Complex genomic rearrangements lead to novel primate gene function.
Orthologous genes that maintain a single-copy status in a broad range of species may indicate a selection against gene duplication. If this is the case, then duplicates of such genes that do survive may have escaped the dosage control by rapid and sizable changes in their function. To test this hypothesis and to develop a strategy for the identification of novel gene functions, we have analyzed 22 primate-specific intrachromosomal duplications of genes with a single-copy ortholog in all other completely sequenced metazoans. When comparing this set to genes not exposed to the single-copy status constraint, we observed a higher tendency of the former to modify their gene structure, often through complex genomic rearrangements. The analysis of the most dramatic of these duplications, affecting approximately 10% of human Chromosome 2, enabled a detailed reconstruction of the events leading to the appearance of a novel gene family. The eight members of this family originated from the highly conserved nucleoporin RanBP2 by several genetic rearrangements such as segmental duplications, inversions, translocations, exon loss, and domain accretion. We have experimentally verified that at least one of the newly formed proteins has a cellular localization different from RanBP2's, and we show that positive selection did act on specific domains during evolution.


High-energy phosphates and function in isolated, working rabbit hearts.
An isolated, working, rabbit heart has been developed for use with nuclear magnetic resonance (NMR) spectroscopy. This model is functionally stable over a 4-h period and displays classic hemodynamic responses to work-load changes. Control 31P spectra of this preparation (n = 5) were obtained with simultaneous recordings of left ventricular pressure (LVP), LVP differentiated with respect to time (dP/dt), heart rate (HR), and cardiac output (CO). ATP, phosphocreatine (PCr), and hemodynamics remained stable over a 90-min perfusion. Hearts were also subjected to 13.5 min of global ischemia (IS) at 37 degrees C followed by 60 min of reperfusion (RE, n = 7) or 45 min of chronic IS (n = 6). Contraction ceased within 60 s of IS. PCr loss was rapid, reaching undetectable limits by 11 min. ATP loss was gradual and bore no relationship to functional loss. ATP fell to 60 +/- 4% (means +/- SE) of pre-IS levels after 13.5 min of IS. With RE, PCr returned to control levels, whereas ATP values remained depressed for the entire 60 min. Functional activity resumed with RE, but dP/dt did not rise above 85 +/- 7% of preischemic values. No correlation between residual ATP at the end of IS and functional recovery during RE was evident.


Dispersibility and biotransformation of oils with different properties in seawater.
Dispersants are used to remove oils slicks from sea surfaces and to generate small oil-droplet dispersions, which may result in enhanced biodegradation of the oil. In this study, dispersibility and biodegradation of chemically dispersed oils with different physical-chemical properties (paraffinic, naphthenic and asphaltenic oils) were compared in natural temperate SW at 13 °C. All selected oils were chemically dispersible when well-known commercial dispersants were used. However, interfacial tension (IFT) studies of the dispersed oils showed different IFT properties of the oils at 13 °C, and also different leaching of the dispersants from oil droplet surfaces. Biodegradation studies of the chemically dispersed oils were performed in a carousel system, with initial median droplet sizes <30 μm and oil concentrations of 2.5-2.8 mg/L. During biodegradation, oil droplet concentrations were rapidly reduced, in association with the emergence of macroscopic 'flocs'. Biotransformation results showed that half-lives of semivolatile total extractable organic carbon (TEOC), single target 2- to 4-ring PAH, and 22 oil compound groups used as input data in the oil spill contingency model OSCAR, did not differ significantly between the oils (P > 0.05), while n-alkanes half-lives differed significantly (P < 0.05). Biotransformation was associated with rapid microbial growth in all oil dispersions, in association with n-alkane and PAH biotransformation. These results have implications for the predictions of biodegradation of oil slicks treated with dispersants in temperate SW.


Coherent energy exchange between components of a vector soliton in fiber lasers.
We report on the experimental evidence of four wave mixing (FWM) between the two polarization components of a vector soliton formed in a passively mode-locked fiber laser. Extra spectral sidebands with out-of-phase intensity variation between the polarization resolved soliton spectra was firstly observed, which was identified to be caused by the energy exchange between the two soliton polarization components. Other features of the FWM spectral sidebands and the soliton internal FWM were also experimentally investigated and numerically confirmed.


Changes in brain 11C-nicotine binding sites in patients with mild Alzheimer's disease following rivastigmine treatment as assessed by PET.
Marked reduction in the cortical nicotinic acetylcholine receptors is observed in the brain of patients suffering from Alzheimer's disease (AD). Although cholinesterase inhibitors are used for symptomatic treatment of mild to moderate AD patients, numerous long-term treatment studies indicate that they might stabilize or halt the progression of the disease by restoring the central cholinergic neurotransmission. Thus, we used positron emission tomography (PET) technique as a sensitive approach to assess longitudinal changes in the nicotine binding sites in the brains of patients with AD. To evaluate changes in brain nicotinic binding sites in relation to inhibition level of cholinesterases in cerebrospinal fluid (CSF) and plasma and changes in cognitive performance of the patients in different neuropsychological tests after rivastigmine treatment. Ten mild AD patients received rivastigmine for 12 months. A dual-tracer PET model with administration of (15)O-water and (S)(-)(11)C-nicotine was used to assess (11)C-nicotine binding sites in the brain at baseline and after 3 and 12 months of the treatment. Cholinesterase activities in CSF and plasma were assessed colorimetrically. The (11)C-nicotine binding sites were significantly increased 12-19% in several cortical brain regions after 3 months compared with baseline, while the increase was not significant after 12 months of the treatment. After 3 months treatment, low enzyme inhibition in CSF and plasma was correlated with higher cortical (11)C-nicotine binding. The (11)C-nicotine binding positively correlated with attentional task at the 12-month follow-up. Changes in the (11)C-nicotine binding during rivastigmine treatment might represent remodeling of the cholinergic and related neuronal network.


Detection of coca alkaloids in oral fluid from coca leaf (tea) consumers: using solid phase extraction to improve validation parameters and widen the detection window.
Hygrine and cuscohygrine, two coca leaf alkaloids, have been previously proposed as markers to differentiate legal and illegal cocaine consumption. This is a very common problem in some countries of South America, where the consumption of coca leaves has a long tradition. Analytical methods focusing on the assessment of coca leaf alkaloids, such as cuscohygrine, hygrine, tropacocaine and t-cinnamoylcocaine, in oral fluid are virtually non-existent in forensic toxicology laboratories worldwide due to their lack of application. However, the problem of differentiating legal and illegal cocaine use in criminal justice, DUID (drug-impaired driving) and WDT (workplace drug testing) programs is growing. Therefore, researchers are obliged to develop methods to measure coca leaf alkaloids (cuscohygrine, hygrine and t-cinnamoylcocaine) in biological matrices for further validation for routine analyses in forensic toxicology laboratories. This work aims to optimize a previously published separation method by protein precipitation in oral fluid by using solid-phase extraction (SPE) coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) operating in multiple reaction monitoring (MRM) mode. The use of SPE allowed the matrix effect and the background to be reduced in the chromatograms due to the obtained cleaner extracts. Consequently, improved detection and quantification limits were reached. Findings showed that the detection windows for coca leaf alkaloids were longer than three hours in real oral fluid samples from volunteers who drank a cup of coca tea. These detection windows are quite higher than those previously obtained when using the method based on separation by protein precipitation.


Neurological soft signs: Effects of trait schizotypy, psychological distress and auditory hallucination predisposition.
Schizotypy is regarded as a trait vulnerability for psychotic disorders, yet alone is insufficient for development of a diagnosable disorder. Additional symptoms and psychological distress are necessary for help seeking and transition from an at risk mental state to a clinical diagnosis. The present study investigated the interaction between trait schizotypy, state auditory verbal hallucination (AVH) predisposition, distress and handedness for the expression of neurological soft signs (NSS), a neurodevelopmental vulnerability factor for psychosis. Cluster analysis formed schizotypy groups statistically across the dimensions captured by the SPQ. It was hypothesized that schizotypy and AVH predisposition would interact, resulting in significantly greater NSS. Psychological distress and handedness were hypothesized to be significant covariates, accounting for some variance in the expression of NSS between the groups. A sample of University students (n = 327) completed the Schizotypal Personality Questionnaire, Launay-Slade Hallucination Scale, General Health Questionnaire and the Neurological Evaluation Scale (NES). Cluster Analysis revealed four schizotypy groups. Distress was not a significant covariate in any analysis. As expected, those with high overall schizotypy and high AVH predisposition expressed significantly greater Motor-Coordination NSS compared to those with high schizotypy and low AVH predisposition. Within the Mixed Interpersonal and Cognitive-Perceptual Schizotypy cluster, those with low AVH predisposition expressed significantly more Motor-Coordination NSS than those with high AVH predisposition. These findings suggest motor coordination NSS are detectable in schizotypy, and AVH predisposition appears to interact with these traits. This study highlights the importance of considering both trait and subclinical state risk factors when investigating risk for psychosis.


Characteristics and Expression Pattern of MYC Genes in Triticum aestivum, Oryza sativa, and Brachypodium distachyon.
Myelocytomatosis oncogenes (MYC) transcription factors (TFs) belong to basic helix-loop-helix (bHLH) TF family and have a special bHLH_MYC_N domain in the N-terminal region. Presently, there is no detailed and systematic analysis of MYC TFs in wheat, rice, and Brachypodium distachyon. In this study, 26 TaMYC, 7 OsMYC, and 7 BdMYC TFs were identified and their features were characterized. Firstly, they contain a JAZ interaction domain (JID) and a putative transcriptional activation domain (TAD) in the bHLH_MYC_N region and a BhlH region in the C-terminal region. In some cases, the bHLH region is followed by a leucine zipper region; secondly, they display tissue-specific expression patterns: wheat MYC genes are mainly expressed in leaves, rice MYC genes are highly expressed in stems, and B. distachyon MYC genes are mainly expressed in inflorescences. In addition, three types of cis-elements, including plant development/growth-related, hormone-related, and abiotic stresses-related were identified in different MYC gene promoters. In combination with the previous studies, these results indicate that MYC TFs mainly function in growth and development, as well as in response to stresses. This study laid a foundation for the further functional elucidation of MYC genes.


The Role of Spontaneous Repetitions During Treatment of Morphosyntactic Forms for Children With Developmental Language Disorder.
Purpose Children with developmental language disorder sometimes spontaneously repeat clinician models of morphemes targeted for treatment. We examine how spontaneous repeating of clinician models in the form of recasts associates with improved child production of those emerging morphemes. Method Forty-seven preschool children with developmental language disorder participated in Enhanced Conversational Recast therapy and were monitored for spontaneous repetitions of morphemes modeled by the clinician through conversational recasting. We calculated proportion of correct and incorrect productions elicited during treatment and for generalization probes as well as treatment effect sizes. We then used odds ratios to determine the probability that a spontaneous repetition may precede treatment gains and calculated correlations of correct repetitions with correct in-treatment productions of targets and treatment effect sizes. Results Spontaneous repetitions were highly likely to happen just prior to meaningful treatment progress. Children with higher frequencies of correct spontaneous repetitions of morpheme targets also showed higher frequencies of correct productions of these forms during the course of treatment. Furthermore, children with an earlier onset of repetitions and higher frequencies of correct repetitions showed overall larger effect sizes at the end of treatment. Conclusions Children's use of correct forms in their repetitions may serve as a self-scaffold for mastering productions of the correct form via structural priming mechanisms. Tracking spontaneously repeated targets may be a useful milestone for identifying response to treatment.


Antipneumococcal activities of cefpirome and cefotaxime, alone and in combination with vancomycin and teicoplanin, determined by checkerboard and time-kill methods.
The checkerboard titration method was used to test the synergy of cefpirome and cefotaxime with teicoplanin or vancomycin against 35 penicillin-susceptible, 34 penicillin-intermediate, and 31 penicillin-resistant pneumococci. The MICs at which 50 and 90% of isolates are inhibited (MIC50s and MIC90s, respectively) of both cefpirome and cefotaxime were 0.016 and 0.06 microgram/ml, respectively, for penicillin-susceptible strains and 0.125 and 0.5 microgram/ml, respectively, for penicillin-intermediate strains. The MIC50s and MIC90s of cefotaxime for penicillin-resistant strains were 1.0 and 2.0 micrograms/ml, respectively, and those of cefpirome were 0.5 and 1.0 microgram/ml, respectively. All pneumococci were inhibited by cefpirome at MICs of < or = 1.0 microgram/ml. The MIC50s and MIC90s of vancomycin and teicoplanin (0.25 and 0.25 microgram/ml and 0.03 and 0.03 microgram/ml, respectively) did not differ for the three groups. Checkerboard synergy studies showed that cefpirome and vancomycin showed synergy for 31 strains (fractional inhibitory concentration [FIC] indices, < or = 0.5) cefpirome and teicoplanin showed synergy for 18 strains, cefotaxime and vancomycin showed synergy for 51 strains, and cefotaxime and teicoplanin showed synergy for 27 strains. Cefpirome and vancomycin had FIC indices indicating indifference (2.0) for two strains, and cefotaxime and vancomycin had FIC indices indicating indifference for one strain. All other FIC indices indicating indifference or additivity were > 0.5 to 1.0. No FIC indices indicating antagonism (> 4.0) were found. Synergy between beta-lactams and glycopeptides for three susceptible, three intermediate, and three resistant strains were tested by the time-kill assay, and all combinations were synergistic by this method. Synergy between cephalosporins and glycopeptides can be demonstrated and may be useful for the treatment of pneumococcal infections, especially meningitis.


Antidepressants vs. Placebo for the Treatment of Functional Gastrointestinal Disorders in Adults: A Systematic Review and Meta-Analysis.
Objective: To integrate high-quality evidence of the efficacy of antidepressants across different subtypes of functional gastrointestinal disorders (FGIDs). Methods: The Medline, PsycINFO, EMBASE, the Cochrane Library, and Chinese local database were searched up to October 1, 2017. Keywords included all subtypes of FGIDs, antidepressants, and randomized controlled trials (RCTs). We included RCTs with low to moderate risks of bias in comparing antidepressants with placebos as the only intervention in treating adult patients with FGIDs (PROSPERO ID: CRD42015030123). Language was restricted to English or Chinese. Data extraction was independently carried out by two authors, following the Cochrane Handbook for systematic reviews. Results: Of 2,460 records identified, 31 studies reporting on 2,340 participants were included in the meta-analysis. Antidepressants were more effective than placebos in terms of the rate of responder [RR = 1.35 (95% CI 1.12 to 1.63)], and the reduction of target gastrointestinal symptoms [SMD = -0.94 (95% CI -1.33 to -0.54)], and disability severity (moderate effect sizes). Those effects partly remained both at the presence and absence of comorbid depression, and among different subtypes of FGIDs. Subgroup analyses confirmed the benefit of tricyclic and tetracyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and trazodone. Efficacy of serotonin and norepinephrine reuptake inhibitors (SNRIs), low doses of antidepressants, and antidepressants in intermediate to long term treatment was inconclusive due to the scarcity of eligible evidence. Compared to placebo, patients on antidepressants reported more adverse events [RR = 1.91 (95% CI 1.23 to 2.96)] and more frequent withdrawal. On average one in 7.4 (95% CI 5.4 to 11.9) patients treated with antidepressants responded, while one in 4.8 (95% CI 3.7 to 6.8) experienced certain adverse effects. Conclusions: Antidepressants were inferior to placebo in terms of tolerability and partly superior regarding efficacy. Before prescribing antidepressants, the benefits and side effects should be carefully evaluated.


Pathways between childhood/adolescent adversity, adolescent socioeconomic status, and long-term cardiovascular disease risk in young adulthood.
The current study investigated mediators between childhood/adolescent adversities (e.g., dating violence, maltreatment, homelessness, and parental death), low socioeconomic status (SES) during adolescence, and cardiovascular disease (CVD) risk in young adulthood. The purpose of these analyses was to understand whether SES during adolescence and childhood/adolescent adversities affect CVD risk through similar pathways, including maternal relationship quality, health behaviors, financial stress, medical/dental care, educational attainment, sleep problems, and depressive symptoms. Using the National Longitudinal Study of Adolescent to Adult Health (N = 14,493), which has followed US adolescents (Wave 1; M = 15.9 years) through early adulthood (Wave 4; M = 28.9 years), associations were examined between childhood/adolescent adversity and SES to 30-year CVD risk in young adulthood. The outcome was a Framingham-based prediction model of CVD risk that included age, sex, body mass index, smoking, systolic blood pressure, diabetes, and antihypertensive medication use at Wave 4. Path analysis was used to examine paths through the adolescent maternal relationship to young adult mediators of CVD risk. Childhood/adolescent adversity significantly predicted greater adult CVD risk through the following pathways: maternal relationship, health behaviors, financial stress, lack of medical/dental care, and educational attainment; but not through depressive symptoms or sleep problems. Lower SES during adolescence significantly predicted greater adult CVD risk through the following pathways: health behaviors, financial stress, lack of medical/dental care, and educational attainment, but not maternal relationship, depressive symptoms, or sleep problems. Childhood/adolescent adversities and SES affected CVD risk in young adulthood through both similar and unique pathways that may inform interventions.


Expression of ABC-type transport proteins in human platelets.
We have identified the ATP-binding cassette (ABC) transporter ABCC4 as an active constituent of mediator-storing granules in human platelets. In addition to multidrug resistance protein 4, other ABC-type transport proteins may contribute to platelet secretory function as well as determine intended or adverse effects of drugs. Here, we provide a comprehensive expression profiling of ABC transporters in human platelets based on a novel screening approach by combining the TaqMan low-density array RNA screening platform with a recently developed liquid chromatography/mass spectrometry (MS)/MS method for the simultaneous detection of membrane proteins. Transcripts of 25 ABC transporters were detected and showed differential expression compared with megakaryocytic progenitor cells. On the protein level ABCA7, ABCB4, ABCC1, ABCC3 and ABCC4 were identified by liquid chromatography/MS/MS and localized by immunofluorescence microscopy. Their functions may be related to glutathione and lipid homeostasis, secretion of lipid mediators, cell protection as well as drug transport.


Discovering implicit associations between genes and hereditary diseases.
We propose an approach to predicting implicit gene-disease associations based on the inference network, whereby genes and diseases are represented as nodes and are connected via two types of intermediate nodes: gene functions and phenotypes. To estimate the probabilities involved in the model, two learning schemes are compared; one baseline using co-annotations of keywords and the other taking advantage of free text. Additionally, we explore the use of domain ontologies to complement data sparseness and examine the impact of full text documents. The validity of the proposed framework is demonstrated on the benchmark data set created from real-world data.


Clomipramine for obsessive-compulsive disorder: prescribing guidelines.
Clomipramine is a newly marketed tricyclic antidepressant drug prescribed for obsessive-compulsive disorder (OCD). It selectively blocks neuronal uptake of serotonin. Clomipramine has been prescribed in Europe and Canada for 20 years in management of depression. Studies have now shown clomipramine to be effective in treating OCD. Dry mouth, visual disturbances, constipation, sexual dysfunction, somnolence, tremors, and dizziness are among the commonly reported side effects. Like other tricyclics, clomipramine exhibits a potential for cardiotoxicity, especially by impairing conduction and/or orthostasis. It also has the effect of lowering seizure threshold. Overdose risk is considerable. Careful medical supervision and adherence to prescribing guidelines are presumed to reduce medication risk factors. The outstanding benefit of this drug is its proved efficacy in the management of obsessive-compulsive disorder, as the first pharmacotherapy approved for this previously rather treatment-resistant condition.


Increased risk of aseptic loosening for posterior stabilized compared with posterior cruciate-retaining uncemented total knee replacements: a cohort study of 13,667 knees from the Dutch Arthroplasty Registry.
While registry studies have suggested a higher risk of revision for posterior-stabilized (PS) compared with posterior cruciate-retaining (CR) total knee replacements (TKR) using cement, it is unknown whether this is also the case for uncemented TKR. We aimed to compare the revision rates of PS and CR designs in patients receiving primary uncemented TKR. Data from the Dutch arthroplasty register (LROI) was analyzed, comprising 12,226 uncemented primary CR TKRs and 750 uncemented PS TKRs registered between 2007 and 2022. Competing risk and multivariable Cox regression analyses were used to compare revision rates, risks of revision, and reasons for revision between groups. Sensitivity analyses were performed to analyze the risk, concerning the 5 most commonly used implants and performing hospitals for each group. Uncemented PS TKRs had higher 10-year revision rates for any reason and aseptic loosening (6.5%, 95% confidence interval [CI] 4.6-9.2 and 3.9%, CI 2.6-6.7) compared with uncemented CR TKRs (4.2%, CI 3.8-4.7 and 1.4%, CI 1.2-1.7). PS TKRs were 1.4 and 2.5 times more likely to be revised for any reason and aseptic loosening, respectively. These results remained consistent after adjustment for age, sex, BMI, previous surgeries, bearing mobility, and surface modification, with sensitivity analyses. We found that uncemented PS implants have a higher rate of revision than uncemented CR implants, mainly due to a higher risk of aseptic loosening.


Composition and Biological Activity of the Essential Oils from Wild Horsemint, Yarrow, and Yampah from Subalpine Meadows in Southwestern Montana: Immunomodulatory Activity of Dillapiole.
Agastache urticifolia (Benth.) Kuntze (horsemint), Achillea millefolium L. (yarrow), and Perideridia gairdneri (Hook. & Arn.) Mathias (yampah) are native, culturally important plants that grow in the subalpine meadows of Montana. Analysis of the composition of essential oils extracted from these plants showed that the main components of essential oils obtained from flowers and leaves of A. urticifolia (designated as AUF/AUL) were menthone (2.7/25.7%), isomenthone (2.6/29.1%), pulegone (78.9/28.8%), and limonene (4.2/6.2%), whereas essential oils obtained from the inflorescence of A. millefolium (designated as AMI) were high in α-thujone (17.1%) and β-thujone (14.9%), 1,8-cineole (17.0%), camphor (13.0%), sabinene (7.0%), guaia-3,9-dien-11-ol (3.2%), and terpinen-4-ol (2.5%). Essential oils obtained from the inflorescence of P. gairdneri (designated as PGI) contained high amounts of dillapiole (30.3%), p-cymen-8-ol (14.1%), terpinolene (12.0%), 4-hydroxy-4-methyl-cyclohex-2-enone (6.2%), and γ-terpinene (2.4%). Evaluation of their immunomodulatory activity demonstrated that essential oils extracted from all of these plants could activate human neutrophils with varying efficacy. Analysis of individual components showed that dillapiole activated human neutrophil intracellular Ca2+ flux ([Ca2+]i) (EC50 = 19.3 ± 1.4 μM), while α-thujone, β-thujone, menthone, isomenthone, and pulegone were inactive. Since dillapiole activated neutrophils, we also evaluated if it was able to down-regulate neutrophil responses to subsequent agonist activation and found that pretreatment with dillapiole inhibited neutrophil activation by the chemoattractant fMLF (IC50 = 34.3 ± 2.1 μM). Pretreatment with P. gairdneri essential oil or dillapiole also inhibited neutrophil chemotaxis induced by fMLF, suggesting these treatments could down-regulate human neutrophil responses to inflammatory chemoattractants. Thus, dillapiole may be a novel modulator of human neutrophil function.


High levels of heavy metals in rice (Oryza sativa L.) from a typical E-waste recycling area in southeast China and its potential risk to human health.
Very few studies have investigated the heavy metal contents in rice samples from a typical E-waste recycling area. In this study, 10 heavy metals (As, Ba, Cd, Co, Cr, Cu, Hg, Mn, Ni and Pb) in 13 polished rice and relevant hull samples, six relevant paddy soil samples were investigated. The geometric mean concentrations of Cd, Cu and Hg in soil samples were 1.19, 9.98 and 0.32 microg g(-1), respectively, which were 4.0, 2.0 and 1.1-folds of the maximum allowable concentration (MAC) (0.30, 50.00, 0.30 microg g(-1), respectively) for Chinese agricultural soils. The analyzed metal concentrations were significantly different between rice and relevant hull except for As, Cd and Hg (p<0.05). All metal concentrations, except for Co, in rice hull were higher than those in polished rice. The geometric mean of Pb in polished rice reached 0.69 microg g(-1), which was 3.5-folds higher than the MAC (0.20 microg g(-1)) by the safety criteria for milled rice. Cd contents in 31% of the rice samples exceeded the national MAC (0.20 microg g(-1)), and the arithmetic mean also slightly exceeded national MAC. In addition, Cd and Pb contents in local rice were much higher than commercial rice samples examined in this work and previous studies. Comparing the tolerable daily intakes given by FAO/WHO with the mean estimated daily intakes; Pb daily intake through rice consumption in this area was 3.7 microg day(-1)kg(-1) body weight (bw), which already exceeded the FAO tolerable daily intake, and the Cd daily intake (0.7 microg day(-1)kg(-1) bw) through rice had already taken up 70% of the total tolerable daily intake (1 microg day(-1)kg(-1) bw). The daily intake of Hg and As through rice was much lower than the tolerable daily intakes, but bioaccumulation of Hg through the food chain and intake of As from other food stuff should also be of concern.


Emergency Preparedness and Disaster Response: There's an App for That 2.0.
In disaster response, smartphone applications (or apps) are being used by the layperson, emergency first responders, and health care providers to aid in everything from incident reporting to clinical decision making. However, quality apps are often diluted by the overwhelming number of apps that exist for both the lay public and first responders in the Apple iTunes (Apple Inc.; Cupertino, California USA) and Google Play (Google LLC; Mountain View, California USA) stores. A systematic review of disaster response apps was originally completed in 2015; a follow-up review was completed here to evaluate trends and explore novel apps. A search of the Apple iTunes and Google Play stores was performed using the following terms obtained from PubMed (National Center for Biotechnology Information; Bethesda, Maryland USA) Medical Subject Headings Database: Emergency Preparedness; Emergency Responders; Disaster; Disaster Planning; Disaster Medicine; Bioterrorism; Chemical Terrorism; Hazardous Materials; and the Federal Emergency Management Agency (FEMA [Washington, DC USA]). After excluding any unrelated apps, a working list of apps was formed and categorized based on topics. Apps were categorized by intended user (first responders or the public) and sub-categorized by topic for discussion. Sub-categories included News/Information, Reference/Education, Weather/Natural Disasters, Travel/Navigation, and Communication/Reunification. A search of the Apple iTunes store revealed 394 unique apps and was narrowed to 342 based on relevance to the field and availability on the iPhone. A search of the Google Play store yielded 645 unique applications and was narrowed to 634 based on relevance. Of note, 49 apps appeared in both app stores using the search terms. An aggregate 927 apps from the Apple iTunes and Google Play stores were then critically reviewed by the authors. Apps were sub-categorized based on intended audience, layperson or first responder, and sorted into one of five disaster response categories. Two apps were chosen for discussion from each of the five sub-categories. The highest quality apps were determined from each group based on relevance to emergency preparedness and disaster response, rating, and number of reviews. After comparisons with the 2015 article, many new apps have been developed and previously described apps have been updated, highlighting that this is a constantly changing field deserving of continued analysis and research.


[Evaluation of the capacity to drive in patients diagnosed of mild cognitive impairment and dementia].
Mild cognitive impairment (MCI) and dementia involve cognitive changes that may influence driving capacity. a) To study if the tests used for renewing the driver's licence are appropriate; b) to study the MCI patient's driving capacity according to ASDE Driver-Test and Useful Field of View (UFOV) test; c) to study mild dementia (MD) patient's driving capacity according to ASDE and UFOV tests; d) to determine which neuropsychological tests may be useful to make decisions on driving capacity in MCI and MD; e) to study the difference in the evaluation of each neuropsychological test between patients who are able to drive and those who are not, in each MCI subgroups, and f) we will establish the correlation between the neuropsychological tests and driving tests used for licence renewal. A total of 184 people were included: 92 MCI, 55 MD and 40 healthy controls. Cognitive functioning was evaluated by Repeatable Battery Assessment for Neuropsychological Status (RBANS), Trail Making Test (TMT) and Kohs' Block Design. Driving capacity was assessed by ASDE and UFOV test. We established the cut-off points for ASDE and UFOV tests. Sensitivity and specificity for the MD on the ASDE test was 86% and 95%, respectively for concentrated attention and monotony resistance subtest. The UFOV test sensitivity was 88%, specificity 81%. For MCI, both tests showed a sensitivity and specificity lower than 70 %. According to the performance on the test only a half of the MCI group could drive. They showed different driving profiles according to MCI subtype. Neuropsychological tests showing the best correlations with performance on driving test were: Kohs' Block Design, Immediate Memory, Delayed Memory and TMT-A. a) People with MD should not drive; b) both ASDE and UFOV tests can detect driving difficulties in people with dementia; c) according to the UFOV and ASDE, half of those diagnosed of MCI should not drive; d) there are significant differences in memory test (RBANS) between Amnesic MCI patients who are able to drive and those who are not (according to ASDE/UFOV tests); e) there are significant differences in TMT-A between multiple functions MCI patients who are able to drive and those who are not (according to ASDE/UFOV tests), and f) the neuropsychological tests that correlate with the driving test were: Kohs' Block Design, Immediate Memory, Delayed Memory and TMT-A.


Antiquity of microRNAs and their targets in land plants.
MicroRNAs (miRNAs) affect the morphology of flowering plants by the posttranscriptional regulation of genes involved in critical developmental events. Understanding the spatial and temporal dynamics of miRNA activity during development is therefore central for understanding miRNA functions. We describe a microarray suitable for detection of plant miRNAs. Profiling of Arabidopsis thaliana miRNAs during normal development extends previous expression analyses, highlighting differential expression of miRNA families within specific organs and tissue types. Comparison of our miRNA expression data with existing mRNA microarray data provided a global intersection of plant miRNA and mRNA expression profiles and revealed that tissues in which a given miRNA is highly expressed are unlikely to also show high expression of the corresponding targets. Expression profiling was also used in a phylogenetic survey to test the depth of plant miRNA conservation. Of the 23 families of miRNAs tested, expression of 11 was detected in a gymnosperm and eight in a fern, directly demonstrating that many plant miRNAs have remained essentially unchanged since before the emergence of flowering plants. We also describe an empirical strategy for detecting miRNA target genes from unsequenced transcriptomes and show that targets in nonflowering plants as deeply branching as ferns and mosses are homologous to the targets in Arabidopsis. Therefore, several individual miRNA regulatory circuits have ancient origins and have remained intact throughout the evolution and diversification of plants.


A deep learning approach to permanent tooth germ detection on pediatric panoramic radiographs.
The aim of this study was to assess the performance of a deep learning system for permanent tooth germ detection on pediatric panoramic radiographs. In total, 4518 anonymized panoramic radiographs of children between 5 and 13 years of age were collected. YOLOv4, a convolutional neural network (CNN)-based object detection model, was used to automatically detect permanent tooth germs. Panoramic images of children processed in LabelImg were trained and tested in the YOLOv4 algorithm. True-positive, false-positive, and false-negative rates were calculated. A confusion matrix was used to evaluate the performance of the model. The YOLOv4 model, which detected permanent tooth germs on pediatric panoramic radiographs, provided an average precision value of 94.16% and an F1 value of 0.90, indicating a high level of significance. The average YOLOv4 inference time was 90 ms. The detection of permanent tooth germs on pediatric panoramic X-rays using a deep learning-based approach may facilitate the early diagnosis of tooth deficiency or supernumerary teeth and help dental practitioners find more accurate treatment options while saving time and effort.


Various modifications to internal mammary vessel anastomosis in breast reconstruction with deep inferior epigastric perforator flap.
Free autologous tissue transfer has been used in mastectomized patients for high-quality reconstruction. Since the deep inferior epigastric perforator flap was developed, it has been considered preferable owing to reduced donor site morbidity. At our institution, anastomosis of internal mammary vessels has been top priority because of better positioning and shorter pedicle length. We publish our experiences with various technical modifications that assure internal mammary vessel anastomosis. From 2003 to 2008, 35 patients received free deep inferior epigastric perforator flap for breast reconstruction by anastomosis with internal mammary vessels. Twenty-nine reconstructions were done immediately upon mastectomy whereas six were delayed. The patterns of anastomosis between the flap pedicle and internal mammary vessel were categorized and the results were followed by flap survival and complications. These deep inferior epigastric perforator flaps were all supplied by a single pedicle artery. Twenty-five of them were drained by a single pedicle vein, and the venous anastomosis pattern was end to end to the single internal mammary vein (IMV) (type I, N = 25). However, the other nine flaps were drained by one pedicle vein anastomosed end to end to double IMV (type II, N = 2), end to end to both proximal and distal ends of single IMV (type III, N = 5), end to end and end to side to single IMV (type IV, N = 2), and end to end to single IMV without anastomosing the other (type V, N = 1). All flaps were successful, except in one patient with type I anastomosis who received vascular reexploration due to pedicle twisting. Another patient with type I anastomosis needed revision due to partial fat necrosis of the flap. No other complications were found. Various modifications of internal mammary vessel anastomosis can be used to ensure the safety of deep inferior epigastric perforator flap in breast reconstruction.


[Spectro-fluorescence analysis of ALA-induced protoporphyrin IX in differential diagnosis of stomach disease].
The results of examination of 47 patients with confirmed diagnosis of cancer of the stomach (21 patients) or 26 suspects were analyzed. 2-4 hours after oral taking of Alasence in the dose 5-10 mg/kg, gastroscopy with spectrofluorescence analysis of ALA-induced protoporphyrin IX was performed. There were no toxic complications due to Alasence taking. The standard spectrodetector LESA-7 was used for fluorescence record registration. The fluorescence spectra were recorded in the range of 650-850 nm. The specific for protoporphyrin IX peak at 700 nm wavelength was analyzed. Fluorescent endoscopic diagnosis allowed to confirm stomach cancer in 21 patients, and to detect cancer in 7 patients, including 2 cases of cancer in situ. The contrast of protoporphyrin IX accumulation (tumor/norm ratio) ranged from 2.5 to 18, that was enough for differential diagnosis in the majority of cases. In analysis of spectrograms for correct contrast calculation it is necessary to take into account the own fluorescence, with was high in some cases.


Effect of Potassium Citrate on Calcium Phosphate Stones in a Model of Hypercalciuria.
Potassium citrate is prescribed to decrease stone recurrence in patients with calcium nephrolithiasis. Citrate binds intestinal and urine calcium and increases urine pH. Citrate, metabolized to bicarbonate, should decrease calcium excretion by reducing bone resorption and increasing renal calcium reabsorption. However, citrate binding to intestinal calcium may increase absorption and renal excretion of both phosphate and oxalate. Thus, the effect of potassium citrate on urine calcium oxalate and calcium phosphate supersaturation and stone formation is complex and difficult to predict. To study the effects of potassium citrate on urine supersaturation and stone formation, we utilized 95th-generation inbred genetic hypercalciuric stone-forming rats. Rats were fed a fixed amount of a normal calcium (1.2%) diet supplemented with potassium citrate or potassium chloride (each 4 mmol/d) for 18 weeks. Urine was collected at 6, 12, and 18 weeks. At 18 weeks, stone formation was visualized by radiography. Urine citrate, phosphate, oxalate, and pH levels were higher and urine calcium level was lower in rats fed potassium citrate. Furthermore, calcium oxalate and calcium phosphate supersaturation were higher with potassium citrate; however, uric acid supersaturation was lower. Both groups had similar numbers of exclusively calcium phosphate stones. Thus, potassium citrate effectively raises urine citrate levels and lowers urine calcium levels; however, the increases in urine pH, oxalate, and phosphate levels lead to increased calcium oxalate and calcium phosphate supersaturation. Potassium citrate induces complex changes in urine chemistries and resultant supersaturation, which may not be beneficial in preventing calcium phosphate stone formation.


The Impact of Obesity and Diabetes on the Risk of Disease and Death due to Invasive Group A Streptococcus Infections in Adults.
Invasive group A Streptococcus (iGAS) infections cause significant morbidity and mortality worldwide. We analyzed whether obesity and diabetes were associated with iGAS infections and worse outcomes among an adult US population. We determined the incidence of iGAS infections using 2010-2012 cases in adults aged ≥ 18 years from Active Bacterial Core surveillance (ABCs), a population-based surveillance system, as the numerator. For the denominator, we used ABCs catchment area population estimates from the 2011 to 2012 Behavioral Risk Factor Surveillance System (BRFSS) survey. The relative risk (RR) of iGAS was determined by obesity and diabetes status after adjusting for age group, gender, race, and other underlying conditions through binomial logistic regression. Multivariable logistic regression was used to determine whether obesity or diabetes was associated with increased odds of death due to iGAS compared to normal weight and nondiabetic patients, respectively. Between 2010 and 2012, 2927 iGAS cases were identified. Diabetes was associated with an increased risk of iGAS in all racial groups (adjusted risk ratio [aRR] ranged from 2.71 to 5.08). Grade 3 obesity (body mass index [BMI] ≥ 40) was associated with an increased risk of iGAS for whites (aRR = 3.47; 95% confidence interval [CI], 3.00-4.01). Grades 1-2 (BMI = 30.0-<40.0) and grade 3 obesity were associated with an increased odds of death (odds ratio [OR] = 1.55, [95% CI, 1.05, 2.29] and OR = 1.62 [95% CI, 1.01, 2.61], respectively) when compared to normal weight patients. These results may help target vaccines against GAS that are currently under development. Efforts to develop enhanced treatment regimens for iGAS may improve prognoses for obese patients.


Platelet glycoprotein Ib alpha receptor polymorphisms and recurrent ischaemic events in acute coronary syndrome patients.
To examine the relationship between polymorphisms in the platelet receptor glycoprotein (GP) Ib(alpha) and recurrent ischaemic events, and assess their impact on response to anti-platelet treatment. 1014 patients presenting with unstable coronary syndrome were recruited from the OPUS-TIMI 16 clinical trial of the platelet GPIIb/IIIa antagonist, orbofiban. The subjects were genotyped for two polymorphisms in the gene for GPIb(alpha). These were a T-5C polymorphism in the 5' untranslated Kozak region of the GPIb(alpha) gene, and the variable number of tandem repeats (VNTR) in the macroglycopeptide region.165 patients had events (recurrent ischaemia, urgent revascularisation, myocardial infarction (MI), stroke and death). There was no effect of the number of -5C alleles on composite endpoint frequency among Caucasian subjects (test for trend, p = 0.47). However, MI risk increased with the number of -5C alleles carried, with MI occurring in 2.3% of patients with the -5T/-5T genotype, 5.0% of -5T/-5C, and 16.7% of -5C/-5C (p < 0.01). The effect of treatment on MI outcome was not significantly modified by genotype (test for interaction, p = 0.10). The overall risk of bleeding was not strongly influenced by either the -5C or the VNTR polymorphisms. In an unstable coronary syndrome population the T-5C polymorphism in GPIb(alpha) influences risk of subsequent MI.


Simulation of sugar kelp (Saccharina latissima) breeding guided by practices to accelerate genetic gains.
Though Saccharina japonica cultivation has been established for many decades in East Asian countries, the domestication process of sugar kelp (Saccharina latissima) in the Northeast United States is still at its infancy. In this study, by using data from our breeding experience, we will demonstrate how obstacles for accelerated genetic gain can be assessed using simulation approaches that inform resource allocation decisions. Thus far, we have used 140 wild sporophytes that were sampled in 2018 from the northern Gulf of Maine to southern New England. From these sporophytes, we sampled gametophytes and made and evaluated over 600 progeny sporophytes from crosses among the gametophytes in 2019 and 2020. The biphasic life cycle of kelp gives a great advantage in selective breeding as we can potentially select both on the sporophytes and gametophytes. However, several obstacles exist, such as the amount of time it takes to complete a breeding cycle, the number of gametophytes that can be maintained in the laboratory, and whether positive selection can be conducted on farm-tested sporophytes. Using the Gulf of Maine population characteristics for heritability and effective population size, we simulated a founder population of 1,000 individuals and evaluated the impact of overcoming these obstacles on rate of genetic gain. Our results showed that key factors to improve current genetic gain rely mainly on our ability to induce reproduction of the best farm-tested sporophytes, and to accelerate the clonal vegetative growth of released gametophytes so that enough gametophyte biomass is ready for making crosses by the next growing season. Overcoming these challenges could improve rates of genetic gain more than 2-fold. Future research should focus on conditions favorable for inducing spring reproduction, and on increasing the amount of gametophyte tissue available in time to make fall crosses in the same year.


Tetramethylpyrazine attenuates adriamycin-induced apoptotic injury in rat renal tubular cells NRK-52E.
Tetramethylpyrazine (TMP), a compound purified from Rhizoma Ligustici, is a widely used active ingredient in Chinese herbal medicine to treat cardiovascular diseases on account of its vasodilatory actions and antiplatelet activity. Studies have shown that TMP can remove oxygen free radicals and protect rat kidney from ischemia-reperfusion injury. In addition, adriamycin-induced nephrosis in rats is commonly used in pharmacological studies of human chronic renal diseases. Apoptosis of renal tubular cells has been reported in adriamycin-treated rats. To examine the therapeutic potential of TMP on chronic progressive renal diseases, adriamycin-induced injury in rat renal tubular cells NRK-52E has been used to monitor its protective effect. In TUNEL staining, TMP showed a dose-dependent protective effect against adriamycin-induced apoptosis in NRK-52E cells. Pretreatment of the cells with 10 or 100 microM of TMP effectively decreased the reactive oxygen species (ROS) formation induced by adriamycin, as measured in fluorescent assays. TMP was found to reduce the adriamycin-stimulated activities of caspase-3, caspase-8 and caspase-9, inhibit adriamycin-induced release of cytochrome C, and elevate the expression of Bcl-x (L). TMP was also able to inhibit the death receptor signaling pathway and suppress the activation of transcription factor NF-kappaB in adriamycin-treated NRK-52E cells. Based on the results of this study, we suggest that TMP can attenuate adriamycin-induced oxidative stress and apoptotic injury in NRK-52E cells, and that it may have therapeutic potential for patients with renal diseases. TMP: tetramethylpyrazine LDH: lactate dehydrogenase ROS: reactive oxygen species DCF: 2',7'-dichlorofluorescein TNF-alpha: tumor necrosis factor-alpha TUNEL: terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling.


Nutritional Deficiency in Early Life Facilitates Aging-Associated Cognitive Decline.
Nutrition is important for the fetal developmental programming. Nutritional deficiency in early life could increase the susceptibility to many aging-related disorders including cognitive decline. Our study aims to investigate the effect of early famine exposure on aging-associated cognitive function. We recruited 6790 subjects born between 1956 to 1964 during which the Great Chinese Famine occurred (1959-1961). Cognitive function of these subjects were evaluated using the Mini-Mental State Examination (MMSE), the Activities of Daily Living scale (ADL), the Instrumental Activities of Daily Living scale (IADL) and the Clinical Dementia Rating (CDR). Our study identified that early exposure to the famine significantly increased the risk of cognitive impairments in later life, leading to higher prevalence of Mild Cognitive Impairment (MCI) and dementia. We also found the sex and rural-urban differences in this malnutrition-induced effect. Illiteracy, history of stroke or diabetes mellitus are great risk factors to facilitate the cognitive decline. These findings demonstrate that exposure to famine during early life including prenatal period and early childhood facilitates aging-associated cognitive deficits.


Candidaemia in a tertiary hospital in Nigeria.
Candidaemia is a widely-studied and reviewed topic in the developed world; however, there is a dearth of information on nosocomial candidaemia in Nigeria, despite the increasing use of more invasive therapeutic modalities, immunosuppressive agents and increasing incidence of immunosuppression as a result of malignancies and HIV. To determine the hospital-based frequency of candidaemia in a tertiary hospital in Ibadan, Nigeria. This was a prospective descriptive study which included 230 immunosuppressed patients. All isolates were identified to the species level using both conventional and automated methods. Thereafter, all Candida species isolated were tested for antifungal susceptibility using the broth microdilution method. Candidaemia occurred in 12 (5.21%) of the 230 study patients, with C. tropicalis accounting for 50% of the infections. Four patients (33.3%) presented with C. parapsilosis, one (8.3%) with C. albicans and one (8.3%) with a mixed infection of C. albicans and C. tropicalis. All 12 isolates were sensitive to fluconazole (minimal inhibitory concentration < 8 mg/mL). Univariate analysis revealed that old age, multiple surgeries and long-term hospitalisation were significant contributing factors for the occurrence of candidaemia. Eleven (91.7%) of the 12 patients with candidaemia had Candida colonisation of other sterile sites including the bladder, peritoneum and trachea. Furthermore, bivariate analysis revealed that mucositis (p = 0.019) and diarrhoea (p = 0.017) were significantly associated with an increased risk of candidaemia. The crude mortality rate of candidaemia was 91.7%. This study highlights the significance of nosocomial candidaemia and the need for proactive laboratory investigation and clinical management of this life-threatening disease.


NanoCell electronic memories.
NanoCells are disordered arrays of metallic islands that are interlinked with molecules between micrometer-sized metallic input/output leads. In the past, simulations had been conducted showing that the NanoCells may function as both memory and logic devices that are programmable postfabrication. Reported here is the first assembly of a NanoCell with disordered arrays of molecules and Au islands. The assembled NanoCells exhibit reproducible switching behavior and two types of memory effects at room temperature. The switch-type memory is characteristic of a destructive read, while the conductivity-type memory features a nondestructive read. Both types of memory effects are stable for more than a week at room temperature, and bit level ratios (0:1) of the conductivity-type memory have been observed to be as high as 10(4):1 and reaching 10(6):1 upon ozone treatment, which likely destroys extraneous leakage pathways. Both molecular electronic and nanofilamentary metal switching mechanisms have been considered, though the evidence points more strongly toward the latter. The approach here demonstrates the efficacy of a disordered nanoscale array for high-yielding switching and memory while mitigating the arduous task of nanoscale patterning.


Effects of the bifunctional antitumor intercalator ditercalinium on DNA in mouse leukemia L1210 cells and DNA topoisomerase II.
Ditercalinium, a 7H-pyridocarbazole dimer (bisintercalator) belongs to a new class of antineoplastic intercalating agents. To investigate its mechanism of cytotoxicity, the effects of ditercalinium on DNA were assessed using normal (L1210) and drug-resistant (L1210/PyDi1) mouse leukemia cells. Alkaline elution assays demonstrated that ditercalinium produced no DNA strand breaks, DNA-protein cross-links, or DNA-DNA cross-links, eliminating these effects as cytotoxic lesions. This result sets ditercalinium apart from other intercalating agents with respect to its interaction with DNA. Nucleoids (histone-depleted chromatin) from ditercalinium-treated L1210 cells were considerably more compact than those from untreated cells, as determined by sedimentation in neutral sucrose gradients. In contrast, nucleoids from ditercalinium-treated L1210/PyDi1 (resistant) cells were similar in compactness to those from control cells. Thus, ditercalinium altered chromatin structure in vivo. The effect of the bisintercalator on purified DNA topoisomerase II, an intracellular target of monointercalators, was measured in vitro. Ditercalinium (5 X 10(-7) M) completely inhibited both the formation of covalent complexes between this enzyme and simian virus 40 DNA and the enzyme-induced DNA cleavage. In addition, ditercalinium induced DNA catenation in the presence of topoisomerase II and adenosine triphosphate. Thus, the cytotoxicity of ditercalinium may derive from a mechanism that, although involving topoisomerase II, is manifested by condensation of DNA rather than by the induction of protein-associated DNA strand breaks.


Low end-tidal CO2 as a real-time severity marker of intra-anaesthetic acute hypersensitivity reactions.
Prompt diagnosis of intra-anaesthetic acute hypersensitivity reactions (AHR) is challenging because of the possible absence and/or difficulty in detecting the usual clinical signs and because of the higher prevalence of alternative diagnoses. Delayed epinephrine administration during AHR, because of incorrect/delayed diagnosis, can be associated with poor prognosis. Low end-tidal CO2 (etCO2) is known to be linked to low cardiac output. Yet, its clinical utility during suspected intra-anaesthetic AHR is not well documented. Clinical data from the 86 patients of the Neutrophil Activation in Systemic Anaphylaxis (NASA) multicentre study were analysed. Consenting patients with clinical signs consistent with intra-anaesthetic AHR to a neuromuscular blocking agent were included. Severe AHR was defined as a Grade 3-4 of the Ring and Messmer classification. Causes of AHR were explored following recommended guidelines. Among the 86 patients, 50% had severe AHR and 69% had a confirmed/suspected IgE-mediated event. Occurrence and minimum values of arterial hypotension, hypocapnia and hypoxaemia increased significantly with the severity of AHR. Low etCO2 was the only factor able to distinguish mild [median 3.5 (3.2;3.9) kPa] from severe AHR [median 2.4 (1.6;3.0) kPa], without overlap in inter-quartile range values, with an area under the receiver operator characteristic curve of 0.92 [95% confidence interval: 0.79-1.00]. Among the 41% of patients who received epinephrine, only half received it as first-line therapy despite international guidelines. An etCO2 value below 2.6 kPa (20 mm Hg) could be useful for prompt diagnosis of severe intra-anaesthetic AHR, and could facilitate early treatment with titrated doses of epinephrine. NCT01637220.


Pediatric Ventricular Assist Device Support in the Netherlands.
This study aimed to evaluate the changes in heart transplantation (HTx) waiting list mortality following the introduction of the Berlin Heart EXCOR (BH EXCOR) in the Netherlands, as well as the occurrence of adverse events in these children. A retrospective, single-center study was conducted including all pediatric patients (≤18 years) awaiting HTx. Patients were grouped in two eras based on availability of the BH EXCOR in our center, era I (1998-2006; not available) and era II (2007 to July 31, 2018; available). In total, 87 patients were included, 15 in era I and 72 in era II. Extracorporeal membrane oxygenator support was required in 1 (7%) patient in era I and in 13 (18%) patients in era II. Overall mortality (7/15 in era I vs 16/72 in era II; 47% vs 22%, P = .06) and transplantation rates (8/15 in era I vs 47/72 in era II; 53% vs 65%, P = .39) did not differ significantly. Eleven (39%) patients of the pediatric ventricular assist device (VAD) population died, with the predominant cause being cerebrovascular accidents (CVAs) in eight (29%) patients. Furthermore, 14 (50%) of the pediatric VAD patients survived to transplantation. Adverse events most frequently occurring in VAD patients included CVA in 14 (50%), mostly (68%) within 30 days after VAD implantation, and bleeding requiring rethoracotomy in 14 (50%), all within 30 days after VAD implantation. The introduction of the BH EXCOR has positively impacted the survival of pediatric patients with end-stage heart failure in our center. The predominant cause of death changed from end-stage heart failure in era I to CVA in era II. We emphasize the need for large prospective registry-based studies.


Can we predict indirect interactions from quantitative food webs?--an experimental approach.
1. Shared enemies may link the dynamics of their prey. Recently, quantitative food webs have been used to infer that herbivorous insect species attacked by the same major parasitoid species will affect each other negatively through apparent competition. Nonetheless, theoretical work predicts several alternative outcomes, including positive effects. 2. In this paper, we use an experimental approach to link food web patterns to realized population dynamics. First, we construct a quantitative food web for three dominant leaf miner species on the oak Quercus robur. We then measure short- and long-term indirect effects by increasing leaf miner densities on individual trees. Finally, we test whether experimental results are consistent with natural leaf miner dynamics on unmanipulated trees. 3. The quantitative food web shows that all leaf miner species share a minimum of four parasitoid species. While only a small fraction of the parasitoid pool is shared among Tischeria ekebladella and each of two Phyllonorycter species, the parasitoid communities of the congeneric Phyllonorycter species overlap substantially. 4. Based on the structure of the food web, we predict strong short- and long-term indirect interactions between the Phyllonorycter species, and limited interactions between them and T. ekebladella. As T. ekebladella is the main source of its own parasitoids, we expect to find intraspecific density-dependent parasitism in this species. 5. Consistent with these predictions, parasitism in T. ekebladella was high on trees with high densities of conspecifics in the previous generation. Among leaf miner species sharing more parasitoids, we found positive rather than negative interactions among years. No short-term indirect interactions (i.e. indirect interactions within a single generation) were detected. 6. Overall, this study is the first to experimentally demonstrate that herbivores with overlapping parasitoid communities may exhibit independent population dynamics - or even apparent mutualism. Hence, it proves the potential for versatile indirect interactions in nature, and suggests that the link between patterns in food web structure and realized population dynamics should be verified by rigorous experiments.


Simulation of malaria-infected red blood cells in microfluidic channels: Passage and blockage.
Malaria-infected red blood cells (iRBCs) become less deformable with the progression of infection and tend to occlude microcapillaries. This process has been investigated in vitro using microfluidic channels. The objective of this paper is to provide a quantitative basis for interpreting the experimental observations of iRBC occlusion of microfluidic channels. Using a particle-based model for the iRBC, we simulate the traverse of iRBCs through a converging microfluidic channel and explore the progressive loss of cell deformability due to three factors: the stiffening of the membrane, the reduction of the cell's surface-volume ratio, and the growing solid parasites inside the cell. When examined individually, each factor tends to hinder the passage of the iRBC and lengthen the transit time. Moreover, at sufficient magnitude, each may lead to obstruction of narrow microfluidic channels. We then integrate the three factors into a series of simulations that mimic the development of malaria infection through the ring, trophozoite, and schizont stages. These simulations successfully reproduce the experimental observation that with progression of infection, the iRBC transitions from passage to blockage in larger and larger channels. The numerical results suggest a scheme for quantifying iRBC rigidification through microfluidic measurements of the critical pressure required for passage.


Results of Surgery for Low-Grade Brain Arteriovenous Malformation Resection by Early Career Neurosurgeons: An Observational Study.
For sustainability of arteriovenous malformation (AVM) surgery, results from early career cerebrovascular neurosurgeons (ECCNs) must be acceptably safe. To determine whether ECCNs performance of Spetzler-Ponce Class A AVM (SPC A) resection can be acceptably safe. ECCNs completing a cerebrovascular fellowship (2004-2015) with the last author were included. Inclusion of the ECCN cases occurred if they: had a prospective database of all AVM cases since commencing independent practice; were the primary surgeon on SPC A; and had made the significant management decisions. All SPC A surgical cases from the beginning of the ECCN's independent surgical practice to a maximum of 8 yr were included. An adverse outcome was considered a complication of surgery leading to a new permanent neurological deficit with a last modified Rankin Scale score >1. A cumulative summation (Cusum) plot examined the performance of each surgery. The highest acceptable level of adverse outcomes for the Cusum was 3.3%, derived from the upper 95% confidence interval of the last author's reported series. Six ECCNs contributed 110 cases for analysis. The median number of SPC A cases operated by each ECCN was 16.5 (range 4-40). Preoperative embolization was performed in 5 (4.5%). The incidence of adverse outcomes was 1.8% (95% confidence interval: <0.01%-6.8%). At no point during the accumulated series did the combined cohort become unacceptable by the Cusum plot. ECCNs with appropriate training appointed to large-volume cerebrovascular centers can achieve results for surgery for SPC A that are not appreciably worse than those published from high-volume neurosurgeons.


An empirical comparison of neural networks and machine learning algorithms for EEG gait decoding.
Previous studies of Brain Computer Interfaces (BCI) based on scalp electroencephalography (EEG) have demonstrated the feasibility of decoding kinematics for lower limb movements during walking. In this computational study, we investigated offline decoding analysis with different models and conditions to assess how they influence the performance and stability of the decoder. Specifically, we conducted three computational decoding experiments that investigated decoding accuracy: (1) based on delta band time-domain features, (2) when downsampling data, (3) of different frequency band features. In each experiment, eight different decoder algorithms were compared including the current state-of-the-art. Different tap sizes (sample window sizes) were also evaluated for a real-time applicability assessment. A feature of importance analysis was conducted to ascertain which features were most relevant for decoding; moreover, the stability to perturbations was assessed to quantify the robustness of the methods. Results indicated that generally the Gated Recurrent Unit (GRU) and Quasi Recurrent Neural Network (QRNN) outperformed other methods in terms of decoding accuracy and stability. Previous state-of-the-art Unscented Kalman Filter (UKF) still outperformed other decoders when using smaller tap sizes, with fast convergence in performance, but occurred at a cost to noise vulnerability. Downsampling and the inclusion of other frequency band features yielded overall improvement in performance. The results suggest that neural network-based decoders with downsampling or a wide range of frequency band features could not only improve decoder performance but also robustness with applications for stable use of BCIs.


The role of ZA channel water-mediated interactions in the design of bromodomain-selective BET inhibitors.
The Bromodomain and Extra-Terminal domain (BET) family of proteins are involved in the regulation of gene transcription, and their dysregulation is implicated in several diseases including cancer. BET proteins contain two tandem bromodomains (BD1 and BD2) that independently recognize acetylated-lysine residues and appear to have distinct biological roles. We compared several published co-crystal structures and found five positions near the substrate binding pocket that vary between BET bromodomains. One position located in the ZA loop has unique properties. In BRD2-4, this residue is glutamine in BD1 and lysine in BD2; in BRDT, this residue is arginine in BD1 and asparagine in BD2. Using molecular modeling, we identified differences in the water-mediated network at this position between bromodomains. Molecular dynamics simulations helped rationalize the observed bromodomain selectivity for exemplar BET inhibitors and a congeneric series of tetrahydroquinolines (THQ) that differed by a single heteroatom near the ZA channel. The 2-furan SJ830599, the most BD2-selective THQ analog, did not disrupt the water-mediated networks in either domain, but was electrostatically-repulsed by the specific arrangement of the W5 water dipole in BD1. Our work underscores the value of exploring water-mediated interactions to study ligand binding, and highlights the difficulty of optimizing polar interactions due to high desolvation penalties. Finally, we suggest further modifications to THQ-based BET inhibitors that would increase BD2-selectivity in BRD2-4, while minimizing affinity for one or both bromodomains of BRDT.


Identification of the epitope for anti-cystatin C antibody.
Human cystatin C (hCC), like many other amyloidogenic proteins, has been shown to form dimers by exchange of subdomains of the monomeric protein. Considering the model of hCC fibrillogenesis by propagated domain swapping, it seems possible that inhibition of this process should also suppress the entire process of dimerization and fibrillogenesis which leads to specific amyloidosis (hereditary cystatin C amyloid angiopathy (HCCAA)). It was reported that exogenous agents like monoclonal antibody against cystatin C are able to suppress formation of cystatin C dimers. In the effort to find a way of controlling the cystatin fibrillization process, the interactions between monoclonal antibody Cyst-13 and cystatin C were studied in detail. The present work describes the determination of the epitope of hCC to a monoclonal antibody raised against cystatin C, Cyst-13, by MALDI mass spectrometry, using proteolytic excision of the immune complex. The shortest epitope sequence was determined as hCC(107-114). Affinity studies of synthetic peptides revealed that the octapeptide with epitope sequence does not have binding ability to Cyst-13, whereas its longer counterpart, hCC(105-114), binds the studied antibody. The secondary structure of the peptides with epitope sequence was studied using circular dichroism and NMR spectroscopy.


Stimulus rate increases lateralisation in linguistic and non-linguistic tasks measured by functional transcranial Doppler sonography.
Studies to date that have used fTCD to examine language lateralisation have predominantly used word or sentence generation tasks. Here we sought to further assess the sensitivity of fTCD to language lateralisation by using a metalinguistic task which does not involve novel speech generation: rhyme judgement in response to written words. Line array judgement was included as a non-linguistic visuospatial task to examine the relative strength of left and right hemisphere lateralisation within the same individuals when output requirements of the tasks are matched. These externally paced tasks allowed us to manipulate the number of stimuli presented to participants and thus assess the influence of pace on the strength of lateralisation. In Experiment 1, 28 right-handed adults participated in rhyme and line array judgement tasks and showed reliable left and right lateralisation at the group level for each task, respectively. In Experiment 2 we increased the pace of the tasks, presenting more stimuli per trial. We measured laterality indices (LIs) from 18 participants who performed both linguistic and non-linguistic judgement tasks during the original 'slow' presentation rate (5 judgements per trial) and a fast presentation rate (10 judgements per trial). The increase in pace led to increased strength of lateralisation in both the rhyme and line conditions. Our results demonstrate for the first time that fTCD is sensitive to the left lateralised processes involved in metalinguistic judgements. Our data also suggest that changes in the strength of language lateralisation, as measured by fTCD, are not driven by articulatory demands alone. The current results suggest that at least one aspect of task difficulty, the pace of stimulus presentation, influences the strength of lateralisation during both linguistic and non-linguistic tasks.


Incidence and Outcomes of Surgical Bailout During TAVR: Insights From the STS/ACC TVT Registry.
The aim of this study was to evaluate the incidence and outcomes of surgical bailout during transcatheter aortic valve replacement (TAVR). The incidence and outcomes of unplanned conversion to open heart surgery, or "surgical bailout," during TAVR are not well characterized. Data from the Society of Thoracic Surgeons/American College of Cardiology TVT (Transcatheter Valve Therapy) Registry was analyzed with respect to whether surgical bailout was performed during the index TAVR procedure. A Cox proportional hazards models was used to evaluate 1-year mortality and major adverse cardiovascular events. Between November 2011 and September 2015, a total of 47,546 patients underwent TAVR. Surgical bailout during TAVR was performed in 1.17% of the cases (n = 558); the most frequent indications were valve dislodgement (22%), ventricular rupture (19.9%), and aortic valve annular rupture (14.2%). The incidence of surgical bailout significantly decreased over time (first tertile 1.25%, second tertile 1.43%, third tertile 1.04%; p = 0.0088). The 30-day and 1-year incidence of major adverse cardiovascular events (54.6% vs. 7.4% [p < 0.0001] and 63.92% vs. 20.29% [p < 0.0001]) and all-cause mortality (50.00% vs. 4.98% [p < 0.0001] and 59.79% vs. 17.06% [p < 0.0001]) were significantly higher in those who underwent bailout. Independent predictors of surgical bailout included female sex, hemoglobin, left ventricular ejection fraction, nonelective cases, and nonfemoral access. Body surface area was the only independent predictor of survival after surgical bailout. In a large, nationally representative registry, the need for surgical bailout in patients undergoing TAVR is low, and its incidence has decreased over time. However, surgical bailout after TAVR is associated with poor outcomes, including 50% mortality at 30 days.


Specific mutations alter fibrillation kinetics, fiber morphologies, and membrane interactions of pentapeptides derived from human calcitonin.
Protein misfolding and fibrillation are fundamental facets underlying a diverse group of amyloid disorders and diseases. The molecular factors responsible for amyloid protein toxicity and pathological consequences, however, are still not fully understood. The involvement of specific residues or sequence elements in fibril formation and the interactions of amyloid protein aggregates with membranes are believed to constitute two critical parameters contributing to amyloidogenesis and amyloid pathologies. This work aims to elucidate sequence determinants and membrane-protein interactions of five-residue peptide fragments derived from a core amyloidogenic sequence of human calcitonin. We show that single-residue mutations within the native pentapeptide sequence significantly modulate the kinetics of peptide self-assembly, alter beta-sheet organization between parallel and antiparallel arrangements, and modify fibrillar morphologies. We further demonstrate that hydrophobic or aromatic interactions are not prerequisites for peptide fiber formation. The experiments also disclose pronounced effects of lipid vesicles comprising cholesterol and negatively charged phospholipids on the rate of fibrillation and fiber structures formed by the short peptides. This work indicates that the structural and kinetic properties of peptide fibrils as well as lipid interactions of fibrillar species are interrelated and are significantly affected by specific residues within amyloid peptide sequences.


Janus kinase inhibitors for atopic dermatitis: a promising treatment modality.
Atopic dermatitis (AD) is chronic, pruritic, inflammatory skin disease that affects a significant portion of the population in industrialized nations. For nonresponders to conventional therapies, AD can significantly reduce sleep quality and quality of life. AD pathogenesis is multifactorial and involves multiple immune pathways, with recent evidence of T helper (Th)2, Th17 and Th22 axis attenuation in various AD endotypes and racial subtypes. Inhibition of the conserved Janus kinase (JAK) signalling pathway represents a promising therapeutic avenue to reduce the activation of multiple proinflammatory mediators involved in AD pathogenesis. JAK inhibitors exist in both oral and topical forms with variable specificity for the receptor tyrosine kinases JAK1, JAK2, JAK3 and tyrosine kinase 2. Oral formulations include abrocitinib, upadacitinib, baricitinib and gusacitinib, and are most appropriate for patients with moderate to severe AD. Emerging topical formulation in development include ruxolitinib and deglocitinib, which may be used in patients with localized AD and also adjunctively with systemic therapy in patients with more severe disease. With observed rapidity in itch relief and accompanying dramatic reduction in inflammatory lesion count, JAK inhibitors represent a promising new treatment to revolutionize the management of AD.


Effect of wheat bran upon gastro-intestinal transit in germ-free and conventional rats.
Germ-free and conventional rats were fed a semi-synthetic diet including 10% wheat bran for 1 month. They were compared to similar rats fed the same diet without bran. Transit of polyethylene glycol (PEG) 4000 was studied in giving the marker either in saline or in the diet. The presence of a bacterial flora was found to accelerate small intestine transit and total transit. The ingestion of solid food slowed gastric emptying but had little effect on small intestine transit. Wheat bran slowed gastric emptying of PEG in most of the experimental groups. It had no significant effect on small intestine transit except in germ-free rats having received the marker in solid food. It accelerated total transit in germ-free and conventional rats. The results suggest that bran mainly exerts its action in the hindgut. The role of microflora in this action of bran is discussed.


Counting sectioned cells via mathematical reconstruction.
A new method for determining the number of neurons in sectioned tissue is presented. The method does not involve identification of subcellular structures; rather, it uses estimates of the mean diameters of sections of the neuronal somata (with or without nuclei). All such sections are termed profiles. A mathematical model is developed to reconstruct the cell population from a size histogram of the profiles. Although the model is simple, the calculations are numerous and best done on a computer. A program that performs these calculations is provided. We discuss the idealizations on which the model is based and test the method in various ways: on hand- and computer-generated data in which imaginary spheres of known size were sectioned; on two small samples of real cells for which both cell and profile size histograms were available; and on a sample of potatoes, sliced by hand. In every case the estimate was within 10% of the actual number of cells (or potatoes). The method is robust in that it is relatively insensitive to section thickness, sample size, somal morphology, and observer error with respect to missing the small or thin profiles from any given cell. Results from the present model are compared to those obtained by using other cell count correction schemes that are currently employed. We call our method recursive translation.


Scanning electron microscopic features of lacrimal drainage silastic stents: Comparison of various Crawford and large-diameter stents.
This study aimed to examine the differences in the biofilms and physical deposits on Crawford stents compared to large-diameter stents. A prospective interventional study was performed on a series of patients undergoing external or endoscopic dacryocystorhinostomy (DCR) and endoluminal lacrimal duct recanalization (ELDR) with either Crawford or large-diameter stents. All the Crawford stents were retrieved at six weeks and the large-diameter ones at eight weeks following the surgical intervention. There was no evidence of post-operative infection in any of the patients. Following extubation, standard protocols of scanning electron microscopy were used to assess the biofilms and physical deposits on the stents. A total of 15 stents were studied. Of these, twelve were Crawford, and three were large-diameter stents. The Crawford stents were from two different manufacturers. All the stents demonstrated evidence of biofilm formation and physical deposits. The Crawford stents showed thin biofilms and sparse physical deposits, but there were no demonstrable differences amongst stents from different manufacturers. However, the deposits and biofilms were thicker and more extensive in the large-diameter stents than the Crawford ones. The biofilms from all stents showed the presence of polymicrobial communities within the exopolysaccharide matrix. The present study found differences in biofilms and physical deposits between Crawford and large-diameter stents. These differences can be partly explained by stent duration, size, and their tissue interactions.


Involvement of the medial preoptic area in the anorectic action of estrogens.
The implication of the medial preoptic area (MPOA) as a site for estrogen in the regulation of energy balance was investigated. Food intake, O2 consumption (VO2), and CO2 production were measured in ovariectomized rats injected with estradiol (E2) in the medial preoptic nucleus (MPN). Moreover, knowing the potential for corticotropin-releasing factor (CRF) in the anorectic effects of estrogens, we identified estrogen receptors (ER) colocalized in CRF-containing cells of the MPOA and how MPN injections of CRF compared with estrogen injections with respect to VO2 and the VO2-to-CO2 production ratio (respiratory quotient RQ). These energy balance measurements after the injections of four different doses of E2 or CRF were carried out in meal-fed rats chronically implanted with a guide cannula targeted to the MPN. The identification of cells colocalizing ER and CRF was determined using a double-immunostaining procedure revealing ER and CRF immunoreactivities with two different couplers. The injection of E2 into the MPN induced a dose-dependent reduction in food intake, whereas it did not affect VO2 or RQ. Conversely, the injection of CRF into the MPN had no effect on food intake but increased VO2 and decreased RQ. The colocalization of ER and CRF immunoreactivities was found in the MPOA and adjacent regions of the bed nucleus of the stria terminalis. In conclusion, the results of this study provide evidence that the MPOA may represent a potential site for the anorectic effects of E2. Furthermore, the presence of ER and CRF in neurons of the MPOA and adjacent areas suggests a direct interaction between estrogens and the CRF system in the MPOA that is consistent with a role for CRF in the anorectic effects of estrogens. Finally, the results of this study indicate that the effects of a CRF injection into the MPOA differ from those of estrogens, suggesting that if CRF neurons are involved in the anorectic effect of estrogens they likely exert their action outside the MPOA.


Divergent Antigen-Specific Cellular Immune Responses during Asymptomatic Subclinical and Clinical States of Disease in Cows Naturally Infected with Mycobacterium avium subsp. paratuberculosis.
Infection of the host with Mycobacterium avium subsp. paratuberculosis results in chronic and progressive enteritis that traverses both subclinical and clinical stages. The mechanism(s) for the shift from an asymptomatic subclinical disease state to advanced clinical disease is not fully understood. In the present study, naturally infected dairy cattle were divided into subclinical and clinical infection groups, along with noninfected control cows of similar parity, to study host immune responses in different stages of infection. Both infection groups had higher levels of secretion of gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin-2 (IL-2) than control cows, whereas only clinical cows had increased secretion of IL-10, IL-12, and IL-18 upon stimulation of peripheral blood mononuclear cells (PBMCs) with antigen. Conversely, secretion of IL-17Α was decreased for clinical cows compared to subclinical and control cows. Proinflammatory cytokine genes were upregulated only for subclinical cows, whereas increased IL-10 and IL-17 gene expression levels were observed for both infection groups. Increased CD4+, CD8+, and γδ T cell receptor-positive (TCR+) T cells were observed for subclinical cows compared to clinical cows. Although clinical cows expressed antigen-specific immune responses, the profile for subclinical cows was one of a dominant proinflammatory response to infection. We reason that a complex coordination of immune responses occurs during M. avium subsp. paratuberculosis infection, with these responses shifting as the host transitions through the different stages of infection and disease (subclinical to clinical). A further understanding of the series of events characterized by Th1/Th2/Th17 responses will provide mechanisms for disease progression and may direct insightful intervention strategies.


Application of Stem Cell-Derived Extracellular Vesicles as an Innovative Theranostics in Microbial Diseases.
Extracellular vesicles (EVs), as nano-/micro-scale vehicles, are membranous particles containing various cargoes including peptides, proteins, different types of RNAs and other nucleic acids, and lipids. These vesicles are produced by all cell types, in which stem cells are a potent source for them. Stem cell-derived EVs could be promising platforms for treatment of infectious diseases and early diagnosis. Infectious diseases are responsible for more than 11 million deaths annually. Highly transmissible nature of some microbes, such as newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), drives researcher's interest to set up different strategies to develop novel therapeutic strategies. Recently, EVs-based diagnostic and therapeutic approaches have been launched and gaining momentum very fast. The efficiency of stem cell-derived EVs on treatment of clinical complications of different viruses and bacteria, such as SARS-CoV-2, hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), Staphylococcus aureus, Escherichia coli has been demonstrated. On the other hand, microbial pathogens are able to incorporate their components into their EVs. The microbe-derived EVs have different physiological and pathological impacts on the other organisms. In this review, we briefly discussed biogenesis and the fate of EVs. Then, EV-based therapy was described and recent developments in understanding the potential application of stem cell-derived EVs on pathogenic microorganisms were recapitulated. Furthermore, the mechanisms by which EVs were exploited to fight against infectious diseases were highlighted. Finally, the deriver challenges in translation of stem cell-derived EVs into the clinical arena were explored.


Morphological diversity of integumentary traits in fowl domestication: Insights from disparity analysis and embryonic development.
The domestication of the fowl resulted in a large diversity of integumental structures in chicken breeds. Several integumental traits have been investigated from a developmental genetics perspective. However, their distribution among breeds and their developmental morphology remain unexplored. We constructed a discrete trait-breed matrix and conducted a disparity analysis to investigate the variation of these structures in chicken breeds; 20 integumental traits of 72 chicken breeds and the red junglefowl were assessed. The analyses resulted in slight groupings of breed types comparable to standard breed classification based on artificial selection and chicken type use. The red junglefowl groups together with bantams and European breeds. We provide new data on the red junglefowl and four chicken breeds, demonstrating where and when variation arises during embryonic development. We document variation in developmental timing of the egg tooth and feather formation, as well as other kinds of developmental patterning as in the anlagen of different type of combs. Changes in epithelial-mesenchymal signaling interactions may drive the highly diverse integument in chickens. Experimental and comparative work has revealed that the cranial neural crest mesenchyme mediates its interactions with the overlying epithelium and is the likely source of patterning that generates diversity in integumental structures.


MED12, TERT and RARA in fibroepithelial tumours of the breast.
Fibroepithelial tumours are biphasic neoplasms of the breast comprising the common benign fibroadenomas and the less common phyllodes tumours (PTs), which have recurrent potential. PTs are classified into benign, borderline or malignant, based on five histopathological criteria, with malignant PTs having the highest metastatic capability. Accurate diagnosis can be challenging due to the subjective assessment of histopathological parameters. Fibroadenomas bear morphological similarities to benign PTs, while borderline and malignant PTs can sometimes be difficult to distinguish from other spindle cell tumours of the breast. From clonality studies to whole-genome sequencing, much research has been conducted to elucidate the molecular pathogenesis of fibroepithelial tumours, which, in turn, have allowed leveraging the findings for diagnostic applications, including grading of PTs. The most noteworthy discovery was of recurrent MED12 mutations in both fibroadenomas and PTs. Subsequent studies also uncovered relatively frequent genetic mutations in TERT promoter and RARA A customised panel of 16 most frequently mutated genes in fibroepithelial tissues has been compiled previously and has contributed to resolving a few diagnostic dilemmas. This review will introduce the 16 genes and focus on the top three that are most frequently mutated in fibroepithelial tumours: MED12, TERT, and RARA.


Mapping the electric field distribution of tightly focused cylindrical vector beams with gold nanorings.
In this paper gold nanorings (NRs) are applied as particularly well-suited sensing elements for mapping the radially symmetric electric fields in the high numerical aperture focus of cylindrical vector beams. The optical properties of gold nanorings are analyzed by a combination of extinction and single particle dark field spectroscopy as well as confocal photoluminescence (PL) imaging. The results are compared to numerical calculations. The in-plane components in the focus of the cylindrical vector beams are estimated through the PL intensity distributions of the NRs. The optimum overlap between the structure and excitation is visualized by a narrow centre spot in the far-field PL scan.


Cell-free cotranslation and selection using in vitro virus for high-throughput analysis of protein-protein interactions and complexes.
We have developed a simple and totally in vitro selection procedure based on cell-free cotranslation using a highly stable and efficient in vitro virus (IVV). Cell-free cotranslation of tagged bait and prey proteins is advantageous for the formation of protein complexes and allows high-throughput analysis of protein-protein interactions (PPI) as a result of providing in vitro instead of in vivo preparation of bait proteins. The use of plural selection rounds and a two-step purification of the IVV selection, followed by in vitro post-selection, is advantageous for decreasing false positives. In a single experiment using bait Fos, more than 10 interactors, including not only direct, but also indirect interactions, were enriched. Further, previously unidentified proteins containing novel leucine zipper (L-ZIP) motifs with minimal binding sites identified by sequence alignment as functional elements were detected as a result of using a randomly primed cDNA library. Thus, we consider that this simple IVV selection system based on cell-free cotranslation could be applicable to high-throughput and comprehensive analysis of PPI and complexes in large-scale settings involving parallel bait proteins.


Emergent Roles of Circular RNAs in Metabolism and Metabolic Disorders.
Circular RNAs (circRNAs) are an emerging group of long non-coding RNAs (lncRNAs) and have attracted attention again according to the progress in high-throughput sequencing in recent years. circRNAs are genome transcripts produced from pre-messenger (m)RNA regions in a specific process called "back-splicing," which forms covalently closed continuous loops. Due to their lack of a 5' cap and 3' poly-adenylated tails, circRNAs are remarkably more stable than linear RNAs. Functionally, circRNAs can endogenously sponge to microRNAs, interact with RNA-binding proteins (RBPs), or translate themselves. Moreover, circRNAs can be expressed in cell type- or tissue-specific expression patterns. Therefore, they are proposed to play essential roles in fine-tuning our body's homeostasis by regulating transcription and translation processes. Indeed, there has been accumulating emergent evidence showing that dysregulation of circRNAs can lead to metabolic disorders. This study explored the current knowledge of circRNAs that regulate molecular processes associated with glucose and lipid homeostasis and related pathogeneses of metabolic disorders. We also suggest the potential role of circRNAs as disease biomarkers and therapeutic targets.


Forgetting, fabricating, and telescoping: the instability of the medical history.
Patients' recollections of their past symptoms, illnesses, and episodes of care are often inconsistent from one inquiry to the next. Patients frequently fail to recall (and therefore underreport) the incidence of previous symptoms and events; tend to combine separate, similar occurrences into a single, generic memory; and falsely recall medical events and symptoms that did not in fact occur. This unreliability of recall is affected by personality characteristics and by the patient's current state at the time of recall. Thus, current anxiety or depression and pain or bodily distress foster the recall of symptoms and events that are not recalled when the patient is more comfortable. Finally, current beliefs about one's health and the nature and causes of one's illness also affect the recall of past symptoms and illness. Physicians can maximize the reliability of the clinical history by (1) noting and taking into account the patient's current physical and emotional state; (2) first establishing historical "anchor points" or memorable milestones; (3) decomposing generic memories by finding features that distinguish them from each other; and (4) recalling the clinical history in retrograde fashion, beginning with the most recent event and working backward.


The specificity and stability of the triton-extracted cytoskeletal framework of gerbil fibroma cells.
Cellular meshworks and topography of gerbil fibroma cells can be preserved by gentle extraction procedures using Triton X-100. We determined the stability and specificity of these cytoskeletal frameworks by measuring extraction rate and its sensitivity to exogenous protein. Two buffers were used, which mimicked the intracellular and extracellular ionic environments. With both buffers, extraction was nearly complete at 5 min. This pattern of extraction was seen both in 5- and 9-day-old cultures. The same pattern of extraction was seen when three different dilutions of cells were examined the second day after plating. Thus, extraction rate was largely independent of minor variations in ionic composition, age in culture, or cell density. Specificity of the cytoskeletal frameworks so produced was determined by competition with two different exogenous proteins (bovine serum albumin or ovalbumin), which did not remove any additional material from the cytoskeletal frameworks, even with over 10% exogenous protein in the extraction buffer. This pattern of extraction is not unique to gerbil fibroma cells. A similar pattern of extraction was seen for a series of cells: mouse 3T3 cells, 3T6 cells and SVPY 3T3 cells. These experiments indicate that the cytoskeletal framework produced by Triton extraction under appropriate conditions is stable after extraction for a period of 10 min or longer, and that the structures are specific, in that they are not disrupted by the presence of exogenous proteins.


Ultraviolet irradiation of herpes simplex virus (type 1): delayed transcription and comparative sensitivites of virus functions.
The delay in the replication of herpes simplex virus surviving u.v. irradiation occurs after the uncoating of virus, as judged by sensitivity to DNase. It occurs before translation, judged by the kinetics of appearance of various virus-specific proteins, and before transcription, judged by the detection of virus-specific RNA by in situ hybridization. Since the delays in both transcription and translation are reversed by photoreactivation, the simplest hypothesis is that pyrimidine dimers directly obstruct transcription;unless these are broken by photoreactivating enzymes, there will be transcriptional delay until reactivating processes have repaired the lesion. The u.v. sensitivities of the abilities to induce various enzymes (thymidine kinase, DNase and DNA polymerase) were only about four times less than that of infectivity. The The ability to induce the three enzymes was three times less sensitive than that of the structural antigen (Band II).


Central serous chorioretinopathy fundus autofluorescence comparison with two different confocal scanning laser ophthalmoscopes.
To compare the lesion characteristics of two different types of confocal scanning laser ophthalmoscopy (cSLO) autofluorescence (AF) images in central serous chorioretinopathy (CSC). The study included 63 eyes of 61 patients; 63 pairs of fundus autofluorescence (FAF) images were compared before CSC resolution in 63 eyes, FAF images of 31 eyes were also compared after CSC resolution. The lesion characteristics (brightness and composite pattern) were compared between Heidelberg Retina Angiograph 2 (HRA2; Heidelberg Engineering, Germany) and Optomap Tx (Optomap; Optos, Scotland) FAF images. The lesion composite pattern was categorized as diffuse or granular. Diffuse AF was defined as homogenously increased or decreased AF, and granular AF was defined as dot-like, coarse changes in AF. The mean disease duration and subretinal fluid (SRF) height in the spectral domain optical coherence tomography were compared according to the FAF image characteristics. Lesion brightness before CSC resolution was hypo-AF in 48 eyes (76.2 %), hyper-AF in three (4.8 %), and mixed-AF in 12 (19.0 %) in HRA2 FAF images. In comparison, nine (14.3 %) images were hypo-AF, 44 (69.8 %) were hyper-AF, and 10 (15.9 %) were mixed-AF in Optomap FAF images (P < 0.0001). There was no significant difference in lesion composite pattern between the two FAF image wavelengths. Patients with lesions that were hyper-AF in Optomap FAF and hypo-AF in HRA2 FAF had a shorter disease duration and greater SRF height (1 month, 281 um) than those who were hyper-AF in both Optomap and HRA2 images (26 months, 153 um; P = 0.004, 0.001). The two types of FAF images of CSC showed different lesion brightness before and after CSC resolution but demonstrated similar lesion composite patterns.