The effect of H1N1 vaccination on serum miRNA expression in children: A tale of caution for microRNA microarray studies.
MicroRNAs (miRNAs) are a class of small regulatory RNAs around 21-25 nucleotides in length which govern many aspects of immunity including the host innate and adaptive responses to infection. RT-qPCR studies of select microRNAs show that vaccination alters the expression circulating microRNAs but the effect of vaccination on the global microRNA population (i.e. micronome) has never been studied. To describe vaccine associated changes in the expression of microRNAs 21 days after vaccination in children receiving a pandemic influenza (H1N1) vaccination. Serum samples were obtained from children aged 6 months to 12 years enrolled in an open label randomised control trial of two pandemic influenza (H1N1) vaccines, in which participants received either ASO3B adjuvanted split virion or a whole virion non-adjuvanted vaccine. MicroRNA expression was profiled in a discovery cohort of participants prior to, and 21 days after vaccination using an Agilent microarray platform. Findings were followed up by RT-qPCR in the original discovery cohort and then in a validation cohort of participants taken from the same study. 44 samples from 22 children were assayed in a discovery cohort. The microarray results revealed 19 microRNAs were differentially expressed after vaccination after adjustment for multiple testing. The microarray detected ubiquitous expression of several microRNAs which could not be validated by RT-qPCR, many of which have little evidence of existence in publicly available RNA sequencing data. Real time PCR (RT-qPCR) confirmed downregulation of miR-142-3p in the discovery cohort. These findings were not replicated in the subsequent validation cohort (n = 22). This study is the first study to profile microRNA expression after vaccination. An important feature of this study is many of the differentially expressed microRNAs could not be detected and validated by RT-qPCR. This study highlights the care that should be taken when interpreting omics biomarker discovery, highlighting the need for supplementary methods to validate microRNA microarray findings, and emphasises the importance of validation cohorts. Data from similar studies which do not meet these requirements should be interpreted with caution.


Inflammatory cytokines epigenetically regulate rheumatoid arthritis fibroblast-like synoviocyte activation by suppressing HDAC5 expression.
Epigenetic modifications play an important role in the regulation of gene transcription and cellular function. Here, we examined if pro-inflammatory factors present in the inflamed joint of patients with rheumatoid arthritis (RA) could regulate histone deacetylase (HDAC) expression and function in fibroblast-like synoviocytes (FLS). Protein acetylation in synovial tissue was assessed by immunohistochemistry. The mRNA levels of HDAC family members and inflammatory mediators in the synovial tissue and the changes in HDAC expression in RA FLS were measured by quantitative (q) PCR. FLS were either transfected with HDAC5 siRNA or transduced with adenoviral vector encoding wild-type HDAC5 and the effects of HDAC5 manipulation were examined by qPCR arrays, ELISA and ELISA-based assays. Synovial class I HDAC expression was associated with local expression of tumour necrosis factor (TNF) and matrix metalloproteinase-1, while class IIa HDAC5 expression was inversely associated with parameters of disease activity (erythrocyte sedimentation rate, C-reactive protein, Disease Activity Score in 28 Joints). Interleukin (IL)-1β or TNF stimulation selectively suppressed HDAC5 expression in RA FLS, which was sufficient and required for optimal IFNB, CXCL9, CXCL10 and CXCL11 induction by IL-1β, associated with increased nuclear accumulation of the transcription factor, interferon regulatory factor 1(IRF1). Inflammatory cytokines suppress RA FLS HDAC5 expression, promoting nuclear localisation of IRF1 and transcription of a subset of type I interferon response genes. Our results identify HDAC5 as a novel inflammatory mediator in RA, and suggest that strategies rescuing HDAC5 expression in vivo, or the development of HDAC inhibitors not affecting HDAC5 activity, may have therapeutic applications in RA treatment.


Anti-cancer effects of cerium oxide nanoparticles and its intracellular redox activity.
Data on medical applications of cerium oxide nanoparticles CeO2 (CONP) are promising, yet information regarding their action in cells is incomplete and there are conflicting reports about in vitro toxicity. Herein, we have studied cytotoxic effect of CONP in several cancer and normal cell lines and their potential to change intracellular redox status. The IC50 was achieved only in two of eight tested cell lines, melanoma 518A2 and colorectal adenocarcinoma HT-29. Self-propagating room temperature method was applied to produce CONP with an average crystalline size of 4 nm. The results confirmed presence of Ce(3+) and O(2-) vacancies. The induction of cell death by CONP and the production of reactive oxygen species (ROS) were analyzed by flow-cytometry. Free radicals related antioxidant capacity of the cells was studied by the reduction of stable free radical TEMPONE using electron spin resonance spectroscopy. CONP showed low or moderate cytotoxicity in cancer cell lines: adenocarcinoma DLD1 and multi-drug resistant DLD1-TxR, non-small cell lung carcinoma NCI-H460 and multi-drug resistant NCI-H460/R, while normal cell lines (keratinocytes HaCaT, lung fetal fibroblasts MRC-5) were insensitive. The most sensitive were 518A2 melanoma and HT-29 colorectal adenocarcinoma cell lines, with the IC50 values being between 100 and 200 μM. Decreased rate of TEMPONE reduction and increased production of certain ROS species (peroxynitrite and hydrogen peroxide anion) indicates that free radical metabolism, thus redox status was changed, and antioxidant capacity damaged in the CONP treated 518A2 and HT-29 cells. In conclusion, changes in intracellular redox status induced by CONP are partly attributed to the prooxidant activity of the nanoparticles. Further, ROS induced cell damages might eventually lead to the cell death. However, low inhibitory potential of CONP in the other human cell lines tested indicates that CONP may be safe for human usage in industry and medicine.


Extraction of stride events from gait accelerometry during treadmill walking.
Evaluating stride events can be valuable for understanding the changes in walking due to aging and neurological diseases. However, creating the time series necessary for this analysis can be cumbersome. In particular, finding heel contact and toe-off events which define the gait cycles accurately are difficult. We proposed a method to extract stride cycle events from tri-axial accelerometry signals. We validated our method via data collected from 14 healthy controls, 10 participants with Parkinson's disease and 11 participants with peripheral neuropathy. All participants walked at self-selected comfortable and reduced speeds on a computer-controlled treadmill. Gait accelerometry signals were captured via a tri-axial accelerometer positioned over the L3 segment of the lumbar spine. Motion capture data were also collected and served as the comparison method. Our analysis of the accelerometry data showed that the proposed methodology was able to accurately extract heel and toe contact events from both feet. We used t-tests, ANOVA and mixed models to summarize results and make comparisons. Mean gait cycle intervals were the same as those derived from motion capture and cycle-to-cycle variability measures were within 1.5%. Subject group differences could be identified similarly using measures with the two methods. A simple tri-axial acceleromter accompanied by a signal processing algorithm can be used to capture stride events. Clinical Impact: The proposed algorithm enables the assessment of stride events during treadmill walking, and is the first step towards the assessment of stride events using tri-axial accelerometers in real-life settings.


Genomic associations with bill length and disease reveal drift and selection across island bird populations.
Island species provide excellent models for investigating how selection and drift operate in wild populations, and for determining how these processes act to influence local adaptation and speciation. Here, we examine the role of selection and drift in shaping genomic and phenotypic variation across recently separated populations of Berthelot's pipit (Anthus berthelotii), a passerine bird endemic to three archipelagos in the Atlantic. We first characterized genetic diversity and population structuring that supported previous inferences of a history of recent colonizations and bottlenecks. We then tested for regions of the genome associated with the ecologically important traits of bill length and malaria infection, both of which vary substantially across populations in this species. We identified a SNP associated with variation in bill length among individuals, islands, and archipelagos; patterns of variation at this SNP suggest that both phenotypic and genotypic variation in bill length is largely shaped by founder effects. Malaria was associated with SNPs near/within genes involved in the immune response, but this relationship was not consistent among archipelagos, supporting the view that disease resistance is complex and rapidly evolving. Although we found little evidence for divergent selection at candidate loci for bill length and malaria resistance, genome scan analyses pointed to several genes related to immunity and metabolism as having important roles in divergence and adaptation. Our findings highlight the utility and challenges involved with combining association mapping and population genetic analysis in nonequilibrium populations, to disentangle the effects of drift and selection on shaping genotypes and phenotypes.


Novel insights into Fukushima nuclear accident from isotopic evidence of plutonium spread along coastal rivers.
The Fukushima Dai-ichi Nuclear Power Plant (FDNPP) accident led to important releases of radionuclides into the environment, and trace levels of plutonium (Pu) were detected in northeastern Japan. However, measurements of Pu isotopic atom and activity ratios are required to differentiate between the contributions of global nuclear test fallout and FDNPP emissions. In this study, we used a double-focusing sector field ICP-MS to measure Pu atom and activity ratios in recently deposited sediment along rivers draining the most contaminated part of the inland radioactive plume. Results showed that plutonium isotopes (i.e., (239)Pu, (240)Pu, (241)Pu, and (242)Pu) were detected in all samples, although in extremely low concentrations. The (241)Pu/(239)Pu atom ratios measured in sediment deposits (0.0017-0.0884) were significantly higher than the corresponding values attributed to the global fallout (0.00113 ± 0.00008 on average for the Northern Hemisphere between 31°-71° N: Kelley, J. M.; Bond, L. A.; Beasley, T. M. Global distribution of Pu isotopes and (237)Np. Sci. Total. Env. 1999, 237/238, 483-500). The results indicated the presence of Pu from FDNPP, in slight excess compared to the Pu background from global fallout that represented up to ca. 60% of Pu in the analyzed samples. These results demonstrate that this radionuclide has been transported relatively long distances (∼45 km) from FDNPP and been deposited in rivers representing a potential source of Pu to the ocean. In future, the high (241)Pu/(239)Pu atom ratio of the Fukushima accident sourced-Pu should be measured to quantify the supply of continental-originating material from Fukushima Prefecture to the Pacific Ocean.


Socio-economic factors associated with maternal health-seeking behaviours among women from poor households in rural Egypt.
Socio-economic inequalities in basic maternal health interventions exist in Egypt, yet little is known about health-seeking of poor households. This paper assesses levels of maternal health-seeking behaviours in women living in poor households in rural Upper Egypt, and compares these to national averages. Secondly, we construct innovative measures of socio-economic resourcefulness among the rural poor in order to examine the association between the resulting variables and the four dimensions of maternal health-seeking behaviour. We analysed a cross-sectional survey conducted in Assiut and Sohag governorates in 2010-2011 of 2,242 women in households below the poverty line in 65 poorest villages in Egypt. The associations between four latent socio-economic constructs (socio-cultural resourcefulness, economic resourcefulness, dwelling quality and woman's status) and receipt of any antenatal care (ANC), regular ANC (four or more visits), facility delivery and private sector delivery for women's most recent pregnancy in five years preceding survey were assessed using multivariate logistic regression. In the sample, 58.5% of women reported using any ANC and 51.1% facility delivery, lower than national coverage (74.2% and 72.4%, respectively). The proportion of ANC users receiving regular ANC was lower (67%) than nationally (91%). Among women delivering in facilities, 18% of women in the poor Upper Egypt sample used private providers (63% nationally). In multivariate analysis, higher economic resourcefulness was associated with higher odds of receiving ANC but with lower odds of facility delivery. Socio-cultural resourcefulness was positively associated with receiving any ANC, regular ANC and facility delivery, whereas it was not associated with private delivery care. Dwelling quality was positively associated with private delivery facility use. Woman's status was not independently associated with any of the four behaviours. Coverage of basic maternal health interventions and utilisation of private providers are lower among rural poor women in Upper Egypt than nationally. Variables capturing socio-cultural resourcefulness and economic resourcefulness were useful predictors of ANC and facility delivery. Further understanding of issues surrounding availability, affordability and quality of maternal health services among the poor is crucial to eliminating inequalities in maternal health coverage in Egypt.


A phase 1 trial of MSP2-C1, a blood-stage malaria vaccine containing 2 isoforms of MSP2 formulated with Montanide® ISA 720.
In a previous Phase 1/2b malaria vaccine trial testing the 3D7 isoform of the malaria vaccine candidate Merozoite surface protein 2 (MSP2), parasite densities in children were reduced by 62%. However, breakthrough parasitemias were disproportionately of the alternate dimorphic form of MSP2, the FC27 genotype. We therefore undertook a dose-escalating, double-blinded, placebo-controlled Phase 1 trial in healthy, malaria-naïve adults of MSP2-C1, a vaccine containing recombinant forms of the two families of msp2 alleles, 3D7 and FC27 (EcMSP2-3D7 and EcMSP2-FC27), formulated in equal amounts with Montanide® ISA 720 as a water-in-oil emulsion. The trial was designed to include three dose cohorts (10, 40, and 80 µg), each with twelve subjects receiving the vaccine and three control subjects receiving Montanide® ISA 720 adjuvant emulsion alone, in a schedule of three doses at 12-week intervals. Due to unexpected local reactogenicity and concern regarding vaccine stability, the trial was terminated after the second immunisation of the cohort receiving the 40 µg dose; no subjects received the 80 µg dose. Immunization induced significant IgG responses to both isoforms of MSP2 in the 10 µg and 40 µg dose cohorts, with antibody levels by ELISA higher in the 40 µg cohort. Vaccine-induced antibodies recognised native protein by Western blots of parasite protein extracts and by immunofluorescence microscopy. Although the induced anti-MSP2 antibodies did not directly inhibit parasite growth in vitro, IgG from the majority of individuals tested caused significant antibody-dependent cellular inhibition (ADCI) of parasite growth. As the majority of subjects vaccinated with MSP2-C1 developed an antibody responses to both forms of MSP2, and that these antibodies mediated ADCI provide further support for MSP2 as a malaria vaccine candidate. However, in view of the reactogenicity of this formulation, further clinical development of MSP2-C1 will require formulation of MSP2 in an alternative adjuvant. Australian New Zealand Clinical Trials Registry 12607000552482.


Diagnosis of Giardia lamblia infections by detection of parasite-specific antigens.
Antigen detection methods may facilitate diagnosis of Giardia lamblia in stool specimens. As determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis and immunoblotting, G. lamblia cysts and trophozoites share several antigens, especially in the 65-kilodalton and 30- to 34-kilodalton regions. By using blind methods, we compared results obtained by counterimmunoelectrophoresis using cyst-immune rabbit serum and by enzyme-linked immunosorbent assay (ELISA) using trophozoite-immune rabbit serum with results obtained by microscopic examination of a preserved, concentrated, and permanently stained stool specimen. Results were similar when these three methods were used to examine 118 stool specimens from clinical microbiology laboratories (53 specimens with G. lamblia) and specimens from 239 day-care-center toddlers (39 specimens with G. lamblia). Compared with microscopy, we found, for counterimmunoelectrophoresis and ELISA, respectively: sensitivity, 88 versus 94%; specificity, 97 versus 95%; positive predictive value, 86 versus 76%; negative predictive value, 98 versus 97%; and concordance, 89%. The false-positive rate by ELISA was 24% (10 of 42) in day-care-center toddlers but only 3% (1 of 32) in healthy adults (P less than 0.04) as corroborated by microscopy. This discrepancy suggests that the ELISA may be more sensitive than microscopy, which is considered the reference standard, and that results may be dependent, in part, on the epidemiology of the infection in the study subjects.


Application of Medical Intelligence Prep of the Environment: A Review of Operational Vignettes.
Medical intelligence is an underused or sometimes misapplied tool in the protection of our Soldiers and the execution of nonkinetic operations. The somewhat improved infrastructure of the operational environment in Iraq and Afghanistan led to an inevitable sense of complacency in regard to the threat of disease nonbattle injury (DNBI). The picture changed somewhat in 2010 with the advent of the village stability program and the establishment of SOF camps in austere locations with degraded living situations rife with exposure risks. In addition, the increasing deployments to unstable locations around the globe, reminiscent of typical Special Operations Forces (SOF) missions before the Global War on Terrorism, indicate a need for better preparation for deployment from the standpoint of disease risk and force health protection. A knowledge gap has developed because we simply did not need to apply as stringent an evaluation of DNBI risk in environments where improved life support mitigated the risk for us. The tools necessary to decrease or even eliminate the impact of DNBI exist but they must be shared and implemented. This article will present four vignettes from current and former SOF Force Health Protection personnel starting with a simple method of executing Medical Intelligence Prep of the Environment (MIPOE) and highlighting situations in which it either was or could have been implemented to mitigate risk and decrease the impact on mission accomplishment and individual operators. A follow-on article will present vignettes of the successful application of MIPOE to nonkinetic operations.


Utilization of inpatient medical care in Germany.
Inpatient care is an important pillar of the health care system. Data from health surveys enable to analyse the utilization of inpatient treatment from the patient's perspective, and to identify associations to social determinants and other influencing factors. As part of the GEDA 2014/2015-EHIS study, data was collected for the indicator 'utilization of inpatient medical care during the last 12 months'. The data analysis shows that 16.9% of women and 15.3% of men were admitted to hospital at least once during the last 12 months. The utilization of inpatient treatment depends on age: among people aged 65 or above, 25.9% of women and 25.8% of men were admitted to hospital during the last 12 months. Almost no significant differences in utilization were identified in regard to gender, with the exception of the 18-to-29 age group, where admittance to hospital was more common among women than men. In terms of education, people with the lowest level of education have a higher utilization of inpatient care, and this is particularly the case in middle age.


Massage Therapy's Effectiveness on the Decoding EEG Rhythms of Left/Right Motor Imagery and Motion Execution in Patients With Skeletal Muscle Pain.
Most of effectiveness assessments of the widely-used Massage therapy were based on subjective routine clinical assessment tools, such as Visual Analogue Scale (VAS) score. However, few studies demonstrated the impact of massage on the Electroencephalograph (EEG) rhythm decoding of Motor imagery (MI) and motion execution (ME) with trunk left/right bending in patients with skeletal muscle pain. We used the sample entropy (SampEn), permutation entropy (PermuEn), common spatial pattern (CSP) features, support vector machine (SVM) and logic regression (LR) classifiers. We also used the convolutional neural network (CNN) and attention-based bi-directional long short-term memory (BiLSTM) for classification. The averaged SampEn and PermuEn values of alpha rhythm decreased in almost fourteen channels for five statuses (quiet, MI with left/right bending, ME with left/right bending). It indicated that massage alleviates the pain for the patients of skeletal pain. Furthermore, compared with the SVM and LR classifiers, the BiLSTM method achieved a better area under curve (AUC) of 0.89 for the classification of MI with trunk left/right bending before massage. The AUC became smaller after massage than that before massage for the classification of MI with trunk left/right bending using CNN and BiLSTM methods. The Permutation direct indicator (PDI) score showed the significant difference for patients in different statuses (before vs after massage, and MI vs ME). Massage not only affects the quiet status, but also affects the MI and ME. Clinical Impact: Massage therapy may affect a bit on the accuracy of MI with trunk left/right bending and it change the topography of MI and ME with trunk left/right bending for the patients with skeletal muscle pain.


Learning and Collective Knowledge Construction With Social Media: A Process-Oriented Perspective.
Social media are increasingly being used for educational purposes. The first part of this article briefly reviews literature that reports on educational applications of social media tools. The second part discusses theories that may provide a basis for analyzing the processes that are relevant for individual learning and collective knowledge construction. We argue that a systems-theoretical constructivist approach is appropriate to examine the processes of educational social media use, namely, self-organization, the internalization of information, the externalization of knowledge, and the interplay of externalization and internalization providing the basis of a co-evolution of cognitive and social systems. In the third part we present research findings that illustrate and support this systems-theoretical framework. Concluding, we discuss the implications for educational design and for future research on learning and collective knowledge construction with social media.


Do Regenerative Medicine Therapies Provide Long-Term Relief in Chronic Low Back Pain: A Systematic Review and Metaanalysis.
Several cell-based therapies have been proposed in recent years the management of low back pain, including the injection of medicinal signaling cells or mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP). However, there is only emerging clinical evidence to support their use at this time. To assess the effectiveness of MSCs or PRP injections in the treatment of low back and lower extremity pain. A systematic review and metaanalysis of the effectiveness of PRP and MSCs injections in managing low back and lower extremity pain. PubMed, Cochrane Library, US National Guideline Clearinghouse, prior systematic reviews, and reference lists. The literature search was performed from 1966 through June 2018. Randomized trials, observational studies, and case reports of injections of biologics into the disc, epidural space, facet joints, or sacroiliac joints. Data extraction and methodological quality assessment were performed utilizing Cochrane review methodologic quality assessment and Interventional Pain Management Techniques - Quality Appraisal of Reliability and Risk of Bias Assessment (IPM-QRB) and Interventional Pain Management Techniques - Quality Appraisal of Reliability and Risk of Bias Assessment for Nonrandomized Studies (IPM-QRBNR). The evidence was summarized utilizing principles of best evidence synthesis on a scale of 1 to 5. Twenty-one injection studies met inclusion criteria. There were 12 lumbar disc injections, 5 epidural, 3 lumbar facet joint, and 3 sacroiliac joint studies RESULTS: Evidence synthesis based on a single-arm metaanalysis, randomized controlled trials (RCTs), and observational studies, disc injections of PRP and MSCs showed Level 3 evidence (on a scale of Level I through V). Evidence for epidural injections based on single-arm metaanalysis, a single randomized controlled trial and other available studies demonstrated Level 4 (on a scale of Level I through V) evidence. Similarly, evidence for lumbar facet joint injections and sacroiliac joint injections without metaanalysis demonstrated Level 4 evidence (on a scale of Level I through V). Lack of high quality RCTs. The findings of this systematic review and single-arm metaanalysis shows that MSCs and PRP may be effective in managing discogenic low back pain, radicular pain, facet joint pain, and sacroiliac joint pain, with variable levels of evidence in favor of these techniques. Chronic low back pain, regenerative therapy, medicinal signaling or mesenchymal stem cells, platelet-rich plasma, disc injection, lumbar facet joint injections, sacroiliac joint injections.


Localization of protective epitopes of the amino terminus of type 5 streptococcal M protein.
We have used a set of overlapping chemically synthesized peptides representing the amino terminus of type 5 streptococcal M protein to localize protective, as opposed to nonprotective and tissue-crossreactive epitopes that might be appropriate for vaccine formulations. Rabbit antisera raised against SM5(1-35) reacted in high titer with pep M5 by ELISA and opsonized type 5 streptococci. None of the antisera crossreacted with human heart tissue or myosin. Antisera against SM5(26-35) reacted with SM5(1-35) and pep M5 but failed to opsonize type 5 streptococci. Particle-phase ELISA indicated that SM5(26-35) antibodies were directed against nonprotective determinants of pep M5 that were not exposed on the surface of viable organisms. Opsonization and ELISA inhibition assays showed that, of the SM5(1-35) antibodies that reacted with M5, all were inhibited by SM5(14-35), whereas none was inhibited by SM5(26-35), suggesting that the protective epitopes of SM5(1-35) resided between residues 14 and 26. This was confirmed by subsequent chemical synthesis of this region; SM5(14-26) totally inhibited SM5(1-35) antibodies that reacted with pep M5 in ELISA, and completely inhibited opsonization of type 5 streptococci by SM5(1-35) antibodies. SM5(14-26) evoked high titers of type-specific, opsonic antibodies against type 5 streptococci, confirming the protective immunogenicity of this 13-residue peptide of type 5 M protein.


Climate change in the Fertile Crescent and implications of the recent Syrian drought.
Before the Syrian uprising that began in 2011, the greater Fertile Crescent experienced the most severe drought in the instrumental record. For Syria, a country marked by poor governance and unsustainable agricultural and environmental policies, the drought had a catalytic effect, contributing to political unrest. We show that the recent decrease in Syrian precipitation is a combination of natural variability and a long-term drying trend, and the unusual severity of the observed drought is here shown to be highly unlikely without this trend. Precipitation changes in Syria are linked to rising mean sea-level pressure in the Eastern Mediterranean, which also shows a long-term trend. There has been also a long-term warming trend in the Eastern Mediterranean, adding to the drawdown of soil moisture. No natural cause is apparent for these trends, whereas the observed drying and warming are consistent with model studies of the response to increases in greenhouse gases. Furthermore, model studies show an increasingly drier and hotter future mean climate for the Eastern Mediterranean. Analyses of observations and model simulations indicate that a drought of the severity and duration of the recent Syrian drought, which is implicated in the current conflict, has become more than twice as likely as a consequence of human interference in the climate system.


Lymphoid proliferations of indeterminate malignant potential arising in adults with common variable immunodeficiency disorders: unusual case studies and immunohistological review in the light of possible causative events.
Patients with common variable immunodeficiency disorders (CVIDs) who developed B cell lymphoproliferation of indeterminate malignant potential are described in order to raise a discussion of the relationship between infection and lymphoproliferation in infection prone patients. Those with CVID are at risk of developing either polyclonal or monoclonal lymphoproliferation in part due to the dysregulation of their adaptive immune systems. The aetiologies of the lymphoproliferations are unknown but intriguing; the relevance of infection being particularly problematic. The patients described here demonstrate variability in preceding infection, age at presentation, response to antibiotics and other types of therapy as well as outcome. The question of treatment is also controversial; issues include whether antibiotics or chemotherapy are the first line of therapy in all patients and whether transformation to aggressive B cell malignancy is inevitable or depends on other factors and if so, the length of time for such progression.


Synaptic transmission from horizontal cells to cones is impaired by loss of connexin hemichannels.
In the vertebrate retina, horizontal cells generate the inhibitory surround of bipolar cells, an essential step in contrast enhancement. For the last decades, the mechanism involved in this inhibitory synaptic pathway has been a major controversy in retinal research. One hypothesis suggests that connexin hemichannels mediate this negative feedback signal; another suggests that feedback is mediated by protons. Mutant zebrafish were generated that lack connexin 55.5 hemichannels in horizontal cells. Whole cell voltage clamp recordings were made from isolated horizontal cells and cones in flat mount retinas. Light-induced feedback from horizontal cells to cones was reduced in mutants. A reduction of feedback was also found when horizontal cells were pharmacologically hyperpolarized but was absent when they were pharmacologically depolarized. Hemichannel currents in isolated horizontal cells showed a similar behavior. The hyperpolarization-induced hemichannel current was strongly reduced in the mutants while the depolarization-induced hemichannel current was not. Intracellular recordings were made from horizontal cells. Consistent with impaired feedback in the mutant, spectral opponent responses in horizontal cells were diminished in these animals. A behavioral assay revealed a lower contrast-sensitivity, illustrating the role of the horizontal cell to cone feedback pathway in contrast enhancement. Model simulations showed that the observed modifications of feedback can be accounted for by an ephaptic mechanism. A model for feedback, in which the number of connexin hemichannels is reduced to about 40%, fully predicts the specific asymmetric modification of feedback. To our knowledge, this is the first successful genetic interference in the feedback pathway from horizontal cells to cones. It provides direct evidence for an unconventional role of connexin hemichannels in the inhibitory synapse between horizontal cells and cones. This is an important step in resolving a long-standing debate about the unusual form of (ephaptic) synaptic transmission between horizontal cells and cones in the vertebrate retina.


In Vitro-In Vivo Extrapolation Scaling Factors for Intestinal P-glycoprotein and Breast Cancer Resistance Protein: Part II. The Impact of Cross-Laboratory Variations of Intestinal Transporter Relative Expression Factors on Predicted Drug Disposition.
Relative expression factors (REFs) are used to scale in vitro transporter kinetic data via in vitro-in vivo extrapolation linked to physiologically based pharmacokinetic (IVIVE-PBPK) models to clinical observations. Primarily two techniques to quantify transporter protein expression are available, immunoblotting and liquid chromatography-tandem mass spectrometry. Literature-collated REFs ranged from 0.4 to 5.1 and 1.1 to 90 for intestinal P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), respectively. The impact of using human jejunum-Caco-2 REFs for P-gp (REFiP-gp) and BCRP (REFiBCRP), generated from the same samples and using different proteomic methodologies from independent laboratories, on PBPK outcomes was assessed. A 5-fold decrease in REFiP-gp for a single oral dose of digoxin resulted in a 1.19- and 1.31-fold higher plasma area under the curve and Cmax, respectively. All generated REFiP-gp values led to simulated digoxin Cmax values within observed ranges; however, combining kinetic data generated from a different laboratory with the 5-fold lower REFiP-gp could not recover a digoxin-rifampicin drug-drug interaction, emphasizing the necessity to obtain transporter-specific kinetic estimates and REFs from the same in vitro system. For a theoretical BCRP compound, with absorption taking place primarily in the jejunum, a decrease in the REFiBCRP from 2.22 (University of Manchester) to 1.11 (Bertin Pharma) promoted proximal intestinal absorption while delaying tmax 1.44-fold. Laboratory-specific differences in REF may lead to different IVIVE-PBPK outcomes. To understand the mechanisms underlying projected pharmacokinetic liabilities, it is important to assess the potential impact of bias on the generation of REFs on an interindividual basis within a target population.


CT694 and pgp3 as serological tools for monitoring trachoma programs.
Defining endpoints for trachoma programs can be a challenge as clinical signs of infection may persist in the absence of detectable bacteria. Antibody-based tests may provide an alternative testing strategy for surveillance during terminal phases of the program. Antibody-based assays, in particular ELISAs, have been shown to be useful to document C. trachomatis genital infections, but have not been explored extensively for ocular C. trachomatis infections. An antibody-based multiplex assay was used to test two C. trachomatis antigens, pgp3 and CT694, for detection of trachoma antibodies in bloodspots from Tanzanian children (n = 160) collected after multiple rounds of mass azithromycin treatment. Using samples from C. trachomatis-positive (by PCR) children from Tanzania (n = 11) and control sera from a non-endemic group of U.S. children (n = 122), IgG responses to both pgp3 and CT694 were determined to be 91% sensitive and 98% specific. Antibody responses of Tanzanian children were analyzed with regard to clinical trachoma, PCR positivity, and age. In general, children with more intense ocular pathology (TF/TI = 2 or most severe) had a higher median antibody response to pgp3 (p = 0.0041) and CT694 (p = 0.0282) than those with normal exams (TF/TI = 0). However, 44% of children with no ocular pathology tested positive for antibody, suggesting prior infection. The median titer of antibody responses for children less than three years of age was significantly lower than those of older children. (p<0.0001 for both antigens). The antibody-based multiplex assay is a sensitive and specific additional tool for evaluating trachoma transmission. The assay can also be expanded to include antigens representing different diseases, allowing for a robust assay for monitoring across NTD programs.


Type 2 diabetes mellitus as a conformational disease.
Conformational diseases are conditions that arise from the dysfunctional aggregation of proteins in non-native conformations. Type 2 diabetes mellitus can be defined as a conformational disease because a constituent beta cell protein, islet amyloid polypeptide, undergoes a change in tertiary structure followed by self-association and tissue deposition. Type 2 diabetes mellitus is associated with multiple metabolic derangements that result in the excessive production of reactive oxygen species and oxidative stress. These reactive oxygen species set in motion a host of redox reactions which can result in unstable nitrogen and thiol species that contribute to additional redox stress. The ability of a cell to deal with reactive oxygen species and oxidative stress requires functional chaperones, antioxidant production, protein degradation and a cascade of intracellular events collectively known as the unfolded protein response. It is known that beta cells are particularly susceptible to perturbations in this quality control system and that reactive oxygen species play an important role in the development and/or progression of diabetes mellitus. Oxidative stress and increased insulin production contribute to endoplasmic reticulum stress, protein misfolding, and induction of the unfolded protein response. As the cell's quality control system becomes overwhelmed, conformational changes occur to islet amyloid polypeptide intermediates, generating stable oligomers with an anti-parallel crossed beta-pleated sheet structure that eventually accumulate as space-occupying lesions within the islets. By approaching type 2 diabetes mellitus as a conformational disease in which there is a structural transition from physiological protein to pathological protein, it is possible that the relentless nature of disease progression can be understood in relation to other conformational diseases.


Diversity in genetic counseling: past, present and future.
Despite decades of efforts to increase ethnic and racial diversity among genetic counselors, African Americans, Hispanics and American Indians, currently constituting almost one-third of Americans, remain only meagerly represented among genetic counselors at a level far under that seen in other health professions. This paper provides the first comprehensive effort to archive published and unpublished initiatives to increase ethnic and racial diversity in the profession. It also provides a review of national data and diversity initiatives in the health workforce in general. The paper reviews diversity initiatives in other health professions and suggests ways to improve recruitment and retention of underrepresented populations into genetic counseling. Increasing the diversity of the genetic counseling workforce stands not only to expand access to genetic services but also to improve the quality of genetic care provided to the American public.


Evaluation of the role of SNCA variants in survival without neurological disease.
A variety of definitions of successful aging have been proposed, many of which relate to longevity, freedom from disease and disability, or preservation of high physical and cognitive function. Many behavioral, biomedical, and psychological factors have been linked with these various measures of successful aging, however genetic predictors are less understood. Parkinson's disease (PD) is an age-related neurodegenerative disorder, and variants in the α-synuclein gene (SNCA) affect susceptibility to PD. This exploratory study examined whether SNCA variants may also promote successful aging as defined by survival without neurological disease. We utilized 769 controls without neurological disease (Mean age: 79 years, Range: 33-99 years) and examined the frequency of 20 different SNCA variants across age groups using logistic regression models. We also included 426 PD cases to assess the effect of these variants on PD risk. There was a significant decline in the proportion of carriers of the minor allele of rs10014396 as age increased (P = 0.021), from 30% in controls younger than 60 to 14% in controls 90 years of age or older. Findings were similar for rs3775439, where the proportion of carriers of the minor allele declined from 32% in controls less than 60 years old to 19% in those 90 or older (P = 0.025). A number of SNCA variants, not including rs10014396 or rs3775439, were significantly associated with susceptibility to PD. In addition to its documented roles in PD and α-synucleinopathies, our results suggest that SNCA has a role in survival free of neurological disease. Acknowledging that our findings would not have withstood correction for multiple testing, validation in an independent series of aged neurologically normal controls is needed.


Effect of Omega-3 Long Chain Polyunsaturated Fatty Acids (n-3 LCPUFA) Supplementation on Cognition in Children and Adolescents: A Systematic Literature Review with a Focus on n-3 LCPUFA Blood Values and Dose of DHA and EPA.
Omega-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) supplementation in the cardiovascular field is effective if a certain Omega-3 index (O3I) is achieved or the daily n-3 LCPUFA dose is high enough. Whether this applies to studies on cognition in children and adolescents is unclear. The aims of the current review were to investigate whether: (1) a certain O3I level and (2) a minimum daily n-3 LCPUFA dose are required to improve cognition in 4-25 year olds. Web of Science and PubMed were searched. Inclusion criteria: placebo controlled randomized controlled trial; participants 4-25 years; supplementation with docosahexaenoic acid (DHA) and/or eicosapentaenoic acid (EPA); assessing cognition; in English and ≥10 participants per treatment arm. Thirty-three studies were included, 21 in typically developing participants, 12 in those with a disorder. A positive effect on cognitive measures was more likely in studies with an increase in O3I to >6%. Half of the studies in typically developing children with daily supplementation dose ≥450 mg DHA + EPA showed improved cognition. For children with a disorder no cut-off value was found. In conclusion, daily supplementation of ≥450 mg DHA + EPA per day and an increase in the O3I to >6% makes it more likely to show efficacy on cognition in children and adolescents.


Efficient region-based test strategy uncovers genetic risk factors for functional outcome in bipolar disorder.
Genome-wide association studies of case-control status have advanced the understanding of the genetic basis of psychiatric disorders. Further progress may be gained by increasing sample size but also by new analysis strategies that advance the exploitation of existing data, especially for clinically important quantitative phenotypes. The functionally-informed efficient region-based test strategy (FIERS) introduced herein uses prior knowledge on biological function and dependence of genotypes within a powerful statistical framework with improved sensitivity and specificity for detecting consistent genetic effects across studies. As proof of concept, FIERS was used for the first genome-wide single nucleotide polymorphism (SNP)-based investigation on bipolar disorder (BD) that focuses on an important aspect of disease course, the functional outcome. FIERS identified a significantly associated locus on chromosome 15 (hg38: chr15:48965004 - 49464789 bp) with consistent effect strength between two independent studies (GAIN/TGen: European Americans, BOMA: Germans; n = 1592 BD patients in total). Protective and risk haplotypes were found on the most strongly associated SNPs. They contain a CTCF binding site (rs586758); CTCF sites are known to regulate sets of genes within a chromatin domain. The rs586758 - rs2086256 - rs1904317 haplotype is located in the promoter flanking region of the COPS2 gene, close to microRNA4716, and the EID1, SHC4, DTWD1 genes as plausible biological candidates. While implication with BD is novel, COPS2, EID1, and SHC4 are known to be relevant for neuronal differentiation and function and DTWD1 for psychopharmacological side effects. The test strategy FIERS that enabled this discovery is equally applicable for tag SNPs and sequence data.


Enhanced photocatalytic reduction activity of uranium(vi) from aqueous solution using the Fe2O3-graphene oxide nanocomposite.
Photocatalytic technologies are a potential solution for remediation of radioactive wastewater, including the reduction of radioactive hexavalent uranium, which is commonly found in wastewater from the nuclear industry. In this study, Fe2O3-graphene oxide composites were synthesized by an easy and scalable impregnation method as a catalyst for the reduction of U(vi). X-ray photoelectron spectroscopy analysis and high-resolution transmission electron microscopy images of this composite clearly showed that the Fe2O3 nanoparticles exist in the layered structure of graphene oxide. The photocatalytic activity of the Fe2O3-graphene oxide composite was evaluated by the reduction of U(vi) to U(iv) in aqueous solution under visible light. The results showed that the photocatalytic process of the Fe2O3-graphene oxide composite was always faster than that of the Fe2O3 nanoparticles. Moreover, the experimental kinetic data for the catalytic process followed a pseudo-first-order model. The stability of the Fe2O3-graphene oxide composites was studied over successive experiments, with the photocatalytic reduction efficiency of U(vi) decreasing to 76.0% after four cycles. Based on these experimental results, the enhanced photocatalytic activity and stability of Fe2O3-graphene oxide composites can be attributed to the improved adsorption properties of U(vi) at GO and the electron transfer from iron oxide to GO.


Prenatal care and adverse pregnancy outcomes among women with depression: a nationwide population-based study.
To evaluate the quantity of prenatal care as a risk factor for giving birth to low birth weight (LBW), preterm, and small for gestational age (SGA) infants in a sample of women diagnosed with depressive disorder. Our study used a population-based dataset, Taiwan's National Health Insurance Research Database, which we linked to Taiwan's birth certificate registry to identify a total of 5283 new mothers with depressive disorder. Multivariate logistic regression analyses were performed to measure the risk of giving birth to LBW, preterm, and SGA infants, relating to the number of prenatal care visits (10 or more, 8 to 9, and 7 or less) made by mothers with depressive disorder. After adjusting for a woman's age, monthly income, urbanization level of place of residence, geographic location, marital status, substance abuse, arterial hypertension, diabetes, anemia, coronary heart disease, malpresentation, insufficient or excessive fetal growth, placenta or previa abruption, and infant's sex and parity, regression analyses revealed that mothers with a history of depressive disorder who received prenatal care 7 times or less were 4.21 (95% CI 3.34 to 5.32, P < 0.001), 5.37 (95% CI 4.33 to 6.67, P < 0.001), and 2.41 (95% CI 2.03 to 2.86, P < 0.001) times as likely to have LBW, preterm, and SGA babies, respectively, compared with mothers with depressive disorder who received prenatal care visits 10 times or more. Mothers with a history of depressive disorder who make fewer prenatal care visits were at an increased risk of LBW, SGA, and preterm birth, compared with women with a history of depressive disorder who made an adequate number of prenatal visits.


Cross-national disparities contribute to heterogeneity in patient outcomes following invasive monitoring: A hierarchical mixed-effects analysis.
There is substantial variability in outcomes following invasive monitoring and surgical treatment of drug-resistant epilepsy (DRE). Patients with DRE are uniquely vulnerable to cross-national health care disparities, as their epilepsy is difficult to treat and requires extensive resources. In a large cross-national database of patients undergoing invasive monitoring for epilepsy surgery, we sought to evaluate the association between social, economic, and educational indicators of the country of treatment and patient outcomes following invasive monitoring. We performed a mixed-effects analysis of an individual patient database of 595 subjects enrolled in 33 studies encompassing 25 neurosurgical centers in 10 countries of invasive monitoring for epilepsy from 1996 to 2019. Upon preliminary univariate analysis, significant nation-level predictors of seizure outcome following either stereoelectroencephalography or subdural electrodes were hospital beds per 100,000 population, physician density, gross domestic product (GDP) growth, male and female educational attainment, and unemployment rate. On multivariate mixed-effects logistic regression, physician density (β = -0.5112, P<.00697) and GDP growth (β = 0.53822, P<.00404) were the only nation-level covariates of significance associated with seizure outcome. A higher physician density was associated with lesser seizure freedom rates, whereas higher GDP growth was associated with greater seizure freedom rates. Although patient-specific variables were the primary determinant of seizure outcomes, cross-national disparities also contribute to heterogeneities. Our findings highlight the importance of a systems-level dialogue to improve surgical outcomes for DRE patients.


Integrated liquid-core optical fibers for ultra-efficient nonlinear liquid photonics.
We have developed a novel integrated platform for liquid photonics based on liquid core optical fiber (LCOF). The platform is created by fusion splicing liquid core optical fiber to standard single-mode optical fiber making it fully integrated and practical - a major challenge that has greatly hindered progress in liquid-photonic applications. As an example, we report here the realization of ultralow threshold Raman generation using an integrated CS₂ filled LCOF pumped with sub-nanosecond pulses at 532 nm and 1064 nm. The measured energy threshold for the Stokes generation is 1nJ, about three orders of magnitude lower than previously reported values in the literature for hydrogen gas, a popular Raman medium. The integrated LCOF platform opens up new possibilities for ultralow power nonlinear optics such as efficient white light generation for displays, mid-IR generation, slow light generation, parametric amplification, all-optical switching and wavelength conversion using liquids that have orders of magnitude larger optical nonlinearities compared with silica glass.


Generation of an atlas for commodity chemical production in Escherichia coli and a novel pathway prediction algorithm, GEM-Path.
The production of 75% of the current drug molecules and 35% of all chemicals could be achieved through bioprocessing (Arundel and Sawaya, 2009). To accelerate the transition from a petroleum-based chemical industry to a sustainable bio-based industry, systems metabolic engineering has emerged to computationally design metabolic pathways for chemical production. Although algorithms able to provide specific metabolic interventions and heterologous production pathways are available, a systematic analysis for all possible production routes to commodity chemicals in Escherichia coli is lacking. Furthermore, a pathway prediction algorithm that combines direct integration of genome-scale models at each step of the search to reduce the search space does not exist. Previous work (Feist et al., 2010) performed a model-driven evaluation of the growth-coupled production potential for E. coli to produce multiple native compounds from different feedstocks. In this study, we extended this analysis for non-native compounds by using an integrated approach through heterologous pathway integration and growth-coupled metabolite production design. In addition to integration with genome-scale model integration, the GEM-Path algorithm developed in this work also contains a novel approach to address reaction promiscuity. In total, 245 unique synthetic pathways for 20 large volume compounds were predicted. Host metabolism with these synthetic pathways was then analyzed for feasible growth-coupled production and designs could be identified for 1271 of the 6615 conditions evaluated. This study characterizes the potential for E. coli to produce commodity chemicals, and outlines a generic strain design workflow to design production strains.


The genome of cultivated peanut provides insight into legume karyotypes, polyploid evolution and crop domestication.
High oil and protein content make tetraploid peanut a leading oil and food legume. Here we report a high-quality peanut genome sequence, comprising 2.54 Gb with 20 pseudomolecules and 83,709 protein-coding gene models. We characterize gene functional groups implicated in seed size evolution, seed oil content, disease resistance and symbiotic nitrogen fixation. The peanut B subgenome has more genes and general expression dominance, temporally associated with long-terminal-repeat expansion in the A subgenome that also raises questions about the A-genome progenitor. The polyploid genome provided insights into the evolution of Arachis hypogaea and other legume chromosomes. Resequencing of 52 accessions suggests that independent domestications formed peanut ecotypes. Whereas 0.42-0.47 million years ago (Ma) polyploidy constrained genetic variation, the peanut genome sequence aids mapping and candidate-gene discovery for traits such as seed size and color, foliar disease resistance and others, also providing a cornerstone for functional genomics and peanut improvement.


A mutation that affects fibril protein, development, cohesion and gene expression in Myxococcus xanthus.
Extracellular matrix fibrils are involved in the cell-cell interactions of the social prokaryote, Myxococcus xanthus. The fibrils are composed of a carbohydrate backbone and a set of five integral fibrillar proteins (IFPs) ranging from 14 to 66 kDa. As part of an attempt to understand the function(s) of the IFPs, a mutant (ifp-1:20) was generated that lacks IFP-1:20, one of the fibril proteins, as shown by Western blot analysis of both whole cells and isolated fibrils. Unlike those of the parent strain, the fibrils of the mutant were removed easily from the cells by shear forces. Development in ifp-1:20 was aberrant--aggregation and early mound formation were delayed by 6-10 h and mature fruiting bodies never formed. Myxospore production was also greatly reduced. Additionally, fibril-mediated cohesion in ifp-1:20 was changed. Cohesion resulted in chains of cells rather than the characteristic clumps of cells seen for the parent strain. Isolated ifp-1:20 fibrils, unlike wild-type fibrils, could not rescue cohesion of non-cohesive, fibril-negative dsp cells, supporting the notion that the fibrils were functionally altered. The mutation also reduced developmental gene expression by three- to fourfold in omega 4521, a transposon insertion mutant expressed early in development. Expression of a later developmental gene fusion was not affected, suggesting that the fibrils may not be required for later developmental gene expression. These data suggest that intact fibrils may function early in development to facilitate close cell proximity for signal exchange.


Facial expressions and complex IAPS pictures: common and differential networks.
Neuroimaging studies investigating emotion have commonly used two different visual stimulus formats, facial expressions of emotion or emotionally evocative scenes. However, it remains an important unanswered question whether or not these different stimulus formats entail the same processes. Facial expressions of emotion may elicit more emotion recognition/perception, and evocative pictures may elicit more direct experience of emotion. In spite of these differences, common areas of activation have been reported across different studies, but little work has investigated activations in response to the two stimulus formats in the same subjects. In this fMRI study, we compared BOLD activation patterns to facial expression of emotions and to complex emotional pictures from the International Affective Picture System (IAPS) to determine if these stimuli would activate similar or distinct brain regions. Healthy volunteers passively viewed blocks of expressive faces and IAPS pictures balanced for specific emotion (happy, sad, anger, fear, neutral), interleaved with blocks of fixation. Eye movement, reaction times, and off-line subjective ratings including discrete emotion, valence, and arousal were also recorded. Both faces and IAPS pictures activated similar structures, including the amygdala, posterior hippocampus, ventromedial prefrontal cortex, and visual cortex. In addition, expressive faces uniquely activated the superior temporal gyrus, insula, and anterior cingulate more than IAPS pictures, despite the faces being less arousing. For the most part, these regions were activated in response to all specific emotions; however, some regions responded only to a subset.


Comparison of COMLEX-USA scores, medical school performance, and preadmission variables between women and men.
Previous studies by the author showed differences in preadmission variables and Comprehensive Osteopathic Medical Licensing Examination-USA (COMLEX-USA) scores between women and men at the New York Institute of Technology College of Osteopathic Medicine (NYIT-COM). It is pertinent to reexamine the preadmission variables, medical school performance, and COMLEX-USA scores of women and men to determine whether these differences still exist. To examine the relationship between student sex and performance on COMLEX-USA Level 1 and Level 2-Cognitive Evaluation (CE), performance during medical school, and preadmission academic variables at NYIT-COM. Scores on COMLEX-USA Level 1 and COMLEX-USA Level 2-CE, grades in all courses taken during the first 2 years of medical school, the National Board of Osteopathic Medical Examiners' clinical science subject examination scores, Medical College Admission Test (MCAT) scores, and undergraduate grade point averages (GPAs) were compared between women and men in the classes graduating between 2009 and 2012. Data from 748 students were analyzed. Men had statistically significantly higher scores than women on COMLEX-USA Level 1 in 2009 (540 vs 500; P<.001) and 2010 (537 vs 496; P<.001). No statistically significant difference in COMLEX-USA Level 2-CE scores was found between women and men. The performance of women and men was comparable during the first 2 years of medical school and on clinical science subject examinations in years 3 and 4. Men had statistically significantly higher MCAT scores than women, but no statistically significant differences were found between women's and men's undergraduate GPAs. Men were found to have higher scores than women on COMLEX-USA Level 1 and the MCAT. However, the reasons behind these data have yet to be elucidated. Although a stronger background in basic science could explain the discrepancy in scores between women and men, women were found to have equally high science GPAs and performed comparably to men in osteopathic medical school. The results were in agreement with previous studies at NYIT-COM.


Effect of relative humidity on oxidation of flaxseed oil in spray dried whey protein emulsions.
Flaxseed oil was emulsified in whey protein isolate (WPI) and spray-dried. Powder characteristics and oxidative stability of oil at relative humidities (RH) from RH approximately 0% to RH 91% at 37 degrees C were analyzed. Oil droplets retained their forms in drying and reconstitution, but the original droplet size of the emulsion was not restored when the powder was dispersed in water. The particles seemed to be covered by a protein-rich surface layer as analyzed by electron spectroscopy for chemical analysis (ESCA). Oxidation of flaxseed oil dispersed in the WPI matrix was retarded from that of bulk oil but followed the same pattern as bulk oil with respect to humidity. A high rate of oxidation was found for both low and high humidity conditions. The lowest rate of oxidation as followed by peroxide values was found at RH 75%, a condition that is likely to diverge significantly from the monolayer moisture value. A weak baseline transition observed for the WPI matrix in a differential scanning calorimetry (DSC) thermogram suggested a glassy state of the matrix at all storage conditions. This was not consistent with the observed caking of the powder at RH 91%. Scanning electron microscopy (SEM) images revealed a considerable structural change in the WPI matrix in these conditions, which was suggested to be linked with a higher rate of oxygen transport. Possible mechanisms for oxygen transport in the whey protein matrix under variable RHs are discussed.


A mutation in the extracellular cysteine-rich repeat region of the beta3 subunit activates integrins alphaIIbbeta3 and alphaVbeta3.
Inside-out signaling regulates the ligand-binding function of integrins through changes in receptor affinity and/or avidity. For example, alphaIIbbeta3 is in a low-affinity/avidity state in resting platelets, and activation of the receptor by platelet agonists enables fibrinogen to bind. In addition, certain mutations and truncations of the integrin cytoplasmic tails are associated with a high-affinity/avidity receptor. To further evaluate the structural basis of integrin activation, stable Chinese hamster ovary (CHO) cell transfectants were screened for high-affinity/avidity variants of alphaIIbbeta3. One clone (AM-1) expressed constitutively active alphaIIbbeta3, as evidenced by (1) binding of soluble fibrinogen and PAC1, a ligand-mimetic antialphaIIbbeta3 antibody; and (2) fibrinogen-dependent cell aggregation. Sequence analysis and mutant expression in 293 cells proved that a single amino acid substitution in the cysteine-rich, extracellular portion of beta3(T562N) was responsible for receptor activation. In fact, T562N also activated alphaVbeta3, leading to spontaneous binding of soluble fibrinogen to 293 cells. In contrast, neither T562A nor T562Q activated alphaIIbbeta3, suggesting that acquisition of asparagine at residue 562 was the relevant variable. T562N also led to aberrant glycosylation of beta3, but this was not responsible for the receptor activation. The binding of soluble fibrinogen to alphaIIbbeta3(T562N) was not sufficient to trigger tyrosine phosphorylation of pp125(FAK), indicating that additional post-ligand binding events are required to activate this protein tyrosine kinase during integrin signaling. These studies have uncovered a novel gain-of-function mutation in a region of beta3 intermediate between the ligand-binding region and the cytoplasmic tail, and they suggest that this region is involved in integrin structural changes during inside-out signaling.


The extent and nature of children's involvement in food practice research: a scoping review of qualitative studies.
Aligning with the United Nations Convention on the Rights of the Child, amplification of children's voice in food practice research aims to inform initiatives that cater to children's needs and thus improve nutritional outcomes. The aim of this study was to describe children's (aged 6-11 years) involvement across qualitative research investigating their food practice perspectives. A scoping review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR). Six electronic databases were searched up until March 2023 (Cochrane, CINAHL, Embase, ERIC, Medline and PsychInfo). The Wellcome Framework for young people's involvement in health research guided data extraction. Data were described according to inclusiveness, geography, food-related study topic, research stage and method, and child involvement. The search identified 120 peer-reviewed studies (134 papers). Active participation was only seen within research implementation stages (i.e. data collection (n 134), analysis (n 31), dissemination (n 9) and re-design (n 7)). More passive forms of participation were identified in research design stages (i.e. agenda setting, resourcing and design). Studies that utilised participatory research methodologies and developmentally appropriate and engaging methods (e.g. PhotoVoice) saw more active participation by children. This review identified a lack of opportunities for children's active participation in all stages of food practice research. Without a radical shift towards providing these opportunities, food and nutrition initiatives, policies or further research that do not meet the needs of children's food-related worlds will continue to be developed. Instead, researchers and their institutions need to advocate for and, where possible, provide voluntary opportunities for children to actively participate in food practice research.


Mouse Genome Database (MGD) 2019.
The Mouse Genome Database (MGD; http://www.informatics.jax.org) is the community model organism genetic and genome resource for the laboratory mouse. MGD is the authoritative source for biological reference data sets related to mouse genes, gene functions, phenotypes, and mouse models of human disease. MGD is the primary outlet for official gene, allele and mouse strain nomenclature based on the guidelines set by the International Committee on Standardized Nomenclature for Mice. In this report we describe significant enhancements to MGD, including two new graphical user interfaces: (i) the Multi Genome Viewer for exploring the genomes of multiple mouse strains and (ii) the Phenotype-Gene Expression matrix which was developed in collaboration with the Gene Expression Database (GXD) and allows researchers to compare gene expression and phenotype annotations for mouse genes. Other recent improvements include enhanced efficiency of our literature curation processes and the incorporation of Transcriptional Start Site (TSS) annotations from RIKEN's FANTOM 5 initiative.


Computational model of electrically coupled, intrinsically distinct pacemaker neurons.
Electrical coupling between neurons with similar properties is often studied. Nonetheless, the role of electrical coupling between neurons with widely different intrinsic properties also occurs, but is less well understood. Inspired by the pacemaker group of the crustacean pyloric network, we developed a multicompartment, conductance-based model of a small network of intrinsically distinct, electrically coupled neurons. In the pyloric network, a small intrinsically bursting neuron, through gap junctions, drives 2 larger, tonically spiking neurons to reliably burst in-phase with it. Each model neuron has 2 compartments, one responsible for spike generation and the other for producing a slow, large-amplitude oscillation. We illustrate how these compartments interact and determine the dynamics of the model neurons. Our model captures the dynamic oscillation range measured from the isolated and coupled biological neurons. At the network level, we explore the range of coupling strengths for which synchronous bursting oscillations are possible. The spatial segregation of ionic currents significantly enhances the ability of the 2 neurons to burst synchronously, and the oscillation range of the model pacemaker network depends not only on the strength of the electrical synapse but also on the identity of the neuron receiving inputs. We also compare the activity of the electrically coupled, distinct neurons with that of a network of coupled identical bursting neurons. For small to moderate coupling strengths, the network of identical elements, when receiving asymmetrical inputs, can have a smaller dynamic range of oscillation than that of its constituent neurons in isolation.


Nonlinear transient chirp signal modeling of the aortic and pulmonary components of the second heart sound.
This paper describes a new approach based on the time-frequency representation of transient nonlinear chirp signals for modeling the aortic (A2) and the pulmonary (P2) components of the second heart sound (S2). It is demonstrated that each component is a narrow-band signal with decreasing instantaneous frequency defined by its instantaneous amplitude and its instantaneous phase. Each component is also a polynomial phase signal, the instantaneous phase of which can be accurately represented by a polynomial having an order of thirty. A dechirping approach is used to obtain the instantaneous amplitude of each component while reducing the effect of the background noise. The analysis-synthesis procedure is applied to 32 isolated A2 and 32 isolated P2 components recorded in four pigs with pulmonary hypertension. The mean +/- standard deviation of the normalized root-mean-squared error (NRMSE) and the correlation coefficient (rho) between the original and the synthesized signal components were: NRMSE = 2.1 +/- 0.3% and rho = 0.97 +/- 0.02 for A2 and NRMSE = 2.52 +/- 0.5% and rho = 0.96 +/- 0.02 for P2. These results confirm that each component can be modeled as mono-component nonlinear chirp signals of short duration with energy distributions concentrated along its decreasing instantaneous frequency.


Integration of Nanobots Into Neural Circuits As a Future Therapy for Treating Neurodegenerative Disorders.
Recent neuroscientific research demonstrates that the human brain is becoming altered by technological devices. Improvements in biotechnologies and computer based technologies are now increasing the likelihood for the development of brain augmentation devices in the next 20 years. We have developed the idea of an "Endomyccorhizae like interface" (ELI) nanocognitive device as a new kind of future neuroprosthetic which aims to facilitate neuronal network properties in individuals with neurodegenerative disorders. The design of our ELI may overcome the problems of invasive neuroprosthetics, post-operative inflammation, and infection and neuroprosthetic degradation. The method in which our ELI is connected and integrated to neuronal networks is based on a mechanism similar to endomyccorhizae which is the oldest and most widespread form of plant symbiosis. We propose that the principle of Endomyccorhizae could be relevant for developing a crossing point between the ELI and neuronal networks. Similar to endomyccorhizae the ELI will be designed to form webs, each of which connects multiple neurons together. The ELI will function to sense action potentials and deliver it to the neurons it connects to. This is expected to compensate for neuronal loss in some neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease.


Simple but long-lasting: A specimen imaging method applicable for small- and medium-sized herbaria.
Major international herbaria, natural history museums and universities have recently begun to digitise their collections to facilitate studies and improve access to collections. In Japan, more than 10 million herbarium specimens are housed in various universities/museums; however, only 1% of these have been digitised. In this paper, we describe a new method for imaging herbarium specimens that is applicable to local/small herbaria. It is safe, fast, simple and inexpensive, but also satisfies usage guidelines for minimum image quality and can produce digital files suitable for long-term storage and future post production. During an eight-month trial at the Museum of Nature and Human Activities, Hyogo, with three part-time workers using a custom-made copy stand and a mirrorless interchangeable lens camera with a large LED light bank system, we were able to image 73,180 herbarium specimens (571 per day on average), obtaining two RAW and two JPEG files for each specimen.


Gene therapy approaches to enhancing plasticity and regeneration after spinal cord injury.
During the past decades, new insights into mechanisms that limit plasticity and functional recovery after spinal cord injury have spurred the development of novel approaches to enhance axonal regeneration and rearrangement of spared circuitry. Gene therapy may provide one means to address mechanisms that underlie the insufficient regenerative response of injured neurons and can also be used to identify factors important for axonal growth. Several genetic approaches aimed to modulate the environment of injured axons, for example by localized expression of growth factors, to enhance axonal sprouting and regeneration and to guide regenerating axons towards their target have been described. In addition, genetic modification of injured neurons via intraparenchymal injection, or via retrograde transport of viral vectors has been used to manipulate the intrinsic growth capacity of injured neurons. In this review we will summarize some of the progress and limitations of cell transplantation and gene therapy to enhance axonal bridging and regeneration across a lesion site, and to maximize the function, collateral sprouting and connectivity of spared axonal systems.


Do predictors exist for a successful withdrawal of preoperative prostaglandin E(1) from neonates with d-transposition of the great arteries and intact ventricular septum?
Prostaglandin E(1) (PGE(1)) is given to neonates with d-transposition of the great arteries (d-TGA) to reduce cyanosis by reopening and maintaining the patency of the ductus arteriosus. To avoid side effects, this medication can be stopped for hemodynamically stable patients after balloon atrial septostomy (BAS). A consecutive series of neonates with d-TGA and an intact ventricular septum (IVS) presenting from 2000 through 2005 was analyzed retrospectively to search for side effects of PGE(1) and to identify predictors for a safe preoperative withdrawal. The medication was stopped for hemodynamically stable patients with transcutaneous oxygen saturations higher than 80% after BAS and reinitiated for patients with an oxygen saturation lower than 65%. Patients successfully weaned were compared with those who had failed weaning in terms of atrial septal defect (ASD) size, ductus arteriosus size, and the transcutaneous oxygen saturation. Prostaglandin E(1) was initiated for all 43 neonates with d-TGA. The median maintenance dose of PGE(1) was 0.00625 μg/kg/min (range, 0.00313-0.050 μg/kg/min) for a median duration of 6 days (range, 1-12 days). For 16 patients, PGE(1) was preoperatively withdrawn but then had to be reinitiated for 7 of the 16 patients. No predictors for a successful weaning of PGE(1) were found based on ASD size, ductus arteriosus size, or oxygen saturation. The adverse effects of PGE(1) were apnea in 10 patients and fever in 19 patients. Neither seizures nor necrotizing enterocolitis was documented. Prostaglandin E(1) was successfully withdrawn for a minority of hemodynamically stable patients with d-TGA. No predictors for a successful weaning could be identified. Because apnea and fever are common side effects, withdrawal of PGE(1) after BAS may improve patient safety and comfort. In this patient group, if PGE(1) withdrawal was not well tolerated, it could be safely reinitiated. There were no serious side effects of PGE(1.).


Infective endocarditis and outcomes of mitral valve replacement.
We investigated the long-term outcomes of mitral valve replacement (MVR) in native mitral valve infective endocarditis (IE). Multicentre, population-based cohort register study consisted of 1233 consecutive adult patients treated with first-time MVR in Finland. Mitral valve IE was diagnosed in 170 of these patients. Propensity score matching resulted in 134 pairs with balanced baseline characteristics. The median follow-up was 6.1 years. Pre-operative native mitral valve IE was associated with an increased hazard of 10-year mortality (38.8% vs 30.5%; HR 2.13; CI 1.17-3.85; P = .013) after MVR. Occurrence of major bleeding was higher in IE patients (26.0%) vs non-IE patients (23.4%) during the 10-year follow-up (HR 2.80; CI 1.01-7.77; P = .048). Hospital admission duration after MVR was longer in IE patients (median 28 vs 11 days; P < .0001). Cumulative ischaemic stroke rate was similar between patient groups (12.1% in IE vs 15.1% in non-IE; P = .493). Re-sternotomy was performed in 13.4% of IE patients and 9.0% of non-IE patients (P = .261). Patients with native mitral valve IE have a higher risk of death and major bleeding after MVR than matched patients without IE. Results highlight the importance of complication prevention in these patients.


Flicker-glare and visual-comfort assessments of light emitting diode billboards.
This study investigated the discomfort glare produced by the high-brightness LED billboards in relation to four factors: flicker frequency, panel luminance, viewing angular sub-tense, and ambient illuminance. The results showed that visual comfort is not affected by ambient illuminance but by the other three factors. Also, interaction was found between luminance and viewing angle. The experimental data were curve fitted to construct visual comfort models of LED billboard displays. By modulating the operating conditions, comfort display with LED billboards can be achieved.


Personality and intelligence: persistence, not self-directedness, cooperativeness or self-transcendence, is related to twins' cognitive abilities.
Background. A person-centered approach focusing on the interaction of an individual's temperament-character-life events is essential in the path of individuals' well-being. In this context, three character traits, Self-directedness (e.g., self-acceptance, self-control, goal-directed behavior), Cooperativeness (e.g., social affiliation, social tolerance, empathy and helpfulness) and Self-transcendence (e.g., spiritual acceptance, transpersonal identification), measured using Cloninger's model of personality are suggested to help the individual to regulate and resolve the conflicts derived from her/his temperament combinations as a reaction to life events. However, if character is related to the individual's cognitive ability, then this association might limit any intervention that focuses on character development. We used data from the Child and Adolescent Twin Study in Sweden (CATSS) to investigate the relationship between personality and cognitive ability. Method. The sample consisted of 370 15-year-old twins (159 girls/211 boys), 192 of whom screen-positive with various types of mental health problems. We used the Temperament and Character Inventory to measure personality and the Wechsler Intelligence Scales for Children (WISC-IV) to measure intelligence. The relationship was investigated using correlation analyses using random-selected twins from each dyad and separately for monozygotic and dizygotic twins. Additional analyses investigated the genetic and environmental effects on personality and cognitive ability in this specific sample. Results. There were no significant correlations between the WISC-IV indices and any of the character traits (i.e., Self-directedness, Cooperativeness, and Self-transcendence). Persistence was significantly related, if weak, to four WISC-IV indices: Verbal Comprehension, Perceptual Reasoning, Working Memory, and the Full WISC-IV Scale. Post-hoc cross-twin/cross-trait analyses showed that the Persistence-cognitive ability correlation might depend on common genetic effects. The WISC-IV indices showed a relatively large genetic influence, while earlier findings about the etiology of temperament and character traits using the whole CATSS sample were replicated in this sub-sample of twins. Conclusions. The results indicate that what individuals make of themselves intentionally (i.e., their character) was not associated to intelligence. Persistence, a temperament dimension that measures heritable individual differences in eagerness of effort, ambition, perfectionism, and resistance to discouragement despite frustration and fatigue, was weakly linked to intelligence. Suggesting that, at least during adolescence, interventions targeting character development are not limited by the individual's intelligence.


A comparative study of standard versus laparoendoscopic single-site surgery (LESS) totally extraperitoneal (TEP) inguinal hernia repair.
Laparoscopic inguinal hernia repair has been around since the 1990s. A novel surgical approach known as laparoendoscopic single-site surgery (LESS) has been developed to reduce the port-related morbidities and improve the cosmetic outcomes of laparoscopic surgery, including totally extraperitoneal (TEP) inguinal hernia repair. The aim of the present study was to evaluate the safety and feasibility of the LESS TEP technique for inguinal hernia repair and compare the outcomes with the standard TEP approach. Between January and May 2009, 54 consecutive healthy patients (48 men and 6 women) underwent LESS TEP inguinal hernia repair at our institute. All procedures were performed using our homemade single port for simultaneous passage of the laparoscope and instruments. The perioperative data, including patient age, sex, body mass index (BMI), hernia characteristics, operative time, complications, length of hospital stay, return to normal activity, pain score, and cosmetic result, were prospectively collected. All LESS TEP procedures were completed successfully without conversion to standard laparoscopic or open surgery. A total of 98 LESS TEP hernia repairs were performed in 54 patients and compared with 152 standard TEP operations. The mean operative time was significantly shorter in the standard TEP series (61.8 ± 26.0 vs. 70.9 ± 23.8 min, p = 0.04). Other perioperative parameters, including the length of hospital stay, time until return to full activity, complication rate, pain score, and cosmetic result, were all comparable between the two techniques. Our short-term experience with LESS TEP inguinal hernia repair has shown that in experienced hands, inguinal hernia repair via the LESS TEP technique is as safe as the standard TEP technique. However, based on our evidence, we currently believe that the LESS TEP technique is not an efficacious surgical alternative to the standard TEP technique for inguinal hernias.


In vivo and in vitro genetic evidence of involvement of neuregulin 1 in immune system dysregulation.
Neuregulin 1 (NRG1) has been implicated in several disorders including breast cancer, multiple sclerosis, and schizophrenia. Also, recent evidence suggests that NRG1 may play a role in regulation of inflammation and immune system response. We therefore hypothesized that a schizophrenia-associated missense mutation (valine to leucine) we identified within the transmembrane region of NRG1 would also be linked to immune dysregulation. We used plasma samples from families carrying the mutation to measure levels of antibodies to 41 autoimmune markers and six cytokines (IL-1b, IL-6, IL-10, IL-8, IL-12p70, and TNF-α) and used these levels as quantitative traits to evaluate association with the NRG1 mutation, using FBAT. Next, we used Epstein-Barr virus-transformed B cells from heterozygous mutation carriers and wild-type individuals to evaluate protein and mRNA cytokine expression in vitro using quantitative PCR and ELISA assays. In vivo, increased levels of 25 autoimmune markers as well as elevated levels of cytokines were significantly associated with the NRG1 mutation. In vitro, we observed a significant increase in protein secretion levels of IL-6, TNF-α, and IL-8 in mutation carriers compared with controls. At the mRNA level, we observed a significant increase in IL-6 expression, while IL-4 levels appeared to be down-regulated in heterozygous individuals compared with wild-type controls. This is the first report of association of a NRG1 mutation with immune dysregulation. This study could contribute towards understanding the role of NRG1 in the pathogenesis of schizophrenia and other disorders in which inflammation plays an important role.


Optical feedback frequency stabilized cavity ring-down spectroscopy.
We introduce optical feedback frequency stabilized cavity ring-down spectroscopy (OFFS-CRDS), a near-shot-noise-limited technique that combines kilohertz resolution with an absorption detection sensitivity of 5×10(-13) cm(-1) Hz(-1/2). Its distributed feedback laser source is stabilized to a highly stable V-shaped reference cavity by optical feedback and fine-tuned by means of single-sideband modulation. The stability of this narrow laser is transferred to a ring-down (RD) cavity using a new fibered Pound-Drever-Hall (PDH) locking scheme without a dedicated electro-optic phase modulator, yielding several hundred RD events per second. We demonstrate continuous coverage of more than 7 nm with a baseline noise of 5×10(-12) cm(-1) and a dynamic range spanning six decades. With its resonant intracavity light intensity on the order of 1 kW/cm2, the spectrometer was used for observing a Lamb dip in a transition of carbon dioxide involving four vibrational quanta. Saturating such a weak transition at 160 μW input power, OFFS-CRDS paves the way to Doppler-free molecular overtone spectroscopy for precision measurements of hyperfine structures and pressure shifts.


The Role of Nutrition in COVID-19 Susceptibility and Severity of Disease: A Systematic Review.
Many nutrients have powerful immunomodulatory actions with the potential to alter susceptibility to coronavirus disease 2019 (COVID-19) infection, progression to symptoms, likelihood of severe disease, and survival. The aim was to review the latest evidence on how malnutrition across all its forms (under- and overnutrition and micronutrient status) may influence both susceptibility to, and progression of, COVID-19. We synthesized information on 13 nutrition-related components and their potential interactions with COVID-19: overweight, obesity, and diabetes; protein-energy malnutrition; anemia; vitamins A, C, D, and E; PUFAs; iron; selenium; zinc; antioxidants; and nutritional support. For each section we provide: 1) a landscape review of pertinent material; 2) a systematic search of the literature in PubMed and EMBASE databases, including a wide range of preprint servers; and 3) a screen of 6 clinical trial registries. All original research was considered, without restriction to study design, and included if it covered: 1) severe acute respiratory syndrome coronavirus (CoV) 2 (SARS-CoV-2), Middle East respiratory syndrome CoV (MERS-CoV), or SARS-CoV viruses and 2) disease susceptibility or 3) disease progression, and 4) the nutritional component of interest. Searches took place between 16 May and 11 August 2020. Across the 13 searches, 2732 articles from PubMed and EMBASE, 4164 articles from the preprint servers, and 433 trials were returned. In the final narrative synthesis, we include 22 published articles, 38 preprint articles, and 79 trials. Currently there is limited evidence that high-dose supplements of micronutrients will either prevent severe disease or speed up recovery. However, results of clinical trials are eagerly awaited. Given the known impacts of all forms of malnutrition on the immune system, public health strategies to reduce micronutrient deficiencies and undernutrition remain of critical importance. Furthermore, there is strong evidence that prevention of obesity and type 2 diabetes will reduce the risk of serious COVID-19 outcomes. This review is registered at PROSPERO as CRD42020186194.


Tick-Borne Diseases in the United States.
Tick-borne diseases are an important cause of human morbidity and mortality in the United States. The past several decades have witnessed an increase in both the number of recognized tick-borne pathogens and the number of tick-borne disease cases, whereas tick surveys have revealed substantial geographic expansions of tick populations throughout the country. Multiple laboratory testing options exist for diagnosis of tick-borne diseases, including serology, microscopy, and molecular-based methods. The preferred approach varies by the specific disease, locally available test options, and the stage of illness at patient presentation. Accurate and timely detection of tick-borne illness is of utmost importance, as prompt treatment is strongly linked to better outcomes. This review covers the clinical manifestations and preferred diagnostic approaches for important bacterial, viral, and parasitic tick-borne diseases in the United States, including Lyme disease, tick-borne relapsing fever, anaplasmosis, ehrlichiosis, spotted fever rickettsioses, and babesiosis. Infection with emerging pathogens such as Borrelia miyamotoi, Powassan virus, Heartland virus, Colorado tick fever virus, and Bourbon virus are also covered. Our understanding of tick-borne diseases in the United States continues to improve with the detection of novel pathogens and development of new diagnostic modalities. While conventional diagnostic methods, including serology and microscopy, will play an ongoing role in the diagnosis of tick-borne diseases, implementation of advanced molecular diagnostics will further broaden our understanding of these diseases by facilitating detection of emerging pathogens and providing more accurate and timely diagnosis.


Functional characterization and comparison of the outer blood-retina barrier and the blood-brain barrier.
To determine efflux systems of the outer blood-retina barrier (oBRB) and compare the oBRB with the blood-brain barrier (BBB). Porcine oBRB structure and transport characteristics of freshly dissected intact tissue sheets were investigated with scanning electron microscopy, immunocytochemistry, vital dye labeling, and pharmacological agents, using HPLC/mass spectrometry. To compare drug permeation across the oBRB and the BBB, three different systems were used: (1) oBRB tissue sheets in a two-chamber device in vitro; (2) an in vitro BBB model composed of purified astrocytes and brain capillary endothelial cells on transfilter membranes; and (3) an in vivo model based on the brain-plasma ratio of drugs in mice. Efflux pumps (multidrug resistance protein [P-gp] and multidrug resistance-associated protein [MRP]) were demonstrated by antibody staining. Side-specific application of three P-gp and MRP substrates and selective transport inhibition suggested that both membrane proteins were preferentially located on the choroidal side of the oBRB. Therefore, the efflux was directed toward the blood, as in the BBB. To relate the transport characteristics of the oBRB to the BBB, up to nine different test compounds were used. The ranking of the permeability coefficients (P(e)) and the brain-plasma ratios of test compounds indicated that the oBRB has barrier and carrier features similar to those of the BBB in vitro and in vivo. Despite the fact that epithelial oBRB and endothelial BBB have developed as separate entities with many site-specific functions, their transport and permeation characteristics display surprising similarities, that include the polarized expression of the two major efflux pumps P-gp and MRP.


[Immunogenicity of a new, highly purified, highly concentrated duck-embryo rabies vaccine].
The protective value and safety of human diploid cell strain rabies vaccine (HDCV) are well established [6, 8, 11]. At present, however, the high cost and small yields of HDCV has restricted its use, particularly in developing countries where rabies vaccine is needed in large amounts. The inexpensive duck embryo rabies vaccine (DEV), also prepared with the Pitman -Moore strain, is potent and generally safe despite occasional allergic complications [9, 13]. The vaccine has been used with success in several million doses during recent decades [12, 14]. Administered according to the prescribed schedule (14 initial inoculations and 3 boosters), the vaccine has been shown to provide protective antibody titers in pre- and post-exposure use [7, 10]. On the other hand, the immunogenicity of this vaccine did not shorten the administration schedule in a similar way to HDCV. Thus, prior clinical studies using the reduced WHO immunization scheme demonstrated that a concentrated and partially purified DEV containing less than 2.5 IU/ml of rabies antigen elicited sufficient neutralizing antibodies in only 75% of vaccinees [3]. Gl uck et al. [4] clarified the reason for this low immunogenicity: We demonstrated that only about 30-50% of the glycoprotein (GP) in DEV was present on the surface of virus particles. GP, a component of the rabies virus envelope, is the antigen responsible for the induction of neutralizing antibodies. During virus production a non-immunogenic soluble GP may also accumulate. Non-immunogenic GP may be coextracted during vaccine preparation.(ABSTRACT TRUNCATED AT 250 WORDS)


Mechanical Circulatory Support: a Comprehensive Review With a Focus on Women.
The purpose of this review is to analyze the evidence for use of mechanical circulatory support (MCS) with a focus on women, namely, intra-aortic balloon pump (IABP), Impella, ventricular assist devices (VAD), and extracorporeal membrane oxygenation (ECMO). There is paucity of data examining management options for cardiogenic shock (CS) in women specifically. In published data, although only a minority of MCS recipients (33%) were women, there is a trend toward even lower use in women relative to men over time. Women presenting with CS tend to have a higher risk profile including older age, greater comorbidities, higher Society of Cardiothoracic Surgery (STS) mortality scores, more hypotension and index vasopressor requirements, and longer duration of CS. Overall, women receiving mechanical support suffer increased bleeding and vascular complications and have higher 30-day readmission rates. The incidence of cardiogenic shock (CS) has been rising at a higher rate in women compared to men. Women in CS tend to present with an overall higher risk profile including older age, greater burden of medical comorbidities, more hypotension and index vasopressor requirements, higher STS mortality scores, and more out-of-hospital cardiac arrest. After adjusting for comorbidities and traditional cardiovascular risk factors, mortality remained higher in younger women compared to men of similar age. In spite of these facts, evidence points to the underutilization of support devices in eligible female patients. Higher complication rates, such as vascular complications requiring surgery and bleeding requiring transfusion, may be deterring factors that limit the use of MCS and hinderoperator confidence and experience with devices in women. This suggests that future research should address the sex disparities in outcomes of contemporary MCS practices.


Chemical communication and dynamics of droplet emulsions in networks of Belousov-Zhabotinsky micro-oscillators produced by microfluidics.
Chemical communication leading to synchronization and collective behaviour of dynamic elements, such as cell colonies, is a widespread phenomenon with biological, physical and chemical importance. Such synchronization between elements proceeds via chemical communication by emmision, interdiffusion and reception of specific messenger molecules. On a lab scale, these phenomena can be modeled by encapsulating an oscillating chemical reaction, which serves as a signal (information) sender/receiver element, inside microcompartments such as droplet emulsions, liposomes and polymersomes. Droplets can thus be regarded as single units, able to generate chemical messengers that diffuse in the environment and hence can interact with other compartments. The Belousov-Zhabotinsky (BZ) reaction is a well-known chemical oscillator largely used as a model for complex nonlinear phenomena, including chemical, physical and biological examples. When the BZ-reaction is encapsulated inside microcompartments, its chemical intermediates can serve as messengers by diffusing among different microcompartments, to trigger specific reactions leading to a collective behavior between the elements. The geometry and constitution of the diffusion pathways play an important role in governing the collective behaviour of the system. In this context, microfluidics is not only a versatile tool for mastering the encapsulation process of the BZ-reaction in monodisperse microcompartments, but also for creating geometries and networks with well defined boundaries. The individual compartments can be engineered with selected properties using different surfactants in the case of simple emulsions, or with specific membrane properties in the case of liposomes. Furthermore, it enables the arrangement of these microcompartments in various geometric configurations, where the diffusive coupling pathways between individual compartments are both spatially and chemically well-defined. In this tutorial paper, we review a number of articles reporting various approaches to generate networks of compartmentalized Belousov-Zhabotinsky (BZ) chemical oscillators using microfluidics. In contrast to biological cellular networks, the dynamical characteristics of the BZ-reaction is well-known and, when confined in microcompartments arranged in different configurations with a pure interdiffusive coupling, these communicative microreactors can serve to mimic various types of bio-physical networks, aiding to comprehend the concept of chemical communication.