Succinoglycan production by Rhizobium meliloti is regulated through the ExoS-ChvI two-component regulatory system.
The Rhizobium meliloti exoS gene is involved in regulating the production of succinoglycan, which plays a crucial role in the establishment of the symbiosis between R. meliloti Rm1021 and its host plant, alfalfa. The exoS96::Tn5 mutation causes the upregulation of the succinoglycan biosynthetic genes, thereby resulting in the overproduction of succinoglycan. Through cloning and sequencing, we found that the exoS gene is a close homolog of the Agrobacterium tumefaciens chvG gene, which has been proposed to encode the sensor protein of the ChvG-ChvI two-component regulatory system, a member of the EnvZ-OmpR family. Further analyses revealed the existence of a newly discovered A. tumefaciens chvI homolog located just upstream of the R. meliloti exoS gene. R. meliloti ChvI may serve as the response regulator of ExoS in a two-component regulatory system. By using ExoS-specific antibodies, it was found that the ExoS protein cofractionated with membrane proteins, suggesting that it is located in the cytoplasmic membrane. By using the same antibodies, it was shown that the exoS96::Tn5 allele encodes an N-terminal truncated derivative of ExoS. The cytoplasmic histidine kinase domain of ExoS was expressed in Escherichia coli and purified, as was the R. meliloti ChvI protein. The ChvI protein autophosphorylated in the presence of acetylphosphate, and the ExoS cytoplasmic domain fragment autophosphorylated at a histidine residue in the presence of ATP. The ChvI protein was phosphorylated in the presence of ATP only when the histidine kinase domain of ExoS was also present. We propose a model for regulation of succinoglycan production by R. meliloti through the ExoS-ChvI two-component regulatory system.


Dyssynchrony, contraction efficiency and regional function with apical and non-apical RV pacing.
Recent work has shown no difference in change of LVEF between RV apical (RVA) pacing and non-RVA pacing in patients with normal LV function. We hypothesised that a more sensitive marker (global longitudinal strain, GLS) could identify a detrimental effect of RVA and that assessment of deformation could identify whether dyssynchrony, contraction inefficiency and regional LV impairment were responsible for functional changes. In this substudy of Protect-PACE (The Protection of Left Ventricular Function During Right Ventricular Pacing. Does Right Ventricular High-septal Pacing Improve Outcome Compared With Right Ventricular Apical Pacing?), a randomised controlled trial of RVA and non-RVA pacing in pacemaker-dependent patients with preserved EF, 145 patients (76 with RVA) with echocardiograms of sufficient quality underwent measurement of LV longitudinal strain (GLS) from speckle tracking just after implantation and at 2 years. LV dyssynchrony, discoordination and regional apical longitudinal strain were also measured. Pacing was associated with reduced GLS after 2 years, although 2-year GLS was lower in RVA (-13.9 ± 4.1 vs -15.5 ± 4.6, p = 0.02). RVA was an independent correlate of ΔGLS, although there was a minor difference in ΔGLS between the RVA and non-RVA groups (-1.8 ± 3.6 vs -0.8 ± 3.4%, p= 0.07), reflecting impairment of GLS at baseline in RVA. Apical strain was significantly lower in RVA than those in non-RVA at baseline and 2 years (both p < 0.01). Dyssynchrony and discoordination parameters at 2 years also showed significant deterioration in RVA. Apical strain, dyssynchrony and discoordination parameters at 2 years were significantly associated with ΔGLS. Inefficient dyssynchronous contraction and the decrease in apical strain appear to be associated with global LV impairment in RVA. PROTECT-PACE ClinicalTrials.gov number NCT00461734.


Preference for an Opioid/Benzodiazepine Mixture over an Opioid Alone Using a Concurrent Choice Procedure in Rhesus Monkeys.
Increased abuse of opioids is contributing to an escalation in overdose deaths. Benzodiazepines are frequently abused with opioids, possibly because they increase the potency and/or effectiveness of opioids to produce reinforcing effects. This study used a concurrent-choice procedure to determine whether monkeys would choose to self-administer a mixture of the opioid remifentanil and the benzodiazepine midazolam over remifentanil alone. Initially, three monkeys could respond on one lever for saline and on a second lever for either remifentanil alone or midazolam alone. Thereafter, monkeys chose between a dose of remifentanil (0.32 µg/kg/infusion) that did not change and a dose of remifentanil that varied across sessions; for some sessions, midazolam was combined with varying doses of remifentanil. All monkeys received more infusions of remifentanil (0.0032-0.32 µg/kg/infusion) than saline, whereas only two monkeys responded more for midazolam than for saline. When 0.32 µg/kg/infusion remifentanil was available on one lever and a dose of remifentanil that varied across sessions (0.1-1 µg/kg/infusion) was available on the other lever, monkeys chose the larger dose. Combining 3.2 µg/kg/infusion midazolam with 0.32 µg/kg/infusion remifentanil increased responding for the mixture over 0.32 µg/kg/infusion remifentanil alone, although monkeys chose remifentanil alone over mixtures containing smaller doses of remifentanil. When 10 µg/kg/infusion midazolam was combined with 0.1 µg/kg/infusion remifentanil, monkeys chose the mixture over 0.32 µg/kg/infusion remifentanil alone. Thus, monkeys prefer some opioid/benzodiazepine mixtures to larger doses of the opioid alone, suggesting that opioid/benzodiazepine coabuse might be due to increased potency (and possibly effectiveness) of opioids to produce reinforcing effects.


Different forms of human liver glutathione S-transferases arise from dimeric combinations of at least four immunologically and functionally distinct subunits.
Four immunologically distinct subunits were characterized in glutathione (GSH) S-transferases of human liver. Five cationic enzymes (pI 8.9, 8.5, 8.3, 8.2 and 8.0) have an apparently similar subunit composition, and are dimers of 26 500-Mr (A) and 24 500-Mr (B) subunits. A neutral enzyme, pI 6.8, is a dimer of B-type subunits. One of the anionic enzymes, pI 5.5, is also a dimer of 26 500-Mr subunits. However, the 26 500-Mr subunits of this anionic enzyme form are immunologically distinct from the A subunits of the cationic enzymes, and have been designated as A'. Immunoabsorption studies with the neutral enzyme, BB, and the antibodies raised against the cationic enzymes (AB) indicate that A and B subunits are immunologically distinct. Hybridization in vitro of the A and B subunits of the cationic enzymes (AB) results in the expected binary combinations of AA, AB and BB. Studies with the hybridized enzyme forms indicate that only the A subunits express GSH peroxidase activity. A' subunits have maximum affinity for p-nitrobenzyl chloride and p-nitrophenyl acetate, and the B subunits have highest activity towards 1-chloro-2,4-dinitrobenzene. The other anionic form, pI 4.5, present in liver is a heterodimer of 22 500-Mr (C) and B subunits. The C subunits of this enzyme are probably the same as the 22 500-Mr subunits present in human lung and placental GSH transferases. The distinct immunological nature of B and C subunits was also demonstrated by immunoaffinity and subunit-hybridization studies. The results of two-dimensional polyacrylamide-gel-electrophoretic analyses indicate that in human liver GSH transferases, three charge isomers of Mr 26 500 (A type), two charge isomers of Mr 24 500 (B type) and two charge isomers of Mr 22 500 (C type) subunits are present.


Genetic variation in the IL7RA/IL7 pathway increases multiple sclerosis susceptibility.
Multiple sclerosis (MS) is characterized as an autoimmune demyelinating disease. Numerous family studies have confirmed a strong genetic component underlying its etiology. After several decades of frustrating research, the advent and application of affordable genotyping of dense SNP maps in large data sets has ushered in a new era in which rapid progress is being made in our understanding of the genetics underlying many complex traits. For MS, one of the first discoveries to emerge in this new era was the association with rs6897932[T244I] in the interleukin-7 receptor alpha chain (IL7RA) gene (Gregory et al. in Nat Genet 39(9):1083-1091, 2007; International Multiple Sclerosis Genetics Consortium in N Engl J Med 357(9):851-862, 2007; Lundmark in Nat Genet 39(9):1108-1113, 2007), a discovery that was accompanied by functional data that suggest this variant is likely to be causative rather than a surrogate proxy (Gregory et al. in Nat Genet 39(9):1083-1091, 2007). We hypothesized that variations in other genes functionally related to IL7RA might also influence MS. We investigated this hypothesis by examining genes in the extended biological pathway related to IL7RA to identify novel associations. We identified 73 genes with putative functional relationships to IL7RA and subsequently genotyped 7,865 SNPs in and around these genes using an Illumina Infinium BeadChip assay. Using 2,961 case-control data sets, two of the gene regions examined, IL7 and SOCS1, had significantly associated single-nucleotide polymorphisms (SNPs) that further replicated in an independent case-control data set (4,831 samples) with joint p values as high as 8.29 x 10(-6) and 3.48 x 10(-7), respectively, exceeding the threshold for experiment-wise significance. Our results also implicate two additional novel gene regions that are likely to be associated with MS: PRKCE with p values reaching 3.47 x 10(-4), and BCL2 with p values reaching 4.32 x 10(-4). The TYK2 gene, which also emerged in our analysis, has recently been associated with MS (Ban et al. 2009). These results help to further delineate the genetic architecture of MS and validate our pathway approach as an effective method to identify novel associations in a complex disease.


Dietary intake and adipose tissue content of long-chain n-3 PUFAs and subsequent 5-y change in body weight and waist circumference.
Background: Adding long-chain n-3 (ω-3) polyunsaturated fatty acids (PUFAs) to a rodent diet reduces fat mass and prevents the development of obesity, but evidence of a similar effect in humans is rather limited.Objectives: We investigated the associations between dietary intake and adipose tissue content of long-chain n-3 PUFAs and subsequent 5-y change in body weight and waist circumference in humans. Effect modification by the carbohydrate:protein ratio and glycemic index was also investigated.Design: A total of 29,152 participants included in the Diet, Cancer, and Health cohort were followed. Dietary intake was assessed with the use of a validated 192-item semiquantitative food-frequency questionnaire. Adipose tissue content of fatty acids was determined by gas chromatography in a random sample of the cohort (n = 1660). Anthropometric measurements were taken at baseline and 5 y later. Associations were investigated with the use of a linear regression model.Results: For high (1.22 g/d) compared with low (0.28 g/d) total n-3 PUFA intake, the difference in 5-y weight change was 147.6 g (95% CI: -42.3, 337.5 g); P-trend = 0.088. No associations between the individual n-3 PUFAs eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid were observed. Intake of n-3 PUFAs was not associated with a 5-y change in waist circumference. For high (0.16%) compared with low (0.06%) adipose tissue content of EPA, the difference in 5-y weight change was -649.6 g (95% CI: -1254.2, -44.9 g); P-trend = 0.027. No associations between total n-3 PUFA, docosapentaenoic acid, and docosahexaenoic acid and 5-y weight change were observed. Adipose tissue content of n-3 PUFAs was not associated with 5-y change in waist circumference. No effect modification by carbohydrate:protein ratio or glycemic index was found.Conclusion: Dietary intake and adipose tissue content of long-chain n-3 PUFAs were neither consistently nor appreciably associated with change in body weight or waist circumference.


Skeletal muscle arteriolar reactivity in SS.BN13 consomic rats and Dahl salt-sensitive rats.
Previous studies have demonstrated that angiotensin II is a crucial factor in maintaining normal vascular reactivity. In this study, we tested the hypothesis that altered reactivity to vasoactive stimuli in Dahl salt-sensitive (S) rats on a high salt diet could be prevented by introgression of chromosome 13 from the normotensive Brown Norway strain, which carries a normally functioning renin gene. Dahl S and consomic SS.BN13 rats were fed a low salt (0.4%) or high salt diet (4%) for 4 to 6 days or 4 weeks. Arteriolar responses to elevated superfusion solution PO2, acetylcholine, and sodium nitroprusside were assessed by videomicroscopy in the cremaster muscle. Arteriolar dilation to sodium nitroprusside was normal in both strains. Arteriolar constriction to elevated PO2 was enhanced in Dahl S and SS.BN13 rats on a high salt diet compared with responses in rats on a low salt diet. Arterioles of Dahl S rats on a high salt diet had an impaired dilation to acetylcholine, whereas dilator responses to acetylcholine were restored in SS.BN13 rats regardless of elevated salt intake. These data suggest that (1) restitution of normal renin control mechanisms by chromosomal transfer contributes to the recovery of dilator responses in SS.BN13 rats versus Dahl S rats but does not affect constrictor responses to oxygen, and (2) factors in the Dahl S genetic background contribute to an enhanced sensitivity of arterioles to elevated PO2 independent of elevated blood pressure.


Helical tubuland diols: a synthetic and crystal engineering quest.
Despite many advances in recent years, crystal engineering remains a risky venture. A successful outcome requires manipulation of the noncovalent bonding and properties such as size, shape, repulsion, attraction, polarity, and chirality. In this Account, we describe the interplay of crystal engineering and synthetic organic chemistry required to develop the family of helical tubuland diol hosts, the members of which exhibit a wide range of tube dimensions and inclusion properties. Certain alicyclic dialcohols crystallize with a hydrogen-bonded network structure, termed the helical tubuland lattice, in space group P3(1)21 (or its enantiomorph P3(2)21). Double helices of diol molecules surround parallel tubes that contain guest molecules, which are included on the basis of size and shape rather than functional group. The crystal structure of (diol)(3).(chloroacetic acid)(1.2) is illustrative. These chiral helical tubulate lattice inclusion compounds are formed when the racemic host diol is allowed to crystallize from solution. Complete enantiomer separation occurs during this process, producing a 1:1 mixture of pure (+)- and pure (-)-crystals (a conglomerate). The challenge of creating this family of compounds required the development of much synthetic chemistry, in particular new pathways to alicyclic ring systems with specific substitution patterns. It was also necessary to understand and control the supramolecular properties of the diol molecules. What makes the original compound tick, and why did it behave in this remarkable manner, when most of its structural neighbors crystallize totally differently? The synthesis of new helical tubuland diols requires not just preparation of a new molecular structure but also a transplant of the original unchanged hydrogen-bonding supramolecular synthon. Synthesis of the specific crystal space group is necessary. This was achieved by defining structural characteristics, termed molecular determinants, which are essential for the helical tubuland structure to occur. If these requirements were met, then the target molecule had a high probability of success. This investigation has close conceptual parallels with the search for pharmacophore properties of bioactive molecules. In both situations, parts of a molecule with little or no chemical reactivity may actually play vital supramolecular roles. The review illustrates how crystal engineering is based on specific supramolecular properties that can be uncovered and then exploited by synthetic chemists.


The influence of fabrication errors on the stopband magnitude responses of SAW devices.
This article is devoted to the analysis of the influence of manufacturing errors on the magnitude responses of surface acoustic wave (SAW) devices. Analytical analysis of these random errors provides statistical distributions of the relevant responses and their parameters. It allows significant reduction in the modeling computations compared to the Monte Carlo method, and it provides possibilities for further analytical analysis. After the application of the statistical analysis to different potential structures of SAW devices, it is possible to choose the least sensitive one during the design process without the need of costly trials. Experimental analysis confirmed the existence of some of the features predicted both theoretically and by modeling. The experimental procedure for the evaluation of the fabrication error variances is described. The application of these results to the design process of the SAW devices allows simplification of the requirements for the manufacturing equipment and/or improvement of the devices' parameters, especially stopband suppression.


The evolution of oscillatory behavior in age-structured species.
A major challenge in ecology is to explain why so many species show oscillatory population dynamics and why the oscillations commonly occur with particular periods. The background environment, through noise or seasonality, is one possible driver of these oscillations, as are the components of the trophic web with which the species interacts. However, the oscillation may also be intrinsic, generated by density-dependent effects on the life history. Models of structured single-species systems indicate that a much broader range of oscillatory behavior than that seen in nature is theoretically possible. We test the hypothesis that it is selection that acts to constrain the range of periods. We analyze a nonlinear single-species matrix model with density dependence affecting reproduction and with trade-offs between reproduction and survival. We show that the evolutionarily stable state is oscillatory and has a period roughly twice the time to maturation, in line with observed patterns of periodicity. The robustness of this result to variations in trade-off function and density dependence is tested.


Testing Basic Assumptions of the Interpersonal Needs Questionnaire-15 in a Sample of Clinically Depressed and Suicidal Youth.
Suicide is a leading cause of death in adolescence. The mechanisms of adolescent suicidality, however, are not fully understood. Although the Interpersonal-Psychological Theory of Suicide, as assessed by the Interpersonal Needs Questionnaire-15 (INQ), may be a promising framework, systematic study of its utility during adolescence is lacking. To this end, we utilized factor analyses and hierarchical regression analyses to test the factor structure, correlates, and predictive validity of the INQ in a sample of clinically depressed and suicidal adolescents (N = 120, aged 12-18). The sample was mostly female (81.9%), ethnically diverse (68.2% non-White) and with nearly a third identifying as a sexual minority (31.8%). Contrary to studies including adult samples in which a two-factor solution is identified, results within this sample indicated three factors: perceived burdensomeness, thwarted belongingness, and perceived isolation. Perceived burdensomeness and the interaction between perceived burdensomeness and perceived isolation predicted suicide ideation above and beyond depression, but thwarted belongingness and perceived isolation did not. Perceived burdensomeness appears to play a role in adolescent suicidality and may be a point of intervention, yet the notable deviation from previous findings and the relative weakness of two of the factors warrant further study.


Leukocyte recognition and metabolism of leukotrienes.
The lipoxygenation of arachidonic acid in many different types of cells generates diverse mediators of hypersensitivity and inflammation. The leukotrienes represent one such family of mediators, which exert potent effects on smooth muscle, the microcirculation, and leukocytes. Leukocytes express distinct subsets of receptors for different leukotrienes. Transpeptidatic, peptidolytic, oxidative, and peroxidative pathways of leukocytes contribute substantially to the interconversion and biodegradation of leukotrienes. The 5-lipoxygenation of endogenous arachidonic acid appears to be a critical prerequisite for the activation of the function of leukocytes and some other cells. Natural and pharmacological inhibitors of 5-lipoxygenation in T lymphocytes noncytotoxically suppress the migration and transformation of the lymphocytes in response to antigens and mitogens. Lipoxygenase products of arachidonic acid thus fulfill important roles both as extracellular mediators and as functional intracellular constituents.


Improving imaging diagnosis of persistent nodal metastases after definitive therapy for oropharyngeal carcinoma: specific signs for CT and best performance of combined criteria.
Criteria for detection of persistent nodal metastases in treated oropharyngeal tumors are sensitive but nonspecific, leading to unnecessary nodal dissections. Developing specific imaging criteria for persistent nodal metastases could improve diagnosis while decreasing patient morbidity. Patients with oropharyngeal squamous cell carcinoma with nodal metastases treated by definitive radiation therapy and subsequent nodal dissection were retrospectively evaluated. One hundred thirty-eight patients had pre- and posttherapy contrast-enhanced CTs evaluated by radiologists blinded to the status of pathologically proved hemineck persistent nodal metastases. Composite scoring criteria for CT, combined from individual parameters, were compared with radiologists' opinions, previous multiparameter criteria, and outcome data. New low-attenuation areas and a lack of size change (<20% cross sectional area) were both highly specific for persistent nodal metastases (99%; P = .0004). Extranodal disease on pretherapy imaging was moderately specific (86%; P = .001). The CSC correctly placed 29 patients in a low-risk category compared with 14 by previously reported criteria and radiologist reports. With good second-rater reliability, the CSC cutoff values stratified patients at highest risk of persistent nodal metastases, thereby improving specificity while maintaining sensitivity. Comparing pre- and posttherapy examinations improves specificity by discriminating focal findings and size change compared with a single time point. The CSC can categorize the risk of persistent nodal metastases more accurately than previous CT methods. This finding has the potential to improve resource use and reduce surgical morbidity.


Rate-limiting transport of positively charged arginine residues through the Sec-machinery is integral to the mechanism of protein secretion.
Transport of proteins across and into membranes is a fundamental biological process with the vast majority being conducted by the ubiquitous Sec machinery. In bacteria, this is usually achieved when the SecY-complex engages the cytosolic ATPase SecA (secretion) or translating ribosomes (insertion). Great strides have been made towards understanding the mechanism of protein translocation. Yet, important questions remain - notably, the nature of the individual steps that constitute transport, and how the proton-motive force (PMF) across the plasma membrane contributes. Here, we apply a recently developed high-resolution protein transport assay to explore these questions. We find that pre-protein transport is limited primarily by the diffusion of arginine residues across the membrane, particularly in the context of bulky hydrophobic sequences. This specific effect of arginine, caused by its positive charge, is mitigated for lysine which can be deprotonated and transported across the membrane in its neutral form. These observations have interesting implications for the mechanism of protein secretion, suggesting a simple mechanism through which the PMF can aid transport by enabling a 'proton ratchet', wherein re-protonation of exiting lysine residues prevents channel re-entry, biasing transport in the outward direction.


Biochemical pattern of thyroid function test and clinical impression of thyroid disorder in a rural tertiary health institution in Nigeria.
Thyroid disorders are one of the most common endocrine disorders seen globally. Diagnostic challenge may arise both clinically and biochemically because of the multiple function of thyroid hormones (THs). Request for thyroid function test (TFT s) may be based on clinical impression that may suggest thyroid dysfunction or obvious symptoms and signs that are diagnostic of hyperthyroidism or hypothyroidism. This retrospective study looks at the biochemical patterns of TFTs and the clinical impression of thyroid disorders in a rural tertiary institution. Information extracted from the laboratory register includes indication for the test, the hospital number, the gender, the age, and the THs assayed. The corresponding biochemical pattern of the TFT result was established. A total of 297 requests were submitted for TH assay; 34 were excluded from the present study because there were no clinical information. There were 239 females and 24 males giving a female-to-male ratio of 9.9:1. Majority of the requests (36.5%) were for goiters, followed by gynecological disorders (20.9%) and clinical thyroid disorders (17.9%). About 46% (45.8%) of the goiter cases were biochemically euthyroid, whereas 13.5% were biochemically primary hyperthyroid. Among the 47 cases of thyroid disorders by the physician's clinical impression, 27.7% were euthyroid, 17% were biochemically hyperthyroid, and 10.6% were hypothyroid. Of the 55 gynecological disorders assessed, only 7.3% show biochemical evidence of TH alteration with 56.4% being euthyroid. About 47% (46.6%) of those that did routine medical examination had altered TH level that includes hyperthyroidism and hypothyroidism. Goiter is the most prevalent thyroid disorder in this environment. Biochemical pattern of thyroid function test in our environment was mostly euthyroid despites clinical features suggestive of thyroid disorders.


The enigma of cytosolic two-component systems: a hypothesis.
One-component systems (OCSs) and cytosolic two-component regulatory systems (TCSs) appear to share the same biological function, which consists in the transcriptional control in response to the cellular concentration of signal molecules. However, cytosolic TCSs as compared with OCSs represent a genetic and metabolic burden to the cell: the genetic information encoding a TCS is significantly larger than that of an OCS, two or more proteins instead of one need to be synthesized for a TCS and operation of the latter system requires the expense of ATP which is not the case for most OCSs. The evolutionary advantages of cytosolic TCSs over OCSs are thus not obvious. We hypothesize here that the increased capacity of cytosolic TCSs to respond to multiple signals is a major advantage over OCSs. Different mechanisms for the incorporation of additional signals into the regulatory circuit are discussed. The inclusion of several signals into the definition of the final regulatory response is proposed to result in a better adaptation of the host to given environmental conditions.


DNA yield and quality of saliva samples and suitability for large-scale epidemiological studies in children.
To evaluate two saliva collection methods for DNA yield and quality as applied to a large, integrated, multicentre, European project involving the collection of biological material from children. Cross-sectional multicentre comparative study in young children. Saliva samples were collected from 14,019 children aged 2-9 years from eight European countries participating in the IDEFICS (Identification and prevention of dietary- and lifestyle-induced health effects in children and infants) study. This involved either the collection of 2 ml of saliva from children who were able to spit, or using a sponge to collect whole saliva and buccal mucosal cells from the inside of the mouth of younger children unable to spit. Samples were assembled centrally in each participating centre and subsequently despatched for DNA extraction and biobanking to the University of Glasgow. A subgroup of 4678 samples (∼33% of sampled individuals) were chosen for DNA extraction before genotyping. The whole-saliva collection method resulted in a higher DNA yield than the sponge collection method (mean±s.d.; saliva: 20.95±2.35 μg, sponge: 9.13±2.25 μg; P<0.001). DNA quality as measured by A (260)/A (280) was similar for the two collection methods. A minimum genotype calling success rate of 95% showed that both methods provide good-quality DNA for genotyping using TaqMan allelic discrimination assays. Our results showed higher DNA yield from the whole-saliva collection method compared with the assisted sponge collection. However, both collection methods provided DNA of sufficient quantity and quality for large-scale genetic epidemiological studies.


Stable-isotope probing and metagenomics reveal predation by protozoa drives E. coli removal in slow sand filters.
Stable-isotope probing and metagenomics were applied to study samples taken from laboratory-scale slow sand filters 0.5, 1, 2, 3 and 4 h after challenging with (13)C-labelled Escherichia coli to determine the mechanisms and organisms responsible for coliform removal. Before spiking, the filters had been continuously operated for 7 weeks using water from the River Kelvin, Glasgow as their influent source. Direct counts and quantitative PCR assays revealed a clear predator-prey response between protozoa and E. coli. The importance of top-down trophic-interactions was confirmed by metagenomic analysis, identifying several protozoan and viral species connected to E. coli attrition, with protozoan grazing responsible for the majority of the removal. In addition to top-down mechanisms, indirect mechanisms, such as algal reactive oxygen species-induced lysis, and mutualistic interactions between algae and fungi, were also associated with coliform removal. The findings significantly further our understanding of the processes and trophic interactions underpinning E. coli removal. This study provides an example for similar studies, and the opportunity to better understand, manage and enhance E. coli removal by allowing the creation of more complex trophic interaction models.


Modulation of HU-DNA interactions by salt concentration and applied force.
HU is one of the most abundant proteins in bacterial chromosomes and participates in nucleoid compaction and gene regulation. We report experiments using DNA stretching that study the dependence of DNA condensation by HU on force, salt and HU concentration. Previous experiments at sub-physiological salt levels revealed that low concentrations of HU could compact DNA, whereas larger HU concentrations formed a DNA-stiffening complex. Here we report that this bimodal binding behavior depends sensitively on salt concentration. Only the compaction mode was observed for 150 mM and higher NaCl levels, i.e. for physiological salt concentrations. Similar results were obtained for the more physiological salt K-glutamate. Real-time studies of dissociation kinetics revealed that HU unbound slowly (minutes to hours under the conditions studied) but completely for salt concentrations at or above 100 mM NaCl; the lifetime of HU complexes was observed to increase with the HU concentration at which the complexes were formed, and to decrease with salt concentration. Higher salt levels of 300 mM NaCl completely eliminated observable HU binding to DNA. Finally, we observed that the dissociation kinetics depend on force applied to the DNA: increased applied force in the sub-piconewton range accelerates dissociation, suggesting a mechanism for DNA tension to regulate chromosome structure and gene expression.


Adipose stem cells for intervertebral disc regeneration: current status and concepts for the future.
New regenerative treatment strategies are being developed for intervertebral disc degeneration of which the implantation of various cell types is promising. All cell types used so far require in vitro expansion prior to clinical use, as these cells are only limited available. Adipose-tissue is an abundant, expendable and easily accessible source of mesenchymal stem cells. The use of these cells therefore eliminates the need for in vitro expansion and subsequently one-step regenerative treatment strategies can be developed. Our group envisioned, described and evaluated such a one-step procedure for spinal fusion in the goat model. In this review, we summarize the current status of cell-based treatments for intervertebral disc degeneration and identify the additional research needed before adipose-derived mesenchymal stem cells can be evaluated in a one-step procedure for regenerative treatment of the intervertebral disc. We address the selection of stem cells from the stromal vascular fraction, the specific triggers needed for cell differentiation and potential suitable scaffolds. Although many factors need to be studied in more detail, potential application of a one-step procedure for intervertebral disc regeneration seems realistic.


Self-devaluative dysphoric experience and the prediction of persistent first-episode major depressive disorder in adolescents.
The quality of subjective experience of dysphoria may predict persistence of depression, independently of severity. This is tested in a clinic sample of adolescents with first episode of major depression using the Depressed States Checklist adapted for adolescents. Ninety-four adolescents with DSM-IV major depressive disorder (MDD) were followed up at 12 months. Self-devaluative components of dysphoric experience, ruminative style, over-general autobiographical memory, and self-reported and observer-rated measures of depression severity were assessed at presentation and evaluated as predictors of persistent MDD. Persistent MDD was predicted by the independent additive effects of the higher self-devaluative component of dysphoria, lower general intelligence and greater observer-rated severity of depression at presentation. Neither self-reported depression score, overgeneral memory retrieval nor ruminative style contributed. High levels of self-devaluative dysphoric experience increase the liability for persistence of first-episode MDD. Other affective-cognitive components also contribute. The adolescent version of the Depressed States Checklist is a useful brief measure of cognitive vulnerability for persistence in currently depressed young people.


Inflammatory bowel disease in Bahrain: single-center experience.
The number of newly diagnosed inflammatory bowel disease (IBD) cases such as ulcerative colitis (UC), Crohn's disease (CD), and indeterminate colitis (IC) is rapidly increasing in Gulf countries and Saudi Arabia. The aim of this study was to investigate the incidence and prevalence of IBD in patients who have attended the Salmaniya Medical Complex, Bahrain, between the years 1984 and 2014. All patients who had attended the Salmaniya Medical Complex, Bahrain, and had been diagnosed with UC, CD, or IC, between the years 1984 and 2014, were included in the analysis. Data collected were: patient demographics, symptoms, clinical signs, complications, surgical interventions, extent of disease, endoscopic findings, histopathology, and lab measurements. A total of 187 cases were included; 61 had CD, 123 had UC, and a further 3 cases presented with IC. A clear increase in the incidence and prevalence of IBD can be seen in this cohort. The prevalence of IBD was calculated to be 26.25/105 cases. The average number of IBD cases increased from 3 cases (average for the years 1984-2001) to 12 cases (average for the years 2002-2014). A number of factors correlate positively or negatively with CD and UC. In the current study, a link between gastrointestinal complications in CD cases and the use of steroids as a treatment was noted (p-value -0.02). Age also had a significant influence on the need for surgery in CD cases (p-value -0.04), and a family history of UC was statistically linked to surgical intervention (p-value -0.05). IBD can no longer be considered a rare disease in Bahrain. The incidence of both UC and CD is steadily increasing. There is a need for increasing awareness of the Bahraini public to IBD in order for proper medical care to be given.


Prenatal arsenic and mercury levels among women practicing geophagy in areas with artisanal and small-scale gold mining activities, Northwestern Tanzania.
Artisanal and small-scale gold mining (ASGM) areas potentially pose increased exposure to arsenic and mercury through community contamination, occupations at gold mines, and/or geophagy when soil is locally sourced. This study examined the effects of geophagy, a deliberate soil eating practice, along with community and occupational exposures in ASGM areas on urinary arsenic and blood mercury levels among pregnant women in the Mining and Health Longitudinal Cohort in northwestern Tanzania. Data on maternal arsenic and mercury levels were captured for 1056 pregnant women using an unprovoked morning urine samples and dried blood spots respectively. We used a step-wise generalized linear regression model to retain the most relevant covariates for the model. A generalized linear regression model with identity link function was used to predict the effect of geophagy practices on arsenic and mercury levels separately. The model was adjusted using sociodemographic correlates, including maternal age, education level, whether respondents lived in mining or non-mining area, years of residence, marital status, maternal occupation, individual partner's education, and occupational, and socioeconomic status. In the adjusted regression model, eating soil during pregnancy increased arsenic concentration by almost 23% (β = 1.229, 95% CI: 1.094, 1.38, p < 0.001) and living in mining areas had a 21.2% (β = 1.212; 95% CI: 1.039,1.414, p = 0.014) increased risk. Geophagy significantly increased mercury levels by 13.3% (β = 1.133, 95% CI: 1.022, 1.257, p = 0.018). Living in areas with ASGM activities was associated with a 142% (β = 2.422, 95% CI: 2.111, 2.776, p < 0.0001) increase in blood mercury. Geophagy practices increased urinary arsenic and blood mercury levels in pregnant women, which was especially true for arsenic when living in areas with ASGM activities. Working in mining = increased risk for blood mercury levels. Community-based environmental health policies should address reductions in occupational and community exposures, along with strategic geophagy reduction interventions.


Overall systematic approach to sepsis damages on urogenital tissues: protective power of lacosamide.
The aim of the study was to evaluate the harmful effects of sepsis on the urogynecological tissues and the ability of Lacosamide (LCM) on Lipopolysaccharide (LPS)-induced cytokine production, oxidative stress and apoptotic pathways, in the experimental rat sepsis model. Twenty-four female Wistar albino rats (12 months old) were divided into 3 groups as follows: control group (Group I) (0.1 ml/oral and i.p. saline, single dose), sepsis group (Group II) (5 mg/kg LPS, i.p. single dose) and sepsis + LCM group (Group III) (5 mg/kg LPS, i.p. single dose and 40 mg/kg LCM). Six hours after the last LPS administration, the animals were sacrificed. Subsequently, the analyses of urogenital tissues total oxidant/antioxidant status, histopathological and immunohistochemical analyses were performed. Total oxidant capacity (TOC) and oxidative stress index (OSI) values in the urogenital tissues were increased in the urogenital tissues in Group II [Total antioxidant capacity (TAC) was decreased] compared to group I (p < 0.05). LCM improved these values (p < 0.05). The immunohistochemical markers (Tumor Necrosis Factor-alpha (TNF-α), interleukin-1 beta (IL-1β), heat shock protein 70 (HSP-70), C-reactive protein (CRP), Malondialdehyde (MDA) were significantly increased in Group II (p < 0.001). With the administration of LCM (Group III), the expressions of above-mentioned markers were markedly decreased (p < 0.001). Marked hyperemia and slight hemorrhages with neutrophil leukocyte infiltrations were seen histopathologically in Group II. LCM treatment ameliorated the pathological findings. These findings demonstrated that sepsis caused oxidative stress, apoptosis and inflammation in the urogenital tissues. We revealed that LCM ameliorated the damage caused by sepsis in urogenital tissue.


One-year outcome of concurrent anterior and posterior transvaginal mesh surgery for treatment of advanced urogenital prolapse: case series.
To estimate the safety and efficacy of performing concurrent anterior and posterior transvaginal mesh surgery using a commercially available kit (Gynecare PROLIFT Pelvic Floor Repair System; Ethicon, Inc., Somerville, NJ) for treatment of advanced urogenital prolapse (stage III or higher, Pelvic Organ Prolapse Quantification [POP-Q] system staging). Case control series study (Canadian Task Force classification II-2). Medical school-affiliated hospital. Forty-three patients with severe prolapse, POP-Q stage III (n=23) or IV (n=20), underwent surgery and were followed up for more than 1 year. In patients with any prolapse greater than stage I, surgery were considered to have functional failure. The Surgical Satisfaction Questionnaire was used for subjective evaluation at 1 year postoperatively. Extensive pelvic reconstructive procedures were primarily performed using a combination of the PROLIFT anterior and posterior pelvic systems (i.e., similar to sparing the intermediate section of the PROLIFT total pelvic system). The concurrent pelvic surgery included sequential vaginal total hysterectomy, perineorrhaphy, and suburethra sling, if indicated. Additional subjective and objective evaluations included POP-Q staging, urodynamic assessment, and preoperative and 12-month postoperative questionnaires. Objective and subjective data were available for 42 patients. The subjective cure rate and objective success rate for prolapse at 12-month follow-up was 95.2% and 97.6%, respectively. Mean follow-up was 15.7 months, operation time was 79.2 minutes, operative blood loss was 109.1 mL, and postoperative hospital stay was 4.1 days. Intraoperative and postoperative complications were minor. All patients voided spontaneously before discharge. One mesh extrusion, no wound defective healing, and no rejection were observed. Two patients developed asymptomatic recurrent rectocele (stage II, POP-Q staging) that required no surgical intervention. Urodynamic parameters related to voiding dysfunction improved after surgery. Significant improvements were found using the Incontinence Impact Questionnaire and the Urogenital Distress Inventory. Using concurrent anterior and posterior transvaginal mesh for pelvic reconstructive surgery is a safe and an effective method for treating advanced pelvic prolapse. Mesh-related complications are likely minimal, and mesh protrusion at the apex is likely to not occur. Further studies with longer follow-up are required to evaluate long-term effectiveness.


Agrin and CD34 immunohistochemistry for the discrimination of benign versus malignant hepatocellular lesions.
Agrin is a recently identified proteoglycan component of vascular and bile duct basement membranes in the liver. The selective deposition of agrin in hepatocellular carcinoma (HCC) microvessels versus sinusoidal walls prompted us to investigate the utility of agrin immunohistochemistry (IHC) in detecting malignant hepatocellular lesions. We focused on the differential diagnostic problems often presented by hepatocellular adenomas (HCAs) and dysplastic nodules. IHC for agrin was performed on 138 formalin-fixed, paraffin-embedded surgical specimens from 93 patients, including cirrhotic liver tissues (25), focal nodular hyperplasia (10), large regenerative nodules (8), low-grade (23) and high-grade (7) dysplastic nodules, small HCC (8), HCC (27), and HCA (30). Agrin immunostaining was compared with that of CD34 and, in selected cases, to glypican-3. The combination of agrin and CD34 sensitively (0.94) and specifically (0.93) identified lesions judged previously as malignant by histology. The majority of benign lesions were clearly agrin-negative, whereas the strength and extent of agrin IHC faithfully reflected dysplasia in "atypical" HCAs and in high-grade dysplastic nodules. Malignant lesions were uniformly positive. In conclusion, as agrin is highly selective for tumor blood vessels, IHC for agrin facilitates the discrimination of benign and malignant hepatocellular lesions. Moreover, whereas glypican-3 in some HCCs may appear in few scattered cells only, agrin is diffusely deposited in virtually all malignant lesions, which may prove advantageous in the evaluation of small specimens such as core biopsies.


Sialorrhea in patients with Parkinson's disease: safety and administration of botulinum neurotoxin.
Sialorrhea may present as a troublesome symptom in patients suffering from Parkinson's disease. Current options for treatment include anticholinergic drugs, irradiation, surgery, oral-motor and behavioural therapies, and injection of botulinum neurotoxin (BoNT) in the salivary glands. The aim of this study is to evaluate the safety and administration of BoNT as a treatment for sialorrhea in patients with Parkinson's disease (PD) based on a review of the studies conducted so far in this field. A PubMed search was conducted using the major keywords sialorrhea, botulinum neurotoxin, botulinum toxin and Parkinson's disease. The literature search identified 12 articles, which were selected for further analysis. Few adverse effects were described in the studies included in this present review. Various treatment strategies, including different medication dosages, were applied in the studies. BoNT treatment is safe for sialorrhea in patients with PD. Positive effect is well documented, and there have been relatively few reported adverse effects, which have been mild and transient. Based on this review, a treatment algorithm is proposed. Ultrasound guidance may not be necessary when injecting the parotid gland but may improve the effect and safety of administration, especially when injecting the submandibular glands.


An enhanced community advanced pharmacy practice experience model to improve patient care.
To quantify the benefits of an enhanced advanced pharmacy practice experience (APPE) community pharmacy model compared to the traditional program by comparing basic and comprehensive pharmaceutical care provided by students and assessing preceptors' perceptions of the APPE. A pilot study consisting of 1 enhanced APPE arm and 2 traditional APPE (control) arms was conducted. The enhanced APPE consisted of a preceptor education program, a 5-day onsite student orientation, and an 8-week experience completed at 1 rather than 2 community sites. The level of interventions provided by students in the enhanced APPE arm significantly surpassed that of students in the control arms. In addition, preceptor questionnaires indicated overwhelming support for the enhanced model over the traditional APPE. The study's findings demonstrated that the enhanced APPE model enabled the participating pharmacies to provide increased level of patient care (as compared to the control sites) and improved preceptor satisfaction with the APPE.


Expression of zebrafish fkd6 in neural crest-derived glia.
The zebrafish fkd6 gene is a marker for premigratory neural crest. In this study, we analyze later expression in putative glia of the peripheral nervous system. Prior to neural crest migration, fkd6 expression is downregulated in crest cells. Subsequently, expression appears initially in loose clusters of cells in positions corresponding to cranial ganglia. Double labelling with a neuronal marker shows that fkd6-expressing cells are not differentiated neurones and generally lie peripheral to neurones in ganglia. Later, expression appears associated with the posterior lateral line and other cranial nerves. For the posterior lateral line nerve, we show that fkd6-labeling extends caudally along this nerve in tight correlation with lateral line primordium migration and axon elongation. Expression in colourless mutant embryos is consistent with these cells being satellite glia and Schwann cells.


Predictability in evolution: Adaptation of the Bonaire anole (Anolis bonairensis) to an extreme environment.
The extent to which evolution is deterministic (predictable), or random, is a fundamental question in evolution. This case study attempts to determine the extent to which interspecific divergence can be predicted from intraspecific trends related species. The mountainous Lesser Antilles are occupied by one or two anole species with very substantial intraspecific differences in the quantitative traits between xeric and rainforest habitats. These ecologically determined differences tend to be in parallel in each island species. A related species (Anolis bonairensis) lives on the far more xeric island of Bonaire, and this study tests the extent to which its interspecific divergence in hue and pattern traits can be predicted from the parallel intraspecific variation exhibited in Lesser Antillean anoles. Regression against a multivariate climate variable suggests that the hue and pattern of the Bonaire anole are consistently predicted from the ecologically determined intraspecific variation of its Lesser Antillean relatives. However, this predictability may be less consistent with other character systems, for example, scalation.


Accuracy of genomic prediction when combining two related crossbred populations.
Charolais bulls are selected for their crossbreed performance when mated to Montbéliard or Holstein dams. To implement genomic prediction, one could build a reference population for each crossbred population independently. An alternative could be to combine both crossbred populations into a single reference population to increase size and accuracy of prediction. The objective of this study was to investigate the accuracy of genomic prediction by combining different crossbred populations. Three scenarios were considered: 1) using 1 crossbred population as reference to predict phenotype of animals from the same crossbred population, 2) combining the 2 crossbred populations into 1 reference to predict phenotype of animals from 1 crossbred population, and 3) using 1 crossbred population as reference to predict phenotype of animals from the other crossbred population. Traits studied were bone thinness, height, and muscular development. Phenotypes and 45,117 SNP genotypes were available for 1,764 Montbéliard × Charolais calves and 447 Holstein × Charolais calves. The population was randomly spilt into 10 subgroups, which were assigned to the validation one by one. To allow fair comparison between scenarios, size of the reference population was kept constant for all scenarios. Breeding values were estimated with BLUP and genomic BLUP. Accuracy of prediction was calculated as the correlation between the EBV and the phenotypic values of the calves in the validation divided by the square root of the heritability. Genomic BLUP showed higher accuracies (between 0.281 and 0.473) than BLUP (between 0.197 and 0.452). Accuracies tended to be highest when prediction was within 1 crossbred population, intermediate when populations were combined into the reference population, and lowest when prediction was across populations. Decrease in accuracy from a prediction within 1 population to a prediction across populations was more pronounced for bone thinness (-27%) and height (-29%) than for muscular development (-14%). Genetic correlation between the 2 crossbred populations was estimated using pedigree relationships. It was 0.70 for bone thinness, 0.80 for height, and 0.99 for muscular development. Genetic correlation indicates the expected gain in accuracy of prediction when combining different populations into 1 reference population. The larger the genetic correlation is, the larger the benefit is to combine populations for genomic prediction.


Communication between general and manipulative practitioners: a survey.
A survey of general practitioners (GPs) in the south of England was undertaken to determine their understanding and communication needs in referring patients to practitioners of manipulation. Eighty-six out of 309 GPs replied to a postal questionnaire (28% response). The results suggest that, while routine communication is important for improving understanding, GPs appear to have a preference for disciplines of which they have personal experience. The majority of responders favoured receiving a report on one side of A5 paper when the patient completes treatment. This should contain the nature of treatment and advice given and an indication of its outcome. Those who desired an initial report wanted it to contain a summary of the nature of the problem, a brief history, a summary of relevant findings from the examination, any investigations and a prognosis. Many GPs commented that they were more comfortable in referring to physiotherapists because they felt they had a better understanding of the treatment involved. Furthermore, chiropractic and osteopathic terminologies were reported to be confusing more often than physiotherapy terminology. Bearing in mind the potential bias in responses due to its geographical limitations and low response rate, this study provides useful indicators for manipulative and GPs who wish to work more closely together.


Copy Number Variant Analysis of Spinocerebellar Ataxia Genes in a Cohort of Dutch Patients With Cerebellar Ataxia.
The spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of neurodegenerative disorders generally caused by single nucleotide variants (SNVs) or indels in coding regions or by repeat expansions in coding and noncoding regions of SCA genes. Copy number variants (CNVs) have now also been reported for 3 genes-ITPR1, FGF14, and SPTBN2-but not all SCA genes have been screened for CNVs as the underlying cause of the disease in patients. In this study, we aim to assess the prevalence of CNVs encompassing 36 known SCA genes. A cohort of patients with cerebellar ataxia who were referred to the University Medical Center Groningen for SCA genetic diagnostics was selected for this study. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed using the Infinium Global Screening Array. Following data processing, genotyping data were uploaded into NxClinical software to perform CNV analysis per patient and to visualize identified CNVs in 36 genes with allocated SCA symbols. The clinical relevance of detected CNVs was determined using evidence from studies based on PubMed literature searches for similar CNVs and phenotypic features. Of the 338 patients with cerebellar ataxia, we identified putative clinically relevant CNV deletions in 3 patients: an identical deletion encompassing ITPR1 in 2 patients, who turned out to be related, and a deletion involving PPP2R2B in another patient. Although the CNV deletion in ITPR1 was clearly the underlying cause of SCA15 in the 2 related patients, the clinical significance of the deletion in PPP2R2B remained unknown. We showed that CNVs detectable with the limited resolution of SNP array are a very rare cause of SCA. Nevertheless, we suggest adding CNV analysis alongside SNV analysis to SCA gene diagnostics using next-generation sequencing approaches, at least for ITPR1, to improve the genetic diagnostics for patients.


Electrophysiological derangements induced by lipid peroxidation in cardiac tissue.
Recently it has been postulated that oxygen-derived free radicals may be involved in reperfusion-induced arrhythmias. This study was undertaken to evaluate cellular electrophysiological alterations produced by peroxidation of membrane lipids in isolated cardiac tissues. In retrogradely perfused guinea pig hearts, perfusion of organic hydroperoxides, cumene hydroperoxide (CH), and tert-butyl hydroperoxide (TBH) caused conduction disturbances and arrhythmias, concomitantly with an increase in malondialdehyde (MDA) content of the myocardium. The hydroperoxides decreased the maximum diastolic potential, action potential amplitude, and maximum upstroke velocity of phase 0 in both canine Purkinje fibers and guinea pig papillary muscles. They also induced abnormal automaticity, such as depolarization-induced automaticity, delayed afterdepolarizations, and triggered activity. Mechanical abnormalities including increased resting tension and aftercontractions, presumably resulting from intracellular Ca2+ overload, were produced by the hydroperoxides. Pretreatment with butylated hydroxytoluene, an antioxidant, significantly inhibited the hydroperoxide-induced electrophysiological derangements and MDA accumulation in the myocardium. These results suggest that lipid peroxidation of membranes causes various electrophysiological and mechanical abnormalities and may play a role in the genesis of reperfusion-induced arrhythmias.


Analysis of Structural Development and Defects during the Anisotropic Growth of Silicon.
High-performance polysilicon (P-Si) is fundamental as a resource for manufacturing semiconductor devices with high photoelectric properties. However, experimentally characterizing the solidification process in detail has been difficult on account of the extremely rapid cooling rate and limited available characterization methods. Therefore, this study used molecular dynamics (MD) to investigate Si crystallization behavior through directional solidification at different cooling rates. The entire system was first analyzed in terms of energy and radial distribution function, after which the microstructural evolution was characterized by visualization. Results indicated that the cooling rate significantly affected the directional solidification of Si, and an excessively high cooling rate resulted in a decrease in the long-range order of the system. At the same cooling rate, the crystallization rates of (1 0 0), (1 1 0), and (1 1 1) crystal faces followed a descending order. The configurations of the S-L interface with different crystal faces were distinct. Specifically, while the atom numbers of defect structures that were formed in systems of (1 0 0) and (1 1 0) crystal faces were few, those formed in the (1 1 1) crystal face were more. It was difficult for the (1 0 0) crystal face to form dislocations regardless of the crystallization degree at different cooling rates, and the (1 1 0) crystal face only formed a few dislocations at high cooling rates. Dislocations formed at all cooling rates during the directional solidification of the (1 1 1) crystal face, and there was a weak correlation between the number of dislocations and cooling rates. Twinning mainly occurred during the solidification process of the (1 1 1) crystal face, and there was no obvious linear relation between its number and the cooling rate. Moreover, when high-energy dislocations occurred more often, the system stability decreased. Overall, this work will be helpful to understand the commonness and difference in directional solidification of Si with different crystal faces at different cooling rates.


The impact of public health messaging and personal experience on the acceptance of mask wearing during the COVID-19 pandemic.
Face coverings have been shown to slow the spread of COVID-19, yet their use is not universal and remains controversial in the United States. Designing effective nudges for widespread adoption is important when federal mandates are politically or legally infeasible. We report the results from a survey experiment in which subjects were exposed to one of three video messages from President Trump, and then indicated their preference for wearing a mask. In the first video, the President simply recited the Centers for Disease Control and Prevention (CDC) guidelines. In the second, the President additionally emphasized that wearing a mask is optional. In the third video, the President added that he will not personally wear a mask. We find that exposure to presidential messages can increase the stated likelihood of wearing a mask-particularly among the President's supporters. We also explore experiential effects of COVID-19, and find that people (especially supporters of the President) are more likely to support wearing a mask if they know someone who has tested positive for COVID-19. These results offer guidance to policy makers and practitioners interested in understanding the factors that influence viral risk mitigation strategies.


Liquid Biopsy in Head and Neck Cancer: Promises and Challenges.
Head and neck cancer is the sixth most common cancer worldwide. It remains one of the leading causes of death, and its early detection is crucial. Liquid biopsy has emerged as a promising tool for detecting and monitoring the disease status of patients with early and advanced cancers. Circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and exosomal miRNAs have received enormous attention because of their apparent clinical implications. Analyses of these circulating biomarkers have paved the way for novel therapeutic approaches and precision medicine. A growing number of reports have implicated the use of circulating biomarkers for detection, treatment planning, response monitoring, and prognosis assessment. Although these new biomarkers can provide a wide range of possible clinical applications, no validated circulating biomarkers have yet been integrated into clinical practice for head and neck cancer. In this review, we summarize the current knowledge of circulating biomarkers in this field, focusing on their feasibility, limitations, and key areas of clinical applications. We also highlight recent advances in salivary diagnostics and their potential application in head and neck cancer.


DNA bending and unwinding due to the major 1,2-GG intrastrand cross-link formed by antitumor cis-diamminedichloroplatinum(II) are flanking-base independent.
Antitumor cisplatin [cis-diamminedichloroplatinum(II)] forms on DNA predominantly intrastrand cross-links between neighboring purine residues. Several discoveries suggested that the toxicity of cisplatin originated from these lesions. The formation of 1,2-GG intrastrand cross-link of cisplatin leads to marked conformational alterations in DNA including a directional, rigid bend toward the major groove and local unwinding. These altered structures attract various cellular proteins. This phenomenon has been postulated to mediate antitumor properties of cisplatin. Importantly, the binding affinity of several proteins that specifically recognize 1,2-GG intrastrand cross-link to platinated DNA is modulated by the nature of the base pairs that immediately flank the platinated d(GpG) site. However, the influence of sequence context on DNA bending and unwinding due to the formation of the 1,2-GG intrastrand cross-link has not been extensively investigated. In the present study we have employed electrophoretic retardation (phasing) assay to analyze bending and unwinding induced by the single, site-specific 1,2-GG intrastrand cross-link immediately flanked by various bases formed by cisplatin in nine oligodeoxyribonucleotide duplexes. The results indicate that bending and unwinding of DNA as a consequence of the formation of the major adduct of cisplatin is, in the first approximation, independent of the base pairs flanking the platinated d(GpG) site.


Network meta-analysis of studies included in the Clinical Practice Guideline on the nonsurgical treatment of chronic periodontitis.
The recent ADA-commissioned Clinical Practice Guideline on the nonsurgical treatment of chronic periodontitis has provided the most exhaustive library of clinical trials on scaling and root planing (SRP) with or without adjuncts. This network meta-analysis (NMA) compared the adjuncts against each other. A star-shaped NMA was performed based on 36 indirect comparisons of clinical attachment-level (CAL) gains among nine adjuncts in 74 studies from the Clinical Practice Guideline. All pairwise differences were accompanied by wide confidence intervals, and none of the adjuncts were statistically significantly superior to another. Local doxycycline hyclate and photodynamic therapy with a diode laser had the highest probabilities for ranking first and second, respectively. Publication bias was evident, with fewer than expected studies with small effects. The lack of these studies inflated the treatment effects by an estimated by 20%. Adjuncts improve CAL gain by about a third of a mm over 6-12 months compared with SRP alone, but no significant differences were found among the adjuncts. The patient-perceived benefit of this gain is unclear because CAL is a physical measure made by the clinician and not a patient-oriented outcome. Publication bias inflated the observed treatment effects.


Nothobranchius furzeri, the Turquoise Killifish: A Model of Age-Related Osteoporosis?
Osteoporosis is a frequent age-related disease, which affects millions of people worldwide. Despite significant progress in the treatment of the disease, a high number of patients still are underdiagnosed and undertreated. Therefore, novel animal models for the investigation of the disease are necessary. Nothobranchius furzeri is the shortest-lived vertebrate (with a lifespan of 3-7 months) that can be kept in captivity. Although it is an established model for aging research, studies on bone are lacking. The aim of this study was therefore to characterize N. furzeri as a potential model for age-related osteoporosis. Bone properties of aging N. furzeri were investigated in male and female fish of the Gona Re Zhou strain, which were between 8 and 20 weeks old. Micro-computed tomography (Scanco Medical µCT35) was performed to determine the bone properties of the vertebral bodies. Bone structure and remodeling were investigated by different histological staining techniques and histomorphometry. The chemical composition of fish vertebrae and intervertebral discs was analyzed by Raman microspectroscopy. Osteoblasts, mono- and multinucleated osteoclasts but no osteocytes could be observed in the vertebral area of N. furzeri. Histomorphometric evaluations revealed a significant decrease of the number of osteoblasts/bone perimeter and for osteoid volume/bone volume (BV) a trend toward a decrease in old male N. furzeri. Comparing male and female fish, males showed higher BV densities and cortical thickness. The relative values of the bone volume density of 20-week-old male N. furzeri were significantly lower than 10-week-old ones. The mineral to matrix ratio increased with age in male and female fish. In the intervertebral discs, proteoglycans in relation to the organic matrix were significantly lower in older female fish. Our finding of a lack of osteocytes is in agreement with the fact that N. furzeri belongs to the evolutionarily advanced teleost fish. Furthermore, not only age-specific but also sex-specific differences were visible in the bone properties of N. furzeri, which can be taken into consideration for the study of gender aspects of age-related musculoskeletal diseases.


Mono-acyl arsenosugar phospholipids in the edible brown alga Kombu (Saccharina japonica).
Twenty one arsenolipids, including eight new compounds (AsSugPL 692, AsSugPL 706, AsSugPL 720, AsSugPL 734, AsSugPL 742, AsSugPL 746, AsSugPL 748, and AsSugPL 776) were identified in the edible brown alga Kombu, Saccharina japonica, by means of HPLC coupled with elemental and molecular mass spectrometry. The hitherto undescribed compounds are all mono-acyl arsenosugar phospholipids, differing from previously reported natural arsenic-containing phospholipids by containing only one fatty acid on the glycerol group. Collectively, this new group of mono-acyl compounds constituted about 30% of total lipid arsenic; other significant groups were the di-acyl arsenosugar phospholipids (50%) and arsenic hydrocarbons (20%). The origin and relevance of the mono-acyl arsenosugar phospholipids in Kombu, a commercial seafood product, is briefly discussed.


Human Immunodeficiency Virus (HIV) Risk Behaviors by African American and Puerto Rican Women in the 4th Decade of Life: Substance Use and Personal Attributes.
African Americans have the most severe burden of human immunodeficiency virus (HIV) of all racial/ethnic groups in the United States. Also, HIV continues to be a serious threat to the health of the Hispanic/Latino community. For prevention purposes, the present study examined the relationship of both cannabis use and self-control with HIV risk behaviors in a sample of African American and Puerto Rican female adolescents, young adults, and adults. Among the total of 343 female participants, half were African American and the other half were Puerto Rican. Logistic regression analyses were used to examine earlier cannabis use as well as self-control and later HIV risk behaviors. High frequency of cannabis use and high self-control measured at ages 19 to 29 were positively and negatively related to having sexual intercourse with someone they just met at ages 32 to 39. Prevention programs should incorporate the role of cannabis use and low self-control as related to HIV risk behaviors. Our results may have particular utility for designing interventions focused on not only cannabis use (a risk factor) but also self-control (a protective factor) as related to HIV sexual risk behaviors.


At the Intersection of Sexual Orientation and Gender Identity: Variations in Emotional Distress and Bullying Experience in a Large Population-based Sample of U.S. Adolescents.
This study examines the intersection of sexual and gender identities among adolescents, including the prevalence of these groups and rates of emotional distress and bullying victimization. Data come from a large population-based sample; two measures of sexual orientation and gender identity create eight identity groups. Youth who report identifying both as lesbian, gay, bisexual, or queer/questioning (LGBQ) and as transgender/gender diverse (TGD) had significantly higher levels of two measures of emotional distress and four measures of bullying victimization than those who report only identifying as LGBQ non-TGD or straight TGD. Implications for research and practice are discussed.


Delivery of SIRT1 by cancer-associated adipocyte-derived extracellular vesicles regulates immune response and tumorigenesis of ovarian cancer cells.
This study intends to investigate the possible molecular mechanism of immune response and tumorigenesis in ovarian cancer cells, mediated by sirtuin 1 (SIRT1)-containing extracellular vesicles (EVs) derived from cancer-associated adipocytes (CAAs) (CAA-EVs). Differentially expressed genes in EVs from CAAs were screened by RNA transcriptome sequencing, and the downstream pathway was predicted in silico. The binding between SIRT1 and CD24 was investigated by luciferase activity and ChIP-PCR assays. EVs were extracted from human ovarian cancer tissue-isolated CAAs, and the internalization of CCA-EVs by ovarian cancer cells was characterized. The ovarian cancer cell line was injected into mice to establish an animal model. Flow cytometry was performed to analyze the proportions of M1 and M2 macrophages, CD8+ T, T-reg, and CD4+ T cells. TUNEL staining was used to detect cell apoptosis in the mouse tumor tissues. ELISA detection was performed on immune-related factors in the serum of mice. CAA-EVs could deliver SIRT1 to ovarian cancer cells, thereby affecting the immune response of ovarian cancer cells in vitro and promoting tumorigenesis in vivo. SIRT1 could transcriptionally activate the expression of CD24, and CD24 could up-regulate Siglec-10 expression. CAA-EVs-SIRT1 activated the CD24/Siglec-10 axis and promoted CD8+ T cell apoptosis, thereby promoting tumorigenesis in mice. CAA-EVs-mediated transfer of SIRT1 regulates the CD24/Siglec-10 axis to curb immune response and promote tumorigenesis of ovarian cancer cells.


Cavitary Coccidioidomycosis: Impact of azole antifungal therapy.
Approximately 5 to 15% of patients with pulmonary coccidioidomycosis subsequently develop pulmonary cavities. These cavities may resolve spontaneously over a number of years; however, some cavities never close, and a small proportion causes complications such as hemorrhage, pneumothorax or empyema. The impact of azole antifungal treatment on coccidioidal cavities has not been studied. Because azoles are a common treatment for symptomatic pulmonary coccidioidomycosis, we aimed to assess the impact of azole therapy on cavity closure. From January 1, 2004, through December 31, 2014, we retrospectively identified 313 patients with cavitary coccidioidomycosis and excluded 42 who had the cavity removed surgically, leaving 271 data sets available for study. Of the 271 patients, 221 (81.5%) received azole therapy during 5-year follow-up; 50 patients did not receive antifungal treatment. Among the 271 patients, cavities closed in 38 (14.0%). Statistical modeling showed that cavities were more likely to close in patients in the treated group than in the nontreated group (hazard ratio, 2.14 [95% CI: 1.45-5.66]). Cavities were less likely to close in active smokers than nonsmokers (11/41 [26.8%] vs 97/182 [53.3%]; P = 0.002) or in persons with than without diabetes (27/74 [36.5%] vs 81/149 [54.4%]; P = 0.01).We did not find an association between cavity size and closure. Our findings provide rationale for further study of treatment protocols in this subset of patients with coccidioidomycosis. Coccidioidomycosis, known as valley fever, is a fungal infection that infrequently causes cavities to form in the lungs, which potentially results in long-term lung symptoms. We learned that cavities closed more often in persons who received antifungal drugs, but most cavities never closed completely.


Diversity of staphylococcal species in food producing animals in Spain, with detection of PVL-positive MRSA ST8 (USA300).
This work aimed to determine the prevalence, diversity, antibiotic-resistance phenotype/genotype and virulence factors in staphylococci of farm-animals. Nasal samples of 117 farm-animals (calve: 72; lamb: 37; goat: 8) were collected from one slaughterhouse in La Rioja/Spain and cultured for staphylococci and methicillin-resistant Staphylococcus (MRS) recovery. Identification was performed by MALDI-TOF. Antimicrobial resistance phenotype/genotype was determined by susceptibility testing and specific PCRs. Molecular typing (spa-typing, multilocus-sequence-typing, agr-typing, SCCmec), and detection of 12 virulence genes and human Immune-evasive-cluster (IEC) genes were performed by PCR/sequencing in S. aureus. Two marker genes of arginine catabolic mobile element (ACME) were determined by PCR (USA300-MRSA detection). Staphylococci were identified in 50%, 54% and 21% of goat, lamb and calve samples, respectively. Among the 13 S. aureus isolates recovered, 11 were susceptible to all antimicrobials tested, and two were multidrug-resistant-MRSA [beta-lactams (blaZ, mecA), macrolides [(msr(A)/msr(B)] and fluoroquinolones]. The MSSA harboured either tst or enterotoxin genes, while the MRSA harboured the lukF/lukS-PV genes. Five sequence-types were detected. The two MRSA strains (from lamb and goat) were typed as t5173/ST8/agr-I/SCCmec-IVa/ACME-positive, corresponding to USA300 clone, and were IEC-B-positive. Among the 47 coagulase-negative staphylococci (CoNS), six species were identified, predominating S. simulans (n = 25) and S. sciuri (n = 11). Fifty-three percent of CoNS showed resistance to at least one antimicrobial agent (six multidrug-resistant strains), and the following resistance phenotypes/genotypes were detected: streptomycin [27.6%; ant(6)-Ia, str], tetracycline [23.4%; tet(M), tet(L), tet(K)], clindamycin [19.1%; lnu(A), vgaA], erythromycin [10.6%; erm(C), msr(A)/msr(B)], chloramphenicol (8.5%; fexA), tobramycin (6.4%), penicillin-cefoxitin (4.3%; blaZ, mecA), and SXT (2.1%). The detection of the MRSA-USA300 lineage in food animals is worrisome and should be further monitored.


Structural characterization of human galectin-4 C-terminal domain: elucidating the molecular basis for recognition of glycosphingolipids, sulfated saccharides and blood group antigens.
Human galectin-4 is a lectin that is expressed mainly in the gastrointestinal tract and exhibits metastasis-promoting roles in some cancers. Its tandem-repeat nature exhibits two distinct carbohydrate recognition domains allowing crosslinking by simultaneous binding to sulfated and non-sulfated (but not sialylated) glycosphingolipids and glycoproteins, facilitating stabilization of lipid rafts. Critically, galectin-4 exerts favourable or unfavourable effects depending upon the cancer. Here we report the first X-ray crystallographic structural information on human galectin-4, specifically the C-terminal carbohydrate recognition domain of human (galectin-4C) in complex with lactose, lactose-3'-sulfate, 2'-fucosyllactose, lacto-N-tetraose and lacto-N-neotetraose. These structures enable elucidation of galectin-4C binding fine-specificity towards sulfated and non-sulfated lacto- and neolacto-series sphingolipids as well as to human blood group antigens. Analysis of the lactose-3'-sulfate complex structure shows that galectin-4C does not recognize the sulfate group using any specific amino acid, but binds the ligand nonetheless. Complex structures with lacto-N-tetraose and lacto-N-neotetraose displayed differences in binding interactions exhibited by the non-reducing-end galactose. That of lacto-N-tetraose points outward from the protein surface whereas that of lacto-N-neotetraose interacts directly with the protein. Recognition patterns of human galectin-4C towards lacto- and neolacto-series glycosphingolipids are similar to those of human galectin-3; however, detailed scrutiny revealed differences stemming from the extended binding site that offer distinction in ligand profiles of these two galectins. Structural characterization of the complex with 2'-fucosyllactose, a carbohydrate with similarity to the H antigen, and molecular dynamics studies highlight structural features that allow specific recognition of A and B antigens, whilst a lack of interaction with the 2'-fucose of blood group antigens was revealed. 4YLZ, 4YM0, 4YM1, 4YM2, 4YM3.


'Whose life are They Going to Save? It's Probably Not Going to be Mine!' Living With a Life-Shortening Condition During the Coronavirus (COVID-19) Pandemic: A Grounded Theory Study of Embodied Precarity.
This article explores the experiences of young adults with a life-shortening condition in the first wave of the Coronavirus (COVID-19) pandemic in the UK. It presents the findings from an inclusive qualitative research study using constructivist grounded theory which aimed to examine the unintended consequences of pandemic control measures (lockdown and 'shielding') on this population. Purposive and theoretical sampling methods were used to recruit young adults with a life-shortening condition, employing a range of recruitment methods such as social media, advertising in newsletters and snowballing. Twenty-six young adults (aged 22-40 years), with a wide range of life-shortening conditions participated in the study. Seventeen participants were female and nine male. The majority identified as White British/Other and the remainder as Black British (2), Mixed Race (2) or Latin American (1). Data were generated iteratively using in-depth guided interviews and analysed collectively by an inclusive research team using the constant comparative method. The article explores a theory of embodied precariousness of living with a life-shortening condition during the first wave of the Coronavirus pandemic in relation to three categories: the rationing of life-saving treatment, the deterioration of health and retraction of healthcare provision, and the disruption of typical care arrangements. The findings show that the pandemic control measures introduced to keep people safe have intensified the precarity of this group promoting inequalities in healthcare and health outcomes. The article identifies some implications for practice to support the future management of unexpected and unwanted change.


Unexpected Race and Ethnicity Differences in the US National Veterans Affairs Kidney Transplant Program.
Racial/ethnic minorities have lower rates of deceased kidney transplantation (DDKT) and living donor kidney transplantation (LDKT) in the United States. We examined whether social determinants of health (eg, demographics, cultural, psychosocial, knowledge factors) could account for differences in the Veterans Affairs (VA) Kidney Transplantation (KT) Program. We conducted a multicenter longitudinal cohort study of 611 Veterans undergoing evaluation for KT at all National VA KT Centers (2010-2012) using an interview after KT evaluation and tracking participants via medical records through 2017. Hispanics were more likely to get any KT (subdistribution hazard ratios [SHR] [95% confidence interval (CI)]: 1.8 [1.2-2.8]) or DDKT (SHR [95% CI]: 2.0 [1.3-3.2]) than non-Hispanic white in univariable analysis. Social determinants of health, including marital status (SHR [95% CI]: 0.6 [0.4-0.9]), religious objection to LDKT (SHR [95% CI]: 0.6 [0.4-1.0]), and donor preference (SHR [95% CI]: 2.5 [1.2-5.1]), accounted for some racial differences, and changes to Kidney Allocation System policy (SHR [95% CI]: 0.3 [0.2-0.5]) mitigated race differences in DDKT in multivariable analysis. For LDKT, non-Hispanic African American Veterans were less likely to receive an LDKT than non-Hispanic white (SHR [95% CI]: 0.2 [0.0-0.7]), but accounting for age (SHR [95% CI]: 1.0 [0.9-1.0]), insurance (SHR [95% CI]: 5.9 [1.1-33.7]), presenting with a living donor (SHR [95% CI]: 4.1 [1.4-12.3]), dialysis duration (SHR [95% CI]: 0.3 [0.2-0.6]), network of potential donors (SHR [95% CI]: 1.0 [1.0-1.1]), self-esteem (SHR [95% CI]: 0.4 [0.2-0.8]), transplant knowledge (SHR [95% CI]: 1.3 [1.0-1.7]), and changes to Kidney Allocation System policy (SHR [95% CI]: 10.3 [2.5-42.1]) in multivariable analysis eliminated those disparities. The VA KT Program does not exhibit the same pattern of disparities in KT receipt as non-VA centers. Transplant centers can use identified risk factors to target patients who may need more support to ensure they receive a transplant.


Slow oscillations of membrane potential in interneurons that control heartbeat in the medicinal leech.
In the preceding paper (Arbas and Calabrese, 1987), we identified several properties that contribute to the activity of neurons (HN cells) that control heartbeat in the medicinal leech. Premotor HN (7) interneurons, which do not generate the heartbeat rhythm, exhibit Na+-dependent fast action potentials, Ca2+-mediated plateau potentials in the absence of Na+, and hyperpolarization-activated "restorative" changes in membrane potential that depolarize the membrane potential on hyperpolarization due to injected currents or synaptic inhibition. HN interneurons of ganglia 3 and 4 (i.e., timing oscillator interneurons) exhibit all of the properties described for HN (7) interneurons and have the additional characteristic that they are connected in oscillatory circuits. Reciprocal oscillations in membrane potential occurred in the bilateral HN interneurons (3) and (4) in the presence of elevated Ca2+ that were independent of Na+ -mediated action potentials. Their ability to oscillate in this way is based on 3 parameters: (1) production of a regenerative plateau potential by one of the pair of HN neurons in either ganglion, (2) inhibition of the contralateral HN neuron by the HN neuron in plateau, and (3) a phase transition mediated by escape from inhibition by the hyperpolarized HN neuron. The conductances responsible for restorative membrane potential shifts activated by hyperpolarization during synaptic inhibition may mediate the escape from inhibition that times the phase transition of the 2 HN neurons.


Modification of apatite materials for bone tissue engineering and drug delivery carriers.
Apatite-related calcium phosphate, the main component of biological hard tissue, has good biocompatibility and is an economical material. Methods for the synthesis of apatite materials including hydroxyapatite (HAp) have previously been established. Therefore, for many years, apatite materials have been utilized as substitute materials for bone in orthopedic and dental fields. Such types of conventional substitute materials, which are implanted in the human body, should ostensibly be chemically stable to maintain their quality over time. However, recent advances in tissue engineering have altered this concept. Physicians and researchers now seek to identify materials that alter their properties temporally and spatially to achieve ideal tissue regeneration. In order to use apatite materials for tissue engineering and as drug delivery systems, the materials require both a high affinity for cells, tissues and/or functional molecules (e.g. growth factors and genes) and controllable bioabsorbability. To achieve these properties, various physicochemical modifications of apatite materials have been attempted. In addition, fabrication desiring three-dimensional structures (e.g. size, morphology and porosity) of apatite materials for implant sites could be one of the crucial techniques used to obtain ideal prognoses. In this review, the latest research trends relating to the techniques for the fabrication and modification of apatite materials are introduced.


Psychometrics and the neuroscience of individual differences: Internal consistency limits between-subjects effects.
In the clinical neuroscience literature, between-subjects differences in neural activity are presumed to reflect reliable measures-even though the psychometric properties of neural measures are almost never reported. The current article focuses on the critical importance of assessing and reporting internal consistency reliability-the homogeneity of "items" that comprise a neural "score." We demonstrate how variability in the internal consistency of neural measures limits between-subjects (i.e., individual differences) effects. To this end, we utilize error-related brain activity (i.e., the error-related negativity or ERN) in both healthy and generalized anxiety disorder (GAD) participants to demonstrate options for psychometric analyses of neural measures; we examine between-groups differences in internal consistency, between-groups effect sizes, and between-groups discriminability (i.e., ROC analyses)-all as a function of increasing items (i.e., number of trials). Overall, internal consistency should be used to inform experimental design and the choice of neural measures in individual differences research. The internal consistency of neural measures is necessary for interpreting results and guiding progress in clinical neuroscience-and should be routinely reported in all individual differences studies. (PsycINFO Database Record


Expression of arthritis-causing HLA-B27 on Hela cells promotes induction of c-fos in response to in vitro invasion by Salmonella typhimurium.
HLA-B27 confers a very strong genetic predisposition to development of a reactive arthritis after infection by bacteria such as Salmonella typhimurium. This study examines the role of HLA-B27 in the initiation of the earliest host activities after exposure to Salmonella, namely activation of the immediate early genes in the epithelial cells. Our major finding is that in Hela cells, the expression of c-fos was induced by Salmonella invasion only when the cells expressed the transfected HLA-B27 gene, but not the HLA-A1 gene or a truncated HLA-B27 gene lacking the exons encoding the cytoplasmic domain. C-fos is potentially capable of complexing with members of the c-jun family to become the AP-1 transcription complex. Parallel to c-fos expression, we found that only with the HLA-B27 transfectant was there expression of AP-1. AP-1 potentially controls the expression of a large number of genes. On screening a panel of proinflammatory molecules, we found that Salmonella invasion induced expression of monocyte chemoattractant protein-1 in the HLA-B27 cells. Since each of these separate positive findings belong to the same cascade of events after cell activation, together they reinforce the hypothesis that HLA-B27 plays a modulatory role in the early signal transduction events induced by Salmonella invasion. This hypothesis adds another item to the list of allele-specific activities carried out by HLA class I molecules. If similar activation also occurs in the joints, it may play a major role in arthritis.


[Italian contribute to the CIASS validation].
Interpersonal relationships contribute to the psychological adjustments to chronic disease, directly affecting health and, more generally, life satisfaction of patients. Those factors are often threatened by the fear of becoming target of prejudices and discrimination from those who share their daily life with. Thus, this study proposes a contribution to the Italian adaptation and validation of the Chronic Illness Anticipated Stigma Scale (CIASS), a brief questionnaire (12 items) that aims to assess perceived stigma of chronic illness patients in family, work and health care contexts. 279 chronic illness patients have completed the questionnaire, comparing the scores with those obtained in depression (BDI-II), anxiety (STAI), and internalized stigma scales. Confirmatory factor analysis (CFA) on the Italian sample has shown the same structure of the original questionnaire, composed by three dimensions of anticipated stigma, experienced with family and friends, work colleagues and health care providers. Correlation analyses confirm the relation between scores of anticipated stigma and other mental health indicators as anxiety and depression. Italian version of CIASS demonstrates to be a valid and reliable instrument, considering it both as an indicator of person's state of health and a promising marker of the specific kind of perceived discrimination in family, care and working contexts.


Locus of word frequency effects in spelling to dictation: Still at the orthographic level!
The present study was aimed at testing the locus of word frequency effects in spelling to dictation: Are they located at the level of spoken word recognition (Chua & Rickard Liow, 2014) or at the level of the orthographic output lexicon (Delattre, Bonin, & Barry, 2006)? Words that varied on objective word frequency and on phonological neighborhood density were orally presented to adults who had to write them down. Following the additive factors logic (Sternberg, 1969, 2001), if word frequency in spelling to dictation influences a processing level, that is, the orthographic output level, different from that influenced by phonological neighborhood density, that is, spoken word recognition, the impact of the 2 factors should be additive. In contrast, their influence should be overadditive if they act at the same processing level in spelling to dictation, namely the spoken word recognition level. We found that both factors had a reliable influence on the spelling latencies but did not interact. This finding is in line with an orthographic output locus hypothesis of word frequency effects in spelling to dictation. (PsycINFO Database Record


Rationalizing historical successes of malaria control in Africa in terms of mosquito resource availability management.
Environmental management of mosquito resources is a promising approach with which to control malaria, but it has seen little application in Africa for more than half a century. Here we present a kinetic model of mosquito foraging for aquatic habitats and vertebrate hosts that allows estimation of malaria transmission intensity by defining the availability of these resources as the rate at which individual mosquitoes encounter and use them. The model captures historically observed responses of malaria transmission to environmental change, highlights important gaps in current understanding of vector ecology, and suggests convenient solutions. Resource availability is an intuitive concept that provides an adaptable framework for models of mosquito population dynamics, gene flow, and pathogen transmission that can be conveniently parameterized with direct field measurements. Furthermore, the model presented predicts that drastic reductions of malaria transmission are possible with environmental management and elucidates an ecologic basis for previous successes of integrated malaria control in Africa before the advent of DDT or chloroquine. Environmental management for malaria control requires specialist skills that are currently lacking in sub-Saharan Africa where they are needed most. Infrastructure and human capacity building in clinical, public health, and environmental disciplines should therefore be prioritized so that growing financial support for tackling malaria can be translated into truly integrated control programs.


Regulation of Life Cycle Checkpoints and Developmental Activation of Infective Larvae in Strongyloides stercoralis by Dafachronic Acid.
The complex life cycle of the parasitic nematode Strongyloides stercoralis leads to either developmental arrest of infectious third-stage larvae (iL3) or growth to reproductive adults. In the free-living nematode Caenorhabditis elegans, analogous determination between dauer arrest and reproductive growth is governed by dafachronic acids (DAs), a class of steroid hormones that are ligands for the nuclear hormone receptor DAF-12. Biosynthesis of DAs requires the cytochrome P450 (CYP) DAF-9. We tested the hypothesis that DAs also regulate S. stercoralis development via DAF-12 signaling at three points. First, we found that 1 μM Δ7-DA stimulated 100% of post-parasitic first-stage larvae (L1s) to develop to free-living adults instead of iL3 at 37°C, while 69.4±12.0% (SD) of post-parasitic L1s developed to iL3 in controls. Second, we found that 1 μM Δ7-DA prevented post-free-living iL3 arrest and stimulated 85.2±16.9% of larvae to develop to free-living rhabditiform third- and fourth-stages, compared to 0% in the control. This induction required 24-48 hours of Δ7-DA exposure. Third, we found that the CYP inhibitor ketoconazole prevented iL3 feeding in host-like conditions, with only 5.6±2.9% of iL3 feeding in 40 μM ketoconazole, compared to 98.8±0.4% in the positive control. This inhibition was partially rescued by Δ7-DA, with 71.2±16.4% of iL3 feeding in 400 nM Δ7-DA and 35 μM ketoconazole, providing the first evidence of endogenous DA production in S. stercoralis. We then characterized the 26 CYP-encoding genes in S. stercoralis and identified a homolog with sequence and developmental regulation similar to DAF-9. Overall, these data demonstrate that DAF-12 signaling regulates S. stercoralis development, showing that in the post-parasitic generation, loss of DAF-12 signaling favors iL3 arrest, while increased DAF-12 signaling favors reproductive development; that in the post-free-living generation, absence of DAF-12 signaling is crucial for iL3 arrest; and that endogenous DA production regulates iL3 activation.


Analgesia and public health: what are the challenges?
Pain is a common problem, but unfortunately, it is one that is still notoriously neglected and poorly managed. Although it usually is not rated highly in public health statistics, it forms a substantial proportion of the everyday work of health care professionals, and thus remains a major public health burden. The first challenge in successful pain management is overcoming the ineffective learning processes most health care practitioners use to update their procedures and therapies in response to the latest research. The ready availability of over-the-counter analgesics means that much of the pain in the community is now self-medicated, and it is vital that they also have ready access to the latest evidence-based recommendations. Second, better methods are needed to tailor treatment to individual patients because differences in comorbidities, drug metabolism, or the nature and severity of disease processes lead to different responses from individual patients. Such tailoring should also account for differences in side-effect profiles of the various treatment options available. Finally, even if health practitioners are aware of the latest in clinical evidence and recommended practices, they may not be able to implement the most appropriate treatment because of legal or financial barriers. This article will to review these three challenges to the management of pain and discuss practical ways in which they may be handled to help reduce the burden of pain care in society.


Induction and suppression of tick cell antiviral RNAi responses by tick-borne flaviviruses.
Arboviruses are transmitted by distantly related arthropod vectors such as mosquitoes (class Insecta) and ticks (class Arachnida). RNA interference (RNAi) is the major antiviral mechanism in arthropods against arboviruses. Unlike in mosquitoes, tick antiviral RNAi is not understood, although this information is important to compare arbovirus/host interactions in different classes of arbovirus vectos. Using an Ixodes scapularis-derived cell line, key Argonaute proteins involved in RNAi and the response against tick-borne Langat virus (Flaviviridae) replication were identified and phylogenetic relationships characterized. Analysis of small RNAs in infected cells showed the production of virus-derived small interfering RNAs (viRNAs), which are key molecules of the antiviral RNAi response. Importantly, viRNAs were longer (22 nucleotides) than those from other arbovirus vectors and mapped at highest frequency to the termini of the viral genome, as opposed to mosquito-borne flaviviruses. Moreover, tick-borne flaviviruses expressed subgenomic flavivirus RNAs that interfere with tick RNAi. Our results characterize the antiviral RNAi response in tick cells including phylogenetic analysis of genes encoding antiviral proteins, and viral interference with this pathway. This shows important differences in antiviral RNAi between the two major classes of arbovirus vectors, and our data broadens our understanding of arthropod antiviral RNAi.