Soluble Epoxide Hydrolase Inhibitor and 14,15-Epoxyeicosatrienoic Acid-Facilitated Long-Term Potentiation through cAMP and CaMKII in the Hippocampus.
Epoxyeicosatrienoic acids (EETs) are derived from arachidonic acid and metabolized by soluble epoxide hydrolase (sEH). The role of EETs in synaptic function in the central nervous system is still largely unknown. We found that pharmacological inhibition of sEH to stabilize endogenous EETs and exogenous 14,15-EET significantly increased the field excitatory postsynaptic potential (fEPSP) response in the CA1 area of the hippocampus, while additionally enhancing high-frequency stimulation- (HFS-) induced long-term potentiation (LTP) and forskolin- (FSK-) induced LTP. sEH inhibitor (sEHI) N-[1-(oxopropyl)-4-piperidinyl]-N'-[4-(trifluoromethoxy) phenyl)-urea (TPPU) and exogenous 14,15-EET increased HFS-LTP, which could be blocked by an N-methyl-D-aspartate (NMDA) receptor subunit NR2B antagonist. TPPU- or 14,15-EET-facilitated FSK-mediated LTP can be potentiated by an A1 adenosine receptor antagonist and a phosphodiesterase inhibitor, but is prevented by a cAMP-dependent protein kinase (PKA) inhibitor. sEHI and 14,15-EET upregulated the activation of extracellular signal-regulated kinases (ERKs) and Ca2+/calmodulin- (CaM-) dependent protein kinase II (CaMKII). Phosphorylation of synaptic receptors NR2B and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR1 was increased by TPPU and 14,15-EET administration. These results indicated that EETs increased NMDAR- and FSK-mediated synaptic potentiation via the AC-cAMP-PKA signaling cascade and upregulated the ERKs and CaMKII, resulting in increased phosphorylation of NR2B and GluR1 in the hippocampus.


Methodologic quality and relevance of references in pharmaceutical advertisements in a Canadian medical journal.
To evaluate the methodologic quality and relevance of references in pharmaceutical advertisements in the Canadian Medical Association Journal (CMAJ). Analytic study. All 114 references cited in the first 22 distinct pharmaceutical advertisements in volume 146 of CMAJ. Mean methodologic quality score (modified from the 6-point scale used to assess articles in the American College of Physicians' Journal Club) and mean relevance score (based on a new 5-point scale) for all references in each advertisement. Twenty of the 22 companies responded, sending 78 (90%) of the 87 references requested. The mean methodologic quality score was 58% (95% confidence limits [CL] 51% and 65%) and the mean relevance score 76% (95% CL 72% and 80%). The two mean scores were statistically lower than the acceptable score of 80% (p < 0.05), and the methodologic quality score was outside the preset clinically significant difference of 15%. The poor rating for methodologic quality was primarily because of the citation of references to low-quality review articles and "other" sources (i.e., other than reports of clinical trials). Half of the advertisements had a methodologic quality score of less than 65%, but only five had a relevance score of less than 65%. Although the relevance of most of the references was within minimal acceptable limits, the methodologic quality was often unacceptable. Because advertisements are an important part of pharmaceutical marketing and education, we suggest that companies develop written standards for their advertisements and monitor their advertisements for adherence to these standards. We also suggest that the Pharmaceutical Advertising Advisory Board develop more stringent guidelines for advertising and that it enforce these guidelines in a consistent, rigorous fashion.


High-throughput NMR-based screening with competition binding experiments.
The Achilles heel of ligand-based NMR screening methods is their failure to detect high-affinity ligands and molecules that bind covalently to the receptor. We have developed a novel approach for performing high-throughput screening with NMR spectroscopy that overcomes this limitation. The method also permits detection of potential high-affinity molecules that are only marginally soluble, thus significantly enlarging the diversity of compounds amenable to NMR screening. The techniques developed utilize transverse and/or selective longitudinal relaxation parameters in combination with competition binding experiments. Mathematical expressions are derived for proper setup of the NMR experiments and for extracting an approximate value of the binding constant for the identified ligand from a single-point measurement. With this approach it is possible to screen thousands of compounds in a short period of time against protein or DNA and RNA fragments. The methodology can also be applied for screening plant and fungi extracts.


Association of Endodontic Lesions with Coronary Artery Disease.
An endodontic lesion (EL) is a common manifestation of endodontic infection where Porphyromonas endodontalis is frequently encountered. EL may associate with increased risk for coronary artery disease (CAD) via similar pathways as marginal periodontitis. The aim of this cross-sectional study was to delineate the associations between EL and CAD. Subgingival P. endodontalis, its immune response, and serum lipopolysaccharide were examined as potential mediators between these 2 diseases. The Finnish Parogene study consists of 508 patients (mean age, 62 y) who underwent coronary angiography and extensive clinical and radiographic oral examination. The cardiovascular outcomes included no significant CAD ( n = 123), stable CAD ( n = 184), and acute coronary syndrome (ACS; n = 169). EL was determined from a panoramic tomography. We combined data of widened periapical spaces (WPSs) and apical rarefactions to a score of EL: 1, no EL ( n = 210); 2, ≥1 WPS per 1 apical rarefaction ( n = 222); 3, ≥2 apical rarefactions ( n = 76). Subgingival P. endodontalis was defined by checkerboard DNA-DNA hybridization analysis, and corresponding serum antibodies were determined by ELISA. In our population, 50.4% had WPSs, and 22.8% apical rarefactions. A total of 51.2% of all teeth with apical rarefactions had received endodontic procedures. Subgingival P. endodontalis levels and serum immunoglobulin G were associated with a higher EL score. In the multiadjusted model (age, sex, smoking, diabetes, body mass index, alveolar bone loss, and number of teeth), having WPSs associated with stable CAD (odds ratio [OR] = 1.94, 95% confidence interval [95% CI] = 1.13 to 3.32, P = 0.016) and highest EL score were associated with ACS (OR = 2.46, 95% CI = 1.09 to 5.54, P = 0.030). This association was especially notable in subjects with untreated teeth with apical rarefactions ( n = 59, OR = 2.72, 95% CI = 1.16 to 6.40, P = 0.022). Our findings support the hypothesis that ELs are independently associated with CAD and in particular with ACS. This is of high interest from a public health perspective, considering the high prevalence of ELs and CAD.


Investigating the impact of the English health inequalities strategy: time trend analysis.
Objective To investigate whether the English health inequalities strategy was associated with a decline in geographical health inequalities, compared with trends before and after the strategy.Design Time trend analysis.Setting Two groups of lower tier local authorities in England. The most deprived, bottom fifth and the rest of England.Intervention The English health inequalities strategy-a cross government strategy implemented between 1997 and 2010 to reduce health inequalities in England. Trends in geographical health inequalities were assessed before (1983-2003), during (2004-12), and after (2013-15) the strategy using segmented linear regression.Main outcome measure Geographical health inequalities measured as the relative and absolute differences in male and female life expectancy at birth between the most deprived local authorities in England and the rest of the country.Results Before the strategy the gap in male and female life expectancy between the most deprived local authorities in England and the rest of the country increased at a rate of 0.57 months each year (95% confidence interval 0.40 to 0.74 months) and 0.30 months each year (0.12 to 0.48 months). During the strategy period this trend reversed and the gap in life expectancy for men reduced by 0.91 months each year (0.54 to 1.27 months) and for women by 0.50 months each year (0.15 to 0.86 months). Since the end of the strategy period the inequality gap has increased again at a rate of 0.68 months each year (-0.20 to 1.56 months) for men and 0.31 months each year (-0.26 to 0.88) for women. By 2012 the gap in male life expectancy was 1.2 years smaller (95% confidence interval 0.8 to 1.5 years smaller) and the gap in female life expectancy was 0.6 years smaller (0.3 to 1.0 years smaller) than it would have been if the trends in inequalities before the strategy had continued.Conclusion The English health inequalities strategy was associated with a decline in geographical inequalities in life expectancy, reversing a previously increasing trend. Since the strategy ended, inequalities have started to increase again. The strategy may have reduced geographical health inequalities in life expectancy, and future approaches should learn from this experience. The concerns are that current policies are reversing the achievements of the strategy.


The correspondence between the conformational and chromophoric properties of amorphous conjugated polymers in mesoscale condensed systems.
For π-conjugated polymers, the notion of spectroscopic units or "chromophores" provides illuminating insights into the experimentally observed absorption/emission spectra and the mechanisms of energy/charge transfer. To date, however, no statistical analysis has revealed a direct correspondence between chromophoric and conformational properties-with the latter being fundamental to polymer semiconductors. Herein, we propose a "persistence length" calculation to re-evaluate chain conformation over a full conjugation length. The mesoscale condensed systems of MEH-PPV and MEH-PPV/C60 hybrid (system size ∼10 × 10 × 10 nm3) are utilized as two prototypical model systems, along with a full range of segmental lengths (2-20-mer) and five lowest singlet excited states to hint at the generality of the features presented. We demonstrate, for the first time, that two properly re-defined conformational factors that characterize chain folding and planarity, respectively, capture excellently the population distribution of chromophores in both systems investigated. In contrast, the conventional strategy of utilizing two adjacent monomer units to characterize (local) chain conformation results in only an inconspicuous correlation between the two, as previously reported. It is further shown that chain folding-and not chain planarity-is more relevant in capturing the associated oscillator strength for the first excited state, where the transient dipole moments are known to align with the chain conformation, although the corresponding excitation energy and exciton size seem relatively unaffected. The observed effects of C60 on the MEH-PPV adsorption spectra also agree with recent experimental trends. Overall, the present findings are expected to aid future multiscale computer simulations and spectroscopy-data interpretations for polymer semiconductors and their hybrid systems.


Effects of glyphosate exposure on sperm concentration in rodents: A systematic review and meta-analysis.
Correlation between exposure to glyphosate and sperm concentrations is important in reproductive toxicity risk assessment for male reproductive functions. Many studies have focused on reproductive toxicity on glyphosate, however, results are still controversial. We conducted a systematic review of epidemiological studies on the association between glyphosate exposure and sperm concentrations of rodents. The aim of this study is to explore the potential adverse effects of glyphosate on reproductive function of male rodents. Systematic and comprehensive literature search was performed in MEDLINE, TOXLINE, Embase, WANFANG and CNKI databases with different combinations of glyphosate exposure and sperm concentration. 8 studies were eventually identified and random-effect model was conducted. Heterogeneity among study results was calculated via chi-square tests. Ten independent experimental datasets from these eight studies were acquired to synthesize the random-effect model. A decrease in sperm concentrations was found with mean difference of sperm concentrations(MDsperm)=-2.774×106/sperm/g/testis(95%CI=-0.969 to -4.579) in random-effect model after glyphosate exposure. There was also a significant decrease after fitting the random-effect model: MDsperm=-1.632×106/sperm/g/testis (95%CI=-0.662 to -2.601). The results of meta-analysis support the hypothesis that glyphosate exposure decreased sperm concentration in rodents. Therefore, we conclude that glyphosate is toxic to male rodent's reproductive system.


Alkyl-eta2-alkene niobocene and tantalocene complexes with the allyldimethylsilyl-eta5-cyclopentadienyl ligand: synthesis, NMR studies and DFT calculations.
Group 5 metal complexes [M(eta5-C5H5)[eta5-C5H4SiMe2(CH2-eta]2-CH=CH2)]X] (M = Nb, X = Me, CH2Ph, CH2SiMe3; M = Ta, X = Me, CH2Ph) and [Ta(eta5-C5Me5)[eta5-C5H4SiMe2(CH2-eta2-CH=CH2)]X] (X = Cl, Me, CH2Ph, CH2SiMe3) containing a chelating alkene ligand tethered to a cyclopentadienyl ring have been synthesized in high yields by reduction with Na/Hg (X = Cl) and alkylation with reductive elimination (X = alkyl) of the corresponding metal(iv) dichlorides [M(eta5-Cp)[eta5-C5H4SiMe2(CH2CH=CH2)]Cl2] (Cp = C5H5, M = Nb, Ta, Cp = C5Me5, M = Ta). These chloro- and alkyl-alkene coordinated complexes react with CO and isocyanides [CNtBu, CN(2,6-Me2C6H3)] to give the ligand-substituted metal(III) compounds [M(eta5-Cp)[eta5-C5H4SiMe2(CH2CH=CH2)]XL] (X = Cl, Me, CH2Ph, CH2SiMe3). Reaction of the chloro-alkene tantalum complex with LiNHtBu results in formation of the imido hydride derivative [Ta(eta5-C5Me5)[eta5-C5H4SiMe2(CH2CH=CH2)]H(NtBu)]. NMR studies for all of the new compounds and DFT calculations for the alkene-coordinated metal complexes are compared with those known for related group 4 metal cations.


Regulation of limb patterning by extracellular microfibrils.
To elucidate the contribution of the extracellular microfibril-elastic fiber network to vertebrate organogenesis, we generated fibrillin 2 (Fbn2)-null mice by gene targeting and identified a limb-patterning defect in the form of bilateral syndactyly. Digit fusion involves both soft and hard tissues, and is associated with reduced apoptosis at affected sites. Two lines of evidence suggest that syndactily is primarily due to defective mesenchyme differentiation, rather than reduced apoptosis of interdigital tissue. First, fusion occurs before appearance of interdigital cell death; second, interdigital tissues having incomplete separation fail to respond to apoptotic clues from implanted BMP-4 beads. Syndactyly is associated with a disorganized matrix, but with normal BMP gene expression. On the other hand, mice double heterozygous for null Fbn2 and Bmp7 alleles display the combined digit phenotype of both nullizygotes. Together, these results imply functional interaction between Fbn2-rich microfibrils and BMP-7 signaling. As such, they uncover an unexpected relationship between the insoluble matrix and soluble factors during limb patterning. We also demonstrate that the Fbn2- null mutation is allelic to the recessive shaker-with-syndactyly (sy) locus on chromosome 18.


Detecting biological associations between genes based on the theory of phase synchronization.
This study presents a novel approach to detect biological associations for gene pairs with cell cycle-specific expression profiles. Previous studies have shown that periodic transcription is commonly regulated by transcription factors that are also periodically transcribed, and there is a growing number of examples where cell cycle regulated genes are conserved in yeast and mammalian cells. Some genes have periodicity for their oscillatory activity throughout cell division. These cell cycle-specific oscillatory activities could be explained by a biological phenomenon in terms of efficiency and logical order. In the yeast data used in this study, about 13% of genes behave in this manner based on a previous yeast study. Microarrays have been applied to determine genome-wide expression patterns during the cell cycle of a number of different cells. Moreover, several previous studies have shown that many pairs of genes, which have linearly correlated expression profiles, have similar cellular roles or physical interactions. Based on this point of view, the traditional clustering methods have focused on similar expression profiles based on the premise that genes with similar expression profiles have similar biological functions or relevant biological interactions. However, there are a number of previous studies indicating that the expression of some genes may be delayed compared to others due to a time lag in their transcriptional control. Therefore, we propose a novel clustering method, named as phase-synchronization clustering, based on the theory of phase synchronization for detecting biological associations using cell cycle-specific expression profiles. We evaluate phase-synchronization clustering here using Saccharomyces cerevisiae microarray data. Phase-synchronization clustering is able to detect biologically associated gene pairs that have linearly correlated (simultaneous and inverted) as well as time-delayed expression profiles. The performance of phase-synchronization clustering is compared with other conventional clustering methods. The likelihood of finding relevant biological associations by phase-synchronization clustering is significantly higher than other clustering methods. Therefore, phase-synchronization clustering is more efficient for detecting known biological interactions for gene pairs than other conventional clustering methods for analyzing cell cycle-specific expression data. The evaluation analysis of the results by phase-synchronization clustering also suggests that the cellular activities during the cell division process could be understood as a phenomenon of collective synchronization.


The Educational Legacy of the UPR School of Tropical Medicine: Curricula, Faculty, Students (1926-1949).
This essay discusses the educational evolution of the University of Puerto Rico-School of Tropical Medicine (UPR-STM) under the auspices of Columbia University. It takes a closer look to what was taught, who taught it and who were the students benefitting from the educational, learning and advanced research activities. It highlights some characteristics of the educational environment that aimed to harvest a well-trained group of scientists, academicians, and practitioners. It examines the characteristics of the faculty and graduates and their role in the teaching and dissemination of knowledge in tropical medicine and closely related fields. The curricula was characterized for its flexibility to accommodate the students' clinical and research interests. With the advent of the 1940s the School started offering public health professionals degrees in addition to the former research-based training. This brought tensions associated to professionalization, the diversification of purposes, the expansion without sufficient resources, and the opening to different levels of students. Maintaining a cadre of well-trained prestigious faculty was always a struggle. Strategies such as visiting professors and joint and ad-honorem appointments were used. Agreements with universities around the world, philanthropic institutions, professional associations, and with different branches of the local and federal government supplemented the resources of the School. In return, the School offered an environment committed to educational standards, networking and a wealth of data for study and discovery.


Comparison of third-generation sequencing approaches to identify viral pathogens under public health emergency conditions.
The capability of high-throughput sequencing (HTS) for detection of known and unknown viruses timely makes it a powerful tool for public health emergency response. Third-generation sequencing (TGS) offers advantages in speed and length of detection over second-generation sequencing (SGS). Here, we presented the end-to-end workflows for both Oxford Nanopore MinION and Pacbio Sequel on a viral disease emergency event, along with Ion Torrent PGM as a reference. A specific pipeline for comparative analysis on viral genomes recovered by each platform was assembled, given the high errors of base-calling for TGS platforms. All the three platforms successfully identified and recovered at least 85% Norovirus GII genomes. Oxford Nanopore MinION spent the least sample-to-answer turnaround time with relatively low but enough accuracy for taxonomy classification. Pacbio Sequel recovered the most accurate viral genome, while spending the longest time. Overall, Nanopore metagenomics can rapidly characterize viruses, and Pacbio Sequel can accurately recover viruses. This study provides a framework for designing the appropriate experiments that are likely to lead to accurate and rapid virus emergency response.


HIV-exposure, early life feeding practices and delivery mode impacts on faecal bacterial profiles in a South African birth cohort.
There are limited data on meconium and faecal bacterial profiles from African infants and their mothers. We characterized faecal bacterial communities of infants and mothers participating in a South African birth cohort. Stool and meconium specimens were collected from 90 mothers and 107 infants at birth, and from a subset of 72 and 36 infants at 4-12 and 20-28 weeks of age, respectively. HIV-unexposed infants were primarily exclusively breastfed at 4-12 (49%, 26/53) and 20-28 weeks (62%, 16/26). In contrast, HIV-exposed infants were primarily exclusively formula fed at 4-12 (53%; 10/19) and 20-28 weeks (70%, 7/10). Analysis (of the bacterial 16S rRNA gene sequences of the V4 hypervariable region) of the 90 mother-infant pairs showed that meconium bacterial profiles [dominated by Proteobacteria (89%)] were distinct from those of maternal faeces [dominated by Firmicutes (66%) and Actinobacteria (15%)]. Actinobacteria predominated at 4-12 (65%) and 20-28 (50%) weeks. HIV-exposed infants had significantly higher faecal bacterial diversities at both 4-12 (p = 0.026) and 20-28 weeks (p = 0.002). HIV-exposed infants had lower proportions of Bifidobacterium (p = 0.010) at 4-12 weeks. Maternal faecal bacterial profiles were influenced by HIV status, feeding practices and mode of delivery. Further longitudinal studies are required to better understand how these variables influence infant and maternal faecal bacterial composition.


Emotional Expressions Reconsidered: Challenges to Inferring Emotion From Human Facial Movements.
It is commonly assumed that a person's emotional state can be readily inferred from his or her facial movements, typically called emotional expressions or facial expressions. This assumption influences legal judgments, policy decisions, national security protocols, and educational practices; guides the diagnosis and treatment of psychiatric illness, as well as the development of commercial applications; and pervades everyday social interactions as well as research in other scientific fields such as artificial intelligence, neuroscience, and computer vision. In this article, we survey examples of this widespread assumption, which we refer to as the common view, and we then examine the scientific evidence that tests this view, focusing on the six most popular emotion categories used by consumers of emotion research: anger, disgust, fear, happiness, sadness, and surprise. The available scientific evidence suggests that people do sometimes smile when happy, frown when sad, scowl when angry, and so on, as proposed by the common view, more than what would be expected by chance. Yet how people communicate anger, disgust, fear, happiness, sadness, and surprise varies substantially across cultures, situations, and even across people within a single situation. Furthermore, similar configurations of facial movements variably express instances of more than one emotion category. In fact, a given configuration of facial movements, such as a scowl, often communicates something other than an emotional state. Scientists agree that facial movements convey a range of information and are important for social communication, emotional or otherwise. But our review suggests an urgent need for research that examines how people actually move their faces to express emotions and other social information in the variety of contexts that make up everyday life, as well as careful study of the mechanisms by which people perceive instances of emotion in one another. We make specific research recommendations that will yield a more valid picture of how people move their faces to express emotions and how they infer emotional meaning from facial movements in situations of everyday life. This research is crucial to provide consumers of emotion research with the translational information they require.


Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis.
In severe early-onset epilepsy, precise clinical and molecular genetic diagnosis is complex, as many metabolic and electro-physiological processes have been implicated in disease causation. The clinical phenotypes share many features such as complex seizure types and developmental delay. Molecular diagnosis has historically been confined to sequential testing of candidate genes known to be associated with specific sub-phenotypes, but the diagnostic yield of this approach can be low. We conducted whole-genome sequencing (WGS) on six patients with severe early-onset epilepsy who had previously been refractory to molecular diagnosis, and their parents. Four of these patients had a clinical diagnosis of Ohtahara Syndrome (OS) and two patients had severe non-syndromic early-onset epilepsy (NSEOE). In two OS cases, we found de novo non-synonymous mutations in the genes KCNQ2 and SCN2A. In a third OS case, WGS revealed paternal isodisomy for chromosome 9, leading to identification of the causal homozygous missense variant in KCNT1, which produced a substantial increase in potassium channel current. The fourth OS patient had a recessive mutation in PIGQ that led to exon skipping and defective glycophosphatidyl inositol biosynthesis. The two patients with NSEOE had likely pathogenic de novo mutations in CBL and CSNK1G1, respectively. Mutations in these genes were not found among 500 additional individuals with epilepsy. This work reveals two novel genes for OS, KCNT1 and PIGQ. It also uncovers unexpected genetic mechanisms and emphasizes the power of WGS as a clinical tool for making molecular diagnoses, particularly for highly heterogeneous disorders.


Relaxation of pig coronary arteries by new and potent cGMP analogs that selectively activate type I alpha, compared with type I beta, cGMP-dependent protein kinase.
Smooth muscle preparations of human aorta or pig coronary arteries contain nearly equal amounts of cGMP-dependent protein kinase isozymes (cGMP kinase I alpha and I beta). In order to understand the roles of these isozymes in relaxing vascular smooth muscle, several new cGMP analogs were synthesized and tested for potencies in activating each enzyme and in relaxing pig coronary arteries. Analogs modified with a derivatized phenylthio group at the 8-position were as much as 72-fold more potent in activating purified cGMP kinase I alpha than cGMP kinase I beta. Electron-donating substituents, such as hydroxy, amino, and methoxy, on the phenyl ring enhanced the potencies of these analogs in activating cGMP kinase I alpha. The most potent of these cGMP analogs [8-(4-hydroxyphenylthio)-cGMP] was 17 times more potent (EC50 = 1.1 microM) as a muscle relaxant than the most efficacious analog tested previously. Among derivatives with an 8-halo group, 8-iodo-cGMP was the most potent compound (Ka = 9 nM for I alpha and 122 nM for I beta) for both I alpha and I beta. Analogs modified at the 1,N2-position or at both the 1,N2-and 8-positions of cGMP were highly potent for activating both isozymes. Within this group, 8-I-beta-phenyl-1,N2-etheno-cGMP had Ka values of 22 nM and 17 nM for cGMP kinase I alpha and I beta, respectively, whereas the Ka values of cGMP were 110 nM and 250 nM for the two isozymes. 8-I-beta-phenyl-1,N2-etheno-cGMP was the most potent muscle relaxant tested, with EC50 of 0.4 microM. For all cGMP analogs tested, there was a positive correlation between potency for activation of cGMP kinase I alpha and that for relaxation of pig coronary arteries. Assuming that the kinase assay conditions yielded a cyclic nucleotide specificity similar to that which would exist in intact cells, it was concluded that the cGMP kinase I alpha isozyme mediates the relaxation of pig coronary artery smooth muscle caused by cGMP elevation. However, an additional role for cGMP kinase I beta in the relaxation process could not be ruled out.


Conduct disorder.
Conduct disorder (CD) is a common and highly impairing psychiatric disorder that usually emerges in childhood or adolescence and is characterized by severe antisocial and aggressive behaviour. It frequently co-occurs with attention-deficit/hyperactivity disorder (ADHD) and often leads to antisocial personality disorder in adulthood. CD affects ~3% of school-aged children and is twice as prevalent in males than in females. This disorder can be subtyped according to age at onset (childhood-onset versus adolescent-onset) and the presence or absence of callous-unemotional traits (deficits in empathy and guilt). The aetiology of CD is complex, with contributions of both genetic and environmental risk factors and different forms of interplay among the two (gene-environment interaction and correlation). In addition, CD is associated with neurocognitive impairments; smaller grey matter volume in limbic regions such as the amygdala, insula and orbitofrontal cortex, and functional abnormalities in overlapping brain circuits responsible for emotion processing, emotion regulation and reinforcement-based decision-making have been reported. Lower hypothalamic-pituitary-adrenal axis and autonomic reactivity to stress has also been reported. Management of CD primarily involves parent-based or family-based psychosocial interventions, although stimulants and atypical antipsychotics are sometimes used, especially in individuals with comorbid ADHD.


Designing polymer nanocomposites with a semi-interpenetrating or interpenetrating network structure: toward enhanced mechanical properties.
Using short polymer chains and through molecular dynamics simulation, we designed a well-dispersed nanoparticle (NP) network, which was then incorporated with the polymer matrix. First, we examined the effects of the dual-end grafted chains flexibility and density on the spatial distribution of this particular polymer nanocomposites system. By changing the interaction strength between the matrix polymer chains and the dual-end grafted chains in the semi-interpenetrating network system (NP network), we analyzed the interpenetration state between the linear polymer matrix and the NP network via calculating the total interfacial interaction energy. Moreover, the uniaxial tensile stress-strain and orientation behavior influenced by the interaction strength between the matrix polymer and the grafted chains were investigated for both the semi-interpenetrating network system and the interpenetrating network system (NP network and matrix network). Furthermore, for the interpenetrating network system, we modulated the integrity of the NP network ranging from 0% to 100%, corresponding to the gradual transition of the dispersion morphology of the NPs from the aggregation state to the uniform dispersion state, to examine the effect of the NP network on the tensile mechanical behavior. In particular, by simulating the dynamic shear process in the semi-interpenetrating network system, the composites were found to exhibit a lower non-linear behavior (the famous Payne effect), a higher storage modulus, and a lower tangent loss at large strain amplitude with increasing NP network integrity. In general, our results could provide a new approach for the design of high-performance polymer nanocomposites by taking advantage of the semi-interpenetrating or interpenetrating network reinforcing structure.


Systemic inflammation impairs microglial Aβ clearance through NLRP3 inflammasome.
Alzheimer's disease is the most prevalent type of dementia and is caused by the deposition of extracellular amyloid-beta and abnormal tau phosphorylation. Neuroinflammation has emerged as an additional pathological component. Microglia, representing the brain's major innate immune cells, play an important role during Alzheimer's. Once activated, microglia show changes in their morphology, characterized by a retraction of cell processes. Systemic inflammation is known to increase the risk for cognitive decline in human neurogenerative diseases including Alzheimer's. Here, we assess for the first time microglial changes upon a peripheral immune challenge in the context of aging and Alzheimer's in vivo, using 2-photon laser scanning microscopy. Microglia were monitored at 2 and 10 days post-challenge by lipopolysaccharide. Microglia exhibited a reduction in the number of branches and the area covered at 2 days, a phenomenon that resolved at 10 days. Systemic inflammation reduced microglial clearance of amyloid-beta in APP/PS1 mice. NLRP3 inflammasome knockout blocked many of the observed microglial changes upon lipopolysaccharide, including alterations in microglial morphology and amyloid pathology. NLRP3 inhibition may thus represent a novel therapeutic target that may protect the brain from toxic peripheral inflammation during systemic infection.


Characterization of a widely expressed gene (LUC7-LIKE; LUC7L) defining the centromeric boundary of the human alpha-globin domain.
We have identified the first gene lying on the centromeric side of the alpha-globin gene cluster on human 16p13.3. The gene, called 16pHQG;16 (HGMW-approved symbol LUC7L), is widely transcribed and lies in the opposite orientation with respect to the alpha-globin genes. This gene may represent a mammalian heterochromatic gene, encoding a putative RNA-binding protein similar to the yeast Luc7p subunit of the U1 snRNP splicing complex that is normally required for 5' splice site selection. To examine the role of the 16pHQG;16 gene in delimiting the extent of the alpha-globin regulatory domain, we mapped its mouse orthologue, which we found to lie on mouse chromosome 17, separated from the mouse alpha-cluster on chromosome 11. Establishing the full extent of the human 16pHQG;16 gene has allowed us to define the centromeric limit of the region of conserved synteny around the human alpha-globin cluster to within an 8-kb segment of chromosome 16.


The non-coding RNA TERRA is a natural ligand and direct inhibitor of human telomerase.
Telomeres, the physical ends of eukaryotes chromosomes are transcribed into telomeric repeat containing RNA (TERRA), a large non-coding RNA of unknown function, which forms an integral part of telomeric heterochromatin. TERRA molecules resemble in sequence the telomeric DNA substrate as they contain 5'-UUAGGG-3' repeats near their 3'-end which are complementary to the template sequence of telomerase RNA. Here we demonstrate that endogenous TERRA is bound to human telomerase in cell extracts. Using in vitro reconstituted telomerase and synthetic TERRA molecules we demonstrate that the 5'-UUAGGG-3' repeats of TERRA base pair with the RNA template of the telomerase RNA moiety (TR). In addition TERRA contacts the telomerase reverse transcriptase (TERT) protein subunit independently of hTR. In vitro studies further demonstrate that TERRA is not used as a telomerase substrate. Instead, TERRA acts as a potent competitive inhibitor for telomeric DNA in addition to exerting an uncompetitive mode of inhibition. Our data identify TERRA as a telomerase ligand and natural direct inhibitor of human telomerase. Telomerase regulation by the telomere substrate may be mediated via its transcription.


Demographic quantification of carbon and nitrogen dynamics associated with root turnover in white clover.
As well as capturing resources, roots lose resources during their lives. We quantified carbon (C) and nitrogen (N) losses associated with root turnover in white clover (Trifolium repens L.). We grew contrasting cultivars for 18 weeks in soil microcosms. Using repeated in situ observations, destructive sampling, and demographic analysis, we measured changes in C and N concentrations in dry matter of 1st- or 2nd-order (terminal) roots to derive C and N fluxes into and out of root cohorts. C and N fluxes from roots during turnover depended on cohort age and order. Ninety per cent of losses occurred from 2nd-order cohorts younger than 18 weeks. Losses were greater from roots of the larger, faster growing cultivar Alice than from the smaller lower yielding cultivar S184. C:N ratios of roots and lost material were similar within each order and between cultivars but smaller in 2nd- compared with 1st-order roots. C and N losses during root turnover could be equivalent to at least 6% of aboveground dry matter production in S184 and 12% in Alice at the field scale. C and N losses associated with root turnover will have potentially significant and previously unrecognized impacts on crop productivity, resource dynamics, and long-term soil fertility.


The Motivational Salience of Faces Is Related to Both Their Valence and Dominance.
Both behavioral and neural measures of the motivational salience of faces are positively correlated with their physical attractiveness. Whether physical characteristics other than attractiveness contribute to the motivational salience of faces is not known, however. Research with male macaques recently showed that more dominant macaques' faces hold greater motivational salience. Here we investigated whether dominance also contributes to the motivational salience of faces in human participants. Principal component analysis of third-party ratings of faces for multiple traits revealed two orthogonal components. The first component ("valence") was highly correlated with rated trustworthiness and attractiveness. The second component ("dominance") was highly correlated with rated dominance and aggressiveness. Importantly, both components were positively and independently related to the motivational salience of faces, as assessed from responses on a standard key-press task. These results show that at least two dissociable components underpin the motivational salience of faces in humans and present new evidence for similarities in how humans and non-human primates respond to facial cues of dominance.


Natural estrogens enhance the engraftment of human hematopoietic stem and progenitor cells in immunodeficient mice.
Hematopoietic Stem and Progenitor Cells are crucial in the maintenance of lifelong production of all blood cells. These Stem Cells are highly regulated to maintain homeostasis through a delicate balance between quiescence, self-renewal and differentiation. However, this balance is altered during the hematopoietic recovery after Hematopoietic Stem and Progenitor Cell Transplantation. Transplantation efficacy can be limited by inadequate Hematopoietic Stem Cells number, poor homing, low level of engraftment, or limited self-renewal. As recent evidences indicate that estrogens are involved in regulating the hematopoiesis, we sought to examine whether natural estrogens (estrone or E1, estradiol or E2, estriol or E3 and estetrol or E4) modulate human Hematopoietic Stem and Progenitor Cells. Our results show that human Hematopoietic Stem and Progenitor Cell subsets express estrogen receptors, and whose signaling is activated by E2 and E4 on these cells. Additionally, these natural estrogens cause different effects on human Progenitors in vitro. We found that both E2 and E4 expand human Hematopoietic Stem and Progenitor Cells. However, E4 was the best tolerated estrogen and promoted cell cycle of human Hematopoietic Progenitors. Furthermore, we identified that E2 and, more significantly, E4 doubled human hematopoietic engraftment in immunodeficient mice without altering other Hematopoietic Stem and Progenitor Cells properties. Finally, the impact of E4 on promoting human hematopoietic engraftment in immunodeficient mice might be mediated through the regulation of mesenchymal stromal cells in the bone marrow niche. Together, our data demonstrate that E4 is well tolerated and enhances human reconstitution in immunodeficient mice, directly by modulating human Hematopoietic Progenitor properties and indirectly by interacting with the bone marrow niche. This application might have particular relevance to ameliorate the hematopoietic recovery after myeloablative conditioning, especially when limiting numbers of Hematopoietic Stem and Progenitor Cells are available.


Event-related potential studies of associative recognition and recall: electrophysiological evidence for context dependent retrieval processes.
To investigate the neural correlates of episodic recollection the ERP correlates of memory for new associations (recently studied novel word pairs) were investigated using two tasks, associative recognition and associative recall. For the recognition task subjects discriminated old from new word pairs and, for pairs judged old, reported whether the pairs were intact or recombined (compared to at study). For the recall task, subjects discriminated old from new words and, for each word judged old, reported its study associate. ERPs were recorded at test from 25 scalp electrodes, with a 1944-ms recording epoch. In Experiment 1, the tasks were randomly interleaved. Consistent with previous findings, relative to the ERPs for correctly classified new items, the ERP correlates of successful associative recognition consisted of a sustained left parietal positivity, and two frontal positivities, one early and bilateral, the other occurring later and showing a right-sided maximum. In contrast to previous findings, successful associative recall elicited similar effects to those found for recognition. Topographic analyses revealed that the distribution of these retrieval-related ERP effects were similar across the two tasks, suggesting that the recognition and recall of associative information gives rise to activity in overlapping, if not the same, neural populations. In Experiment 2 the tasks were blocked. In contrast to the findings of Experiment 1, successful associative recall elicited left parietal and late onsetting right frontal positivities, in the absence of the early bilateral frontal positivity. This finding suggests that frontally-distributed memory-related ERP effects are both neurally and functionally dissociable. Specifically, we argue that the functional significance of the early frontally distributed ERP effect cannot be accounted for by the 'post-retrieval processing' hypothesis that is taken to account for the late right frontal effect, suggesting that episodic recollection itself is neither neurally nor functionally homogenous.


Use of the direct puncture technique in management of capillaro-venous malformations: case report.
BACKGROUND: Preoperative devascularization of the capillaro-venous malformations located in the aero-digestive tract is important for surgeons, to minimize blood loss during surgical excision of malformations. CASE PRESENTATION: Here we present two cases of capillaro-venous malformation in which we could successfully achieve preoperative devascularization, by directly injecting n-butyl cyano acrylate into the capillaro-venous bed. This technique is relatively easy, safe and cheap, and can be carried out immediately before surgery.


Characterization of the 23 S ribosomal RNA m5U1939 methyltransferase from Escherichia coli.
An Escherichia coli open reading frame, ygcA, was identified as a putative 23 S ribosomal RNA 5-methyluridine methyltransferase (Gustafsson, C., Reid, R., Greene, P. J., and Santi, D. V. (1996) Nucleic Acids Res. 24, 3756-3762). We have cloned, expressed, and purified the 50-kDa protein encoded by ygcA. The purified enzyme catalyzed the AdoMet-dependent methylation of 23 S rRNA but did not act upon 16 S rRNA or tRNA. A high performance liquid chromatography-based nucleoside analysis identified the reaction product as 5-methyluridine. The enzyme specifically methylated U1939 as determined by a nuclease protection assay and by methylation assays using site-specific mutants of 23 S rRNA. A 40-nucleotide 23 S rRNA fragment (nucleotide 1930--1969) also served as an efficient substrate for the enzyme. The apparent K(m) values for the 40-mer RNA oligonucleotide and AdoMet were 3 and 26 microm, respectively, and the apparent k(cat) was 0.06 s(-1). The enzyme contains two equivalents of iron/monomer and has a sequence motif similar to a motif found in iron-sulfur proteins. We propose to name this gene rumA and accordingly name the protein product as RumA for RNA uridine methyltransferase.


Functional brain connectivity and neurocognitive functioning in patients with long-standing type 1 diabetes with and without microvascular complications: a magnetoencephalography study.
Hyperglycemia-associated microvascular disease may underlie changes in cerebral functioning and cognitive performance in patients with type 1 diabetes. Functional connectivity, an indicator of functional interactions and information exchange between brain regions, provides a measure of cerebral functioning. This study addresses functional connectivity and cognition in type 1 diabetic patients with and without proliferative retinopathy, relative to healthy control subjects, using magnetoencephalography. Fluctuations in magnetic field at scalp for Delta, theta, lower and upper alpha, beta, and lower and upper gamma frequency bands were measured using magnetoencephalography. Synchronization likelihood, a measure of functional connectivity, was computed. Using neuropsychological tests, cognitive functioning was assessed and its associations with functional connectivity were determined. Compared with control subjects, type 1 diabetic patients performed poorer on general cognitive ability, information processing speed, and motor speed, irrespective of their microvascular complication status. Functional connectivity, however, was lowest for type 1 diabetic patients with retinopathy, compared with type 1 diabetic patients without microvascular complications and control subjects, whereas type 1 diabetic patients without microvascular complications showed an increase relative to control subjects. Positive associations were found between functional connectivity and executive functioning, memory, information processing speed, motor speed, and attention. Compared with healthy control subjects, functional connectivity and cognition differed in type 1 diabetic patients irrespective of microvascular complication status, indicating that chronic hyperglycemia, among other factors, may negatively affect brain functioning even before microvascular damage becomes manifest. The association found between synchronization likelihood and cognition suggests functional connectivity plays a significant role in cognitive functioning.


High-fidelity, inexpensive surgical middle ear simulator.
A high-fidelity, inexpensive middle ear simulator could be created to enhance surgical training that would be rated as having high face validity by experts. With rapid prototyping using additive manufacturing technology (AMT), one can create high-resolution 3-dimensional replicas of the middle ear at low cost and high fidelity. Such a simulator could be of great benefit for surgical training, particularly in light of new resident training guidelines. AMT was used to create surgical middle ear simulator (SMS) with 2 different materials simulating bone and soft tissue. The simulator is composed of an outer box with dimensions of an average adult external auditory canal without scutum and an inner cartridge based on an otosclerosis model. The simulator was then rated by otology experts in terms of face validity and fidelity as well as their opinion on the usefulness of such a device. Eighteen otologists from 6 tertiary academic centers rated the simulator; 83.3% agreed or highly agreed that SMS has accurate dimensions and 66.6% that it has accurate tactile feedback. When asked if performance of stapedotomy with the SMS improves with practice, 46% agreed. As to whether practicing stapedotomy with the SMS translates to improvement with live surgery, 78% agreed with this statement. Experts' average rating of the components of SMS (of possible 5) was as follows: middle ear dimensions, 3.9; malleus, 3.7; incus, 3.6; stapes, 3.6; chorda tympani, 3.7; tensor tympani, 4.1; stapedius, 3.8; facial nerve, 3.7; and promontory, 3.5. Overall, 83% found SMS to be at least "very useful" in training of novices, particularly for junior and senior residents. Most experts found the SMS to be accurate, but there was a large discrepancy in rating of individual components. Most found it to be very useful for training of novice surgeons. With these results, we are encouraged to proceed with further refinements that will strengthen the SMS as a training tool for otologic surgery.


Preferences for gender of family physician among Canadian European-descent and South-Asian immigrant women.
The aim of this study was to investigate expressed preferences for family physician (FP) gender among Canadian European-descent (CED) and Canadian South-Asian (CSA) immigrant women. An 'on-site' survey was conducted in community-based institutions in Toronto in order to determine preferences for the gender of FP under various health care scenarios: overall health care; gender-sensitive examinations; emotional problems; general ailments; and life-threatening conditions. Ninety-four women responded to this survey (CED = 50, CSA = 44), response rate 77.3%. For all health care scenarios, CED and CSA women similarly expressed either a preference for a female FP or no preference. More than two-thirds of women preferred a female FP for gynaecological examinations (CED, 72.9%; CSA, 83.7%) or examinations with private body part exposure (CED, 72%; CSA, 81.8%). For 'emotional problems', half of the women preferred a female FP and the other half had no preference. A similar pattern was observed for 'overall health care', with some shift to female physician preference among CSA women (60.5%) compared with CED women (53.2%). For the 'overall health care' scenario, CED and CSA women who preferred a female FP had a higher frequency of seeing female physicians within the last 5 years (CED, P < or = 0.01; CSA, P < or = 0.05), and attributed 'positive' social skills more to female physicians (CED, P < or = 0.01; CSA, P < or = 0.01) compared with women with no preference for the gender of the FP. Yet, CED women with a female FP preference were more likely to have a concurrent female FP (P < or = 0.01), and to rate past experiences with female physicians as high (P < or = 0.01) and with male physicians as low (P < or = 0.05) compared with CED women with no preference. In the CSA group, women with a preference for a female FP were more likely to be unemployed (P < or = 0.01) and have low social support (P < or = 0.01). Despite similar physician gender preference patterns, factors associated with these preferences show some differences between CED and CSA women.


Uneven-Layered Coding Metamaterial Tile for Ultra-wideband RCS Reduction and Diffuse Scattering.
In this paper, a novel uneven-layered coding metamaterial tile is proposed for ultra-wideband radar cross section (RCS) reduction and diffuse scattering. The metamaterial tile is composed of two kinds of square ring unit cells with different layer thickness. The reflection phase difference of 180° (±37°) between two unit cells covers an ultra-wide frequency range. Due to the phase cancellation between two unit cells, the metamaterial tile has the scattering pattern of four strong lobes deviating from normal direction. The metamaterial tile and its 90-degree rotation can be encoded as the '0' and '1' elements to cover an object, and diffuse scattering pattern can be realized by optimizing phase distribution, leading to reductions of the monostatic and bi-static RCSs simultaneously. The metamaterial tile can achieve -10 dB RCS reduction from 6.2 GHz to 25.7 GHz with the ratio bandwidth of 4.15:1 at normal incidence. The measured and simulated results are in good agreement and validate the proposed uneven-layered coding metamaterial tile can greatly expanding the bandwidth for RCS reduction and diffuse scattering.


Increased risk of tuberculosis in patients with rheumatoid arthritis in Japan.
To determine the risk for tuberculosis infection in patients with rheumatoid arthritis before the anti-cytokine era in Japan. A database of a single-institute-based large observational cohort study for rheumatoid arthritis at the Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan, was analysed. Information on the history of tuberculosis infection was collected by patient self-reporting during April and October 2003. The age-adjusted incidence rate and relative risk for tuberculosis infection were investigated. Among 5044 patients with rheumatoid arthritis, 483 (9.6%) patients claimed to have a history of tuberculosis infection before October 2002. The frequency of history of tuberculosis increased according to the age of the patient. Four cases of new-onset tuberculosis were identified among 5544 patients with rheumatoid arthritis during 1 year. The age-adjusted incidence of tuberculosis was 42.4/100,000 patients. The relative risk for tuberculosis was 3.21 (95% confidence interval (CI) 1.21 to 8.55), and that of men and women was 10.59 (95% CI 3.42 to 32.78) and 1.41 (95% CI 0.2 to 10), respectively. There was an increased risk of tuberculosis infection in Japanese patients with rheumatoid arthritis, especially in male patients before the introduction of anti-tumour necrosis factor treatment. These data should form the basis for the risk management of anti-cytokine treatment in Japan.


Microbiological and molecular characterization of Corynebacterium diphtheriae isolated in Algeria between 1992 and 2015.
The objectives of this study were to undertake the microbiological and molecular characterization of Corynebacterium diphtheriae isolates collected in Algeria during epidemic and post-epidemic periods between 1992 and 2015. Microbiological characterization includes the determination of biotype and toxigenicity status using phenotypic and genotypic methods. Antimicrobial susceptibility was determined by the E-test method. Molecular characterization was performed by multi-locus sequence typing. In total, there were 157 cases of C. diphtheriae isolates, 127 in patients with respiratory diphtheria and 30 with ozena. Isolates with a mitis biotype were predominant (122 out of 157; 77.7%) followed by belfanti (28 out of 157; 17.8%) and gravis biotype (seven out of 157; 4.5%). Toxigenic isolates were predominant in the period 1992-2006 (74 out of 134) whereas in the period 2007-2015, only non-toxigenic isolates circulated (23 out of 23). All 157 isolates were susceptible to erythromycin, gentamicin, vancomycin and cotrimoxazole. Reduced susceptibility to penicillin G, cefotaxime, tetracycline and chloramphenicol was detected in 90 (57.3%), 88 (56.1%), 112 (71.3%) and 90 (57.3%) isolates, respectively. Multi-locus sequence typing analysis indicates that sequence type 116 (ST-116) was the most frequent, with 65 out of 100 isolates analysed, in particular during the epidemic period 1992-1999 (57 out of 65 isolates). In the post-epidemic period, 2000-2015, 13 different sequence types were isolated. All belfanti isolates (ten out of 100 isolates) belonged to closely related sequence types grouped in a phylogenetically distinct eBurst group and were collected exclusively in ozena cases. In conclusion, the epidemic period was associated with ST-116 while the post-epidemic period was characterized by more diversity. Belfanti isolates are grouped in a phylogenetically distinct clonal complex.


Challenges with Novel Clinical Trial Designs: Master Protocols.
The 2018 Accelerating Anticancer Agent Development (AAADV) Workshop assembled a panel of experts for an in-depth discussion session to present "Challenges with Novel Clinical Trial Designs." This panel offered assessments of the challenges faced by industry, the FDA, investigators, institutional review boards, and patients. The panel focused on master protocols, which include umbrella trials, platform trials, and basket trials. Umbrella trials and platform trials share many commonalities, whereas basket trials are more distinct. Umbrella and platform trials are generally designed with multiple arms where patients of the same histology or other unifying characteristics are enrolled into different arms and multiple investigational agents are evaluated in a single protocol. In contrast, basket studies generally enroll patients with different tumor types based on the presence of a specific mutation or biomarker regardless of histology; these trials may include expansion cohorts. These novel designs offer the promise of expedited drug assessment and approval, but they also place new challenges on all the stakeholders involved in the drug development process. Only by identifying the challenges of these complex, innovative clinical trial designs and highlighting challenges from each perspective can we begin to address these challenges. The 2018 AAADV Workshop convened a panel of experts from relevant disciplines to highlight the challenges that are created by master protocols, and, where appropriate, offer strategies to address these challenges.


A comparison of three fiber tract delineation methods and their impact on white matter analysis.
Diffusion magnetic resonance imaging (dMRI) is an important method for studying white matter connectivity in the brain in vivo in both healthy and clinical populations. Improvements in dMRI tractography algorithms, which reconstruct macroscopic three-dimensional white matter fiber pathways, have allowed for methodological advances in the study of white matter; however, insufficient attention has been paid to comparing post-tractography methods that extract white matter fiber tracts of interest from whole-brain tractography. Here we conduct a comparison of three representative and conceptually distinct approaches to fiber tract delineation: 1) a manual multiple region of interest-based approach, 2) an atlas-based approach, and 3) a groupwise fiber clustering approach, by employing methods that exemplify these approaches to delineate the arcuate fasciculus, the middle longitudinal fasciculus, and the uncinate fasciculus in 10 healthy male subjects. We enable qualitative comparisons across methods, conduct quantitative evaluations of tract volume, tract length, mean fractional anisotropy, and true positive and true negative rates, and report measures of intra-method and inter-method agreement. We discuss methodological similarities and differences between the three approaches and the major advantages and drawbacks of each, and review research and clinical contexts for which each method may be most apposite. Emphasis is given to the means by which different white matter fiber tract delineation approaches may systematically produce variable results, despite utilizing the same input tractography and reliance on similar anatomical knowledge.


Giant adrenal endothelial cyst associated with acute and chronic morbidity in a young female: a case report.
Adrenal cysts are rare clinical entities that can present as acute abdomen through rupture and internal hemorrhage as well as chronic symptoms such as gastrointestinal disturbances. A 20-year-old girl presented to our hospital with a 4-years history of abdominal pain and diarrhea. Ultrasound of the abdomen revealed a cystic area measuring 10 x 10 cm between the spleen and left kidney. Computed tomography scan showed a large cystic, homogeneous mass measuring 12.8 x 9.5 x 9.4 cm in the left hypochondrium with most likely origin from the left adrenal gland. Limited work up for hormone hypersecretion was negative. The patient was then encountered in the emergency room with an acute abdomen secondary to intracystic hemorrhage. A laparotomy with left adrenalectomy was performed. Final pathology showed a benign adrenal endothelial cyst. Post-operatively, the patient's long standing complaints of diarrhea and abdominal pain completely resolved. Surgical resection appears a safe and reasonable management strategy in a patient with intracystic hemorrhage of adrenal cyst.


Providers' Perspectives on Provision of Family Planning to HIV-Positive Individuals in HIV Care in Nyanza Province, Kenya.
Objective. To inform an intervention integrating family planning into HIV care, family planning (FP) knowledge, attitudes and practices, and perspectives on integrating FP into HIV care were assessed among healthcare providers in Nyanza Province, Kenya. Methods. Thirty-one mixed-method, structured interviews were conducted among a purposive sample of healthcare workers (HCWs) from 13 government HIV care facilities in Nyanza Province. Structured questions and case scenarios assessed contraceptive knowledge, training, and FP provision experience. Open-ended questions explored perspectives on integration. Data were analyzed descriptively and qualitatively. Results. Of the 31 HCWs interviewed, 45% reported previous FP training. Few providers thought long-acting methods were safe for HIV-positive women (19% viewed depot medroxyprogesterone acetate as safe and 36% viewed implants and intrauterine contraceptives as safe); fewer felt comfortable recommending them to HIV-positive women. Overall, providers supported HIV and family planning integration, yet several potential barriers were identified including misunderstandings about contraceptive safety, gendered power differentials relating to fertility decisions, staff shortages, lack of FP training, and contraceptive shortages. Conclusions. These findings suggest the importance of considering issues such as patient flow, provider burden, commodity supply, gender and cultural issues affecting FP use, and provider training in FP/HIV when designing integrated FP/HIV services in high HIV prevalence areas.


C3: An R package for cross-species compendium-based cell-type identification.
Cell type identification from an unknown sample can often be done by comparing its gene expression profile against a gene expression database containing profiles of a large number of cell-types. This type of compendium-based cell-type identification strategy is particularly successful for human and mouse samples because a large volume of data exists for these organisms. However, such rich data repositories often do not exist for most non-model organisms. This makes transcriptome-based sample classification in these species challenging. We propose to overcome this challenge by performing a cross-species compendium comparison. The key is to utilise a recently published cross-species gene set analysis (XGSA) framework to correct for biases that may arise due to potentially complex homologous gene mapping between two species. The framework is implemented as an open source R package called C3. We have evaluated the performance of C3 using a variety of public data in NCBI Gene Expression Omnibus. We also compared the functionality and performance of C3 against some similar gene expression profile matching tools. Our evaluation shows that C3 is a simple and effective method for cell type identification. C3 is available at https://github.com/VCCRI/C3.


Objective Assessment of Vergence after Treatment of Concussion-Related CI: A Pilot Study.
To evaluate changes in objective measures of disparity vergence after office-based vision therapy (OBVT) for concussion-related convergence insufficiency (CI) and determine the feasibility of using this objective assessment as an outcome measure in a clinical trial. This was a prospective, observational trial. All participants were treated with weekly OBVT with home reinforcement. Participants included two adolescents and three young adults with concussion-related, symptomatic CI. The primary outcome measure was average peak velocity for 4° symmetrical convergence steps. Other objective outcome measures of disparity vergence included time to peak velocity, latency, accuracy, settling time, and main sequence. We also evaluated saccadic eye movements using the same outcome measures. Changes in clinical measures (near point of convergence, positive fusional vergence at near, Convergence Insufficiency Symptom Survey [CISS] score) were evaluated. There were statistically significant and clinically meaningful changes in all clinical measures for convergence. Four of the five subjects met clinical success criteria. For the objective measures, we found a statistically significant increase in peak velocity, response accuracy to 4° symmetrical convergence and divergence step stimuli, and the main sequence ratio for convergence step stimuli. Objective saccadic eye movements (5 and 10°) appeared normal pre-OBVT and did not show any significant change after treatment. This is the first report of the use of objective measures of disparity vergence as outcome measures for concussion-related convergence insufficiency. These measures provide additional information that is not accessible with clinical tests about underlying physiological mechanisms leading to changes in clinical findings and symptoms. The study results also demonstrate that patients with concussion can tolerate the visual demands (over 200 vergence and versional eye movements) during the 25-minute testing time and suggest that these measures could be used in a large-scale randomized clinical trial of concussion-related CI as outcome measures.


Can Preoperative Patient-reported Outcome Measures Be Used to Predict Meaningful Improvement in Function After TKA?
Despite the overall effectiveness of total knee arthroplasty (TKA), a subset of patients do not experience expected improvements in pain, physical function, and quality of life as documented by patient-reported outcome measures (PROMs), which assess a patient's physical and emotional health and pain. It is therefore important to develop preoperative tools capable of identifying patients unlikely to improve by a clinically important margin after surgery. The purpose of this study was to determine if an association exists between preoperative PROM scores and patients' likelihood of experiencing a clinically meaningful change in function 1 year after TKA. A retrospective study design was used to evaluate preoperative and 1-year postoperative Knee injury and Osteoarthritis Outcome Score (KOOS) and SF-12 version 2 (SF12v2) scores from 562 patients who underwent primary unilateral TKA. This cohort represented 75% of the 750 patients who underwent surgery during that time period; a total of 188 others (25%) either did not complete PROM scores at the designated times or were lost to follow-up. Minimum clinically important differences (MCIDs) were calculated for each PROM using a distribution-based method and were used to define meaningful clinical improvement. MCID values for KOOS and SF12v2 physical component summary (PCS) scores were calculated to be 10 and 5, respectively. A receiver operating characteristic analysis was used to determine threshold values for preoperative KOOS and SF12v2 PCS scores and their respective predictive abilities. Threshold values defined the point after which the likelihood of clinically meaningful improvement began to diminish. Multivariate regression was used to control for the effect of preoperative mental and emotional health, patient attributes quantified by SF12v2 mental component summary (MCS) scores, on patients' likelihood of experiencing meaningful improvement in function after surgery. Threshold values for preoperative KOOS and SF12v2 PCS scores were a maximum of 58 (area under the curve [AUC], 0.76; p < 0.001) and 34 (AUC, 0.65; p < 0.001), respectively. Patients scoring above these thresholds, indicating better preoperative function, were less likely to experience a clinically meaningful improvement in function after TKA. When accounting for mental and emotional health with a multivariate analysis, the predictive ability of both KOOS and SF12v2 PCS threshold values improved (AUCs increased to 0.80 and 0.71, respectively). Better preoperative mental and emotional health, as reflected by a higher MCS score, resulted in higher threshold values for KOOS and SF12v2 PCS. We identified preoperative PROM threshold values that are associated with clinically meaningful improvements in functional outcome after TKA. Patients with preoperative KOOS or SF12v2 PCS scores above the defined threshold values have a diminishing probability of experiencing clinically meaningful improvement after TKA. Patients with worse baseline mental and emotional health (as defined by SF12v2 MCS score) have a lower probability of experiencing clinically important levels of functional improvement after surgery. The results of this study are directly applicable to patient-centered informed decision-making tools and may be used to facilitate discussions with patients regarding the expected benefit after TKA. Level III, prognostic study.


Diabetes and long-term outcomes of ischaemic stroke: findings from Get With The Guidelines-Stroke.
There is a paucity of data on the influence of diabetes on long-term outcomes after ischaemic stroke (IS). We assessed whether outcomes after IS differ between patients with and without diabetes. Patients aged ≥65 years (n = 409 060) in Get With The Guidelines-Stroke (nationwide registry of stroke patients from 1690 sites in the USA) were followed for 3 years post-discharge. The outcomes of interest were mortality, cardiovascular and non-cardiovascular hospitalizations, heart failure (HF), and recurrence of IS/transient ischaemic attack (TIA). Patients with diabetes (29.6%) were younger and had more comorbidities. At 3 years post-discharge after IS, diabetes was associated with higher risks of adverse outcomes: all-cause mortality [cumulative incidence 46.0% vs. 44.2%, absolute difference (AD) 1.8%; adjusted hazard ratio (aHR) 1.24, 95% confidence interval 1.23-1.25], all-cause readmission (71.3% vs. 63.7%, AD 7.6%; aHR 1.22, 1.21-1.23), composite of mortality and all-cause readmission (84.1% vs. 79.3%, AD 4.8%; aHR 1.21, 1.20-1.22), composite of mortality and cardiovascular readmission (69.5% vs. 64.3%, AD 5.2%; aHR 1.19, 1.18-1.20), IS/TIA readmission (15.9% vs. 13.3%, AD 2.6%; aHR 1.18, 1.16-1.20), HF readmission (10.3% vs. 6.4%, AD 3.9%; aHR 1.60, 1.56-1.64), non-cardiovascular readmission (58.3% vs. 50.3%, AD 8.0%; aHR 1.28, 1.26-1.29), and non-IS/TIA readmission (67.6% vs. 59.7%, AD 7.9%; aHR 1.23, 1.22-1.25). Accounting for the initial severity of stroke using the National Institute of Health Stroke Scale as well as using propensity score matching method as a sensitivity analysis, did not modify the results. Among older IS patients diabetes was associated with increased risks of death, cardiovascular and non-cardiovascular hospitalizations, HF, and IS/TIA recurrence.


Ultra-high-frequency piecewise-linear chaos using delayed feedback loops.
We report on an ultra-high-frequency (>1 GHz), piecewise-linear chaotic system designed from low-cost, commercially available electronic components. The system is composed of two electronic time-delayed feedback loops: A primary analog loop with a variable gain that produces multi-mode oscillations centered around 2 GHz and a secondary loop that switches the variable gain between two different values by means of a digital-like signal. We demonstrate experimentally and numerically that such an approach allows for the simultaneous generation of analog and digital chaos, where the digital chaos can be used to partition the system's attractor, forming the foundation for a symbolic dynamics with potential applications in noise-resilient communications and radar.


A hybrid procedure for detecting global treatment effects in multivariate clinical trials: theory and applications to fMRI studies.
In multivariate clinical trials, a key research endpoint is ascertaining whether a candidate treatment is more efficacious than an established alternative. This global endpoint is clearly of high practical value for studies, such as those arising from neuroimaging, where the outcome dimensions are not only numerous but they are also highly correlated and the available sample sizes are typically small. In this paper, we develop a two-stage procedure testing the null hypothesis of global equivalence between treatments effects and demonstrate its application to analysing phase II neuroimaging trials. Prior information such as suitable statistics of historical data or suitably elicited expert clinical opinions are combined with data collected from the first stage of the trial to learn a set of optimal weights. We apply these weights to the outcome dimensions of the second-stage responses to form the linear combination z and t tests statistics while controlling the test's false positive rate. We show that the proposed tests hold desirable asymptotic properties and characterise their power functions under wide conditions. In particular, by comparing the power of the proposed tests with that of Hotelling's T(2), we demonstrate their advantages when sample sizes are close to the dimension of the multivariate outcome. We apply our methods to fMRI studies, where we find that, for sufficiently precise first stage estimates of the treatment effect, standard single-stage testing procedures are outperformed.


Occurrence of celiac disease after onset of type 1 diabetes: a 6-year prospective longitudinal study.
To investigate the prevalence of celiac disease in a large cohort of children and adolescents at the onset of type 1 diabetes and the occurrence of new cases during a 6-year follow-up. We prospectively studied, by repeated serologic screening, 274 consecutive patients at the onset of type 1 diabetes (age [mean +/- standard deviation]: 8.28 +/- 4.65 years) for 6 subsequent years. One patient had a diagnosis of celiac disease before the onset of diabetes. The immunoglobulin A-antiendomysium antibody test was selected as the screening test; patients with positive results (++ or +++) or with 2 consecutive weak positive tests (+) were considered appropriate for the jejunal biopsy. At diabetes onset, 15 (5.5%) of 273 patients tested positive with the antiendomysium test; jejunal biopsy was performed in 10, and celiac disease was diagnosed in 9. The prevalence of biopsy-confirmed celiac disease at the manifestation of diabetes was 3.6% (10 of 274 patients). Twelve more patients with a negative antiendomysium antibody test at diabetes onset tested positive during the follow-up within 4 years; 10 of them had biopsies performed, and 7 had celiac disease. Therefore, the overall prevalence of biopsy-confirmed celiac disease in the entire cohort of patients was 6.2%. The age at diabetes onset in patients with and without celiac disease was not different (7.88 +/- 5.69 vs 8.3 +/- 4.58 years). The majority of cases of celiac disease were asymptomatic in their presentation, and no signs of overt malnutrition were documented. The prevalence of celiac disease in patients with type 1 diabetes is approximately 20 times higher than in the general population. Sixty percent of cases are already present at diabetes onset, mostly undetected, but an additional 40% of patients develop celiac disease a few years after diabetes onset. Extending screening programs for celiac disease after the onset of type 1 diabetes is recommended, even in the absence of clinical symptoms.


A compact native 24-residue supersecondary structure derived from the villin headpiece subdomain.
Many small proteins fold highly cooperatively in an all-or-none fashion and thus their native states are well protected from thermal fluctuations by an extensive network of interactions across the folded structure. Because protein structures are stabilized by local and nonlocal interactions among distal residues, dissecting individual substructures from the context of folded proteins results in large destabilization and loss of unique three-dimensional structure. Thus, mini-protein substructures can only rarely be derived from natural templates. Here, we describe a compact native 24-residues-long supersecondary structure derived from the hyperstable villin headpiece subdomain consisting of helices 2 and 3 (HP24). Using a combination of experimental techniques, including NMR and small-angle x-ray scattering, as well as all-atom replica exchange molecular-dynamics simulations, we show that a variant with stabilizing substitutions (HP24stab) forms a densely packed and compact conformation. In HP24stab, interactions between helices 2 and 3 are similar to those observed in native folded HP35, and the two helices cooperatively stabilize each other by completing the hydrophobic core lining the central part of HP35. Interestingly, even though the HP24wt fragment shows a more expanded and less structured conformation, NMR and simulations demonstrate a preference for a native-like topology. Thus, the two stabilizing residues in HP24stab shift the energy balance toward the native state, leading to a minimal folding motif.


Human immunodeficiency virus type 1 assembly and lipid rafts: Pr55(gag) associates with membrane domains that are largely resistant to Brij98 but sensitive to Triton X-100.
The assembly and budding of human immunodeficiency virus type 1 (HIV-1) at the plasma membrane are directed by the viral core protein Pr55(gag). We have analyzed whether Pr55(gag) has intrinsic affinity for sphingolipid- and cholesterol-enriched raft microdomains at the plasma membrane. Pr55(gag) has previously been reported to associate with Triton X-100-resistant rafts, since both intracellular membranes and virus-like Pr55(gag) particles (VLPs) yield buoyant Pr55(gag) complexes upon Triton X-100 extraction at cold temperatures, a phenotype that is usually considered to indicate association of a protein with rafts. However, we show here that the buoyant density of Triton X-100-treated Pr55(gag) complexes cannot be taken as a proof for raft association of Pr55(gag), since lipid analyses of Triton X-100-treated VLPs demonstrated that the detergent readily solubilizes the bulk of membrane lipids from Pr55(gag). However, Pr55(gag) might nevertheless be a raft-associated protein, since confocal fluorescence microscopy indicated that coalescence of GM1-positive rafts at the cell surface led to copatching of membrane-bound Pr55(gag). Furthermore, extraction of intracellular membranes or VLPs with Brij98 yielded buoyant Pr55(gag) complexes of low density. Lipid analyses of Brij98-treated VLPs suggested that a large fraction of the envelope cholesterol and phospholipids was resistant to Brij98. Collectively, these results suggest that Pr55(gag) localizes to membrane microdomains that are largely resistant to Brij98 but sensitive to Triton X-100, and these membrane domains provide the platform for assembly and budding of Pr55(gag) VLPs.


Evaluation of equine breeding farm characteristics as risk factors for development of Rhodococcus equi pneumonia in foals.
To identify farm characteristics as risk factors for the development of Rhodococcus equi pneumonia in foals. Prospective matched case-control study. 2,764 foals on 64 equine breeding farms with 9,991 horses. During 1997, participating veterinarians completed paired data collection forms, 1 for a farm with > or = 1 foal with R equi pneumonia and 1 for an unaffected control farm. Matched data were compared by use of conditional logistic regression analysis. Farm characteristics found in bivariate analyses to be associated with increased risk for pneumonia caused by R equi in foals included > 200 farm acres, > or = 60 acres used in the husbandry of horses, > 160 horses, > or = 10 mares housed permanently on the farm (resident mares), > 17 foals, > 0.25 foals/acre, and the presence of transient mares (mares brought temporarily to the farm for breeding or foaling) and their foals. Affected farms were significantly more likely to be > 200 acres in size and have > or = 10 resident dam-foal pairs, whereas control farms were significantly more likely to have > or = 75% of their dam-foal pairs housed permanently on the farm. Breeding farms with large acreage, a large number of mares and foals, high foal density, and a population of transient mares and foals are at high risk for foals developing pneumonia caused by R equi.


Social communication disorder: a narrative review on current insights.
Social communication disorder (SCD) is a novel diagnosis listed under the rubric of communication disorders within the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) and it is reported to be characterized by impairment in use of verbal and nonverbal communication for social aims. This review attempts to summarize the current understanding of the SCD concept along with its evolution and presents data from previous studies conducted. Suggestions for further research are also delineated. As listed in DSM-5, the criteria for this novel diagnosis are vague, display elevated comorbidity with other neurodevelopmental disorders and other childhood psychopathologies, and show partial overlap with autistic spectrum disorders both in terms of genetics and family histories. Data on cross-cultural presentations and temporal stability are also limited. The social communication model proposed by Catani and Bambini may help integrate the neurobiological findings pertaining to SCD. Valid and reliable assessment methods need to be developed for SCD. This may involve either development of novel instruments capturing the DSM-5 criteria or application of statistical methods such as item response theory to existing instruments. The relationships between broad autism phenotype, pragmatic language impairment, nonverbal learning disorder, learning disorders, autistic spectrum disorders, and SCD should be evaluated with further studies.


Normal Pressure Hydrocephalus.
Since it was first described in 1965, normal pressure hydrocephalus (NPH) has been a controversial subject. New studies have shed light on its epidemiology and pathogenesis and provided objective ways to measure outcome in patients with NPH. Neuroimaging has improved and allows better recognition of both NPH and the presence of overlapping diseases RECENT FINDINGS: Several recent epidemiologic studies confirm that NPH is a rare disease, but the presence of large ventricles is a common finding with aging. NPH may be multifactorial, including congenital causes, vascular disease, and impaired CSF absorption. MRI features of NPH include enlarged ventricular size and CSF fluid collection outside the ventricles not due to atrophy. The term disproportionately enlarged subarachnoid space hydrocephalus (DESH) has been used to describe prognostic MRI features in NPH, including a "tight high convexity" and enlargement of CSF spaces in the sylvian fissure. DESH has been included in the Japanese guideline for the diagnosis and treatment of NPH. A new NPH scale has been published that provides an objective framework for evaluating patients with NPH before and after shunt placement. Programmable shunts can noninvasively manage overdrainage complications. Surgical outcome has been improving over time. Recent studies have led to improved recognition of overlapping diseases such as Alzheimer pathology, which co-occurs in about 30% of NPH cases. Fludeoxyglucose positron emission tomography (FDG-PET) is a promising imaging modality for diagnosing NPH and detecting concomitant degenerative disease. A systematic approach to patients with possible NPH allows recognition of the subset of patients who will respond to shunt surgery and identification of those with alternative diagnoses.


Laparoscopic partial nephrectomy: The McMaster University experience.
: Laparoscopic partial nephrectomy (LPN) remains one of the more challenging procedures in urology. Minimizing warm ischemia time (WIT) and bleeding requires efficient intracorporeal suturing. In addition, achieving negative surgical margins requires complete excision of the tumour. We report a large Canadian series of laparoscopic partial nephrectomy with intermediate follow-up. : Between September 2000 and August 2008, 152 consecutive laparoscopic partial nephrectomies were performed at our centre. Demographic, pathological and clinical data were collected through a retrospective review of the charts. : The average tumour size was 2.68 cm (Range: 0.5-8.8. The vast majority of tumours were malignant (80%). All margins were negative, except for 2 patients who underwent an immediate re-resection. There were no local recurrences or distant metastasis during the follow-up period of 44.3 months. Most procedures required hilar clamping (93.4%) with a mean WIT of 34 minutes, with a clear trend for declining WIT with increasing experience. Five procedures were converted to laparoscopic radical nephrectomy, 10 converted to a hand-assisted procedure, and 1 was converted to an open partial nephrectomy. The average blood loss was 162 cc. Complications related to the procedure were classified according to the Clavien grading system. The average drop in the glomerular filtration rate was calculated by the Modification of Diet in Renal Disease (MDRD) Study equation between preoperative and 2.5 months postoperative was 8.6 mL/min/1.73 m(2). : LPN is a challenging procedure that requires advanced laparoscopic skills. LPN is feasible with excellent oncological outcomes, and an acceptable complication profile. The short-term impact on overall renal function is minimal. The most common postoperative complication was pseudo-aneurysm requiring embolization, which reinforces the intra-operative need for meticulous and a quick suture-ligation of blood vessels during LPN.


Comparison of Shoulder Management Strategies after Stage I of Fingertip Skin Defect Repair with a Random-Pattern Abdominal Skin Flap.
In the absence of scientific evidence regarding the effectiveness of shoulder management strategies after stage I of fingertip reconstruction, the purpose of this study was to compare the clinical outcomes of various rehabilitation procedures. Patients who underwent fingertip reconstruction with a random-pattern abdominal skin flap between March 2007 and February 2013 were enrolled in the study (n=95). Thirty performed only active exercise (group A), 29 performed only passive exercise (group B), and 32 received a combination of active exercise and pulsed electromagnetic field (PEMF) (group C). The mean age at the time of treatment was 30.2 years in group A, 29.6 years in group B, and 31.8 years in group C. At the final follow-up, there were significant differences between group A and B in terms of Constant score (P=.001), VAS (P=.047), forward flexion of the shoulder (P=0.049), and muscle strength with forward flexion and external rotation (P=0.049 and P=0.042, respectively). A higher Constant score was observed in group C compared to group A, and although there were no differences in the other evaluations between groups A and C, a trend toward better function of the shoulder was demonstrated in group C. The most important findings in our study are that a combination of active exercise and PEME produces superior patient-reported outcomes regarding relief of shoulder signs and symptoms. Given the limitations of this study, better-designed studies with large sample sizes and long-term follow-up are required.


Genetic recombination of bacteriophage T7 in vivo studied by use of a simple physical assay.
A new physical method was developed to assay genetic recombination of phage T7 in vivo. The assay utilized T7 mutants that carry unique restriction sites and was based on the detection of a new restriction fragment generated by recombination. Using this assay, we reexamined the genetic requirements for recombination of T7 DNA. Our results were in total agreement with previous findings in that recombination required the products of genes 3 (endonuclease), 4 (primase), 5 (DNA polymerase), and 6 (exonuclease). Recombination was found to be independent of DNA ligase and DNA packaging and maturation functions.


Heightened male aggression toward sexualized women following romantic rejection: The mediating role of sex goal activation.
Research from a variety of disciplines suggests a positive relationship between Western cultural sexualization and women's likelihood of suffering harm. In the current experiment, 157 young men were romantically rejected by a sexualized or non-sexualized woman then given the opportunity to blast the woman with loud bursts of white noise. We tested whether the activation of sexual goals in men would mediate the relationship between sexualization and aggressive behavior after romantic rejection. We also tested whether behaving aggressively toward a woman after romantic rejection would increase men's feelings of sexual dominance. Results showed that interacting with a sexualized woman increased men's sex goals. Heightened sex goal activation, in turn, predicted increased aggression after romantic rejection. This result remained significant despite controlling for the effects of trait aggressiveness and negative affect. The findings suggest that heightened sex goal activation may lead men to perpetrate aggression against sexualized women who reject them.


Pure optical contrast in scattering-type scanning near-field microscopy.
We have enhanced the apertureless scattering-type scanning near-field optical microscope by two improvements which together achieve a recording of the true near field without any height-induced artefact. These are the use of interferometric detection of the scattered light on one hand, and the use of higher-harmonic dither demodulation of the scattered signal on the other. Here we present the basic rationale for these techniques, and give examples measured with two different experiments, one in the infrared (10 microm wavelength), the other in the visible (633 nm). The latter operates in a fully heterodyne mode and displays simultaneous images of optical near-field phase and amplitude, at below 10 nm resolution.


Cholesterol-lowering effects of oat β-glucan.
Elevated total and low-density lipoprotein (LDL) cholesterol levels are considered major risk factors for cardiovascular disease. Oat β-glucan, a soluble dietary fiber that is found in the endosperm cell walls of oats, has generated considerable interest due to its cholesterol-lowering properties. The United States Food and Drug Administration (FDA) approved a health claim for β-glucan soluble fiber from oats for reducing plasma cholesterol levels and risk of heart disease in 1997. Similarly, in 2004 the United Kingdom Joint Health Claims Initiative (JHCI) allowed a cholesterol-lowering health claim for oat β-glucan. The present review aims to investigate if results from more recent studies are consistent with the original conclusions reached by the FDA and JHCI. Results of this analysis show that studies conducted during the past 13 years support the suggestion that intake of oat β-glucan at daily doses of at least 3 g may reduce plasma total and low-density lipoprotein (LDL) cholesterol levels by 5-10% in normocholesterolemic or hypercholesterolemic subjects. Studies described herein have shown that, on average, oat consumption is associated with 5% and 7% reductions in total and LDL cholesterol levels, respectively. Significant scientific agreement continues to support a relationship between oat β-glucan and blood cholesterol levels, with newer data being consistent with earlier conclusions made by the FDA and JHCI.


SARS-CoV-2 peptides bind to NKG2D and increase NK cell activity.
Immune dysregulation is commonly observed in patients with coronavirus disease 2019 (COVID-19). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces severe lung inflammation and innate immune cell dysregulation. However, the precise interaction between SARS-CoV-2 and the innate immune system is currently unknown. To understand the interaction between SARS-CoV-2 and natural killer (NK) cells, several SARS-CoV-2 S protein peptides capable of binding to the NKG2D receptor were screened by in silico analysis. Among them, two peptides, cov1 and cov2, bound to NK cells and NKG2D receptors. These cov peptides increased NK cytotoxicity toward lung cancer cells, stimulated interferon gamma (IFN-γ) production by NK cells, and likely mediated these responses through the phosphorylation of Vav1, a key downstream-signaling molecule of NKG2D and NK activation genes. The direct interaction between SARS-CoV-2 and NK cells is a novel finding, and modulation of this interaction has potential clinical application as a therapeutic target for COVID-19.


Spatial control of surface plasmon polariton excitation at planar metal surface.
We illustrate that the surface plasmon polariton (SPP) excitation through the prism coupling method is fundamentally limited by destructive interference of spatial light components. We propose that the destructive interference can be canceled out by tailoring the relative phase for the different wave-vector components. As a numerical demonstration, we show that through the phase modulation the excited SPP field is concentrated to a hot energy spot, and the SPP field intensity is dramatically enhanced about three-fold in comparison with a conventional Gaussian beam illumination. The proposed phase-shaped beam approach provides a new degree of freedom to fundamentally control the SPP excitation and benefits the development of surface-enhanced applications.


Pro-Inflammatory CXCR3 Impairs Mitochondrial Function in Experimental Non-Alcoholic Steatohepatitis.
Mitochondrial dysfunction plays a crucial role in the development of non-alcoholic steatohepatitis (NASH). However, the regulator of mitochondrial dysfunction in the pathogenesis of NASH is still largely unclear. CXCR3 is an essential pro-inflammatory factor in chronic liver diseases. We explored the significance of CXCR3 in regulating mitochondrial function during NASH development in animal models and cultured hepatocytes. The effects of CXCR3 on mitochondrial function were evaluated by genetic knockout or pharmacological inhibition in mouse models and in vitro. The ultrastructural changes of mitochondria were assessed by transmission electron microscopy (TEM). Hepatic levels of mitochondrial reactive oxygen species (ROS), DNA damage, membrane potential and ATP were examined. CXCR3 ablation by genetic knockout or pharmacological inhibition in mice protected against NASH development by influencing mitochondrial function. Similarly, depletion of CXCR3 reduced steatohepatitis injury in cultured hepatocytes. TEM analysis revealed that liver mitochondrial integrity was much improved in CXCR3 knockout (CXCR3-/-) compared to wildtype (WT) mice. In agreement with this, impaired mitochondrial function was pronounced in WT mice compared to CXCR3-/- mice, evidenced by increased protein expression of dynamic-related protein-1 (DRP1) and fission-1 (FIS1) and decreased protein expression of mitofusin-1 (MFN1). Mitochondrial dysfunction was induced in AML-12 hepatocytes by methionine and choline deficient medium and in HepG2 cells by palmitic acid. The impaired mitochondrial function in both cell lines was evidenced by reduced membrane potential and ATP content, and by increased mitochondrial ROS accumulation and DNA damage. However, CXCR3 knockdown by siCXCR3 significantly diminished the mitochondrial dysfunction in both AML-12 and HepG2 hepatocytes. In addition, inhibition of CXCR3 by CXCR3 specific antagonists SCH546738 and AMG487 restored mitochondrial function and inhibited mitochondrial-dependent apoptosis in the liver of WT mice fed with methionine and choline deficient diet. CXCR3 induces mitochondrial dysfunction, which contributes to the pathogenesis of steatohepatitis. Pharmacologic blockade of CXCR3 prevents mitochondrial dysfunction and restores the severity of steatohepatitis, indicating a potential clinical impact for controlling the disease.


Is There a Role for Glutaredoxins and BOLAs in the Perception of the Cellular Iron Status in Plants?
Glutaredoxins (GRXs) have at least three major identified functions. In apoforms, they exhibit oxidoreductase activity controlling notably protein glutathionylation/deglutathionylation. In holoforms, i.e., iron-sulfur (Fe-S) cluster-bridging forms, they act as maturation factors for the biogenesis of Fe-S proteins or as regulators of iron homeostasis contributing directly or indirectly to the sensing of cellular iron status and/or distribution. The latter functions seem intimately connected with the capacity of specific GRXs to form [2Fe-2S] cluster-bridging homodimeric or heterodimeric complexes with BOLA proteins. In yeast species, both proteins modulate the localization and/or activity of transcription factors regulating genes coding for proteins involved in iron uptake and intracellular sequestration in response notably to iron deficiency. Whereas vertebrate GRX and BOLA isoforms may display similar functions, the involved partner proteins are different. We perform here a critical evaluation of the results supporting the implication of both protein families in similar signaling pathways in plants and provide ideas and experimental strategies to delineate further their functions.