absorption, distribution, metabolism and elimination (ADME) properties of dendrimers have been examined and the implications of these findings for delivery system design are discussed.


Desmosomal glycoproteins 2 and 3 (desmocollins) show N-terminal similarity to calcium-dependent cell-cell adhesion molecules.
The N-terminal sequence of a mixture of desmosomal glycoproteins 2 and 3 (dg2/3, desmocollins) from bovine nasal epidermis, prepared by electro-elution from polyacrylamide gels, was determined by solid-phase Edman degradation. A sequence of 23 amino acids was obtained. This showed 43% identity with that of the N terminus of the calcium-dependent cell adhesion molecule, N-cadherin. A lesser degree of identity with other members of the cadherin-uvomorulin-L-CAM family was also found. In order to confirm that the sequence was derived from the dg2/3 molecules a rabbit antiserum was raised against a synthetic peptide corresponding to the sequence, conjugated to keyhole limpet haemocyanin (KLH). The antiserum obtained showed high (titre) activity against both the peptide and KLH in ELISA. Each activity could be specifically adsorbed with the appropriate ligand. The antiserum reacted specifically with both dg2 and dg3 of bovine nasal epidermis on immunoblots, this binding was blocked by the N-terminal peptide but was unaffected by KLH. The identity of dg2 and -3 in these preparations was confirmed by immunoblotting with two monoclonal antibodies and one polyclonal antiserum raised against the whole molecules. The N-terminal peptide antiserum was shown to bind to the intercellular space of desmosome profiles by immunoelectron microscopy on ultra-thin frozen sections. One of the two monoclonal antibodies (07-4D) also reacted with the desmosomal intercellular space. dg2 and -3 were shown by Staphylococcus aureus V8 protease digestion to have identical one-dimensional peptide maps. Both the N-terminal antiserum and 07-4D reacted with a V8 fragment of 19,000 Mr derived from dg2 and dg3.(ABSTRACT TRUNCATED AT 250 WORDS)


Functional opioid activity variates according to the different fashion of alcohol abuse.
Two groups of alcohol addicts (total of 14 subjects), were submitted to Traditional Manual Acupuncture and pituitary hormone plasma levels, including B-Endorphin (B-EP), were measured in basal condition and after 1, 5, 20 and 60 minutes from needle withdrawal. Group A patients had a polarity towards negative affective tone presenting signs of dysphoria while group B was composed of the so-called "social drinkers". No difference existed in basal hormonal values, except slightly elevated plasma B-EP levels in group A. No significant responses to TMA were recorded in plasma ACTH, Cortisol, Prolactin or GH levels in groups A and B. Social drinkers showed an increase of B-EP plasma levels in response to TMA (128 +/- 62.1%, mean +/- SD) which on the contrary was absent in dysphoric alcoholics (2.8 +/- 38.6%, p less than 0.01). The same was true for B-Lipotropin plasma levels. These preliminary results suggest that different fashions of alcohol abuse may be associated with different reactivity of the endogenous opioid system.


Pocket-sized device for measuring forced expiratory volume in one second and forced vital capacity.
An inexpensive pocket-sized instrument--the turbine spirometer--has been developed that measures and gives a direct digital display of the forced expiratory volume in one second and forced vital capacity. The instrument is as accurate as and considerably cheaper than spirometers in general use. Condensation does not affect the calibration. The turbine spirometer will enable spirometry to be easily monitored in hospital wards and general practice and by patients at home.


Altered gene expression in cerulein-stimulated pancreatic acinar cells: pathologic mechanism of acute pancreatitis.
Acute pancreatitis is a multifactorial disease associated with the premature activation of digestive enzymes. The genes expressed in pancreatic acinar cells determine the severity of the disease. The present study determined the differentially expressed genes in pancreatic acinar cells treated with cerulein as an in vitro model of acute pancreatitis. Pancreatic acinar AR42J cells were stimulated with 10(-8) M cerulein for 4 h, and genes with altered expression were identified using a cDNA microarray for 4,000 rat genes and validated by real-time PCR. These genes showed a 2.5-fold or higher increase with cerulein: lithostatin, guanylate cyclase, myosin light chain kinase 2, cathepsin C, progestin-induced protein, and pancreatic trypsin 2. Stathin 1 and ribosomal protein S13 showed a 2.5-fold or higher decreases in expression. Real-time PCR analysis showed time-dependent alterations of these genes. Using commercially available antibodies specific for guanylate cyclase, myosin light chain kinase 2, and cathepsin C, a time-dependent increase in these proteins were observed by Western blotting. Thus, disturbances in proliferation, differentiation, cytoskeleton arrangement, enzyme activity, and secretion may be underlying mechanisms of acute pancreatitis.


The Association of Diurnal Blood Glucose Variability With Subclinical Cardiac Disease in Patients With Type 2 Diabetes Mellitus.
The relationship between glycemic control and the risk of cardiac disease in patients with Type 2 Diabetes Mellitus (T2DM) is controversial. 1,5-Anhydroglucitol (1,5-AG) is a biomarker of Glucose Variability (GV) and has been associated with clinical cardiovascular disease. However, its association with Subclinical Cardiac Disease (SCD) is unknown. Study the association between GV and SCD. A cross-sectional study was conducted on 46 asymptomatic patients with T2DM as T2DM individuals group. Another 46 non-diabetic age and sex matched subjects were included as the healthy group. 1,5-AG was measured for all subjects. M-mode echocardiography in parasternal long axis view was used to measure Left Ventricular (LV) end diastolic dimension, LV end systolic dimension, ejection fraction, interventricular septum, LV posterior wall thickness, LV fractional shortening, left atrial dimension and aortic root dimension. Global Longitudinal Strain (GLS) was assessed by speckled tracking echocardiography. There were no significant differences between both groups as regarding age, sex, BMI, AST, ALT, and serum creatinine. 1,5-AG was lower in T2DM individuals group. As regarding the echo parameters no significant difference found between both groups regarding left ventricular, left atrial and aortic root dimensions. T2DM individuals group showed a statistically significant higher mitral valve area, apical 2 chambers, apical 4 chambers, apical longitudinal axis and GLS. No correlation found between HbA1c and any echo parameters while 1,5-AG showed a significantly negative correlation with apical 2 chambers, apical 4 chambers, apical longitudinal axis and GLS. ROC curve analysis detected 1,5-AG less than 7.51 ng/ml as the best cut off value with sensitivity of 85.7%, specificity 75% to diagnose patients with T2DM and SCD. 1,5-AG might be used as an additional surrogate marker to identify patients with T2DM and SCD.


The design of venous thromboembolism prophylaxis trials: fondaparinux is definitely more effective than enoxaparin in orthopaedic surgery.
The fondaparinux trials in venous thromboembolism (VTE) prevention after orthopaedic surgery have been subject to methodological criticisms recently summarised in this journal. These criticisms merit comments and corrections. Fondaparinux reduced the risk of VTE and of proximal deep-vein thrombosis by more than 55% compared with enoxaparin, based on the efficacy endpoint that supported the registration and use of low-molecular-weight heparins (LMWH) in all their prophylactic indications, an endpoint endorsed by international consensus statements and health authorities. Fondaparinux is the only antithrombotic agent that significantly reduced the rate of symptomatic VTE in a single orthopaedic surgery trial that was powered to detect this effect. In contrast to the paucity of data available on LMWH, the relationship between the timing of first administration and efficacy and safety has been well documented for fondaparinux. Fondaparinux used according to its approved regimen provides a simple, easy-to-use, effective and safe post-operative regimen for all orthopaedic surgery patients.


Invited review: Nitrogen in ruminant nutrition: A review of measurement techniques.
Nitrogen is a component of essential nutrients critical for the productivity of ruminants. If excreted in excess, N is also an important environmental pollutant contributing to acid deposition, eutrophication, human respiratory problems, and climate change. The complex microbial metabolic activity in the rumen and the effect on subsequent processes in the intestines and body tissues make the study of N metabolism in ruminants challenging compared with nonruminants. Therefore, using accurate and precise measurement techniques is imperative for obtaining reliable experimental results on N utilization by ruminants and evaluating the environmental impacts of N emission mitigation techniques. Changeover design experiments are as suitable as continuous ones for studying protein metabolism in ruminant animals, except when changes in body weight or carryover effects due to treatment are expected. Adaptation following a dietary change should be allowed for at least 2 (preferably 3) wk, and extended adaptation periods may be required if body pools can temporarily supply the nutrients studied. Dietary protein degradability in the rumen and intestines are feed characteristics determining the primary AA available to the host animal. They can be estimated using in situ, in vitro, or in vivo techniques with each having inherent advantages and disadvantages. Accurate, precise, and inexpensive laboratory assays for feed protein availability are still needed. Techniques used for direct determination of rumen microbial protein synthesis are laborious and expensive, and data variability can be unacceptably large; indirect approaches have not shown the level of accuracy required for widespread adoption. Techniques for studying postruminal digestion and absorption of nitrogenous compounds, urea recycling, and mammary AA metabolism are also laborious, expensive (especially the methods that use isotopes), and results can be variable, especially the methods based on measurements of digesta or blood flow. Volatile loss of N from feces and particularly urine can be substantial during collection, processing, and analysis of excreta, compromising the accuracy of measurements of total-tract N digestion and body N balance. In studying ruminant N metabolism, nutritionists should consider the longer term fate of manure N as well. Various techniques used to determine the effects of animal nutrition on total N, ammonia- or nitrous oxide-emitting potentials, as well as plant fertilizer value, of manure are available. Overall, methods to study ruminant N metabolism have been developed over 150 yr of animal nutrition research, but many of them are laborious and impractical for application on a large number of animals. The increasing environmental concerns associated with livestock production systems necessitate more accurate and reliable methods to determine manure N emissions in the context of feed composition and ruminant N metabolism.


Twist1 Is a TNF-Inducible Inhibitor of Clock Mediated Activation of Period Genes.
Activation of the immune system affects the circadian clock. Tumor necrosis factor (TNF) and Interleukin (IL)-1β inhibit the expression of clock genes including Period (Per) genes and the PAR-bZip clock-controlled gene D-site albumin promoter-binding protein (Dbp). These effects are due to cytokine-induced interference of E-box mediated transcription of clock genes. In the present study we have assessed the two E-box binding transcriptional regulators Twist1 and Twist2 for their role in cytokine induced inhibition of clock genes. The expression of the clock genes Per1, Per2, Per3 and of Dbp was assessed in NIH-3T3 mouse fibroblasts and the mouse hippocampal neuronal cell line HT22. Cells were treated for 4h with TNF and IL-1β. The functional role of Twist1 and Twist2 was assessed by siRNAs against the Twist genes and by overexpression of TWIST proteins. In luciferase (luc) assays NIH-3T3 cells were transfected with reporter gene constructs, which contain a 3xPer1 E-box or a Dbp E-box. Quantitative chromatin immunoprecipitation (ChIP) was performed using antibodies to TWIST1 and CLOCK, and the E-box consensus sequences of Dbp (CATGTG) and Per1 E-box (CACGTG). We report here that siRNA against Twist1 protects NIH-3T3 cells and HT22 cells from down-regulation of Period and Dbp by TNF and IL-1β. Overexpression of Twist1, but not of Twist2, mimics the effect of the cytokines. TNF down-regulates the activation of Per1-3xE-box-luc, the effect being prevented by siRNA against Twist1. Overexpression of Twist1, but not of Twist2, inhibits Per1-3xE-box-luc or Dbp-E-Box-luc activity. ChIP experiments show TWIST1 induction by TNF to compete with CLOCK binding to the E-box of Period genes and Dbp. Twist1 plays a pivotal role in the TNF mediated suppression of E-box dependent transactivation of Period genes and Dbp. Thereby Twist1 may provide a link between the immune system and the circadian timing system.


G-quadruplex DNA sequences are evolutionarily conserved and associated with distinct genomic features in Saccharomyces cerevisiae.
G-quadruplex DNA is a four-stranded DNA structure formed by non-Watson-Crick base pairing between stacked sets of four guanines. Many possible functions have been proposed for this structure, but its in vivo role in the cell is still largely unresolved. We carried out a genome-wide survey of the evolutionary conservation of regions with the potential to form G-quadruplex DNA structures (G4 DNA motifs) across seven yeast species. We found that G4 DNA motifs were significantly more conserved than expected by chance, and the nucleotide-level conservation patterns suggested that the motif conservation was the result of the formation of G4 DNA structures. We characterized the association of conserved and non-conserved G4 DNA motifs in Saccharomyces cerevisiae with more than 40 known genome features and gene classes. Our comprehensive, integrated evolutionary and functional analysis confirmed the previously observed associations of G4 DNA motifs with promoter regions and the rDNA, and it identified several previously unrecognized associations of G4 DNA motifs with genomic features, such as mitotic and meiotic double-strand break sites (DSBs). Conserved G4 DNA motifs maintained strong associations with promoters and the rDNA, but not with DSBs. We also performed the first analysis of G4 DNA motifs in the mitochondria, and surprisingly found a tenfold higher concentration of the motifs in the AT-rich yeast mitochondrial DNA than in nuclear DNA. The evolutionary conservation of the G4 DNA motif and its association with specific genome features supports the hypothesis that G4 DNA has in vivo functions that are under evolutionary constraint.


e-INEBRIA Special Interest Group Roadmap for Best Practices for Research on Brief Digital Interventions for Problematic Alcohol and Illicit Drug Use.
There is great potential for scaling up the delivery of brief interventions for alcohol and illicit drug use, given the increasing coverage of mobile devices and technologies for digital interventions, including apps for smartphones and tablets. However, while the number of digital interventions is increasing rapidly, the involvement of brief-intervention researchers and the development of good practices has just begun. In 2018, the Special Interest Group on digital interventions of the International Network on Brief Interventions for Alcohol & Other Drugs (e-INEBRIA SIG) initiated a conversation regarding possible avenues of future research, which subsequently became a roadmap for digital interventions. This roadmap consists of points considered relevant for future research, ongoing technological developments, and their implementation across a continuum of prevention and care. Moreover, it outlines starting points for the diversification of brief digital interventions, as well as next steps for quality improvement and implementation in public health and clinical practice. The roadmap of the e-INEBRIA SIG on digital interventions is a starting point that indicates relevant next steps and provides orientation for researchers and interested practitioners with regard to the ambiguous literature and the complexity of current digital interventions.


Freezing as a path to build complex composites.
Materials that are strong, ultralightweight, and tough are in demand for a range of applications, requiring architectures and components carefully designed from the micrometer down to the nanometer scale. Nacre, a structure found in many molluscan shells, and bone are frequently used as examples for how nature achieves this through hybrid organic-inorganic composites. Unfortunately, it has proven extremely difficult to transcribe nacre-like clever designs into synthetic materials, partly because their intricate structures need to be replicated at several length scales. We demonstrate how the physics of ice formation can be used to develop sophisticated porous and layered-hybrid materials, including artificial bone, ceramic-metal composites, and porous scaffolds for osseous tissue regeneration with strengths up to four times higher than those of materials currently used for implantation.


Early and late outcomes of 517 consecutive adult patients treated with extracorporeal membrane oxygenation for refractory postcardiotomy cardiogenic shock.
Adult postcardiotomy cardiogenic shock potentially requiring mechanical circulatory support occurs in 0.5% to 1.5% of cases. Risk factors influencing early or long-term outcome after extracorporeal membrane oxygenation implantation are not well described. Between May 1996 and May 2008, 517 adult patients received extracorporeal membrane oxygenation support for postcardiotomy cardiogenic shock. Procedures were isolated coronary artery bypass grafting (37.4%), isolated valve surgery (14.3%), coronary artery bypass grafting plus valve surgery (16.8%), thoracic organ transplantation (6.5%), and other combinations (25.0%). Fifty-four preoperative and 42 procedural risk factors concerning in-hospital mortality were evaluated by logistic regression analyses. Mean age was 63.5 years, 71.5% were male, ejection fraction was 45.9% +/- 17.6%, logistic EuroSCORE was 21.6% +/- 20.7%. Extracorporeal membrane oxygenation was established through thoracic (60.8%) or extrathoracic (39.2%) cannulation. Extracorporeal membrane oxygenation support was 3.28 +/- 2.85 days. Intra-aortic balloon pumps were implanted in 74.1%. Weaning from extracorporeal membrane oxygenation was successful for 63.3%, and 24.8% were discharged. Cerebrovascular events occurred in 17.4%, gastrointestinal complications in 18.8%, and renal replacement therapy in 65.0%. Risk factors for hospital mortality were age older than 70 years (odds ratio, 1.6), diabetes (odds ratio, 2.5), preoperative renal insufficiency (odds ratio, 2.1), obesity (odds ratio, 1.8), logistic EuroSCORE greater than 20% (odds ratio, 1.8), operative lactate greater than 4 mmol/L (odds ratio, 2.2). Isolated coronary artery bypass grafting (odds ratio, 0.44) was protective. Cumulative survivals were 17.6% after 6 months, 16.5% after 1 year, and 13.7% after 5 years. Extracorporeal membrane oxygenation support is an acceptable option for patients with postcardiotomy cardiogenic shock who otherwise would die and is justified by good long-term outcome of hospital survivors. Because of high morbidity and mortality, extracorporeal membrane oxygenation must be decided by individual risk profile.


Intravascular Polarimetry: Clinical Translation and Future Applications of Catheter-Based Polarization Sensitive Optical Frequency Domain Imaging.
Optical coherence tomography (OCT) and optical frequency domain imaging (OFDI) visualize the coronary artery wall and plaque morphology in great detail. The advent of these high-resolution intracoronary imaging modalities has propelled our understanding of coronary atherosclerosis and provided enhanced guidance for percutaneous coronary intervention. Yet, the lack of contrast between distinct tissue types and plaque compositions impedes further elucidation of the complex mechanisms that contribute to acute coronary syndrome (ACS) and hinders the prospective identification of plaques susceptible to rupture. Intravascular polarimetry with polarization-sensitive OFDI measures polarization properties of the coronary arterial wall using conventional intravascular imaging catheters. The quantitative polarization metrics display notable image contrast between several relevant coronary plaque microstructures that are difficult to identify with conventional OCT and OFDI. Tissues rich in collagen and smooth muscle cells exhibit birefringence, while lipid and macrophages cause depolarization. In this review, we describe the basic principles of intravascular polarimetry, discuss the interpretation of the polarization signatures, and outline promising avenues for future research and clinical implications.


Vagal nerve stimulation modifies neuronal activity and the proteome of excitatory synapses of amygdala/piriform cortex.
Vagal Nerve Stimulation (VNS) Therapy® is a United States Food and Drug Administration approved neurotherapeutic for medically refractory partial epilepsy and treatment-resistant depression. The molecular mechanisms underlying its beneficial effects are unclear. We hypothesized that one mechanism involves neuronal activity-dependent modifications of central nervous system excitatory synapses. To begin to test this hypothesis, we asked whether VNS modifies the activity of neurons in amygdala and hippocampus. Neuronal recordings from adult, freely moving rats revealed that activity in both amygdala and hippocampus was modified by VNS immediately after its application, and changes were detected following 1 week of stimulation. To investigate whether VNS modifies the proteome of excitatory synapses, we established a label-free, quantitative liquid chromatography-tandem mass spectrometry workflow that enables global analysis of the constituents of the postsynaptic density (PSD) proteome. PSD proteins were biochemically purified from amygdala/piriform cortex of VNS- or dummy-treated rats following 1-week stimulation, and individual PSD protein levels were quantified by liquid chromatography-tandem mass spectrometry analysis. We identified 1899 unique peptides corresponding to 425 proteins in PSD fractions, of which expression levels of 22 proteins were differentially regulated by VNS with changes greater than 150%. Changes in a subset of these proteins, including significantly increased expression of neurexin-1α, cadherin 13 and voltage-dependent calcium channel α2δ1, the primary target of the antiepileptic drug gabapentin, and decreased expression of voltage-dependent calcium channel γ3, were confirmed by western blot analysis of PSD samples. These results demonstrate that VNS modulates excitatory synapses through regulating a subset of the PSD proteome. Our study reveals molecular targets of VNS and point to possible mechanisms underlying its beneficial effects, including activity-dependent formation of excitatory synapses.


Peroxisome proliferator-activated receptor alpha target genes.
The peroxisome proliferator-activated receptor alpha (PPARα) is a ligand-activated transcription factor involved in the regulation of a variety of processes, ranging from inflammation and immunity to nutrient metabolism and energy homeostasis. PPARα serves as a molecular target for hypolipidemic fibrates drugs which bind the receptor with high affinity. Furthermore, PPARα binds and is activated by numerous fatty acids and fatty acid-derived compounds. PPARα governs biological processes by altering the expression of a large number of target genes. Accordingly, the specific role of PPARα is directly related to the biological function of its target genes. Here, we present an overview of the involvement of PPARα in lipid metabolism and other pathways through a detailed analysis of the different known or putative PPARα target genes. The emphasis is on gene regulation by PPARα in liver although many of the results likely apply to other organs and tissues as well.


Bifidobacteria exert species-specific effects on constipation in BALB/c mice.
Constipation is one of the most common gastrointestinal complaints worldwide. The aim of this study was to determine whether edible bifidobacteria (Bifidobacterium longum, B. infantis, B. animalis, B. bifidum, B. adolescentis or B. breve) exhibit interspecies differences in alleviating constipation induced by loperamide in BALB/c mice and to analyse the main reasons for the interspecies differences. BALB/c mice were given bifidobacteria by gavage once per day for 8 days. The primary outcome measures, which included related constipation indicators, and the secondary outcome measures, which included changes in the concentration of short-chain fatty acids in faeces and changes in the faecal flora, were used to evaluate the therapeutic effects of the edible bifidobacteria on constipation. The findings show that the six species of Bifidobacterium differed in their ability to relieve constipation. B. longum, B. infantis and B. bifidum were the most effective in relieving constipation, B. adolescentis and B. breve were partially effective and B. animalis was not effective. Furthermore, edible Bifidobacterium treated constipation by increasing the abundance of Lactobacillus and decreasing the abundance of Alistipes, Odoribacter and Clostridium. Higher concentrations of short-chain fatty acids were found in the faecal samples from the edible Bifidobacterium treatment groups. Meanwhile, an increased concentration of acetic acid could alleviate constipation. In conclusion, edible bifidobacteria exhibit interspecies differences in the alleviation of constipation. Meanwhile, bifidobacteria improved constipation symptoms by increasing the concentration of acetic acid and the relative abundance of Lactobacillus and reducing the content of Alistipes, Odoribacter and Clostridium.


Assessing the role of stimulus probability on the Colavita visual dominance effect.
Participants presented with unimodal auditory (A), unimodal visual (V), or bimodal audiovisual stimuli (AV) in a task in which they have to identify the modality of the targets as rapidly as possible, fail to respond to the auditory component of bimodal targets significantly more often than they fail to respond to the visual component. In the majority of published studies on this phenomenon, known as the Colavita effect, the auditory, visual, and bimodal stimuli have been presented in the ratio 40A:40V:20AV. In the present study, we investigated whether the relatively low frequency with which the bimodal targets in previous studies have been presented may have contributed to participants' difficulty in responding to such targets correctly. We manipulated the bimodal target probability by presenting the stimuli in the ratios 20A:20V:60AV, in Experiment 1; 5A:5V:90AV, 25A:25V:50AV, and 45A:45V:10AV, in Experiment 2. A significant Colavita visual dominance effect was observed when the bimodal targets were presented on 60% of the trials or less. We suggest that increasing the frequency of bimodal targets may have provided an exogenous cue to performance, that reduced the necessity for endogenous attention when selecting the appropriate response to make to bimodal targets.


Longitudinal morphological and performance profiles for American, NCAA Division I football players.
The aim of this study was to determine the changes in anthropomorphism and performance over a 4-year eligibility career of American football players. A total of 92 offensive and defensive linemen and 64 skill (wide receivers and defensive backs) player observations were included in the analysis. Data from preseason testing over a 7-year period were compiled, sorted, and analyzed by players' year in school. Assessments of strength included 1 repetition maximum bench press, squat, power clean, and a 225-lb maximum repetition muscle endurance test. Power and speed measures included vertical jump (VJ) and 40-yd (36.6-m) sprint. All strength measures improved significantly (p < 0.05) over the years of training. Skill players demonstrated a significant increase in power between years 1 and 2 but at no other time. Linemen did not demonstrate significant changes in VJ. Speed did not change significantly for either group over the 4 years of training. These data provide a theoretically predictable 4-year rate of change in anthropometric, strength, and power variables for Division I football players. By having a longitudinal assessment of expected physical improvement, it may be possible for strength training personnel to determine those who may need additional attention in an area to more closely improve as expected. Additionally, it is suggested that elite athletes may possess genetically superior attributes and therefore, when selecting athletes, particular attention should be paid to the selection of those who have previously demonstrated superior speed and power.


Rotational propulsion enabled by inertia.
The fluid mechanics of small-scale locomotion has recently attracted considerable attention, due to its importance in cell motility and the design of artificial micro-swimmers for biomedical applications. Most studies on the topic consider the ideal limit of zero Reynolds number. In this paper, we investigate a simple propulsion mechanism --an up-down asymmetric dumbbell rotating about its axis of symmetry-- unable to propel in the absence of inertia in a Newtonian fluid. Inertial forces lead to continuous propulsion for all finite values of the Reynolds number. We study computationally its propulsive characteristics as well as analytically in the small-Reynolds-number limit. We also derive the optimal dumbbell geometry. The direction of propulsion enabled by inertia is opposite to that induced by viscoelasticity.


Anatomic study of the abductor pollicis longus: a source for grafting material of the hand.
Interposition grafting material is used frequently to treat osteoarthritis of the base of the thumb or tendinous and ligamentous injuries of the hand. The observation of duplicated tendons in the first dorsal compartment of the hand prompted us to explore the possibility of using the accessory abductor pollicis longus (AAPL) tendon as grafting material. Based on dissections of 78 cadaveric upper limbs, we describe the number of tendons in the first dorsal compartment of the hand, the number of muscle bellies, their innervation, their insertion site, and the tendon dimensions to determine whether the AAPL can be considered a true tendon. The AAPL was present in 85% of the hands. Average length, width, and thickness (in millimeters) of the APL were of 69.3, 5.2, and 2.1, respectively. Average length, width, and thickness (in millimeters) of the AAPL were of 69.2, 3.3, and 1.6, respectively. No differences in dimension of the tendons were found between the APL and the AAPL. The dimensions of the tendinous portion of the AAPL are similar to those of the APL and can be considered a true tendon. When present, the AAPL is a suitable source of local grafting material.


Emerging strategies targeting CB2 cannabinoid receptor: Biased agonism and allosterism.
During these last years, the CB2 cannabinoid receptor has emerged as a potential anti-inflammatory target in diseases such as multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, ischemic stroke, autoimmune diseases, osteoporosis, and cancer. However, the development of clinically useful CB2 agonists reveals to be very challenging. Allosterism and biased-signaling mechanisms at CB2 receptor may offer new avenues for the development of improved CB2 receptor-targeted therapies. Although there has been some exploration of CB1 receptor activation by new CB1 allosteric or biased-signaling ligands, the CB2 receptor is still at initial stages in this domain. In an effort to understand the molecular basis behind these pharmacological approaches, we have analyzed and summarized the structural data reported so far at CB2 receptor.


Purification and characterization of human heart fatty acid ethyl ester synthase/carboxylesterase.
Fatty acid ethyl ester synthase metabolizes ethanol non-oxidatively in those extrahepatic organs most commonly damaged by alcohol abuse. This study was designed to purify human myocardial fatty acid ethyl ester synthase (FAEES)/carboxylesterase from human heart. The enzyme was purified to homogeneity after chromatography over DEAE-cellulose, Sephadex G-100 and hydroxylapatite. The homogenous enzyme, 62 kDa, has both synthase and carboxylesterase activities. The N-terminal amino acid sequence of the first 17 residues of the purified enzymes were 88% homologous to that of the carboxylesterase from rat liver and adipose tissue. Antibody was raised against pure synthase/carboxylesterase cross-reacted with human cytosolic and microsomal fractions. With a constant oleic acid concentration of 0.25 mM, a calculated apparent Km and Vmax for ethanol were 0.30 M and 3700 nmol/mg protein/h., respectively. With constant ethanol concentrations of 1.2 M, the activity increased with the concentration of oleic acid to 0.17 mM, plateau to 0.25 mM. Because synthase/carboxylesterase esterifies free fatty acids with ethanol to produce its esters with potentially toxic effects, it may now be feasible to establish a link between alcohol consumption and end-organ damage.


An investigation into techniques for cleaning mold-contaminated home contents.
This study examined the efficacy of the following treatments to reduce selected fungal spore and mycotoxin levels on materials commonly found in home contents: (1) gamma irradiation at a 10-13 kiloGray exposure, (2) a detergent/bleach wash, and (3) a steam cleaning technique. A minimum of six replicates were performed per treatment. Paper, cloth, wood, and carpet were inoculated with either fungal spores (Stachybotrys chartarum, Aspergillus niger, Penicillium chrysogenum, or Chaetomium globosum) at 240,000 spores/2.54 cm2 of material or with the mycotoxins roridin A, T-2, and verrucarin A at 10 microg per 2.54 cm2 of material. Treatments were evaluated with an agar plating technique for fungal spores and a yeast toxicity culture assay for mycotoxins. Results showed that gamma irradiation inactivated fungal spores, but the treatment was not successful in inactivating mycotoxins. The washing technique completely inactivated or removed spores on all materials except for C. globosum, which was reduced on all items except paper (p < 0.05). Washing inactivated all mycotoxins on paper and cloth but not on carpet or untreated wood (p < 0.001). The steam cleaning treatment did not completely eliminate any fungal spores; however, it reduced P. chrysogenum numbers on all materials, C. globosum was reduced on wood and carpet, and S. chartarum was reduced on wood (p < 0.05). Steam cleaning was unsuccessful in inactivating any of the tested mycotoxins. These results show that the bleach/detergent washing technique was more effective overall in reducing spore and mycotoxin levels than gamma irradiation or steam cleaning. However, the other examined techniques were successful in varying degrees.


Evidence for the role of nitric oxide in macula densa control of glomerular hemodynamics.
There is evidence that nitric oxide, an endothelium-derived relaxing factor, may be produced by the macula densa, as well as by blood vessels, within the kidney. To examine the role of nitric oxide in macula densa control of glomerular hemodynamics directly, we performed in vitro microperfusions of both rabbit afferent arterioles (with the glomerulus intact) and adherent tubular segments consisting of portions of the thick ascending limb, macula densa, and early distal tubule. While keeping afferent arteriolar pressure constant at 60 mmHg, we examined the effect of Nw-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthesis, added to a macula densa perfusate. When the macula densa perfusate was changed from low to high NaCl, the diameter of the arterioles decreased from 16.3 +/- 1.0 to 14.0 +/- 1.1 microns (n = 10; P < 0.001). Addition of 10(-5) M L-NAME to the high NaCl solution further decreased the diameter to 11.9 +/- 1.1 microns (P < 0.001). In contrast, when macula densa perfusion was maintained with the low NaCl solution, addition of L-NAME had no effect. L-NAME-induced constriction was completely reversed by adding 10(-3) M L-arginine (the precursor of nitric oxide) but not D-arginine (an inactive isomer) to the macula densa perfusate. We confirmed that perfusing the macula densa with L-NAME did not affect the vasodilator action of acetylcholine added to the lumen of the afferent arteriole, indicating that NO synthesis by the arteriole was not altered. Thus, our findings suggest that the macula densa may produce nitric oxide, which in turn modulates the afferent arteriolar constriction induced by high concentrations of NaCl at the macula densa.


Evaluating environmental tobacco smoke exposure in a group of Turkish primary school students and developing intervention methods for prevention.
In countries like Turkey where smoking is highly prevalent, children's exposure to tobacco smoke is an important public health problem. The goals of this study were to determine the self-reported environmental tobacco smoke exposure status of primary school students in grades 3 to 5, to verify self-reported exposure levels with data provided from a biomarker of exposure, and to develop methods for preventing school children from passive smoking. The study was conducted on 347 primary school students by using a standard questionnaire and urinary cotinine tests. Children with verified ETS exposure were randomly assigned to 2 intervention groups. Two phone interviews were conducted with the parents of the first group regarding their children's passive smoking status and its possible consequences. On the other hand, a brief note concerning urinary cotinine test result was sent to parents of the second group. Nine months after the initial urinary cotinine tests, measurements were repeated in both groups. According to questionnaire data, 59.9% of the study group (208 of 347) were exposed to ETS. Urinary cotinine measurements of children were highly consistent with the self-reported exposure levels (P < 0.001). Two different intervention methods were applied to parents of the exposed children. Control tests suggested a remarkable reduction in the proportion of those children demonstrating a recent exposure to ETS in both groups. Proportions of children with urinary cotinine concentrations 10 ng/ml or lower were 79.5% in Group I and 74.2% in Group II (P > 0.05). Self-reported ETS exposure was found to be pretty accurate in the 9-11 age group when checked with urinary cotinine tests. Only informing parents that their children' ETS exposure were confirmed by a laboratory test seems to be very promising in preventing children from ETS.


Symptomatic "isolated" carotid sinus hypersensitivity: natural history and results of treatment with anticholinergic drugs or pacemaker.
Because syncope may occur intermittently in patients with carotid sinus hypersensitivity, a knowledge of its natural history is needed as a basis for interpreting the usefulness of therapy. Fifty-six consecutive patients are described (47 men and 9 women; mean age 61 years) with carotid sinus hypersensitivity and syncope in whom 24 hour ambulatory monitoring and intracardiac electrophysiologic study revealed no other cause for the syncope. The mean duration of symptoms was 44 months (range 1 to 480) and the mean number of episodes was 4.0 (range 1 to 20). During a follow-up period of 6 to 120 months (median 40), syncope recurred in 3 of 13 patients who received no treatment, in 2 of 23 patients who received a pacemaker and in 4 of 20 patients who received anticholinergic drugs (incidences corrected for totals available at follow-up: 27, 9 and 22%, respectively). Two-thirds of the patients receiving no treatment were asymptomatic compared with all nine of the patients with syncope and a pure cardioinhibitory response to carotid sinus massage who received an atrioventricular (AV) sequential pacemaker. Although pacing was effective in abolishing syncope, its use should be reserved for recurrent episodes because of the high rate of spontaneous remission of symptoms.


A case of neonate effectively treated with everolimus for giant hepatic hemangioma complicated with congenital duodenal atresia and Kasabach-Merritt syndrome.
Disseminated intravascular coagulation (DIC) with Kasabach-Merrit syndrome from a large hepatic hemangioma is life-threatening. We report a case of giant hepatic hemangioma of the newborn with KMS. The patient was born at 37 gestational weeks and 2 days via cesarean section; weight at birth was 2952 g. Congenital duodenal atresia was noted during the fetal period. DIC developed after delivery and a giant liver hemangioma was diagnosed via abdominal CT. The cause of DIC was Kasabach-Merritt syndrome owing to a giant hepatic hemangioma. First, combination therapy of 2 mg/kg/day of prednisolone and 0.2 mg/kg/day of propranolol was initiated form enterostomy. However, the size of the hepatic hemangioma did not alter, as observed via image evaluation. Therefore, 0.3 mg/kg/day of everolimus was administered frorm enterostomy. Subsequently, the size of the hepatic hemangioma was assessed via image evaluation. Although it did not alter, blood flow to the hepatic hemangioma decreased and thrombocytopenia was also suppressed. We performed hepatic lateral segmentectomy, radical operation for duodenal atresia. The pathological diagnosis of the removed tumor was infantile hemangioma. We report everolimus may be useful when PSL and propranolol are ineffective.


IFN-γ and TNF-α drive a CXCL10+ CCL2+ macrophage phenotype expanded in severe COVID-19 lungs and inflammatory diseases with tissue inflammation.
Immunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. Understanding the immune cell states shared between COVID-19 and other inflammatory diseases with established therapies may help nominate immunomodulatory therapies. To identify cellular phenotypes that may be shared across tissues affected by disparate inflammatory diseases, we developed a meta-analysis and integration pipeline that models and removes the effects of technology, tissue of origin, and donor that confound cell-type identification. Using this approach, we integrated > 300,000 single-cell transcriptomic profiles from COVID-19-affected lungs and tissues from healthy subjects and patients with five inflammatory diseases: rheumatoid arthritis (RA), Crohn's disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE), and interstitial lung disease. We tested the association of shared immune states with severe/inflamed status compared to healthy control using mixed-effects modeling. To define environmental factors within these tissues that shape shared macrophage phenotypes, we stimulated human blood-derived macrophages with defined combinations of inflammatory factors, emphasizing in particular antiviral interferons IFN-beta (IFN-β) and IFN-gamma (IFN-γ), and pro-inflammatory cytokines such as TNF. We built an immune cell reference consisting of > 300,000 single-cell profiles from 125 healthy or disease-affected donors from COVID-19 and five inflammatory diseases. We observed a CXCL10+ CCL2+ inflammatory macrophage state that is shared and strikingly abundant in severe COVID-19 bronchoalveolar lavage samples, inflamed RA synovium, inflamed CD ileum, and UC colon. These cells exhibited a distinct arrangement of pro-inflammatory and interferon response genes, including elevated levels of CXCL10, CXCL9, CCL2, CCL3, GBP1, STAT1, and IL1B. Further, we found this macrophage phenotype is induced upon co-stimulation by IFN-γ and TNF-α. Our integrative analysis identified immune cell states shared across inflamed tissues affected by inflammatory diseases and COVID-19. Our study supports a key role for IFN-γ together with TNF-α in driving an abundant inflammatory macrophage phenotype in severe COVID-19-affected lungs, as well as inflamed RA synovium, CD ileum, and UC colon, which may be targeted by existing immunomodulatory therapies.


Caspase-3 activation in astrocytes following postnatal excitotoxic damage correlates with cytoskeletal remodeling but not with cell death or proliferation.
Caspase-3 has classically been defined as the main executioner of programmed cell death. However, recent data supports the participation of this protease in non-apoptotic cellular events including cell proliferation, cell cycle regulation, and cellular differentiation. In this study, astroglial cleavage of caspase-3 was analyzed following excitotoxic damage in postnatal rats to determine if its presence is associated with apoptotic cell death, cell proliferation, or cytoskeletal remodeling. A well-characterized in vivo model of excitotoxicity was studied, where damage was induced by intracortical injection of N-methyl-D-asparate (NMDA) in postnatal day 9 rats. Our results demonstrate that cleaved caspase-3 was mainly observed in the nucleus of activated astrocytes in the lesioned hemisphere as early as 4 h postlesion and persisted until the glial scar was formed at 7-14 days, and it was not associated with TUNEL labeling. Caspase-3 enzymatic activity was detected at 10 h and 1 day postlesion in astrocytes, and co-localized with caspase-cleaved fragments of glial fibrillary acidic protein (CCP-GFAP). However, at longer survival times, when astroglial hypertrophy was observed, astroglial caspase-3 did not generally correlate with GFAP cleavage, but instead was associated with de novo expression of vimentin. Moreover, astroglial caspase-3 cleavage was not associated with BrdU incorporation. These results provide further evidence for a nontraditional role of caspases in cellular function that is independent of cell death and suggest that caspase activation is important for astroglial cytoskeleton remodeling following cellular injury.


Regression models for twin studies: a critical review.
Twin studies have long been recognized for their value in learning about the aetiology of disease and specifically for their potential for separating genetic effects from environmental effects. The recent upsurge of interest in life-course epidemiology and the study of developmental influences on later health has provided a new impetus to study twins as a source of unique insights. Twins are of special interest because they provide naturally matched pairs where the confounding effects of a large number of potentially causal factors (such as maternal nutrition or gestation length) may be removed by comparisons between twins who share them. The traditional tool of epidemiological 'risk factor analysis' is the regression model, but it is not straightforward to transfer standard regression methods to twin data, because the analysis needs to reflect the paired structure of the data, which induces correlation between twins. This paper reviews the use of more specialized regression methods for twin data, based on generalized least squares or linear mixed models, and explains the relationship between these methods and the commonly used approach of analysing within-twin-pair difference values. Methods and issues of interpretation are illustrated using an example from a recent study of the association between birth weight and cord blood erythropoietin. We focus on the analysis of continuous outcome measures but review additional complexities that arise with binary outcomes. We recommend the use of a general model that includes separate regression coefficients for within-twin-pair and between-pair effects, and provide guidelines for the interpretation of estimates obtained under this model.


Variation at presentation among colon cancer patients with metastases: a population-based study.
The study aimed to describe and follow a 2 year cohort of colon cancer patients with Stage IV disease from presentation to long-term outcome. The records of 177 colon cancer patients diagnosed in southeast Sweden during 2009-2010 with disseminated disease at presentation were reviewed retrospectively. The patients were heterogeneous with respect to age, performance status and survival. Despite metastatic disease, local symptoms from the primary tumour dominated the initial clinical picture. Forty-one per cent had anaemia. The time from suspicion of colon cancer to established diagnosis of disseminated disease varied from 0 to 231 days (emergency cases included, median 12 days). The majority (77%) were diagnosed in hospital. In 53% the primary tumour and the metastases were not diagnosed on the same occasion which may increase the risk for misinformation or delays in the care process. The possibility of simultaneous diagnosis was doubled when the patient was investigated as an inpatient. Patients were seen by one to 12 physicians (median three) in the investigation phase, and one to 47 (median 11) from diagnosis until the last record in the hospital notes. The 1-year survival was 46%. Patients with metastatic colon cancer at presentation are heterogeneous and warrant an adapted multidisciplinary approach to achieve the goal of individualized treatment for each patient in accordance with the Swedish national cancer strategy.


Holographic motion picture by Eu(3+):Y(2)SiO(5).
Real-time recording of a moving object was made with persistent spectral hole burning of a cryogenic Eu(3+):Y(2)SiO(5) crystal. In a basic holographic configuration the ultrastable laser frequency was continuously scanned within the (7)F(0)-(5)D(0) absorption line (typically 200 MHz in 20 s) while the object was in motion, thus permitting the storage and reconstruction of the moving image. The success of this motion picture is attributable to (1) the kilohertz-wide hole width, (2) the quasi-persistent hole lifetime, and (3) the high hole-burning quantum efficiency of this material.


Training with blood flow restriction. Mechanisms, gain in strength and safety.
Blood flow restriction training has proven to be effective, but it is not well known and is limited by initially producing discomfort. Blood flow restriction (BFR) induces hypoxia and metabolic effects, as well as reduction of proteolysis and induction of anabolic processes. Growth hormone levels are regularly increased. Controversies exist concerning neuromuscular effects. Twenty-eight of 30 studies, showed an increase in strength usually associated with muscle hypertrophy in both men and women, although data for women are sparse. Initial reports exist on positive effects on bone health after measuring rises in bone markers. A gain in strength has also been reported in non-occluded muscles after BFR training. BFR without training can lead to a rise in strength and reduce atrophy in knee extensor muscles during immobilisation. Controversial results have been observed concerning changes in aerobic capacity. Up to now no standard BFR training guidelines exist. Occlusion pressure, intensity of training, number of sets and duration of a training unit remain unclear. Presently, an occlusion pressure of 150 mmHg may be recommended with an intensity of 20 % 1-repetition maximum (1 RM), and wider cuffs are more efficient than narrow ones. Between training sets BFR should be continued. Rheologic investigations after BFR have shown no evidence for increased risk of thrombosis, when studying possible contraindications. Safety aspects for older patients must be more thoroughly addressed. The low-intensity needed may establish this training method in cardiac and pulmonary patients after future research.


Admission of nursing home patients to geriatric medical wards.
Comparison was made between patients admitted from a nursing home and all other patients admitted to a geriatric medical unit in 1990 and 1993. The number of nursing home patient admissions rose from 26 in 1990 to 106 in 1993. Nursing home patients were frailer both physically and mentally with a dementia rate of 78% (in those who survived, 1993) and a mortality rate of 19.8% (1993), compared with a dementia rate of 19% and a mortality rate of 11.3% in all other admissions in 1993. Male patients admitted from a nursing home were more likely to die than females (33% versus 14.5%, 1993). Lengths of stay of nursing home patients were shorter, largely due to the availability of a 'safe environment' when discharged, but also related to shorter survival times. 61% of patient admissions from nursing homes in 1993 were considered 'unnecessary' and could have been avoided if specialist advice had been available before admission.


iTools: a framework for classification, categorization and integration of computational biology resources.
The advancement of the computational biology field hinges on progress in three fundamental directions--the development of new computational algorithms, the availability of informatics resource management infrastructures and the capability of tools to interoperate and synergize. There is an explosion in algorithms and tools for computational biology, which makes it difficult for biologists to find, compare and integrate such resources. We describe a new infrastructure, iTools, for managing the query, traversal and comparison of diverse computational biology resources. Specifically, iTools stores information about three types of resources--data, software tools and web-services. The iTools design, implementation and resource meta-data content reflect the broad research, computational, applied and scientific expertise available at the seven National Centers for Biomedical Computing. iTools provides a system for classification, categorization and integration of different computational biology resources across space-and-time scales, biomedical problems, computational infrastructures and mathematical foundations. A large number of resources are already iTools-accessible to the community and this infrastructure is rapidly growing. iTools includes human and machine interfaces to its resource meta-data repository. Investigators or computer programs may utilize these interfaces to search, compare, expand, revise and mine meta-data descriptions of existent computational biology resources. We propose two ways to browse and display the iTools dynamic collection of resources. The first one is based on an ontology of computational biology resources, and the second one is derived from hyperbolic projections of manifolds or complex structures onto planar discs. iTools is an open source project both in terms of the source code development as well as its meta-data content. iTools employs a decentralized, portable, scalable and lightweight framework for long-term resource management. We demonstrate several applications of iTools as a framework for integrated bioinformatics. iTools and the complete details about its specifications, usage and interfaces are available at the iTools web page http://iTools.ccb.ucla.edu.


Effects of system inaccuracies on the probability of bit error for pulsed communication systems.
Digital communication systems using the narrow pulses generated by a mode-locked laser are extremely efficient in their use of average laser power. However, these narrow pulses require precise system timing and decision intervals matched to the pulse width. This paper extends previous work by Gagliardi in this area to consider the effects of pulse timing errors and pulse width mismatch on the probability of bit error for on-off keying, binary pulse position modulation, and quarternary pulse position modulation formats. The general expressions are derived, and a number of examples are plotted.


Garnet-type solid-state fast Li ion conductors for Li batteries: critical review.
Batteries are electrochemical devices that store electrical energy in the form of chemical energy. Among known batteries, Li ion batteries (LiBs) provide the highest gravimetric and volumetric energy densities, making them ideal candidates for use in portable electronics and plug-in hybrid and electric vehicles. Conventional LiBs use an organic polymer electrolyte, which exhibits several safety issues including leakage, poor chemical stability and flammability. The use of a solid-state (ceramic) electrolyte to produce all-solid-state LiBs can overcome all of the above issues. Also, solid-state Li batteries can operate at high voltage, thus, producing high power density. Various types of solid Li-ion electrolytes have been reported; this review is focused on the most promising solid Li-ion electrolytes based on garnet-type metal oxides. The first studied Li-stuffed garnet-type compounds are Li5La3M2O12 (M = Nb, Ta), which show a Li-ion conductivity of ∼10(-6) at 25 °C. La and M sites can be substituted by various metal ions leading to Li-rich garnet-type electrolytes, such as Li6ALa2M2O12, (A = Mg, Ca, Sr, Ba, Sr0.5Ba0.5) and Li7La3C2O12 (C = Zr, Sn). Among the known Li-stuffed garnets, Li6.4La3Zr1.4Ta0.6O12 exhibits the highest bulk Li-ion conductivity of 10(-3) S cm(-1) at 25 °C with an activation energy of 0.35 eV, which is an order of magnitude lower than that of the currently used polymer, but is chemically stable at higher temperatures and voltages compared to polymer electrolytes. Here, we discuss the chemical composition-structure-ionic conductivity relationship of the Li-stuffed garnet-type oxides, as well as the Li ion conduction mechanism.


Media use and child sleep: the impact of content, timing, and environment.
Media use has been shown to negatively affect a child's sleep, especially in the context of evening use or with a television in the child's bedroom. However, little is known about how content choices and adult co-use affect this relationship. To describe the impact of media content, timing, and use behaviors on child sleep. These data were collected in the baseline survey and media diary of a randomized controlled trial on media use in children aged 3 to 5 years. Sleep measures were derived from the Children's Sleep Habits Questionnaire. Media diaries captured time, content title, and co-use of television, video-game, and computer usage; titles were coded for ratings, violence, scariness, and pacing. Nested linear regression models were built to examine the impact of timing, content, and co-use on the sleep problem score. On average, children consumed 72.9 minutes of media screen time daily, with 14.1 minutes occurring after 7:00 pm. Eighteen percent of parents reported at least 1 sleep problem; children with a bedroom television consumed more media and were more likely to have a sleep problem. In regression models, each additional hour of evening media use was associated with a significant increase in the sleep problem score (0.743 [95% confidence interval: 0.373-1.114]), as was daytime use with violent content (0.398 [95% confidence interval: 0.121-0.676]). There was a trend toward greater impact of daytime violent use in the context of a bedroom television (P=.098) and in low-income children (P=.07). Violent content and evening media use were associated with increased sleep problems. However, no such effects were observed with nonviolent daytime media use.


Method to produce American Thoracic Society flow-time waveforms using a mechanical pump.
The American Thoracic Society (ATS) recently adopted a new set of 26 standard flow-time waveforms for use in testing both diagnostic and monitoring devices. Some of these waveforms have a higher frequency content than present in the ATS-24 standard volume-time waveforms, which, when produced by a mechanical pump, may result in a pump flow output that is less than the desired flow due to gas compression losses within the pump. To investigate the effects of gas compression, a mechanical pump was used to generate the necessary flows to test mini-Wright and Assess peak expiratory flow (PEF) meters. Flow output from the pump was measured by two different independent methods, a pneumotachometer and a method based on piston displacement and pressure measured within the pump. Measuring output flow based on piston displacement and pressure has been validated using a pneumotachometer and mini-Wright PEF meter, and found to accurately measure pump output. This method introduces less resistance (lower back-pressure) and dead space volume than using a pneumotachometer in series with the meter under test. Pump output flow was found to be lower than the desired flow both with the mini-Wright and Assess meters (for waveform No. 26, PEFs 7.1 and 10.9% lower, respectively). To compensate for losses due to gas compression, we have developed a method of deriving new input waveforms, which, when used to drive a commercially available mechanical pump, accurately and reliably produces the 26 ATS flow-time waveforms, even those with the fastest rise-times.


Levodopa reinstates connectivity from prefrontal to premotor cortex during externally paced movement in Parkinson's disease.
Dopamine deficiency affects functional integration of activity in distributed neural regions. It has been suggested that lack of dopamine induces disruption of neural interactions between prefrontal and premotor areas, which might underlie impairment of motor control observed in patients with Parkinson's disease (PD). In this study we recorded cortical activity with high-density electroencephalography in 11 patients with PD as a pathological model of dopamine deficiency, and 13 healthy control subjects. Participants performed repetitive extension-flexion movements of their right index finger, which were externally paced at a rate of 0.5 Hz. This required participants to align their movement velocity to the slow external pace. Patients were studied after at least 12-hour withdrawal of dopaminergic medication (OFF state) and after intake of the dopamine precursor levodopa (ON state) in order to examine oscillatory coupling between prefrontal and premotor areas during respectively low and high levels of dopamine. In 10 patients and 12 control participants multiple source beamformer analysis yielded task-related activation of a contralateral cortical network comprising prefrontal cortex (PFC), lateral premotor cortex (lPM), supplementary motor area (SMA) and primary motor cortex (M1). Dynamic causal modelling was used to characterize task-related oscillatory coupling between prefrontal and premotor cortical areas. Healthy participants showed task-induced coupling from PFC to SMA, which was modulated within the γ-band. In the OFF state, PD patients did not express any frequency-specific coupling between prefrontal and premotor areas. Application of levodopa reinstated task-related coupling from PFC to SMA, which was expressed as high-β-γ coupling. Additionally, strong within-frequency γ-coupling as well as cross-frequency θ-γ coupling was observed from PFC to lPM. Enhancement of this cross-frequency θ-γ coupling after application of levodopa was positively correlated with individual improvement in motor function. The results demonstrate that dopamine deficiency impairs the ability to establish oscillatory coupling between prefrontal and premotor areas during an externally paced motor task. Application of extrinsic dopamine in PD patients reinstates physiological prefrontal-premotor coupling and additionally induces within- and cross-frequency coupling from prefrontal to premotor areas, which is not expressed in healthy participants.