Safety and immunogenicity of HCV E1E2 vaccine adjuvanted with MF59 administered to healthy adults.
Hepatitis C virus (HCV) causes chronic liver disease that often leads to cirrhosis and hepatocellular carcinoma. In animal studies, chimpanzees were protected against chronic infection following experimental challenge with either homologous or heterologous HCV genotype 1a strains which predominate in the USA and Canada. We describe the first in humans clinical trial of this prophylactic HCV vaccine. HCV E1E2 adjuvanted with MF59C.1 (an oil-in-water emulsion) was given at 3 different dosages on day 0 and weeks 4, 24 and 48 in a phase 1, placebo-controlled, dose escalation trial to healthy HCV-negative adults. There was no significant difference in the proportion of subjects reporting adverse events across the groups. Following vaccination subjects developed antibodies detectable by ELISA, CD81 neutralization and VSV/HCV pseudotype neutralization. There were no significant differences between vaccine groups in the number of responders and geometric mean titers for each of the three assays. All subjects developed lymphocyte proliferation responses to E1E2 and an inverse response to increasing amounts of antigen was noted. The vaccine was safe and generally well-tolerated at each of the 3 dosage levels and induced antibody and lymphoproliferative responses. A larger study to further evaluate safety and immunogenicity is warranted.


Stratospheric Mean Ages and Transport Rates from Observations of Carbon Dioxide and Nitrous Oxide
Measurements of stratospheric carbon dioxide (CO2) and nitrous oxide (N2O) concentrations were analyzed to investigate stratospheric transport rates. Temporal variations in tropospheric CO2 were observed to propagate into the stratosphere, showing that tropospheric air enters the lower tropical stratosphere continuously, ascends, and is transported rapidly (in less than 1 month) to both hemispheres. The mean age A of stratospheric air determined from CO2 data is approximately 5 years in the mid-stratosphere. The mean age is mathematically equivalent to a conserved tracer analogous to exhaust from stratospheric aircraft. Comparison of values for A from models and observations indicates that current model simulations likely underestimate pollutant concentrations from proposed stratospheric aircraft by 25 to 100 percent.


Coma in thrombotic thrombocytopenic purpura.
Thrombotic thrombocytopenic purpura (TTP) is characterised by a thrombotic, haemolytic microangiopathy leading to microvascular occlusion, haemolysis and ischaemic dysfunction of various organs including the brain. TTP may present with a variety of neurological symptoms, including headache, focal deficits, seizures and coma. The authors describe a 55-year-old man presenting with abdominal pain and rapidly progressive deterioration into coma without focal neurological deficits or seizures. A concomitant, transient, rapid increase in blood pressure raised the suspicion of a hypertensive crisis. Yet, our patient did not improve after vigorous treatment with antihypertensives. Brain imaging excluded a hypertensive leucoencephalopathy. Despite the absence of a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13 (ADAMTS13) deficiency, the diagnosis idiopathic TTP was made after excluding secondary causes of TTP. Upon treatment with plasma exchange, corticosteroids and vincristin our patient gradually improved. On discharge to a rehabilitation centre he was awake and alert, had minor cognitive deficits and a mild proximal tetraparesis consistent with a critical illness poly(neuro)myopathy.


Randomised controlled trial of the efficacy of a high-fluoride gel self-applied by toothbrushing in children at high caries risk.
The primary objective of this clinical trial was to assess the caries-preventive efficacy of 2 years of twice weekly supervised brushing with a self-applied gel containing 12,500 ppm fluoride on schooldays compared with weekly supervised use in children at high caries risk (with prior caries experience on first permanent molars). The secondary objective was to assess efficacy compared with similar children who continued with their usual oral hygiene care. This was a single-centre, single-blind, randomised, parallel-groups trial comprising two test groups and one untreated control group. 1,075 pupils aged 12-13 years at baseline received a baseline and final examination 2 years later. For all children completing the trial no significant difference was found between groups. For children compliant with study protocol no significant difference was found in the primary outcome (D(1)FS caries increment), but significant differences were found between the three groups overall in the secondary outcome, D(3)FT caries increment, with a significant pairwise difference between control and twice per week gel brushing (29%, p = 0.023 D(3)FT visual + fibre-optic transillumination). Analysis of the relationship between number of gel applications and caries showed that children who brushed with the gel at least 60 times over a 2-year period developed significantly fewer carious lesions into dentine than children who followed their usual oral hygiene routine. Some caution is needed as greatest benefit was shown by compliant children. Where schools are co-operative, it is recommended that the gel be used twice a week within a school-based programme over a 2-year period.


Sleep Duration, Number of Awakenings and Arterial Stiffness in Industrial Shift Workers: A Five-Week Follow-Up Study.
Shift work may increase the risk for hypertension and arterial stiffness, potentially a consequence of disturbed sleep. The aim of this study was to investigate possible correlations between sleep length and spontaneous awakenings with selected cardiovascular risk factors in shift workers at an industrial plant. We examined 19 shift workers by means of blood pressure and arterial stiffness, measured as pulse wave velocity (PWV), prior to and after a 5-week shift period. Sleep patterns were monitored on a daily basis with the assistance of a smartphone-based sleep diary (the entire test period) and by actigraphy (limited to 2 weeks). The number of awakenings and total sleep time were calculated. Shorter sleep duration was associated with higher blood pressure and partly with higher PWV, indicating an increased risk of cardiovascular disease (CVD) with reduced sleep duration. Unexpectedly, a lower number of awakenings was associated with an increase in blood pressure, indicating a reduced risk of CVD. No other significant associations were determined. The results from the present study among shift workers in Norway could support the hypothesis that short sleep duration is associated with elevated blood pressure and arterial stiffness.


Asiatic acid suppresses neuroinflammation in BV2 microglia via modulation of the Sirt1/NF-κB signaling pathway.
Asiatic acid, a triterpenoid derived from Centella asiatica, has been found to exhibit multiple bioactivities. In this study, we investigated the effects of asiatic acid on lipopolysaccharide (LPS)-induced neuroinflammation and explored the mechanism of its action in BV2 microglia. We found that asiatic acid (0.1 to 100 μM) treatment significantly attenuated nitric oxide (NO) production and inhibited inducible nitric oxide synthase (iNOS) expression in a concentration-dependent manner following LPS exposure. Asiatic acid reduced LPS-induced expression and secretion of inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in BV2 cells. In addition, asiatic acid enhanced Sirt1 expression, reduced NF-κB p65 acetylation, and suppressed NF-κB activation after LPS stimulation. However, EX-527, an inhibitor of Sirt1, abolished the inhibitory effects of asiatic acid on LPS-stimulated microglia activation. These findings suggest that asiatic acid prevents LPS-induced neuroinflammation via regulating the Sirt1/NF-κB signaling pathway.


Reversal of acquired resistance to adriamycin in CHO cells by tamoxifen and 4-hydroxy tamoxifen: role of drug interaction with alpha 1 acid glycoprotein.
Tamoxifen and 4-OH tamoxifen were used to reverse multidrug resistance (MDR) in CHO cells with acquired resistance to adriamycin (CHO-Adrr). Because alpha 1 acid glycoprotein (AAG) can bind a range of calcium channel blockers that also reverse MDR and rises in malignancy, its interactions with tamoxifen and 4-OH tamoxifen were also studied. Tamoxifen decreased the IC50 of 10 microM adriamycin 4.8-fold in the parent CHO-K1 cell line and 16-fold in CHO-Adrr. Similarly 4-OH tamoxifen decreased the IC50 3-fold in the parent cells, but 13-fold in the resistant cells. Tamoxifen and 4-OH tamoxifen were similarly potent in reversing MDR, although their anti-oestrogen potency differs 100-fold. AAG was added in increasing concentrations to the combination of adriamycin and tamoxifen. As AAG concentrations increased from 0.5 to 2 mg ml-1 (the range found in vivo) the effect of tamoxifen on reversing MDR was gradually decreased. At the highest AAG concentrations, there was complete reversal of the effects of both tamoxifen and 4-OH tamoxifen. AAG was found to bind 3H-tamoxifen in a non-saturable non-specific manner, in contrast to the binding of tamoxifen to albumin. Thus the use of tamoxifen as a reversal agent for MDR in vivo may be impaired by high binding to AAG. However, at the lower range of normal values of AAG, there was still an effect of 10 microM tamoxifen. It may be desirable to select patients for modifier studies based on AAG plasma levels.


The occurrence of pathogenic bacteria in some ships' ballast water incoming from various marine regions to the Sea of Marmara, Turkey.
The composition and frequency of antibiotic resistance of pathogenic bacteria, the abundance of heterotrophic aerobic bacteria (HPC) and possible in-situ use of chromogenic agar were investigated in the ships' ballast water coming from different regions of the world to the Sea of Marmara, Turkey for the first time. The samples that were taken from 21 unit ships coming from various marine environments of the Southern China Sea, the Atlantic Ocean, the Mediterranean and the Black Sea to the Sea of Marmara, Turkey in 2009 and 2010 were tested. 38 bacteria species, 27 of them pathogenic bacteria belonging to 17 familia, were detected. Vibrio cholera was not detected in the samples. However, the presence of a high number of HPC, including a cocktail of pathogenic bacteria showed that the ships carry a potential risk for the Sea of Marmara.


Psychosocial working conditions among high-skilled workers: A latent transition analysis.
Theories of psychosocial working conditions assume an interaction of different work environment characteristics. Most studies detail various aspects of such interactions, while fewer investigate the comprehensive patterns of interrelated variables. This exploratory study distinguishes patterns of psychosocial working conditions, describes their characteristics, and investigates their change over 6 years. The working conditions of 1,744 high-skilled workers in Sweden, of a representative sample of the working population, were empirically classified into 4 distinct patterns: (a) the Supporting pattern with a very low workload, very low time pressure, medium learning opportunities, high creativity requirements, and very high autonomy; (b) the Constraining pattern with a very low workload, very low time pressure, low learning opportunities, medium creativity requirements, and very low autonomy; (c) the Demanding pattern with a high workload, high time pressure, medium learning opportunities, high creativity requirements, and very low autonomy; and (d) the Challenging pattern with a high workload, high time pressure, very high learning opportunities, very high creativity requirements, and very high autonomy. Importantly, these patterns were associated with significant differences in worker well-being. From an individual perspective, working conditions most often changed from patterns with a high workload and time pressure to patterns with lower levels of these demands. Over time, the prevalence of the Constraining pattern increased while that of the Challenging pattern decreased. To conclude, a person-centered approach broadens the understanding of the complex interplay between psychosocial working conditions and their longitudinal change, which can improve the tailoring of occupational health interventions. (PsycINFO Database Record


PDMS microwells for multi-parametric monitoring of single mitochondria on a large scale: a study of their individual membrane potential and endogenous NADH.
Microwell arrays have been developed to monitor simultaneously, and on a large scale, multiple metabolic responses of single mitochondria. Wells of 50 to 1000 μm-diameter were prepared based on easy structuration of thin polydimethylsiloxane layers (PDMS; 100 μm thickness). Their surface treatment with oxygen plasma allowed the immobilization in situ and observation with time of populations of single isolated mitochondria. Their metabolic activities could be monitored individually by fluorescence microscopy under several activation/inhibition conditions. We measured the concomitant variations of two main metabolic parameters - the endogenous NADH level and the internal membrane potential difference Δψ owing to a cationic fluorescent probe (TMRM) - at energized, uncoupled and inhibited stages of the mitochondrial respiratory chain. Microwell arrays allowed analyses on large populations, and consequently statistical studies with a single organelle resolution. Thus, we observed rapid individual polarizations and depolarizations of mitochondria following their supply with the energetic substrate, while an averaged global polarization (increase of TMRM fluorescence within mitochondria) and NADH increase were detected for the whole population. In addition, statistical correlation studies show that the NADH content of all mitochondria tends toward a metabolic limit and that their polarization-depolarization ability is ubiquitous. These results demonstrate that PDMS microwell platforms provide an innovative approach to better characterize the individual metabolic status of isolated mitochondria, possibly as a function of their cell or organ origin or in different physio-pathological situations.


High-Performance Chemical Isotope Labeling Liquid Chromatography Mass Spectrometry for Exosome Metabolomics.
Circulating exosomes in bodily fluids such as blood are being actively studied as a rich source of chemical biomarkers for cancer diagnosis and monitoring. Although nucleic acid analysis is a primary tool for the discovery of circulating biomarkers in exosomes, metabolomics holds the potential of expanding the chemical diversity of biomarkers that may be easy and rapid to detect. However, only trace amounts of exosomes can be isolated from a small volume of patient blood, and thus a very sensitive technique is required to analyze the metabolome of exosomes. In this report, we present a workflow that involves multiple cycles of ultracentrifugation for exosome isolation using a starting material of 2 mL of human serum, freeze-thaw-cycles in 50% methanol/water for exosome lysis and metabolite extraction, differential chemical isotope labeling (CIL) of metabolites for enhancing liquid chromatography (LC) separation and improving mass spectrometry (MS) detection, and nanoflow LC-MS (nLC-MS) with captivespray for analysis. As a proof-of-principle, we used dansylation labeling to analyze the amine- and phenol-submetabolomes in two sets of exosome samples isolated from the blood samples of five pancreatic cancer patients before and after chemotherapy treatment. The average number of peak pairs or metabolites detected was 1964 ± 60 per sample for a total of 2446 peak pairs ( n = 10) in the first set and 1948 ± 117 per sample for a total of 2511 peak pairs ( n = 10) in the second set. There were 101 and 94 metabolites positively identified in the first and second set, respectively, and 1580 and 1590 peak pairs with accurate masses matching those of metabolites in the MyCompoundID metabolome database. Analyzing the mixtures of 12C-labeled individual exosome samples spiked with a 13C-labeled pooled sample which served as an internal standard allowed relative quantification of metabolomic changes of exosomes of blood samples collected before and after treatment.


Context-aware sparse decomposition for image denoising and super-resolution.
Image prior models based on sparse and redundant representations are attracting more and more attention in the field of image restoration. The conventional sparsity-based methods enforce sparsity prior on small image patches independently. Unfortunately, these works neglected the contextual information between sparse representations of neighboring image patches. It limits the modeling capability of sparsity-based image prior, especially when the major structural information of the source image is lost in the following serious degradation process. In this paper, we utilize the contextual information of local patches (denoted as context-aware sparsity prior) to enhance the performance of sparsity-based restoration method. In addition, a unified framework based on the markov random fields model is proposed to tune the local prior into a global one to deal with arbitrary size images. An iterative numerical solution is presented to solve the joint problem of model parameters estimation and sparse recovery. Finally, the experimental results on image denoising and super-resolution demonstrate the effectiveness and robustness of the proposed context-aware method.


Sepsis-induced cardiac mitochondrial dysfunction involves altered mitochondrial-localization of tyrosine kinase Src and tyrosine phosphatase SHP2.
Our previous research demonstrated that sepsis produces mitochondrial dysfunction with increased mitochondrial oxidative stress in the heart. The present study investigated the role of mitochondria-localized signaling molecules, tyrosine kinase Src and tyrosine phosphatase SHP2, in sepsis-induced cardiac mitochondrial dysfunction using a rat pneumonia-related sepsis model. SD rats were given an intratracheal injection of Streptococcus pneumoniae, 4×10(6) CFU per rat, (or vehicle for shams); heart tissues were then harvested and subcellular fractions were prepared. By Western blot, we detected a gradual and significant decrease in Src and an increase in SHP2 in cardiac mitochondria within 24 hours post-inoculation. Furthermore, at 24 hours post-inoculation, sepsis caused a near 70% reduction in tyrosine phosphorylation of all cardiac mitochondrial proteins. Decreased tyrosine phosphorylation of certain mitochondrial structural proteins (porin, cyclophilin D and cytochrome C) and functional proteins (complex II subunit 30kD and complex I subunit NDUFB8) were evident in the hearts of septic rats. In vitro, pre-treatment of mitochondrial fractions with recombinant active Src kinase elevated OXPHOS complex I and II-III activity, whereas the effect of SHP2 phosphatase was opposite. Neither Src nor SHP2 affected complex IV and V activity under the same conditions. By immunoprecipitation, we showed that Src and SHP2 consistently interacted with complex I and III in the heart, suggesting that complex I and III contain putative substrates of Src and SHP2. In addition, in vitro treatment of mitochondrial fractions with active Src suppressed sepsis-associated mtROS production and protected aconitase activity, an indirect marker of mitochondrial oxidative stress. On the contrary, active SHP2 phosphatase overproduced mtROS and deactivated aconitase under the same in vitro conditions. In conclusion, our data suggest that changes in mitochondria-localized signaling molecules Src and SHP2 constitute a potential signaling pathway to affect mitochondrial dysfunction in the heart during sepsis.


Preclinical development and clinical use of perillyl alcohol for chemoprevention and cancer therapy.
Perillyl alcohol (POH) is a naturally occurring dietary monoterpene isolated from the essential oils of lavender, peppermint, and other plants. Medical interest in this compound was generated by research findings showing that POH was able to inhibit the growth of tumor cells in cell culture and exert cancer preventive and therapeutic activity in a variety of animal tumor models. Based on this promising preclinical work, POH was formulated in soft gelatine capsules and orally administered to cancer patients several times a day on a continuous basis. However, such clinical trials in humans yielded disappointing results, also because the large number of capsules that had to be swallowed caused hard-to-tolerate intestinal side effects, causing many patients to withdraw from treatment due to unrelenting nausea, fatigue, and vomiting. As a result, efforts to treat cancer patients with oral POH were abandoned and did not enter clinical practice. Intriguingly, clinical trials in Brazil have explored intranasal POH delivery as an alternative to circumvent the toxic limitations of oral administration. In these trials, patients with recurrent malignant gliomas were given comparatively small doses of POH via simple inhalation through the nose. Results from these studies show this type of long-term, daily chemotherapy to be well tolerated and effective. In this review, we will present the vicissitudes of POH's evaluation as an anticancer agent, and its most recent success in therapy of patients with malignant brain tumors.


The influence of solid retention time on IFAS-MBR systems: analysis of system behavior.
A University of Cape Town Integrated Fixed-Film Activated Sludge Membrane Bioreactor (UCT-IFAS-MBR) pilot plant was operated at different values of the sludge retention time (SRT). Three SRTs were investigated at different durations: indefinitely, 30 and 15 days. The organic carbon, nitrogen and phosphorus removal, kinetic/stoichiometric parameters, membrane fouling tendency and sludge filtration properties were assessed. The findings showed that by decreasing the SRT, the pilot plant could maintain excellent carbon removal efficiencies throughout the experiments. In contrast, the biological carbon removal showed a slight nitrification and was slightly affected by the decrease of the SRT, showing high performance (approximately 91%, on average). Thus, the biofilm might have helped sustain the nitrification throughout the experiments. The average phosphorus removal performance increased slightly with a decrease in SRT, achieving the maximum efficiency (61.5%) at a SRT of 15 days. After a 30-day SRT, an increase in resistance due to pore blocking and a general worsening of the membrane filtration properties occurred.


Conceptual and data-based investigation of genetic influences and brain asymmetry: a twin study of multiple structural phenotypes.
Right-left regional cerebral differences are a feature of the human brain linked to functional abilities, aging, and neurodevelopmental and mental disorders. The role of genetic factors in structural asymmetry has been incompletely studied. We analyzed data from 515 individuals (130 monozygotic twin pairs, 97 dizygotic pairs, and 61 unpaired twins) from the Vietnam Era Twin Study of Aging to answer three questions about genetic determinants of brain structural asymmetry: First, does the magnitude of heritability differ for homologous regions in each hemisphere? Despite adequate power to detect regional differences, heritability estimates were not significantly larger in one hemisphere versus the other, except left > right inferior lateral ventricle heritability. Second, do different genetic factors influence left and right hemisphere size in homologous regions? Interhemispheric genetic correlations were high and significant; in only two subcortical regions (pallidum and accumbens) did the estimate statistically differ from 1.0. Thus, there was little evidence for different genetic influences on left and right hemisphere regions. Third, to what extent do genetic factors influence variability in left-right size differences? There was no evidence that variation in asymmetry (i.e., the size difference) of left and right homologous regions was genetically determined, except in pallidum and accumbens. Our findings suggest that genetic factors do not play a significant role in determining individual variation in the degree of regional cortical size asymmetries measured with MRI, although they may do so for volume of some subcortical structures. Despite varying interpretations of existing data, we view the present results as consistent with previous findings.


Endoplasmic reticulum export sites and Golgi bodies behave as single mobile secretory units in plant cells.
In contrast with animals, plant cells contain multiple mobile Golgi stacks distributed over the entire cytoplasm. However, the distribution and dynamics of protein export sites on the plant endoplasmic reticulum (ER) surface have yet to be characterized. A widely accepted model for ER-to-Golgi transport is based on the sequential action of COPII and COPI coat complexes. The COPII complex assembles by the ordered recruitment of cytosolic components on the ER membrane. Here, we have visualized two early components of the COPII machinery, the small GTPase Sar1p and its GTP exchanging factor Sec12p in live tobacco (Nicotiana tabacum) leaf epidermal cells. By in vivo confocal laser scanning microscopy and fluorescence recovery after photobleaching experiments, we show that Sar1p cycles on mobile punctate structures that track with the Golgi bodies in close proximity but contain regions that are physically separated from the Golgi bodies. By contrast, Sec12p is uniformly distributed along the ER network and does not accumulate in these structures, consistent with the fact that Sec12p does not become part of a COPII vesicle. We propose that punctate accumulation of Sar1p represents ER export sites (ERES). The sites may represent a combination of Sar1p-coated ER membranes, nascent COPII membranes, and COPII vectors in transit, which have yet to lose their coats. ERES can be induced by overproducing Golgi membrane proteins but not soluble bulk-flow cargos. Few punctate Sar1p loci were observed that are independent of Golgi bodies, and these may be nascent ERES. The vast majority of ERES form secretory units that move along the surface of the ER together with the Golgi bodies, but movement does not influence the rate of cargo transport between these two organelles. Moreover, we could demonstrate using the drug brefeldin A that formation of ERES is strictly dependent on a functional retrograde transport route from the Golgi apparatus.


Therapeutic potential of Phyllanthus emblica (amla): the ayurvedic wonder.
Medicinal plants are nature's gift to human beings to promote a disease free healthy life. Many medicinal plants are present in a group of herbal preparations of the Indian traditional health care system (Ayurveda) named Rasayana proposed for their interesting antioxidant activities. Phyllanthus emblica Linn. (syn. Emblica officinalis), commonly known as Indian gooseberry or amla, family Euphorbiaceae, is an important herbal drug used in unani (Graceo - arab) and ayurvedic systems of medicine. The plant is used both as a medicine and as a tonic to build up lost vitality and vigor. Phyllanthus emblica is highly nutritious and could be an important dietary source of vitamin C, amino acids, and minerals. The plant also contains phenolic compounds, tannins, phyllembelic acid, phyllembelin, rutin, curcum-inoids, and emblicol. All parts of the plant are used for medicinal purposes, especially the fruit, which has been used in Ayurveda as a potent rasayana and in traditional medicine for the treatment of diarrhea, jaundice, and inflammation. Various plant parts show antidiabetic, hypolipidemic, antibacterial, antioxidant, antiulcerogenic, hepatoprotective, gastroprotective, and chemopreventive properties. Here we discuss its historical, etymological, morphological and pharmacological aspects.


Chromosome painting and molecular dating indicate a low rate of chromosomal evolution in golden moles (Mammalia, Chrysochloridae).
Golden moles (Chrysochloridae) are poorly known subterranean mammals endemic to Southern Africa that are part of the superordinal clade Afrotheria. Using G-banding and chromosome painting we provide a comprehensive comparison of the karyotypes of five species representing five of the nine recognized genera: Amblysomus hottentotus, Chrysochloris asiatica, Chrysospalax trevelyani, Cryptochloris zyli and Eremitalpa granti. The species are karyotypically highly conserved. In total, only four changes were detected among them. Eremitalpa granti has the most derived karyotype with 2n = 26 and differs from the remaining species (all of whom have 2n = 30) by one centric and one telomere:telomere fusion. In addition, two intrachromosomal rearrangements were detected in A. hottentotus. The painting probes also suggest the presence of a unique satellite DNA family located on chromosomes 11 and 12 of both C. asiatica and C. zyli. This represents a synapomorphy linking these two sympatric species as sister taxa. A molecular clock was calibrated adopting a relaxed Bayesian approach for multigene data sets comprising publicly available sequences derived from five gene fragments representative of three golden moles and 39 other eutherian species. The data suggest that golden moles diverged from a common ancestor approximately 28.5 mya (95% credibility interval = 21.5-36.5 mya). Based on an inferred chrysochlorid ancestral karyotype of 2n = 30, the estimated rate of 0.7 rearrangements per 10 my (95% Credibility Interval = 0.54-0.93) differs from the 'default rate' of mammalian chromosomal evolution which has been estimated at one change per 10 million years, thus placing the Chrysochloridae among the slower-evolving chromosomal lineages thus far recorded.


Management of Cancer Cachexia: ASCO Guideline.
To provide evidence-based guidance on the clinical management of cancer cachexia in adult patients with advanced cancer. A systematic review of the literature collected evidence regarding nutritional, pharmacologic, and other interventions, such as exercise, for cancer cachexia. PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) and systematic reviews of RCTs published from 1966 through October 17, 2019. ASCO convened an Expert Panel to review the evidence and formulate recommendations. The review included 20 systematic reviews and 13 additional RCTs. Dietary counseling, with or without oral nutritional supplements, was reported to increase body weight in some trials, but evidence remains limited. Pharmacologic interventions associated with improvements in appetite and/or body weight include progesterone analogs and corticosteroids. The other evaluated interventions either had no benefit or insufficient evidence of benefit to draw conclusions on efficacy. Limitations of the evidence include high drop-out rates, consistent with advanced cancer, as well as variability across studies in outcomes of interest and methods for outcome assessment. Dietary counseling may be offered with the goals of providing patients and caregivers with advice for the management of cachexia. Enteral feeding tubes and parenteral nutrition should not be used routinely. In the absence of more robust evidence, no specific pharmacological intervention can be recommended as the standard of care; therefore, clinicians may choose not to prescribe medications specifically for the treatment of cancer cachexia. Nonetheless, when it is decided to trial a drug to improve appetite and/or improve weight gain, currently available pharmacologic interventions that may be used include progesterone analogs and short-term (weeks) corticosteroids.


Definition and Characteristics of Behavioral Medicine, and Main Tasks and Goals of the International Society of Behavioral Medicine-an International Delphi Study.
In the past decades, behavioral medicine has attained global recognition. Due to its global reach, a critical need has emerged to consider whether the original definition of behavioral medicine is still valid, comprehensive, and inclusive, and to reconsider the main tasks and goals of the International Society of Behavioral Medicine (ISBM), as the umbrella organization in the field. The purpose of the present study was to (i) update the definition and scope of behavioral medicine and its defining characteristics; and (ii) develop a proposal on ISBM's main tasks and goals. Our study used the Delphi method. A core group prepared a discussion paper. An international Delphi panel rated questions and provided comments. The panel intended to reach an a priori defined level of consensus (i.e., 70%). The international panel reached consensus on an updated definition and scope of behavioral medicine as a field of research and practice that builds on collaboration among multiple disciplines. These disciplines are concerned with development and application of behavioral and biomedical evidence across the disease continuum in clinical and public health domains. Consensus was reached on a proposal for ISBM's main tasks and goals focused on supporting communication and collaboration across disciplines and participating organizations; stimulating research, education, and practice; and supporting individuals and organizations in the field. The consensus on definition and scope of behavioral medicine and ISBM's tasks and goals provides a foundational step toward achieving these goals.


Depletion of O6-methylguanine-DNA methyltransferase by O6-benzylguanine enhances 5-FU cytotoxicity in colon and oral cancer cell lines.
O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme whose expression is controlled by its promoter methylation. A cell that expresses a low amount of MGMT is known to be more sensitive to the antiproliferative effects of alkylating agents. We have previously shown that the colorectal cancer patients treated with 5-fluorouracil (5-FU) as adjuvant chemotherapy had a better prognosis when the tumor revealed hypermethylation in its MGMT promoter. Therefore, we sought to investigate the relationship between the expression levels of MGMT and the anti-tumor effect of 5-FU in vitro by using two colon adenocarcinoma and four oral cancer cell lines with a variety of MGMT expression. We also investigated the effects of MGMT depletion by O6-benzylguanine (O6-BG), a potent inhibitor of MGMT. The 5-FU treatment uniformly depleted protein and mRNA expression of MGMT in all cell lines examined. Cell lines expressing low levels of MGMT were sensitive to 5-FU. On the other hand, cells expressing high levels of MGMT were less sensitive to 5-FU. The 5-FU treatment exhibited a better antiproliferative effect on the cells expressing high levels of MGMT by the pretreatment of O6-BG. Depletion of MGMT by O6-BG enhanced the anti-tumor effect of 5-FU. Assessment of the levels of MGMT expression in cancer cells and the control of its expression could contribute to the effective chemotherapy by 5-FU especially in patients who previously were considered as low-responsive individuals whose tumors have high levels of MGMT.


Rapid Systematic Review: The Impact of Social Isolation and Loneliness on the Mental Health of Children and Adolescents in the Context of COVID-19.
Disease containment of COVID-19 has necessitated widespread social isolation. We aimed to establish what is known about how loneliness and disease containment measures impact on the mental health in children and adolescents. For this rapid review, we searched MEDLINE, PsycInfo, and Web of Science for articles published between January 1, 1946, and March 29, 2020. Of the articles, 20% were double screened using predefined criteria, and 20% of data was double extracted for quality assurance. A total of 83 articles (80 studies) met inclusion criteria. Of these, 63 studies reported on the impact of social isolation and loneliness on the mental health of previously healthy children and adolescents (n = 51,576; mean age 15.3 years). In all, 61 studies were observational, 18 were longitudinal, and 43 were cross-sectional studies assessing self-reported loneliness in healthy children and adolescents. One of these studies was a retrospective investigation after a pandemic. Two studies evaluated interventions. Studies had a high risk of bias, although longitudinal studies were of better methodological quality. Social isolation and loneliness increased the risk of depression, and possibly anxiety at the time at which loneliness was measured and between 0.25 and 9 years later. Duration of loneliness was more strongly correlated with mental health symptoms than intensity of loneliness. Children and adolescents are probably more likely to experience high rates of depression and most likely anxiety during and after enforced isolation ends. This may increase as enforced isolation continues. Clinical services should offer preventive support and early intervention where possible and be prepared for an increase in mental health problems.


Nontypeable Haemophilus influenzae genetic islands associated with chronic pulmonary infection.
Haemophilus influenzae (Hi) colonizes the human respiratory tract and is an important pathogen associated with chronic obstructive pulmonary disease (COPD). Bacterial factors that interact with the human host may be important in the pathogenesis of COPD. These factors, however, have not been well defined. The overall goal of this study was to identify bacterial genetic elements with increased prevalence among H. influenzae strains isolated from patients with COPD compared to those isolated from the pharynges of healthy individuals. Four nontypeable H. influenzae (NTHi) strains, two isolated from the airways of patients with COPD and two from a healthy individual, were subjected to whole genome sequencing using 454 FLX Titanium technology. COPD strain-specific genetic islands greater than 500 bp in size were identified by in silico subtraction. Open reading frames residing within these islands include known Hi virulence genes such as lic2b, hgbA, iga, hmw1 and hmw2, as well as genes encoding urease and other enzymes involving metabolic pathways. The distributions of seven selected genetic islands were assessed among a panel of 421 NTHi strains of both disease and commensal origins using a Library-on-a-Slide high throughput dot blot DNA hybridization procedure. Four of the seven islands screened, containing genes that encode a methyltransferase, a dehydrogenase, a urease synthesis enzyme, and a set of unknown short ORFs, respectively, were more prevalent in COPD strains than in colonizing strains with prevalence ratios ranging from 1.21 to 2.85 (p ≤ 0.0002). Surprisingly, none of these sequences show increased prevalence among NTHi isolated from the airways of patients with cystic fibrosis. Our data suggest that specific bacterial genes, many involved in metabolic functions, are associated with the ability of NTHi strains to survive in the lower airways of patients with COPD.


A Myc-regulated transcriptional network controls B-cell fate in response to BCR triggering.
The B cell antigen receptor (BCR) is a signaling complex that mediates the differentiation of stage-specific cell fate decisions in B lymphocytes. While several studies have shown differences in signal transduction components as being key to contrasting phenotypic outcomes, little is known about the differential BCR-triggered gene transcription downstream of the signaling cascades. Here we define the transcriptional changes that underlie BCR-induced apoptosis and proliferation of immature and mature B cells, respectively. Comparative genome-wide expression profiling identified 24 genes that discriminated between the early responses of the two cell types to BCR stimulation. Using mice with a conditional Myc-deletion, we validated the microarray data by demonstrating that Myc is critical to promoting BCR-triggered B-cell proliferation. We further investigated the Myc-dependent molecular mechanisms and found that Myc promotes a BCR-dependent clonal expansion of mature B cells by inducing proliferation and inhibiting differentiation. This work provides the first comprehensive analysis of the early transcriptional events that lead to either deletion or clonal expansion of B cells upon antigen recognition, and demonstrates that Myc functions as the hub of a transcriptional network that control B-cell fate in the periphery.


Developing an objective marker to optimize patient selection and predict survival benefit in early-phase cancer trials.
Several prognostic indices have been devised to optimize patient selection for phase 1 oncology trials with no consensus as to the optimal score and none qualifying as a marker of treatment response. Multivariate predictors of overall survival (OS) were tested on 118 referred patients to develop the Hammersmith Score (HS). The score's ability to predict OS, progression-free survival (PFS), and 90-day mortality (90DM) was compared with other prognostic indices. Changes in HS were recalculated during treatment. Albumin<35 g/L, lactate dehydrogenase>450 U/L, and sodium<135 mmol/L emerged as independent prognostic factors. These were used with equal weighting to devise the HS, a compound prognostic index ranging from 0 to 3. High (HS=2-3) score predicted worse OS (hazard ratio [HR]=6.5, P<.001), PFS (HR=2.8, P=.01), and 90DM (OR=9.0, P<.001). HS was a more accurate multivariate predictor of OS (HR=6.4, P<.001, C-index=0.72), PFS (HR=2.7, P=.03), and 90DM (area under the ROC curve 0.703) compared with other scores. Worsening of the HS during treatment predicted for shorter OS (P<.001). HS retained prognostic and predictive ability following external validation. HS is a simple, validated index to optimize patient selection and predict survival benefit from phase 1 oncology treatments. Prospective validation is ongoing.


A novel virally inactivated human platelet lysate preparation rich in TGF-beta, EGF and IGF, and depleted of PDGF and VEGF.
There is emerging interest in the use of standardized virally inactivated human platelet lysate preparations rich in GFs (growth factors) for cell cultures, cell therapy and clinical applications. In the present paper, we report a simple process to prepare a virally inactivated platelet lysate preparation rich in TGF-beta1 (transforming growth factor-beta1), EGF (epidermal growth factor) and IGF (insulin-like growth factor) and depleted of PDGF (platelet-derived growth factor) and VEGF (vascular endothelial growth factor). Apheresis platelet concentrates were treated by the S/D (solvent/detergent) viral inactivation procedure, then subjected to an oil extraction followed by adsorption with activated charcoal and finally sterile-filtered. The resulting preparation contained a mean of 368.4, 2.4 and 54.7 ng/ml of TGF-beta1, EGF and IGF respectively. PDGF-AB and VEGF were essentially completely removed by the charcoal treatment. The mean albumin, IgG, IgM and IgA and fibrinogen contents were approx. 40.0, 8.5, 0.87, 1.66 and 2.65 mg/ml respectively, cholesterol and triglycerides were at 15 and 20.7 mg/ml respectively and TnBP (tri-n-butyl phosphate) and Triton X-45 were at 8.7 and 8.8 p.p.m. respectively. Supplementing MEM (minimum essential medium) with 1-10% of this S/D-treated platelet lysate promoted the proliferation of MG63 and SIRC cell lines as well as, or better than, 10% (v/v) FBS (fetal bovine serum), as based on the MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay. The process used to prepare such S/D-treated platelet lysates is easily scalable for industrial production. Our results open up the possibility to evaluate the potential of this new preparation for stem cell expansion and/or bone tissue engineering and regeneration.


Metabolic network rewiring of propionate flux compensates vitamin B12 deficiency in C. elegans.
Metabolic network rewiring is the rerouting of metabolism through the use of alternate enzymes to adjust pathway flux and accomplish specific anabolic or catabolic objectives. Here, we report the first characterization of two parallel pathways for the breakdown of the short chain fatty acid propionate in Caenorhabditis elegans. Using genetic interaction mapping, gene co-expression analysis, pathway intermediate quantification and carbon tracing, we uncover a vitamin B12-independent propionate breakdown shunt that is transcriptionally activated on vitamin B12 deficient diets, or under genetic conditions mimicking the human diseases propionic- and methylmalonic acidemia, in which the canonical B12-dependent propionate breakdown pathway is blocked. Our study presents the first example of transcriptional vitamin-directed metabolic network rewiring to promote survival under vitamin deficiency. The ability to reroute propionate breakdown according to B12 availability may provide C. elegans with metabolic plasticity and thus a selective advantage on different diets in the wild.


Peptide Self-Assembly Is Linked to Antibacterial, but Not Antifungal, Activity of Histatin 5 Derivatives.
The rise of multidrug-resistant pathogens has awakened interest in new drug candidates such as antimicrobial peptides and their derivatives. Recent work suggests that some antimicrobial peptides have the ability to self-assemble into ordered amyloid-like nanostructures which facilitate their antibacterial activity. Here, we evaluate a histatin-based antimicrobial peptide, and its self-assembling derivative, in the interplay between self-assembly, membrane interactions, and antibacterial and antifungal activities. We demonstrate substantial membrane targeting by both peptides, as well as mechanistic insights into this mode of action, which correlates to their antifungal activity and is not affected by their self-assembling state. The ability to self-assemble does, however, significantly affect peptide antibacterial activity against both Gram-negative and Gram-positive bacteria. These results are surprising and hint at important distinctions between antifungal and antibacterial peptide activities in prokaryotes and eukaryotic microbes.IMPORTANCE Antimicrobial peptides are important modulators of host defense against bacterial, fungal, and viral pathogens in humans and other multicellular organisms. Two converging paradigms point to a link between antimicrobial peptides that self-assemble into amyloid-like nanoassemblies and classical amyloidogenic peptides that often have potent broad-spectrum antimicrobial activity, suggesting that antimicrobial and amyloidogenic peptides may represent two sides of the same coin. Here, we asked if the ability of an antifungal peptide to self-assemble affects its antifungal or antibacterial activity. We found that modifications of classical antifungal peptide derivative allowed it to self-assemble and did not alter its antifungal activity, and yet self-assembly substantially increased the antibacterial activity of the peptide. These results support the idea that peptide self-assembly can enhance antibacterial activities and emphasize a distinction between the action of antifungal peptides and that of antibacterial peptides. Accordingly, we suggest that the possible generality of this distinction should be widely tested.


Immobilization of histidine-tagged proteins on electrodes.
The development of new enzyme immobilization techniques that do not affect catalytic activity or conformation of a protein is an important research task in biotechnology including biosensor applications and heterogeneous reaction systems. One of the most promising approaches for controlled protein immobilization is based on the immobilized metal ion affinity chromatography (IMAC) principle originally developed for protein purification. Here we describe the current status and future perspectives of immobilization of His-tagged proteins on electrode surfaces. Recombinant proteins comprising histidine-tags or histidine rich native proteins have a strong affinity to transition metal ions. For metal ion immobilization at the electrode surface different matrices can be used such as self-assembled monolayers or conductive polymers. This specific technique allows a reversible immobilization of histidine-tagged proteins at electrodes in a defined orientation which is an important prerequisite for efficient electron transfer between the electrode and the biomolecule. Any application requiring immobilized biocatalysts on electrodes can make use of this immobilization approach, making future biosensors and biocatalytic technologies more sensitive, simpler, reusable and less expensive while only requiring mild enzyme modifications.


Prevention of bicycle-related injuries in children and youth: a systematic review of bicycle skills training interventions.
Bicycling is a popular means of recreation and transportation for children; however, it is a leading cause of recreational injury. Bicycle skill development and safety education are important methods of bicycle injury prevention. To determine the effectiveness of bicycle skills training programmes in reducing bicycle-related injuries in children and youth. Sixteen databases were systematically searched to include studies involving children less than 19 years of age who participated in interventions that targeted bicycle skills and safety education. Outcome measures included injury, behaviour, knowledge and attitudes. Data extraction included study characteristics, intervention and outcomes. Quality of evidence was assessed using the Downs and Black criteria. Twenty-five studies, including both observational (ie, case-control) and experimental (ie, randomised controlled trials) designs met the inclusion criteria. Overall, there was no statistically significant intervention effect on measures of injury. Eight of 16 studies measuring knowledge reported significant knowledge gains as a result of the intervention. Of 13 studies evaluating behavioural and attitude changes, five reported significant improvement. There was no significant difference in quality index scores between studies that showed an improvement in knowledge or behaviour (61%, 95% CI 49% to 74%) and studies that did not (57%, 95% CI 48% to 66%). There is a paucity of high-quality research in the area of bicycle skills training programmes. Educational and skills training bicycling programmes may increase knowledge of cycling safety, but this does not seem to translate into a decrease in injury rate, or improved bicycle handling ability and attitudes.


Diagnosis of osteomyelitis by MR imaging.
Bone scans are highly sensitive for the diagnosis of acute osteomyelitis, but the difficulty of separating bone-marrow processes from soft-tissue disease limits the specificity and accuracy. A diagnostic technique capable of distinguishing bone-marrow processes from soft-tissue disease would improve the diagnostic accuracy of osteomyelitis. To evaluate the use of MR in the diagnosis of osteomyelitis, MR examinations were performed in 35 patients with suspected acute osteomyelitis. Twelve of these were proved to have osteomyelitis either by surgery (nine patients) or by clinical follow-up (three patients). In the other 23, osteomyelitis was excluded by surgery (12 patients) or by the clinical course (11 patients). Evidence of osteomyelitis on MR consisted of abnormalities of the bone marrow with decreased signal intensity on the T1-weighted images and increased signal intensity on the T2-weighted or short-T1 inversion recovery (STIR) images. MR and bone scintigraphy were interpreted by two radiologists who were given no clinical information other than to rule out osteomyelitis. The sensitivities of MR and static bone scan were 100% for bone-marrow abnormality. Because bone-marrow abnormality in osteomyelitis associated with healing fractures was incorrectly diagnosed by MR (one case) and bone scintigraphy (two cases), the sensitivities of MR and scintigraphy for the diagnosis of osteomyelitis were 92% and 82%, respectively. The specificities of MR and scintigraphy were 96% and 65%, respectively (p less than .05). The overall accuracy for the diagnosis of osteomyelitis was 94% for MR and 71% for bone scan (p less than .05). Because of its ability to separate soft-tissue disease from underlying bone marrow, MR may be used to evaluate patients with positive bone scintigraphy to improve the specificity and accuracy of diagnosis for osteomyelitis.


Role of connexin-based gap junction channels and hemichannels in ischemia-induced cell death in nervous tissue.
Gap junction channels and hemichannels formed of connexin subunits are found in most cell types in vertebrates. Gap junctions connect cells via channels not open to the extracellular space and permit the passage of ions and molecules of approximately 1 kDa. Single connexin hemichannels, which are connexin hexamers, are present in the surface membrane before docking with a hemichannel in an apposed membrane. Because of their high conductance and permeability in cell-cell channels, it had been thought that connexin hemichannels remained closed until docking to form a cell-cell channel. Now it is clear that at least some hemichannels can open to allow passage of molecules between the cytoplasm and extracellular space. Here we review evidence that gap junction channels may allow intercellular diffusion of necrotic or apoptotic signals, but may also allow diffusion of ions and substances from healthy to injured cells, thereby contributing to cell survival. Moreover, opening of gap junction hemichannels may exacerbate cell injury or mediate paracrine or autocrine signaling. In addition to the cell specific features of an ischemic insult, propagation of cell damage and death within affected tissues may be affected by expression and regulation of gap junction channels and hemichannels formed by connexins.


TOXINS AND ANTITOXINS--SNAKE VENOMS AND ANTIVENINS.
A specific antivenin against crotalus venom can be prepared bv the immunization of goats. A specific antivenin against water moccasin venom can be produced by the immunization of goats with this venom, modified by hydrochloric acid. Immunization with the unmodified venom is very difficult. The toxicity of crotalus venom is diminished more than fifty percent. by passage through a Chamberland filter. There is a simple relation between the toxicity and the body weight for guinea-pigs weighing from 250 to 500 grams. Smaller guinea-pigs (125 grams) are comparatively less resistant. The toxicity is smaller by subcutaneous than by intraperitoneal injection (guinea-pigs), or by intravenous injection (rabbits). White rats are very resistant. The toxicity of cobra venom is not measurably diminished by filtration through a Chamberland filter. The relation between the amount of venom and the corresponding time of death is very regular, and can be expressed by a curve of asymptotic nature. Lecithin does not increase the toxicity. The tracings representing toxin-antitoxin neutralization for the three venoms (crotalus, cobra and moccasin) show deviation from the straight line. This deviation is most pronounced for the toxic quota of the venoms. The tracing representing crotalus venomantivenin neutralization, determined on guinea-pigs, can, within errors of experiment, be expressed by the equation: Free toxin . Free antitoxin = K . toxin-antitoxin. The corresponding tracing determined on rabbits is somewhat different, but both tracings are much more markedly curved than that for cobra venom-antivenin. The neutralization tracing of water moccasin venom shows the peculiarity, that small amounts of antivenin decrease the toxicity to a minimum, but the toxicity is again increased by further addition of antitoxin. The tracing representing neutralization of the haemolysins of the three venoms are different from the tracings of neutralization of the toxins, and approach very closely to a straight line. Still, in all instances, the determinations with great concentrations of antilysin show pronounced deviation, perhaps due to some dissociation of the toxin-antitoxin combination.


Restoration of spermatogenesis and male fertility using an androgen receptor transgene.
Androgens signal through the androgen receptor (AR) to regulate male secondary sexual characteristics, reproductive tract development, prostate function, sperm production, bone and muscle mass as well as body hair growth among other functions. We developed a transgenic mouse model in which endogenous AR expression was replaced by a functionally modified AR transgene. A bacterial artificial chromosome (BAC) was constructed containing all AR exons and introns plus 40 kb each of 5' and 3' regulatory sequence. Insertion of an internal ribosome entry site and the EGFP gene 3' to AR allowed co-expression of AR and EGFP. Pronuclear injection of the BAC resulted in six founder mice that displayed EGFP production in appropriate AR expressing tissues. The six founder mice were mated into a Sertoli cell specific AR knockout (SCARKO) background in which spermatogenesis is blocked at the meiosis stage of germ cell development. The AR-EGFP transgene was expressed in a cyclical manner similar to that of endogenous AR in Sertoli cells and fertility was restored as offspring were produced in the absence of Sertoli cell AR. Thus, the AR-EGFP transgene under the control of AR regulatory elements is capable of rescuing AR function in a cell selective, AR-null background. These initial studies provide proof of principle that a strategy employing the AR-EGFP transgene can be used to understand AR functions. Transgenic mice expressing selective modifications of the AR-EGFP transgene may provide crucial information needed to elicit the molecular mechanisms by which AR acts in the testis and other androgen responsive tissues.


Multi-waveform fast-scan cyclic voltammetry mapping of adsorption/desorption kinetics of biogenic amines and their metabolites.
Fast-scan cyclic voltammetry (FSCV) is an effective method for investigating electro-active neurochemical species. In recent years, FSCV has been used to measure electro-active neurotransmitters in a variety of neuroscience studies. We previously reported on the use of paired-pulse voltammetry (PPV) that enables FSCV to differentiate various analytes and minimize confounding factors by taking advantage of the adsorption characteristics of the analyte on carbon fiber microelectrodes. In spite of a number of studies regarding adsorption/desorption characteristics of neurotransmitters, the difference in adsorption/desorption properties among neurotransmitters has yet to be fully explored. To calculate adsorption/desorption constants for neurotransmitters, we propose the use of multi-waveform FSCV (M-FSCV), which consists of decade triangular waveforms in a single scan. Within the multiple waveforms, the voltammetric response of dopamine decayed exponentially because of the decreased adsorption time period. The decay pattern was mathematically described using adsorption/desorption characteristics and two additional initial points: an exponential decay constant (K) and an initial quantity (A), which were extracted from the decay equation. Using this method, we were able to quantify the decay constant (K-map) and an initial quantity (A-map) color plot in addition to a conventional pseudo color plot. M-FSCV was evaluated with two biogenic amine groups (catecholamines and indolamines) to characterize their inherent adsorption/desorption constants. As a result, the A-map showed a high correlation with concentration and the K-map for each group to be significantly differentiated. These results demonstrate that M-FSCV has the potential to be a useful technique for acquiring additional adsorption/desorption information regarding neurotransmitters.


A randomized placebo-controlled pilot trial of omega-3 fatty acids and alpha lipoic acid in Alzheimer's disease.
Oxidative stress, inflammation, and increased cholesterol levels are all mechanisms that have been associated with Alzheimer's disease (AD) pathology. Several epidemiologic studies have reported a decreased risk of AD with fish consumption. This pilot study was designed to evaluate the effects of supplementation with omega-3 fatty acids alone (ω-3) or omega-3 plus alpha lipoic acid (ω-3 + LA) compared to placebo on oxidative stress biomarkers in AD. The primary outcome measure was peripheral F2-isoprostane levels (oxidative stress measure). Secondary outcome measures included performance on: Mini-Mental State Examination (MMSE), Activities of Daily Living/Instrumental Activities of Daily Living (ADL/IADL), and Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog). Thirty-nine AD subjects were randomized to one of three groups: 1) placebo, 2) ω-3, or 3) ω-3 + LA for a treatment duration of 12 months. Eighty seven percent (34/39) of the subjects completed the 12-month intervention. There was no difference between groups at 12 months in peripheral F2-isoprostane levels (p = 0.83). The ω-3 + LA and ω-3 were not significantly different than the placebo group in ADAS-cog (p = 0.98, p = 0.86) and in ADL (p = 0.15, p = 0.82). Compared to placebo, the ω-3 + LA showed less decline in MMSE (p < 0.01) and IADL (p = 0.01) and the ω-3 group showed less decline in IADL (p < 0.01). The combination of ω-3 + LA slowed cognitive and functional decline in AD over 12 months. Because the results were generated from a small sample size, further evaluation of the combination of omega-3 fatty acids plus alpha-lipoic acid as a potential treatment in AD is warranted.


Gene expression profiling in lung fibroblasts reveals new players in alveolarization.
Little is known about the molecular basis of lung alveolarization. We used a microarray profiling strategy to identify novel genes that may regulate the secondary septation process. Rat lung fibroblasts were extemporaneously isolated on postnatal days 2, 7, and 21, i.e., before, during, and after septation, respectively. Total RNA was extracted, and cRNAs were hybridized to Affymetrix rat genome 230 2.0 microarrays. Expression levels of a selection of genes were confirmed by real-time PCR. In addition to genes already known to be upregulated during alveolarization including drebrin, midkine, Fgfr3, and Fgfr4, the study allowed us to identify two remarkable groups of genes with opposite profiles, i.e., gathering genes either transiently up- or downregulated on day 7. The former group includes the transcription factors retinoic acid receptor (RXR)-gamma and homeobox (Hox) a2, a4, and a5 and genes involved in Wnt signaling (Wnt5a, Fzd1, and Ndp); the latter group includes the extracellular matrix components Comp and Opn and the signal molecule Slfn4. Profiling in whole lung from fetal life to adulthood confirmed that changes were specific for alveolarization. Two treatments that arrest septation, hyperoxia and dexamethasone, inhibited the expression of genes that are upregulated during alveolarization and conversely enhanced that of genes weakly expressed during alveolarization and upregulated thereafter. The possible roles of these genes in secondary septation are discussed. Gene expression profiling analysis on freshly isolated cells represents a powerful approach to provide new information about differential regulation of genes during alveolarization and pathways potentially involved in the pathogenesis of bronchopulmonary dysplasia.


Resolution investigation of a ratiometric wavelength measurement system.
Theoretical analysis and experimental investigations are presented on the resolution of a ratiometric wavelength measurement system. Theoretical modeling indicates that the resolution of a ratiometric wavelength measurement system is determined by the signal-to-noise ratio of the input signal and the noise of the photodetectors associated with optical-to-electronic conversion. For experimental verification, a ratiometric system employing a macrobending standard single-mode fiber is developed and corresponding results are in good agreement with the theoretical prediction.


Modeling-based bone formation transforms trabeculae to cortical bone in the sclerotic areas in Buschke-Ollendorff syndrome. A case study of two females with LEMD3 variants.
Buschke-Ollendorff syndrome is a rare autosomal dominant condition caused by pathogenic variants in LEMD3 and characterized by connective tissue nevi and sclerotic bone abnormalities known as osteopoikilosis. The bone phenotype in Buschke-Ollendorff syndrome including osteopoikilosis remains unclear. We investigated bone turnover markers, pelvis and crura X-rays; lumbar spine and femoral neck DXA; bone activity by NaF-PET/CT, bone structure by μCT and dynamic histomorphometry in adults with Buschke-Ollendorff syndrome. Two women aged 25 and 47 years with a BMI of 30 and 32 kg/m2, respectively, were included in the investigation. Bone turnover markers were within normal range. aBMD Z-scores were comparable to that of controls in the lumbar spine and increased at the hip. Radiographies exposed spotted areas in crura and pelvis, and NaF-PET/CT exposed abnormal pattern of irregular shaped NaF uptake in the entire skeleton. In both biopsies, μCT showed trabecular structure comparable to that of controls with stellate shaped sclerotic noduli within the cavity and on the endocortex. Histomorphometric analyses of the sclerotic lesions revealed compact lamellar bone with a normal bone remodeling rate, but partly replaced by modeling-based bone formation. Woven bone was not observed in the nodules. Therefore, while bone turnover and BMD were largely within normal reference range in patients with the Buschke-Ollendorff syndrome, osteosclerotic lesions appear to emerge due to modeling-based bone formation with secondary bone remodeling. These observations indicate that LEMD3 may be important for the activation of bone lining cells leading to modeling-based bone formation.


Cavity-enhanced spectroscopy of a rare-earth-ion-doped crystal: observation of a power law for inhomogeneous broadening.
We experimentally demonstrate cavity-enhanced spectroscopy of a rare-earth-ion-doped crystal (Pr³⁺:Y₂SiO₅). We succeeded in observing very small absorption due to the ions appropriately prepared by optical pumping, which corresponds to the single-pass absorption of 4 × 10-6. We also observed a power law for the inhomogeneous broadening of optical transitions of ions in the crystal. Compared with a theoretical model, the result of the power law indicates that the dominant origin of the inhomogeneous broadening may be some charged defects.


Genetic characterization of the Mutator system in maize: behavior and regulation of Mu transposons in a minimal line.
Most Mutator lines of maize harbor several different classes of Mu transposons, each of which may be present in high copy number. The regulatory element is also often found in high copy number, and it is this element's behavior that is presumed to cause the non-Mendelian inheritance of Mutator activity. Using a very simple Mutator line, we demonstrate tha MuDR-1, a regulator of the Mutator system, can functionally replace standard non-Mendelian Mutator activity and that MuDR-1 is associated with the loss of methylation of the termini of another Mu transposon. Further, we show that Mu transposons can transpose duplicatively, that reinsertion tends to be into unlinked sites, and that MuDR-1 frequently suffers deletions. Changes in chromosomal position and the mode of sexual transmission are shown to be associated with changes in the frequency of MuDR-1 duplication and with the activity of MuDR-1 as monitored by the excision frequency of a reporter transposon of the Mu family, Mu1. Our data are derived from a Minimal Mutator Line in which there are relatively few Mu transposons, including one MuDR-1 regulator and as few as one Mu1 reporter. The seemingly enigmatic results that have been obtained using more complicated Mu genotypes are reinterpreted using simple Mendelian principles. We have borrowed a gap-repair model from Drosophila biologists to explain both duplications and deletions of MuDR-1.


Compromised RNA polymerase III complex assembly leads to local alterations of intergenic RNA polymerase II transcription in Saccharomyces cerevisiae.
Assembled RNA polymerase III (Pol III) complexes exert local effects on chromatin processes, including influencing transcription of neighboring RNA polymerase II (Pol II) transcribed genes. These properties have been designated as 'extra-transcriptional' effects of the Pol III complex. Previous coding sequence microarray studies using Pol III factor mutants to determine global effects of Pol III complex assembly on Pol II promoter activity revealed only modest effects that did not correlate with the proximity of Pol III complex binding sites. Given our recent results demonstrating that tDNAs block progression of intergenic Pol II transcription, we hypothesized that extra-transcriptional effects within intergenic regions were not identified in the microarray study. To reconsider global impacts of Pol III complex binding, we used RNA sequencing to compare transcriptomes of wild type versus Pol III transcription factor TFIIIC depleted mutants. The results reveal altered intergenic Pol II transcription near TFIIIC binding sites in the mutant strains, where we observe readthrough of upstream transcripts that normally terminate near these sites, 5'- and 3'-extended transcripts, and de-repression of adjacent genes and intergenic regions. The results suggest that effects of assembled Pol III complexes on transcription of neighboring Pol II promoters are of greater magnitude than previously appreciated, that such effects influence expression of adjacent genes at transcriptional start site and translational levels, and may explain a function of the conserved ETC sites in yeast. The results may also be relevant to synthetic biology efforts to design a minimal yeast genome.


Studies on chemistry, spectroscopy and antioxidant activities of chromium(III)-hydrazide complexes.
Acid hydrazides are vital chemical entities due to their biological activities. Upon complexation with certain metal ions, their biological activities are known to be positively enhanced. The present work describes the synthesis of Cr(III)-hydrazide complexes, and their structural, spectroscopic and antioxidant properties to reveal their chemistry and biochemistry. Physical (magnetic moment, conductivity measurements), analytical (C, H, N and Cr analysis) and spectral (EI-Mass, FTIR) techniques are used for the characterization of synthesized compounds. All Cr(III)-hydrazide complexes exhibit octahedral geometry with general formula [Cr(L)2(H2O)2]Cl3. In these complexes, the hydrazide ligands are coordinated via carbonyl oxygen and terminal amino nitrogen in a bidentate fashion. All Cr(III)-hydrazide complexes were screened for in vitro diphenyldipicryl hydrazine (DPPH), superoxide dismutase and nitric oxide radical scavenging activities. Majority of the Cr(III)-hydrazide complexes were found to be more potent scavengers than their uncoordinated hydrazide ligands. This study demonstrates an interesting structure-activity relationship (SAR) which is presented here.


Development of paediatric non-stage prognosticator guidelines for population-based cancer registries and updates to the 2014 Toronto Paediatric Cancer Stage Guidelines.
Population-based cancer registries (PBCRs) generate measures of cancer incidence and survival that are essential for cancer surveillance, research, and cancer control strategies. In 2014, the Toronto Paediatric Cancer Stage Guidelines were developed to standardise how PBCRs collect data on the stage at diagnosis for childhood cancer cases. These guidelines have been implemented in multiple jurisdictions worldwide to facilitate international comparative studies of incidence and outcome. Robust stratification by risk also requires data on key non-stage prognosticators (NSPs). Key experts and stakeholders used a modified Delphi approach to establish principles guiding paediatric cancer NSP data collection. With the use of these principles, recommendations were made on which NSPs should be collected for the major malignancies in children. The 2014 Toronto Stage Guidelines were also reviewed and updated where necessary. Wide adoption of the resultant Paediatric NSP Guidelines and updated Toronto Stage Guidelines will enhance the harmonisation and use of childhood cancer data provided by PBCRs.


Application of transtheoretical model to assess the compliance of chronic periodontitis patients to periodontal therapy.
The present cross-sectional survey study was conducted to assess whether the transtheoretical model for oral hygiene behavior was interrelated in theoretically consistent directions in chronic periodontitis patients and its applicability to assess the compliance of the chronic periodontitis patients to the treatment suggested. A total of 150 chronic periodontitis patients were selected for the proposed study. The selected patients were given four questionnaires that were constructed based on transtheoretical model (TTM), and the patients were divided subsequently into five different groups (precontemplation, contemplation, preparation, action, and maintenance groups) based on their answers to the questionnaires. Then, each patient was given four appointments for their periodontal treatment spaced with a time gap of 10 days. The patients visit for each appointments scheduled to them was documented. The results obtained were assessed using TTM. Higher mean pro scores of decisional balance, self-efficacy, and process of change scores was recorded in maintenance group followed by action group, preparation group, contemplation group, and precontemplation group, respectively, whereas higher mean cons score was recorded in precontemplation group followed by contemplation group, preparation group, action group, and maintenance group, respectively. The difference scores of TTM constructs were statistically highly significant between all the five groups. Furthermore, the number of appointment attended in were significantly more than maintenance group followed by action group, preparation group, contemplation group, and precontemplation group. Within the limitations of this study, it can be concluded that transtheoretical model can be successfully applied to chronic periodontitis patients to assess their compliance to the suggested periodontal treatment.


Viral microRNA targetome of KSHV-infected primary effusion lymphoma cell lines.
Primary effusion lymphoma (PEL) is caused by Kaposi's sarcoma-associated herpesvirus (KSHV) and frequently also harbors Epstein-Barr virus (EBV). The expression of KSHV- and EBV-encoded microRNAs (miRNAs) in PELs suggests a role for these miRNAs in latency and lymphomagenesis. Using PAR-CLIP, a technology which allows the direct and transcriptome-wide identification of miRNA targets, we delineate the target sites for all viral and cellular miRNAs expressed in PEL cell lines. The resulting data set revealed that KSHV miRNAs directly target more than 2000 cellular mRNAs, including many involved in pathways relevant to KSHV pathogenesis. Moreover, 58% of these mRNAs are also targeted by EBV miRNAs, via distinct binding sites. In addition to a known viral analog of cellular miR-155, we show that KSHV encodes a viral miRNA that mimics cellular miR-142-3p function. In summary, this study identifies an extensive list of KSHV miRNA targets, which are likely to influence viral replication and pathogenesis.


Repetition priming without identification of the primes: evidence for a component process view of priming.
The aim of the present study was to examine whether priming can occur due to recent perceptual processing of the same stimulus with minimal influence from conceptual process and also to investigate its underlying neural mechanisms using fMRI. Words were presented in mirror orientation in a word identification priming task. The presentation durations of the primes were titrated individually so that each participant could only identify approximately half of the primes, while the remainder disappeared before participants could identify the meaning of the word. A substantial behavioral priming effect was found when these unidentified primes were repeated later, suggesting that recent exposure to the perceptual processes without accessing the meaning is sufficient to prime later identical processes of the same repeated stimuli. Imaging data showed significant repetition suppression in several brain regions mediating perceptual, but not semantic or conceptual, processes. Together, our findings are consistent with the general predictions of transfer appropriate processing (TAP) and the component process view of priming, positing that priming is a function of more efficient cognitive processes that are repeated from study to test, and this increased efficiency is reflected in repetition suppression effects evident on fMRI.


Green pesticides based on cinnamate anion incorporated in layered double hydroxides and dispersed in pectin matrix.
This paper reports the preparation of green pesticides based on nano-hybrids composed of a Layered Double Hydroxide (LDH) with cinnamate anion. The dispersion into a pectin matrix was obtained using high energy ball milling in wet conditions. Structure and physical properties of the fillers and the composites films were evaluated. Controlled release of cinnamate was followed using UV spectrophotometry and the release kinetics were found to be dependent on the filler loading. The experimental results were analyzed by the Gallagher-Corrigan model. Antimicrobial activity was evaluated on different bacterial strains, as well as plant pathogens belonging to the genus Phytophthora using modified agar diffusion, broth microdilution and dual culture methods, respectively. Experimental results suggested the possibility to use the analyzed composites as green protective coatings for crops' protection.


Development and implementation of a customised rapid syndromic diagnostic test for severe pneumonia.
Background: The diagnosis of pneumonia has been hampered by a reliance on bacterial cultures which take several days to return a result, and are frequently negative. In critically ill patients this leads to the use of empiric, broad-spectrum antimicrobials and compromises good antimicrobial stewardship. The objective of this study was to establish the performance of a syndromic molecular diagnostic approach, using a custom TaqMan array card (TAC) covering 52 respiratory pathogens, and assess its impact on antimicrobial prescribing. Methods: The TAC was validated against a retrospective multi-centre cohort of broncho-alveolar lavage samples. The TAC was assessed prospectively in patients undergoing investigation for suspected pneumonia, with a comparator cohort formed of patients investigated when the TAC laboratory team were unavailable. Co-primary outcomes were sensitivity compared to conventional microbiology and, for the prospective study, time to result. Metagenomic sequencing was performed to validate findings in prospective samples. Antibiotic free days (AFD) were compared between the study cohort and comparator group. Results: 128 stored samples were tested, with sensitivity of 97% (95% confidence interval (CI) 88-100%). Prospectively, 95 patients were tested by TAC, with 71 forming the comparator group. TAC returned results 51 hours (interquartile range 41-69 hours) faster than culture and with sensitivity of 92% (95% CI 83-98%) compared to conventional microbiology. 94% of organisms identified by sequencing were detected by TAC. There was a significant difference in the distribution of AFDs with more AFDs in the TAC group (p=0.02). TAC group were more likely to experience antimicrobial de-escalation (odds ratio 2.9 (95%1.5-5.5)). Conclusions: Implementation of a syndromic molecular diagnostic approach to pneumonia led to faster results, with high sensitivity and impact on antibiotic prescribing.


My body is a lantern: Oscillopsia and an experience of Ayurveda.
February 9, 2017. The alarm on my phone was set to a pre-dawn hour. We were to leave for a holiday in the hills, a long drive that I had planned for days, eager for hours of camaraderie with the steering wheel. But the waking was a shock. The walls and ceiling of the room were swirling, my body felt as if strapped to a rotating carnival wheel. Sitting, standing, walking, nothing eased it. I threw up from the nausea. Maybe it will slow, maybe it will stop, maybe it is nothing. It is vertigo, said my cousin (a doctor) on the phone, and prescribed an over-the-counter medication. The world steadied. I made the drive, the vacation, but the condition was now with me, for several hours each day.


Physician-reported practices on continuous deep sedation until death: A descriptive and comparative study.
Research on continuous deep sedation until death has focused on estimating prevalence and describing clinical practice across care settings. However, evidence on sedation practices by physician specialty is scarce. To compare and contrast physician-reported practices on continuous deep sedation until death between general practitioners and medical specialists. A secondary analysis drawing upon data from a large-scale, population-based, retrospective survey among physicians in Flanders, Belgium in 2007. Symptom prevalence and characteristics of sedation (drugs used, artificial nutrition and hydration administered, intentions, and decision-making) were measured. Response rate was 58.4%. The frequency of continuous deep sedation until death among all deaths was 11.3% for general practitioners and 18.4% for medical specialists. General practitioners reported significantly higher rates of severity and mean intensity of pain, delirium, dyspnea, and nausea in the last 24 h of life for sedated patients and a higher number of severe symptoms than medical specialists. No differences were found between groups in the drugs used, except in propofol, reported only by medical specialists (in 15.8% of all cases). Artificial nutrition and hydration was withheld or withdrawn in 97.2% of general practitioner and 36.2% of medical specialist cases. Explicit life-shortening intentions were reported by both groups (for 3%-4% of all cases). Continuous deep sedation until death was initiated without consent or request of either the patient or the family in 27.9% (medical specialists) and 4.7% (general practitioners) of the cases reported. Considerable variation, often largely deviating from professional guidelines, was observed in physician-reported performance and decision-making, highlighting the importance of providing clearer guidance on the specific needs of the context in which continuous deep sedation until death is to be performed.


Pulmonary alveolar proteinosis induced by hydrofluoric acid exposure during fire extinguisher testing.
Automatic fire suppression systems use hydrofluorocarbons (HF) to extinguish fires chemically. At high temperatures, HF can release hydrofluoric acid (HFA), a toxic, potentially lethal gas. A 52-year-old male visited our Pulmonary Division with dyspnea of 8-months duration. He had been working at a facility that manufactured fire extinguishers. Bronchoscopy was performed and a transbronchial lung biopsy was taken from the right lower lobe. After the patient was diagnosed with pulmonary alveolar proteinosis (PAP), whole-lung lavage was performed. In this case, fire extinguisher gas induced pulmonary alveolar proteinosis. This material should be used with care and investigated further. HFA is corrosive and penetrates organic materials, including body tissues. Depending on the mode of exposure, skin ulceration, pulmonary injury, or even systemic shock can result. This report describes PAP that developed after chronic, repeated exposure to fire extinguisher spray. Hydrofluoric acid can induce pulmonary disorders such as PAP.


Forest restoration as a strategy to mitigate climate impacts on wildfire, vegetation, and water in semiarid forests.
Climate change and wildfire are interacting to drive vegetation change and potentially reduce water quantity and quality in the southwestern United States, Forest restoration is a management approach that could mitigate some of these negative outcomes. However, little information exists on how restoration combined with climate change might influence hydrology across large forest landscapes that incorporate multiple vegetation types and complex fire regimes. We combined spatially explicit vegetation and fire modeling with statistical water and sediment yield models for a large forested landscape (335,000 ha) on the Kaibab Plateau in northern Arizona, USA. Our objective was to assess the impacts of climate change and forest restoration on the future fire regime, forest vegetation, and watershed outputs. Our model results predict that the combination of climate change and high-severity fire will drive forest turnover, biomass declines, and compositional change in future forests. Restoration treatments may reduce the area burned in high-severity fires and reduce conversions from forested to non-forested conditions. Even though mid-elevation forests are the targets of restoration, the treatments are expected to delay the decline of high-elevation spruce-fir, aspen, and mixed conifer forests by reducing the occurrence of high-severity fires that may spread across ecoregions. We estimate that climate-induced vegetation changes will result in annual runoff declines of up to 10%, while restoration reduced or reversed this decline. The hydrologic model suggests that mid-elevation forests, which are the targets of restoration treatments, provide around 80% of runoff in this system and the conservation of mid- to high-elevation forests types provides the greatest benefit in terms of water conservation. We also predict that restoration treatments will conserve water quality by reducing patches of high-severity fire that are associated with high sediment yield. Restoration treatments are a management strategy that may reduce undesirable outcomes for multiple ecosystem services.


InsertionMapper: a pipeline tool for the identification of targeted sequences from multidimensional high throughput sequencing data.
The advent of next-generation high-throughput technologies has revolutionized whole genome sequencing, yet some experiments require sequencing only of targeted regions of the genome from a very large number of samples. These regions can be amplified by PCR and sequenced by next-generation methods using a multidimensional pooling strategy. However, there is at present no available generalized tool for the computational analysis of target-enriched NGS data from multidimensional pools. Here we present InsertionMapper, a pipeline tool for the identification of targeted sequences from multidimensional high throughput sequencing data. InsertionMapper consists of four independently working modules: Data Preprocessing, Database Modeling, Dimension Deconvolution and Element Mapping. We illustrate InsertionMapper with an example from our project 'New reverse genetics resources for maize', which aims to sequence-index a collection of 15,000 independent insertion sites of the transposon Ds in maize. Identified sequences are validated by PCR assays. This pipeline tool is applicable to similar scenarios requiring analysis of the tremendous output of short reads produced in NGS sequencing experiments of targeted genome sequences. InsertionMapper is proven efficacious for the identification of target-enriched sequences from multidimensional high throughput sequencing data. With adjustable parameters and experiment configurations, this tool can save great computational effort to biologists interested in identifying their sequences of interest within the huge output of modern DNA sequencers. InsertionMapper is freely accessible at https://sourceforge.net/p/insertionmapper and http://bo.csam.montclair.edu/du/insertionmapper.


The sex-biased brain: sexual dimorphism in gene expression in two species of songbirds.
Despite virtually identical DNA sequences between the sexes, sexual dimorphism is a widespread phenomenon in nature. To a large extent the systematic differences between the sexes must therefore arise from processes involving gene regulation. In accordance, sexual dimorphism in gene expression is common and extensive. Genes with sexually dimorphic regulation are known to evolve rapidly, both in DNA sequence and in gene expression profile. Studies of gene expression in related species can shed light on the flexibility, or degree of conservation, of the gene expression profiles underlying sexual dimorphism. We have studied the extent of sexual dimorphism in gene expression in the brain of two species of songbirds, the zebra finch (Taeniopygia guttata) and the common whitethroat (Sylvia communis), using large-scale microarray technology. Sexual dimorphism in gene expression was extensive in both species, and predominantly sex-linked: most genes identified were male-biased and Z-linked. Interestingly, approximately 50% of the male-biased Z-linked genes were sex-biased only in one of the study species. Our results corroborate the results of recent studies in chicken and zebra finch which have been interpreted as caused by a low degree of dosage compensation in female birds (i.e. the heterogametic sex). Moreover, they suggest that zebra finches and common whitethroats dosage compensate partly different sets of genes on the Z chromosome. It is possible that this pattern reflects differences in either the essentiality or the level of sexual antagonism of these genes in the respective species. Such differences might correspond to genes with different rates of evolution related to sexual dimorphism in the avian brain, and might therefore be correlated with differences between the species in sex-specific behaviours.


Kin recognition and the 'armpit effect': evidence of self-referent phenotype matching.
In species with multiple paternity or maternity, animals may best assess their relatedness to unfamiliar conspecifics by comparing their own phenotype(s) with those of unidentified individuals. Yet whether animals can recognize kin through self-matching is controversial. Because golden hamsters (Mesocricetus auratus) mate multiply and can produce multiply sired litters, they were tested for their ability to use self-matching for kin recognition. Hamsters that were reared only with non-kin since birth responded differentially to odours of unfamiliar relatives and non-relatives. Postnatal association with kin was not necessary for this discrimination. Prenatal learning was unlikely because of delayed production and perception of social odours. To our knowledge, this is the first demonstration that a vertebrate can use its own phenotype for kin-recognition purposes without prior experience with kin. By using itself as a referent, rather than its siblings or parents, a golden hamster may be better able to direct nepotism towards the most appropriate individuals. Kin discrimination via self-inspection may be especially important in nepotistic contexts (to identify most closely related conspecifics), whereas inclusion of the phenotypes of close kin as referents may be favoured in mate-choice contexts (to identify all related individuals).


Diffusion and bulk flow in phloem loading: a theoretical analysis of the polymer trap mechanism for sugar transport in plants.
Plants create sugar in the mesophyll cells of their leaves by photosynthesis. This sugar, mostly sucrose, has to be loaded via the bundle sheath into the phloem vascular system (the sieve elements), where it is distributed to growing parts of the plant. We analyze the feasibility of a particular loading mechanism, active symplasmic loading, also called the polymer trap mechanism, where sucrose is transformed into heavier sugars, such as raffinose and stachyose, in the intermediary-type companion cells bordering the sieve elements in the minor veins of the phloem. Keeping the heavier sugars from diffusing back requires that the plasmodesmata connecting the bundle sheath with the intermediary cell act as extremely precise filters, which are able to distinguish between molecules that differ by less than 20% in size. In our modeling, we take into account the coupled water and sugar movement across the relevant interfaces, without explicitly considering the chemical reactions transforming the sucrose into the heavier sugars. Based on the available data for plasmodesmata geometry, sugar concentrations, and flux rates, we conclude that this mechanism can in principle function, but that it requires pores of molecular sizes. Comparing with the somewhat uncertain experimental values for sugar export rates, we expect the pores to be only 5%-10% larger than the hydraulic radius of the sucrose molecules. We find that the water flow through the plasmodesmata, which has not been quantified before, contributes only 10%-20% to the sucrose flux into the intermediary cells, while the main part is transported by diffusion. On the other hand, the subsequent sugar translocation into the sieve elements would very likely be carried predominantly by bulk water flow through the plasmodesmata. Thus, in contrast to apoplasmic loaders, all the necessary water for phloem translocation would be supplied in this way with no need for additional water uptake across the plasma membranes of the phloem.


Identification of functional peptides from natural and synthetic products on their anticancer activities by tumor targeting.
Cancer cells can express specific membrane proteins, which act as biomarkers for chemotherapeutic targeting. Functional peptides possess unique properties that will ensure efficacy, selectivity, specificity and low toxicity when used as therapeutic agents. Therapeutic peptides have been derived in treatment of cancers through improvement of cellular uptake, drug targeting and vaccine development. Peptides from natural source have been used for chemoprevention and therapy of various cancers. These include peptides derived from food, marine products, venom components and other animal constituents. Besides, chemically- and recombinantly-synthesized peptides have also been produced and extensively studied in contemporary applications. Improvement of tumor targeting is essential for chemotherapeutic development. This can be achieved through enhancement of intracellular delivery and/or increased specific binding affinity to cancer cells by pore-forming and cytotoxic peptides. Cytotoxic peptides such as the Bcl-2 family members can induce receptor-specific binding to tumor cells and promote apoptosis by targeting lipid membranes. This approach has some limitations in targeting, penetration and localization within tumors. Cell-penetrating peptides (CPPs) belong to a new class of tumor-targeting peptides that can facilitate internalization of tumor markers and/or chemotherapeutic drugs. In order to overcome the problem of serum instability in classical CPPs (e.g. Tat), newer classes of CPPs has been recently introduced. Nevertheless, some cyclized CPPs can further enhance cellular uptake and binding selectivity when compared to activities of their linear counterpart, especially when treating chemoresistant tumors. This review compiles the use of effective tumor-targeting peptides including novel CPPs that represents new therapeutic strategies for the treatment of cancers.


Subjectivity and complexity of facial attractiveness.
The origin and meaning of facial beauty represent a longstanding puzzle. Despite the profuse literature devoted to facial attractiveness, its very nature, its determinants and the nature of inter-person differences remain controversial issues. Here we tackle such questions proposing a novel experimental approach in which human subjects, instead of rating natural faces, are allowed to efficiently explore the face-space and "sculpt" their favorite variation of a reference facial image. The results reveal that different subjects prefer distinguishable regions of the face-space, highlighting the essential subjectivity of the phenomenon. The different sculpted facial vectors exhibit strong correlations among pairs of facial distances, characterising the underlying universality and complexity of the cognitive processes, and the relative relevance and robustness of the different facial distances.


When and How to Provide Feedback and Instructions to Athletes?-How Sport Psychology and Pedagogy Insights Can Improve Coaching Interventions to Enhance Self-Regulation in Training.
In specialist sports coaching, the type and manner of augmented information that the coach chooses to use in communicating and training with individual athletes can have a significant impact on skill development and performance. Informed by insights from psychology, pedagogy, and sport science, this position paper presents a practitioner-based approach in response to the overarching question: When, why, and how could coaches provide information to athletes during coaching interventions? In an ecological dynamics rationale, practice is seen as a search for functional performance solutions, and augmented feedback is outlined as instructional constraints to guide athletes' self-regulation of action in practice. Using the exemplar of team sports, we present a Skill Training Communication Model for practical application in the context of the role of a specialist coach, using a constraints-led approach (CLA). Further based on principles of a non-linear pedagogy and using the recently introduced Periodization of Skill Training (PoST) framework, the proposed model aims to support practitioners' understanding of the pedagogical constraints of feedback and instruction during practice. In detail, the PoST framework's three skill development and training stages work to (1) directly impact constraint manipulations in practice designs and (2) indirectly affect coaches' choices of external (coach-induced) information. In turn, these guide practitioners on how and when to apply different verbal instruction methodologies and aim to support the design of effective skill learning environments. Finally, several practical guidelines in regard to sports coaches' feedback and instruction processes are proposed.