Effect of Bio-Oss on osseointegration of dental implants surrounded by circumferential bone defects of different dimensions: an experimental study in the dog.
This study was designed to evaluate the effect of gap width and graft placement on bone healing around implants placed in simulated extraction sockets of various widths in four Labrador dogs. Five Osseotite implants per dog were placed in the mandible of four dogs. Two implants were inserted into sites with a 2.37 mm and two with a 1 mm gap present between the implants and bone around the coronal 6 mm of the implants in each dog. For one of each gap sizes, the gap was filled with Bio-Oss, and the other two with blood alone. A fifth implant was inserted without a gap and used as a control. Ground sections were prepared from biopsies taken at 4 months and histometric measurements of osseointegration and bone between the threads made for the coronal 6 mm. The medians for osseointegration ranged from 5.2 mm for control to 1-2.6 mm for the test modalities. There were significant differences for linear measurements of osseointegration (chi(2) 18.27; df 4; P=0.0011) and bone area within threads (chi(2) 23.4; df 4; P=0.0001) between test modalities. The results suggest that the wider the gap around the implants, the less favourable the histological outcome at short time intervals following treatment. They also infer that bone grafting with an organic bovine bone xenograft seems to lead to a more favourable histological outcome for wider circumferential defects but not for narrower defects.


Lineage-specific control of convergent differentiation by a Forkhead repressor.
During convergent differentiation, multiple developmental lineages produce a highly similar or identical cell type. However, few molecular players that drive convergent differentiation are known. Here, we show that the C. elegans Forkhead transcription factor UNC-130 is required in only one of three convergent lineages that produce the same glial cell type. UNC-130 acts transiently as a repressor in progenitors and newly-born terminal cells to allow the proper specification of cells related by lineage rather than by cell type or function. Specification defects correlate with UNC-130:DNA binding, and UNC-130 can be functionally replaced by its human homolog, the neural crest lineage determinant FoxD3. We propose that, in contrast to terminal selectors that activate cell type-specific transcriptional programs in terminally differentiating cells, UNC-130 acts early and specifically in one convergent lineage to produce a cell type that also arises from molecularly distinct progenitors in other lineages.


Surface Modification of Polymeric Biomaterials Using Recombinant Spider Silk Proteins.
The performance of biomaterials largely depends on the materials biocompatibility, which is directly related to unwanted side effects like foreign body responses and inflammation, and the potential of interaction of cells with its surface, for example, cell adhesion. In the distinct application of catheters, low or even no cell adhesion is eligible. To influence the properties of existing and commonly used biomaterials and to further increase their biocompatibility, a coating with a recombinantly produced spider silk protein as outer layer was applied on three selected catheter polymers (polyurethane, polytetrafluoroethylene, silicone) and evaluated based on cell adhesion. The tested cell types, HaCaT keratinocytes (epidermal cells), B50 neuronal cells, C2C12 myoblasts (muscle cells) and BALB/3T3 fibroblasts (connective tissue), exhibited low or no adhesion on the silk-coated materials. In combination with the lack of toxicity, the good biocompatibility, and the low body response, it could be shown that silk coatings have a high potential as a biomedical coating material, e.g., for catheters.


The role of cysteine proteinases and their inhibitors in the host-pathogen cross talk.
Proteinases and their inhibitors play essential functional roles in basic biological processes in both hosts and pathogens. Endo/lysosomal cathepsins participate in immune response in pathogen recognition and elimination. They are essential for both antigen processing and presentation (host adaptive immune response) and activation of endosomal Toll like receptors (innate immune response). Pathogens can produce proteases and also natural inhibitors to subvert the host immune response. Several pathogens are sensed through the intracellular pathogen recognition receptors, but only some of them use the host proteolytic system to escape into the cytosol. In this review, I provide an update on the most recent developments regarding the role of proteinases and their inhibitors in the initiation and regulation of immune responses.


Hospital Strategies for Reducing Emergency Department Crowding: A Mixed-Methods Study.
Emergency department (ED) crowding and patient boarding are associated with increased mortality and decreased patient satisfaction. This study uses a positive deviance methodology to identify strategies among high-performing, low-performing, and high-performance improving hospitals to reduce ED crowding. In this mixed-methods comparative case study, we purposively selected and recruited hospitals that were within the top and bottom 5% of Centers for Medicare & Medicaid Services case-mix-adjusted ED length of stay and boarding times for admitted patients for 2012. We also recruited hospitals that showed the highest performance improvement in metrics between 2012 and 2013. Interviews were conducted with 60 key leaders (physicians, nurses, quality improvement specialists, and administrators). We engaged 4 high-performing, 4 low-performing, and 4 high-performing improving hospitals, matched on hospital characteristics including geographic designation (urban versus rural), region, hospital occupancy, and ED volume. Across all hospitals, ED crowding was recognized as a hospitalwide issue. The strategies for addressing ED crowding varied widely. No specific interventions were associated with performance in length-of-stay metrics. The presence of 4 organizational domains was associated with hospital performance: executive leadership involvement, hospitalwide coordinated strategies, data-driven management, and performance accountability. There are organizational characteristics associated with ED decreased length of stay. Specific interventions targeted to reduce ED crowding were more likely to be successfully executed at hospitals with these characteristics. These organizational domains represent identifiable and actionable changes that other hospitals may incorporate to build awareness of ED crowding.


Upstairs downstairs: vertical integration of a pediatric service.
The combined effects of recent changes in health care financing and training priorities have compelled academic medical centers to develop innovative structures to maintain service commitments yet conform to health care marketplace demands. In 1992, a municipal hospital in the Bronx, New York, affiliated with a major academic medical center reorganized its pediatric service into a vertically integrated system of four interdependent practice teams that provided comprehensive care in the ambulatory as well as inpatient settings. One of the goals of the new system was to conserve inpatient resources. To describe the development of a new vertically integrated pediatric service at an inner-city municipal hospital and to test whether its adoption was associated with the use of fewer inpatient resources. A descriptive analysis of the rationale, goals, implementation strategies, and structure of the vertically integrated pediatric service combined with a before-and-after comparison of in-hospital resource consumption. A before-and-after comparison was conducted for two periods: the period before vertical integration, from January 1989 to December 1991, and the period after the adoption of vertical integration, from July 1992 to December 1994. Four measures of inpatient resource use were compared after adjustment for case mix index: mean certified length of stay per case, mean number of radiologic tests per case, mean number of ancillary tests per case, and mean number of laboratory tests per case. Difference-in-differences-in-differences estimators were used to control for institution-wide trends throughout the time period and regional trends in inpatient pediatric practice occurring across institutions. Results. In 1992, the Department of Pediatrics at the Albert Einstein College of Medicine reorganized the pediatric service at Jacobi Medical Center, one of its principal municipal hospital affiliates, into a vertically integrated pediatric service that combines ambulatory and inpatient activities into four interdependent practice teams composed of attending pediatricians, allied health professionals, house officers, and social workers. The new vertically integrated service was designed to improve continuity of care for patients, provide a model of practice for professional trainees, conserve scarce resources, and create a clinical research infrastructure. The vertically integrated pediatric service augmented the role of attending pediatricians, extended the use of allied health professionals from the ambulatory to the inpatient sites, established interdisciplinary practice teams that unified the care of pediatric patients and their families, and used less inpatient resources. Controlling for trends within the study institution and trends in the practice of pediatrics across institutions throughout the time period, the vertical integration was associated with a decline in 0.6 days per case, the use of 0.62 fewer radiologic tests per case, 0.21 fewer ancillary tests per case, and 2.68 fewer laboratory tests per case. We conclude that vertical integration of a pediatric service at an inner-city municipal hospital is achievable; conveys advantages of improved continuity of care, enhanced opportunities for primary care training, and increased participation of senior clinicians; and has the potential to conserve significant amounts of inpatient resources.


Neurovascular complications of marfan syndrome: a retrospective, hospital-based study.
Small case series have associated Marfan syndrome with cerebral and spinal ischemia or hemorrhage. However, there has been no investigation of the frequency and etiology of neurovascular disorders in a large series of Marfan patients. We conducted a retrospective, hospital-based study of all Marfan syndrome patients seen in an 8-year period. Records were reviewed in detail, and clinical characteristics of those with and without a neurovascular diagnosis compared. Of 513 patients, 18 (3.5%) had a neurovascular diagnosis, as follows: transient ischemic attack (11), cerebral infarction (2), spinal cord infarction (2), subdural hematoma (2), and spinal subarachnoid hemorrhage (1). A cardioembolic source was identified in 12 of 13 patients with cerebral ischemia, as follows: prosthetic heart valves (9), mitral valve prolapse (2), and atrial fibrillation (1). Chronic anticoagulant therapy was a likely cause in 2 of 3 patients with hemorrhagic events. Compared with other Marfan syndrome patients, those with neurovascular events were older (39.6 versus 31.7 years, P=0.04) and more likely to be in atrial fibrillation (22.2% versus 3.2%, P=<0.01), to have prosthetic heart valves (61.1% versus 7.7%, P=0.001), and to be taking anticoagulant therapy (72.2% versus 16.1%, P<0.001). Aortic disease, a putative factor in the etiology of neurovascular complications, was present in equal measure in Marfan patients with and without neurovascular complications (78% versus 65%, P=NS). Neurovascular complications of Marfan syndrome are rare during 8 years of follow-up, and generally are ischemic in nature. A high-risk cardiac source was identified in the majority. A significant association with vascular dissection was not established.


Conserved Functional Motifs and Homology Modeling to Predict Hidden Moonlighting Functional Sites.
Moonlighting functional centers within proteins can provide them with hitherto unrecognized functions. Here, we review how hidden moonlighting functional centers, which we define as binding sites that have catalytic activity or regulate protein function in a novel manner, can be identified using targeted bioinformatic searches. Functional motifs used in such searches include amino acid residues that are conserved across species and many of which have been assigned functional roles based on experimental evidence. Molecules that were identified in this manner seeking cyclic mononucleotide cyclases in plants are used as examples. The strength of this computational approach is enhanced when good homology models can be developed to test the functionality of the predicted centers in silico, which, in turn, increases confidence in the ability of the identified candidates to perform the predicted functions. Computational characterization of moonlighting functional centers is not diagnostic for catalysis but serves as a rapid screening method, and highlights testable targets from a potentially large pool of candidates for subsequent in vitro and in vivo experiments required to confirm the functionality of the predicted moonlighting centers.


Scaling analysis for the investigation of slip mechanisms in nanofluids.
The primary objective of this study is to investigate the effect of slip mechanisms in nanofluids through scaling analysis. The role of nanoparticle slip mechanisms in both water- and ethylene glycol-based nanofluids is analyzed by considering shape, size, concentration, and temperature of the nanoparticles. From the scaling analysis, it is found that all of the slip mechanisms are dominant in particles of cylindrical shape as compared to that of spherical and sheet particles. The magnitudes of slip mechanisms are found to be higher for particles of size between 10 and 80 nm. The Brownian force is found to dominate in smaller particles below 10 nm and also at smaller volume fraction. However, the drag force is found to dominate in smaller particles below 10 nm and at higher volume fraction. The effect of thermophoresis and Magnus forces is found to increase with the particle size and concentration. In terms of time scales, the Brownian and gravity forces act considerably over a longer duration than the other forces. For copper-water-based nanofluid, the effective contribution of slip mechanisms leads to a heat transfer augmentation which is approximately 36% over that of the base fluid. The drag and gravity forces tend to reduce the Nusselt number of the nanofluid while the other forces tend to enhance it.


Antimicrobial-resistant Shigella infections from Iran: an overlooked problem?
In this study, we wanted to assess the level of antimicrobial resistance, the presence of genes encoding resistance to cephalosporins and plasmid-mediated quinolone resistance (PMQR), and genetic relatedness among Shigella isolates obtained from Iranian patients. A total of 44 Shigella isolates were collected from Iranian patients admitted to Milad Hospital, Tehran, Iran, during 2008-10. Of these, 37 were serotyped and characterized by MIC determination. A subset of eight suspected extended-spectrum β-lactamase (ESBL) producers (six Shigella sonnei phase II and two Shigella flexneri type 1b) were examined for the presence of genes encoding cephalosporin resistance. The presence of PMQR was assessed in one S. flexneri isolate exhibiting low-level resistance to ciprofloxacin and susceptibility to nalidixic acid. PFGE was performed on 25 S. sonnei phase II isolates. Of the isolates, 25 (68%) were S. sonnei phase II, with 5 (14%) S. flexneri, 5 (14%) Shigella dysenteriae type 2, and 2 (5%) Shigella boydii type 2. Resistance to at least threeclasses of antimicrobials was detected in all species. The presence of bla(CTX-M-15) and the AmpC β-lactamase producer bla(CMY-2) was confirmed in five and one S. sonnei phase II isolates, respectively. One of the two S. flexneri type 1b that contained bla(CTX-M-15) also harboured a qnrS1 gene. PFGE identified sevenPFGE profiles; the main cluster included 15 of the strains, suggesting low genetic diversity between isolates or the presence of an endemic clone in Iran. This is the first known description of ESBL-producing and AmpC β-lactamase-producing Shigella and of PMQR Shigella in Iran. The emergence of CTX-15, CMY-2 and qnrS1 genes may compromise the treatment of shigellosis. Strategies to minimize the spread of ESBL-producing and AmpC-β-lactamase-producing Shigella should be implemented.


Whole-genome sequencing of the efficient industrial fuel-ethanol fermentative Saccharomyces cerevisiae strain CAT-1.
The Saccharomyces cerevisiae strains widely used for industrial fuel-ethanol production have been developed by selection, but their underlying beneficial genetic polymorphisms remain unknown. Here, we report the draft whole-genome sequence of the S. cerevisiae strain CAT-1, which is a dominant fuel-ethanol fermentative strain from the sugarcane industry in Brazil. Our results indicate that strain CAT-1 is a highly heterozygous diploid yeast strain, and the ~12-Mb genome of CAT-1, when compared with the reference S228c genome, contains ~36,000 homozygous and ~30,000 heterozygous single nucleotide polymorphisms, exhibiting an uneven distribution among chromosomes due to large genomic regions of loss of heterozygosity (LOH). In total, 58 % of the 6,652 predicted protein-coding genes of the CAT-1 genome constitute different alleles when compared with the genes present in the reference S288c genome. The CAT-1 genome contains a reduced number of transposable elements, as well as several gene deletions and duplications, especially at telomeric regions, some correlated with several of the physiological characteristics of this industrial fuel-ethanol strain. Phylogenetic analyses revealed that some genes were likely associated with traits important for bioethanol production. Identifying and characterizing the allelic variations controlling traits relevant to industrial fermentation should provide the basis for a forward genetics approach for developing better fermenting yeast strains.


Is foraging innovation lost following colonization of a less variable environment? A case study in surface- vs. cave-dwelling Asellus aquaticus.
Behavioral innovation is a key process for successful colonization of new habitat types. However, it is costly due to the necessary cognitive and neural demands and typically connected to ecological generalism. Therefore, loss of behavioral innovativeness is predicted following colonization of new, simple, and invariable environments. We tested this prediction by studying foraging innovativeness in the freshwater isopod Asellus aquaticus. We sampled its populations along the route of colonizing a thermokarstic water-filled cave (simple, stable habitat with only bacterial mats as food) from surface habitats (variable environment, wide variety of food). The studied cave population separated from the surface populations at least 60,000 years ago. Animals were tested both with familiar and novel food types (cave food: bacterial mats; surface food: decaying leaves). Irrespective of food type, cave individuals were more likely to feed than surface individuals. Further, animals from all populations fed longer on leaves than on bacteria, even though leaves were novel for the cave animals. Our results support that cave A. aquaticus did not lose the ability to use the ancestral (surface) food type after adapting to a simple, stable, and highly specialized habitat.


openEHR Based Systems and the General Data Protection Regulation (GDPR).
The concerns about privacy and personal data protection resulted in reforms of the existing legislation in European Union (EU). The General Data Protection Regulation (GDPR) aims to reform the existing measures on the topic of personal data protection of the European Union citizens, with a strong input on the rights and freedoms of people and in the establishment of rules for the processing of personal data. OpenEHR is a standard that embodies many principles of interoperable and secure software for electronic health records. This work aims to understand to what extent the openEHR standard can be considered a solution for the requirements needed by GDPR. A list of requirements for a Hospital Information Systems (HIS) compliant with GDPR and an identification of openEHR specifications was made. The requirements were categorized and compared with the specifications. The requirements identified for the systems were matched with the openEHR specifications, which result in 16 requirements matched with openEHR. All the specifications identified matched at least one requirement. OpenEHR is a solution for the development of HIS that reinforce privacy and personal data protection, ensuring that they are contemplated in the system development. The institutions can secure that their Eletronic Health Record are compliant with GDPR while safeguarding the medical data quality and, as a result, the healthcare delivery.


Heterogeneity in topographic control on velocities of Western Himalayan glaciers.
Studies of the seasonal and annual patterns of glacier velocities improve our understanding of the ice volume, topography, responses to climate change, and surge events of glaciers. Such studies are especially relevant and equally rare for the Himalayan glaciers, which supply many rivers that sustain some of the most heavily populated mountainous regions in the world. In particular, the control of the hypsometric distribution of geomorphometric parameters, such as slope, aspect, and curvature, on the dynamics of Himalayan glaciers have never been studied so far, at the river basin scale. Here, we present the degree to which topographic and hypsometric parameters affect the seasonal and annual average flow velocities of 112 glaciers in the Baspa River basin in the Western Indian Himalaya by analysing Global Land Ice Velocity Extraction from Landsat 8 (GoLIVE) datasets for the years 2013-2017. We observe, (i) significant heterogeneity in topographic controls on the velocities of these glaciers, (ii) elevation and the seasons play important roles in regulating the degree to which morphometric parameters (slope, aspect, and curvature) affect these velocities, (iii) a possible polythermal regime promoting both sliding and deformational forms of motion in a majority of these glaciers, and (iv) a detailed analysis of complex topographic controls within various elevation zones using a novel hypso-morphometric approach. These findings can help us to better model the dynamics of Himalayan glaciers and their responses to the future climatic scenarios. The inferences also suggest the need to incorporate dynamic topography in glacio-hydrological models in the wake of constant glacial evolutions.


Integration of VDR genome wide binding and GWAS genetic variation data reveals co-occurrence of VDR and NF-κB binding that is linked to immune phenotypes.
The nuclear hormone receptor superfamily acts as a genomic sensor of diverse signals. Their actions are often intertwined with other transcription factors. Nuclear hormone receptors are targets for many therapeutic drugs, and include the vitamin D receptor (VDR). VDR signaling is pleotropic, being implicated in calcaemic function, antibacterial actions, growth control, immunomodulation and anti-cancer actions. Specifically, we hypothesized that the biologically significant relationships between the VDR transcriptome and phenotype-associated biology could be discovered by integrating the known VDR transcription factor binding sites and all published trait- and disease-associated SNPs. By integrating VDR genome-wide binding data (ChIP-seq) with the National Human Genome Research Institute (NHGRI) GWAS catalog of SNPs we would see where and which target gene interactions and pathways are impacted by inherited genetic variation in VDR binding sites, indicating which of VDR's multiple functions are most biologically significant. To examine how genetic variation impacts VDR function we overlapped 23,409 VDR genomic binding peaks from six VDR ChIP-seq datasets with 191,482 SNPs, derived from GWAS-significant SNPs (Lead SNPs) and their correlated variants (r 2 > 0.8) from HapMap3 and the 1000 genomes project. In total, 574 SNPs (71 Lead and 503 SNPs in linkage disequilibrium with Lead SNPs) were present at VDR binding loci and associated with 211 phenotypes. For each phenotype a hypergeometric test was used to determine if SNPs were enriched at VDR binding sites. Bonferroni correction for multiple testing across the 211 phenotypes yielded 42 SNPs that were either disease- or phenotype-associated with seven predominately immune related including self-reported allergy; esophageal cancer was the only cancer phenotype. Motif analyses revealed that only two of these 42 SNPs reside within a canonical VDR binding site (DR3 motif), and that 1/3 of the 42 SNPs significantly impacted binding and gene regulation by other transcription factors, including NF-κB. This suggests a plausible link for the potential cross-talk between VDR and NF-κB. These analyses showed that VDR peaks are enriched for SNPs associated with immune phenotypes suggesting that VDR immunomodulatory functions are amongst its most important actions. The enrichment of genetic variation in non-DR3 motifs suggests a significant role for the VDR to bind in multimeric complexes containing other transcription factors that are the primary DNA binding component. Our work provides a framework for the combination of ChIP-seq and GWAS findings to provide insight into the underlying phenotype-associated biology of a given transcription factor.


Interventions for noisy breathing in patients near to death.
Noisy breathing (death rattle) occurs in 23 to 92% of people who are dying. The cause of death rattle remains unproven but is presumed to be due to an accumulation of secretions in the airways. It is therefore managed physically (repositioning and clearing the upper airways of fluid with a mechanical sucker) or pharmacologically (with anticholinergic drugs). To describe and assess the evidence for the effectiveness of interventions used to treat death rattle in patients close to death. Randomised controlled trials (RCTs), before and after studies and interrupted time series (ITS) studies in adults and children with death rattle were sought by MEDLINE (1966 to 2007), EMBASE (1980 to 2007), CINAHL (1980 to 2007), the Cochrane Pain, Palliative and Supportive Care Trials Register and the Cochrane Central Register of Controlled Trials. In addition, the reference lists of all relevant trials and reports were checked and investigators who are known to be researching this area were contacted for unpublished data or knowledge of the grey literature. RCTs, controlled before and after studies and ITS reporting the outcome of pharmacological and non-pharmacological interventions for treating death rattle. Data was extracted by two independent review authors and trials were quality scored. There was insufficient data to carry out an analysis. Thirty studies were identified, of which only one study met the inclusion criteria. This small study was a randomised placebo-controlled trial of the use of hyoscine hydrobromide in patients with death rattle. Hyoscine hydrobromide tended to reduce death rattle compared to placebo but this was not significant. A larger randomised study, comparing atropine, hyoscine butylbromide and scopolamine, is in progress. There is currently no evidence to show that any intervention, be it pharmacological or non-pharmacological, is superior to placebo in the treatment of death rattle. We acknowledge that in the face of heightened emotions when death is imminent, it is difficult for staff not to intervene. It is therefore likely that the current therapeutic options will continue to be used. However, patients need to be closely monitored for lack of therapeutic benefit and adverse effects while relatives need time, explanation and reassurance to relieve their fears and concerns. There is a need for more well-designed multi-centre studies with objective outcome measures and the ability to recruit sufficient numbers.


Incidence and Clinical Significance of Heterotopic Ossification After Partial Ray Resection.
Heterotopic bone growth is a common finding after partial foot amputation that can predispose to recurrent wounds, osteomyelitis, and reamputation. Heterotopic ossification is the formation of excessive mature lamellar bone in the soft tissues adjacent to bone that is exacerbated by trauma or surgical intervention. The relevance of heterotopic ossification is dependent on its anatomic location. Its occurrence as a sequela of partial foot amputation can lead to prominence on the plantar aspect of the foot that can predispose the patient to recurrent neuropathic ulceration or preclude appropriate wound healing. Reulceration puts the high-risk patient who has already undergone local amputation at greater risk of recurrent infection and further amputation. The present study aimed to assess the incidence and risk factors for heterotopic ossification to further evaluate its role in partial foot amputation. A retrospective analysis of 72 consecutive patients who had undergone partial metatarsal resection was performed, with 90% of the cohort having peripheral neuropathy and 88% diabetes mellitus. Our findings revealed a heterotopic ossification incidence of 75% diagnosed radiographically. The initial onset of heterotopic ossification was not appreciated >10 weeks postoperatively. Ten patients (18.5%) exhibited heterotopic ossification-associated ulceration. The incidence of heterotopic ossification was 30% less in patients with peripheral vascular disease. These results indicate that heterotopic ossification is a common sequela of partial ray resection in an already high-risk patient population. The perioperative use of pharmacologic or radiation prophylaxis in an attempt to minimize amputation-related morbidity should be considered.


The NAADP receptor: new receptors or new regulation?
Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent calcium mobilizing messenger yet discovered. Its action has now been reported in a large number of cell types from a diverse array of organisms, and in some cases linked to the transduction of specific cellular stimuli. However, what is controversial is the nature of its target calcium release channel, as well as the subcellular localization of its receptor. Some have proposed that NAADP activates a novel calcium release channel distinct from the two major classes of channels known, the inositol trisphosphate receptors and ryanodine receptors. However, others have suggested that it acts in a novel way to regulate a known calcium release channel, the ryanodine receptor.


Uniform ripening encodes a Golden 2-like transcription factor regulating tomato fruit chloroplast development.
Modern tomato (Solanum lycopersicum) varieties are bred for uniform ripening (u) light green fruit phenotypes to facilitate harvests of evenly ripened fruit. U encodes a Golden 2-like (GLK) transcription factor, SlGLK2, which determines chlorophyll accumulation and distribution in developing fruit. In tomato, two GLKs--SlGLK1 and SlGLK2--are expressed in leaves, but only SlGLK2 is expressed in fruit. Expressing GLKs increased the chlorophyll content of fruit, whereas SlGLK2 suppression recapitulated the u mutant phenotype. GLK overexpression enhanced fruit photosynthesis gene expression and chloroplast development, leading to elevated carbohydrates and carotenoids in ripe fruit. SlGLK2 influences photosynthesis in developing fruit, contributing to mature fruit characteristics and suggesting that selection of u inadvertently compromised ripe fruit quality in exchange for desirable production traits.


Analysis of interleukin-20 receptor complexes in trabecular meshwork cells and effects of cytokine signaling in anterior segment perfusion culture.
Inflammatory responses may be involved in the glaucomatous process. Our previous studies mapped a T104M mutation in interleukin-20 receptor beta (IL-20RB) in a family with primary open angle glaucoma (POAG). IL-20RB can heterodimerize with IL-20RA to propagate signals from IL-20 family cytokines, IL-19, IL-20, and IL-24 (the type I receptor complex), or it can heterodimerize with IL-22RA to propagate signals from IL-20 and IL-24 (type II receptor complex). In this study, we investigated IL-20 heterodimeric receptor complexes in the trabecular meshwork (TM) compared to dermal fibroblast cell cultures, and examined the phosphorylation of signal transducer and activator of transcription (STAT)-1, -3, and -5 following exposure to IL-20 family cytokines. Additionally, we determined the effects of IL-20 family cytokines on outflow rates in anterior segment perfusion culture, an in vitro model of intraocular pressure (IOP) regulation. Primary human TM (HTM) cells were grown from dissected TM tissue, and IL-20 receptor expression was investigated with PCR. A Duolink assay was performed to investigate in situ IL-20 receptor protein interactions in HTM or dermal fibroblasts, and Imaris software was used to quantitate the association of the heterodimeric complexes. Phosphorylation of STAT-1, -3, and -5 were evaluated in HTM or dermal fibroblasts using Western immunoblotting after exposure to IL-10, IL-19, IL-20, IL-22, or IL-24. Anterior segment perfusion culture was performed in human cadaver and porcine eyes treated with IL-20, IL-19, or IL-24. All of the IL-20 receptors, IL-20RA, IL-20RB, and IL-22RA1 were expressed in HTM cells. Two isoforms of IL-20RA were expressed: The V1 variant, which is the longest, is the predominant isoform, while the V3 isoform, which lacks exon 3, was also expressed. The Duolink assay demonstrated that the type I (IL-20RA-IL-20RB) and type II (IL-22RA1-IL-20RB) receptors were expressed in HTM cells and dermal fibroblasts. However, in the HTM cells, the type I receptor was present at significantly higher levels, while the type II receptor was preferentially used in the dermal fibroblasts. The HTM cells and the dermal fibroblasts predominantly phosphorylate the Ser727 site in STAT-3. The dermal fibroblasts had higher induction of phosphorylated STAT-1 compared to the HTM cells, while neither cell type had phosphorylated STAT-5 in the cell lysates. The outflow rates in the human anterior segment cultures were increased 2.3-fold by IL-20. However, IL-19 and IL-24 showed differential responses. For IL-19 and IL-24, 50% of the eyes responded with a 1.7- or 1.5-fold increase, respectively, while the other half did not respond. Similarly, perfused porcine anterior segments showed "responders" and "non-responders": IL-20 responders (2.3-fold increase in outflow, n=12) and non-responders (n=11); IL-19 responders (2.1-fold increase, n=7) and non-responders (n=5); and IL-24 responders (1.8-fold increase, n=12) and non-responders (n=5). Type I and type II IL-20 receptor complexes are expressed in human TM cells with predominant expression of the type I receptor (IL-20RA and IL-20RB), which propagates signals from all three IL-20 family cytokines. However, there was a variable response in the outflow rates following perfusion of cytokines in two different species. This may explain why some people are more susceptible to developing elevated IOP in response to inflammation.


The help for people with money, employment or housing problems (HOPE) intervention: pilot randomised trial with mixed methods feasibility research.
Job loss, austerity measures, financial difficulties and house repossession contribute to the risk of self-harm and suicide during recessions. Navigating the benefits system and accessing sources of welfare and debt advice is a difficult experience for vulnerable people, further contributing to their distress. Whilst there is some evidence that advice-type interventions can lead to financial gain, there is mixed evidence for their effectiveness in improving mental health in those experiencing financial difficulties. There have been no interventions targeting those who have self-harmed due to economic hardship. Our aim was to determine the feasibility and acceptability of a brief psychosocial intervention (the 'HOPE' service) for people presenting to hospital emergency departments (ED) following self-harm or in acute distress because of financial, employment or welfare (benefit) difficulties. Nineteen people consented to random allocation to the intervention or control arm on a 2:1 basis. Participants randomised to the intervention arm (n = 13) received up to six sessions of 1:1 support provided by community support staff trained in Motivational Interviewing (MI). Control participants (n = 6) received a one-off session signposting them to relevant support organisations. Fourteen participants were followed up after 3 months. Participants and mental health workers took part in qualitative interviews. The acceptability of outcome measures including the PHQ-9, GAD-7, repeat self-harm, EQ5D-5 L and questions about debt, employment and welfare benefits were explored. Interviews indicated the main benefits of the service as the resolution of specific financial problems and receiving support when participants were feeling most vulnerable. Randomisation was acceptable to most participants although not always fully understood and control participants could be disappointed. Recruitment was slow (1-2 per month). The outcome measures were acceptable and appeared sensitive to change. The HOPE intervention is feasible and acceptable. There was evidence of need and it is a relatively inexpensive intervention. Refining aspects of the intervention would be straightforward. A full-scale RCT would be feasible, if broadened eligibility criteria led to increased recruitment and improvements were made to staff training and support. ISRCTN58531248.


A model for human ventricular tissue.
The experimental and clinical possibilities for studying cardiac arrhythmias in human ventricular myocardium are very limited. Therefore, the use of alternative methods such as computer simulations is of great importance. In this article we introduce a mathematical model of the action potential of human ventricular cells that, while including a high level of electrophysiological detail, is computationally cost-effective enough to be applied in large-scale spatial simulations for the study of reentrant arrhythmias. The model is based on recent experimental data on most of the major ionic currents: the fast sodium, L-type calcium, transient outward, rapid and slow delayed rectifier, and inward rectifier currents. The model includes a basic calcium dynamics, allowing for the realistic modeling of calcium transients, calcium current inactivation, and the contraction staircase. We are able to reproduce human epicardial, endocardial, and M cell action potentials and show that differences can be explained by differences in the transient outward and slow delayed rectifier currents. Our model reproduces the experimentally observed data on action potential duration restitution, which is an important characteristic for reentrant arrhythmias. The conduction velocity restitution of our model is broader than in other models and agrees better with available data. Finally, we model the dynamics of spiral wave rotation in a two-dimensional sheet of human ventricular tissue and show that the spiral wave follows a complex meandering pattern and has a period of 265 ms. We conclude that the proposed model reproduces a variety of electrophysiological behaviors and provides a basis for studies of reentrant arrhythmias in human ventricular tissue.


Aligning and Assessing Core Attributes of Spiritual Fitness for Optimizing Human Performance.
The United States Special Operations Command (SOCOM)'s Preservation of the Force and Family Program (POTFF) identifies spiritual performance (SP) as a key pillar for holistically caring for and optimizing the performance of all Special Operations Forces (SOF) and their families. Enhancing SP is key to sustaining core spiritual beliefs, values, awareness, relationships and experiences. The SOCOM Spiritual Fitness Scale (SSFS) enables religious support teams in SOF communities and beyond to reliably measure SP according to POTFF's definition of SP and the Chairman of the Joint Chiefs of Staff Instruction (CJCSI) on Spiritual Fitness (SF). The three subscales of the SSFS relate to core attributes of SP/SF, which were identified through factor analysis during iterations of the tool's development. Directly aligning SP/SF programs with the core attributes of SSFS will allow chaplains to support both theists and nontheists and to retain certain traditional chaplain activities which no longer have universal connection to religious ministry in the public discourse. Chaplains are also empowered to immediately begin conducting relevant and spiritual assessments. We will illustrate how a chaplain can align SP initiatives with the three core attributes of SP/SF and leverage the SSFS to assess baseline unit needs, conceive and develop evidence-based initiatives, conduct rolling program assessments, and articulate program efficacy to key leaders and collaborators.


Stepwise crystallographic visualization of dynamic guest binding in a nanoporous framework.
Binding sites are at the heart of all host-guest systems, whether biological or chemical. When considering binding sites that form covalent bonds with the guest, we generally envision a single, highly specific binding motif. Through single-crystal X-ray crystallography, the dynamic binding of a guest that displays a variety of covalent binding motifs in a single site of adsorption is directly observed for the first time. The stepwise crystallographic visualization of the incorporation of I2 within a porous MOF is presented, wherein the preferred binding motifs throughout the uptake process are identified. The guest I2 molecules initially bind with terminal iodide atoms of the framework to form [I4]2- units. However, as the adsorption progresses, the I2 molecules are observed to form less energetically favorable I3- groups with the same framework iodide atoms, thereby allowing for more guest molecules to be chemisorbed. At near saturation, even more binding motifs are observed in the same pores, including both physisorbed and chemisorbed guest molecules. Herein, we present the successful identification of a unique set of host-guest interactions which will drive the improvement of high capacity iodine capture materials.


Spatial-frequency tuning as a function of temporal frequency and stimulus motion.
Spatial-frequency tuning at two different spatial frequencies was determined by measuring the detectability of a signal grating that was made difficult to see by low- or high-pass visual noise. The signals were vertical sinusoidal gratings of different spatial frequencies. The detectability of the signal was measured in two-alternative forced-choice tasks with different temporal envelopes: (1) a slowly changing raised-cosine (Hanning) window, (2) a rectangularly gated 2-Hz counterphase flickering envelope, and (3) a rectangularly gated 10-Hz counterphase flickering envelope. Additional measurements were made using drifting stimuli with the signal and noise drifting in the same or in opposite directions. The temporal envelopes were chosen because they have different effects on the contrast-sensitivity function and it was desired to know how temporal factors affect the spatial-frequency tuning of the relatively narrowly tuned channels thought to underlie contrast sensitivity. The results show that, for counterphase flickering stimuli, spatial-frequency tuning does not depend on temporal envelopes applied identically to the signal and to the masking noise. A similar picture emerges at slow (2.7-deg/sec) but not at fast (10.9-deg/sec) drift rates.


Temperature regulation of the Tetrahymena mimbres glycosylphosphatidylinositol-anchored protein lipid composition.
By incubating Tetrahymena mimbres cells with [3H]myristic acid, [3H]ethanolamine, [3H]inositol, and [3H]mannose, proteins having apparent molecular masses of 23 and 63 kDa were identified as the cells' principal glycosylphosphatidylinositol (GPI)-anchored proteins. These proteins accounted for as much as 2-5% of the whole cell proteins, with the higher levels being recovered from non-growing cells. The two proteins, gpi 23 and gpi 63, were purified to near homogeneity through Triton X-114/water partitioning followed by preparative SDS/PAGE. The lipid components of the GPI anchors were determined by chemical and enzymic hydrolysis. Both proteins were anchored by ceramides, with the principal long-chain base being C18 sphinganine containing an O-methyl group at the 3 position. O-Methylation was shown not to be an artifact of hydrolysis. When T. mimbres was cultured at 15 degrees C, the ceramide fatty acid component of the GPI anchors was principally palmitic acid (75% in gpi 23 and 76% in gpi 63). GPI anchors from 28 degrees C-grown cells contained mainly stearic acid (79% in gpi 23 and 70% in gpi 63). Temperature change had little effect on the long-chain-base composition. The direction of temperature-induced lipid change in the protein-bound anchors was the same as found in the inositolphosphorylceramide putative precursors of the protein anchors described in the accompanying paper [Hung, Ko and Thompson (1995) Biochem. J. 307, 107-113], but the detailed fatty acid compositions of the precursors and the protein-bound lipids were quite different. The precise metabolic regulation of anchor lipid chain length supports the concept that composition of the lipid anchor is important in the function and/or metabolism of the anchored protein.


Testosterone as potential effective therapy in treatment of obesity in men with testosterone deficiency: a review.
Obesity negatively affects human health. Limiting food intake, while producing some weight loss, results in reduction of lean body mass. Combined with moderate exercise it produces significant weight loss, maintains lean body mass and improves insulin sensitivity, but appears difficult to adhere to. Bariatric surgery is clinically effective for severely obese individuals compared with non-surgical interventions, but has limitations. Clinical and pre-clinical studies have implicated a role for testosterone (T) in the patho-physiology of obesity. A literature search in PubMed on the role of T in counteracting obesity and its complications. Obesity per se impairs testicular T biosynthesis. Furthermore, lower-than-normal T levels increase accumulation of fat depots, particularly abdominal (visceral) fat. This fat distribution is associated with development of metabolic syndrome (MetS) and its sequels, namely type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). T treatment reverses fat accumulation with significant improvement in lean body mass, insulin sensitivity and biochemical profiles of cardiovascular risk. The contribution of T to combating obesity in hypogonadal men remains largely unknown to medical professionals managing patients with obesity and metabolic syndrome. Many physicians associate T treatment in men with risks for prostate malignancy and CVD. These beliefs are not supported by recent insights. While overall treatment of obesity is unsuccessful, T treatment of hypogonadal men may be effective, also because it improves mood, energy, reduces fatigue and may motivate men to adhere to diet and exercise regimens designed to combat obesity.


Capsule endoscopy for small-intestinal disorders: Current status.
Small-bowel capsule endoscopy (SBCE) is used widely because of its non-invasive and patient-friendly nature. SBCE can visualize entire small-intestinal mucosa and facilitate detection of small-intestinal abnormalities. In this review article, we focus on the current status of SBCE. Several platforms for SBCE are available worldwide. Third-generation SBCE (PillCam® SB3) has a high-resolution camera equipped with an adaptive frame rate system. Several software modes have been developed to reduce the reading time for capsule endoscopy and to minimize the possibility of missing lesions. The main complication of SBCE is capsule retention. Thus, the main contraindication for SBCE is known or suspected gastrointestinal obstruction unless intestinal patency is proven. Possible indications for SBCE are obscure gastrointestinal bleeding, Crohn's disease, small-intestinal polyps and tumors, and celiac disease. Colon capsule endoscopy (CCE) can observe inflamed colonic mucosa non-invasively, and allows for the continuous and non-invasive observation of the entire intestinal tract (pan-endoscopy). Recently, application of CCE as pan-enteric endoscopy for inflammatory bowel diseases (including Crohn's disease) has been reported. In the near future, reading for CE will be assisted by artificial intelligence, and reading CE videos for long periods will not be required.


Quality of life in inflammatory neuropathies: the IN-QoL.
No consensus exists which quality of life (QoL) measure should be used in patients with inflammatory neuropathies. Moreover, most QoL measures are ordinal-based scales with their known deficiencies. To establish a new disease-specific interval-based QoL questionnaire in inflammatory neuropathies (IN-QoL) using the Rasch model and evaluate its scientific properties (validity, reliability and responsiveness). 264 patients with inflammatory neuropathies completed six commonly used QoL questionnaires. The obtained data were stacked and subjected to Rasch analysis. Responsiveness was determined by using the concept of minimum clinically important differences related to varying individually obtained SEs (responsiveness definition: MCID-SE≥1.96 after 1-year follow-up compared with baseline). The IN-QoL fulfilled all Rasch's model requirements with high internal reliability values (patient separation index of 0.94), except being multidimensional. Additional factor analysis resulted in two (functional and mental) subsets that were unidimensional on their own. The IN-QoL showed good correlation with the EuroQol-health quality visual analogue scale (EQ-VAS) (Spearman's rho 0.72). It demonstrated acceptable responsiveness in patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), as did the EQ-VAS. In patients with monoclonal gammopathy-related neuropathy and multifocal motor neuropathy, hardly any changes were seen over time. The IN-QoL questionnaire fulfils modern clinimetric requirements and correlates strongly with a patient's self-assessment of their own quality of health, while also showing responsiveness in patients with GBS and CIDP. We propose using the IN-QoL and the EQ-VAS for assessing the QoL of patients with inflammatory neuropathies in future studies.


Biophysical mechanisms of the neutralization of endotoxins by lipopolyamines.
Endotoxins (lipopolysaccharides, LPS) are one of the strongest immunostimulators in nature, responsible for beneficial effects at low, and pathophysiological effects at high concentrations, the latter frequently leading to sepsis and septic shock associated with high mortality in critical care settings. There are no drugs specifically targeting the pathophysiology of sepsis, and new therapeutic agents are therefore urgently needed. The lipopolyamines are a novel class of small molecules designed to sequester and neutralize LPS. To understand the mechanisms underlying the binding and neutralization of LPS toxicity, we have performed detailed biophysical analyses of the interactions of LPS with candidate lipopolyamines which differ in their potencies of LPS neutralization. We examined gel-to-liquid crystalline phase behavior of LPS and of its supramolecular aggregate structures in the absence and presence of lipopolyamines, the ability of such compounds to incorporate into different membrane systems, and the thermodynamics of the LPS:lipopolyamine binding. We have found that the mechanisms which govern the inactivation process of LPS obey similar rules as found for other active endotoxin neutralizers such as certain antimicrobial peptides.


BMA-Mod: A Bayesian model averaging strategy for determining dose-response relationships in the presence of model uncertainty.
Successful pharmaceutical drug development requires finding correct doses. The issues that conventional dose-response analyses consider, namely whether responses are related to doses, which doses have responses differing from a control dose response, the functional form of a dose-response relationship, and the dose(s) to carry forward, do not need to be addressed simultaneously. Determining if a dose-response relationship exists, regardless of its functional form, and then identifying a range of doses to study further may be a more efficient strategy. This article describes a novel estimation-focused Bayesian approach (BMA-Mod) for carrying out the analyses when the actual dose-response function is unknown. Realizations from Bayesian analyses of linear, generalized linear, and nonlinear regression models that may include random effects and covariates other than dose are optimally combined to produce distributions of important secondary quantities, including test-control differences, predictive distributions of possible outcomes from future trials, and ranges of doses corresponding to target outcomes. The objective is similar to the objective of the hypothesis-testing based MCP-Mod approach, but provides more model and distributional flexibility and does not require testing hypotheses or adjusting for multiple comparisons. A number of examples illustrate the application of the method.


Anchoring in Numeric Judgments of Visual Stimuli.
This article investigates effects of anchoring in age estimation and estimation of quantities, two tasks which to different extents are based on visual stimuli. The results are compared to anchoring in answers to classic general knowledge questions that rely on semantic knowledge. Cognitive load was manipulated to explore possible differences between domains. Effects of source credibility, manipulated by differing instructions regarding the selection of anchor values (no information regarding anchor selection, information that the anchors are randomly generated or information that the anchors are answers from an expert) on anchoring were also investigated. Effects of anchoring were large for all types of judgments but were not affected by cognitive load or by source credibility in either one of the researched domains. A main effect of cognitive load on quantity estimations and main effects of source credibility in the two visually based domains indicate that the manipulations were efficient. Implications for theoretical explanations of anchoring are discussed. In particular, because anchoring did not interact with cognitive load, the results imply that the process behind anchoring in visual tasks is predominantly automatic and unconscious.


Peptide nanovesicles formed by the self-assembly of branched amphiphilic peptides.
Peptide-based packaging systems show great potential as safer drug delivery systems. They overcome problems associated with lipid-based or viral delivery systems, vis-a-vis stability, specificity, inflammation, antigenicity, and tune-ability. Here, we describe a set of 15 & 23-residue branched, amphiphilic peptides that mimic phosphoglycerides in molecular architecture. These peptides undergo supramolecular self-assembly and form solvent-filled, bilayer delimited spheres with 50-200 nm diameters as confirmed by TEM, STEM and DLS. Whereas weak hydrophobic forces drive and sustain lipid bilayer assemblies, these all-peptide structures are stabilized potentially by both hydrophobic interactions and hydrogen bonds and remain intact at low micromolar concentrations and higher temperatures. A linear peptide lacking the branch point showed no self-assembly properties. We have observed that these peptide vesicles can trap fluorescent dye molecules within their interior and are taken up by N/N 1003A rabbit lens epithelial cells grown in culture. These assemblies are thus potential drug delivery systems that can overcome some of the key limitations of the current packaging systems.


Pregnancy-associated plasma protein A in obese children: relationship to markers and risk factors of atherosclerosis and members of the IGF system.
Pregnancy-associated plasma protein A (PAPPA) is a large placenta-derived glycoprotein, which serves as a protease of several IGF-binding proteins (IGFBPs). In non-pregnant adults, measurable PAPPA levels were detected and have been implicated in the pathophysiology of atherosclerotic plaques. However, data in children is lacking. To study the relationship between PAPPA, markers of atherosclerosis, and members of the IGF system in pediatric obesity. Eighty-two obese and 52 nonobese children and 1-year longitudinal follow-up study for obese cohort. Outpatient 1-year intervention program based on exercise, behavior, and nutrition therapy. Changes in PAPPA levels, carotid intima media thickness (IMT), weight, blood pressure, lipids, metabolic markers, and members of IGF system. Baseline PAPPA (PAPPA(BL)) serum levels did not differ between obese and lean subjects. PAPPA(BL) correlated significantly with IGF1, IGFBP1, and serum cholesterol. During the 1-year-program mean IMT decreased from 0.66 ± 0.01 to 0.63 ± 0.01 mm (P<0.05) and PAPPA from 1.83 ± 0.12 to 1.58 ± 0.11 μU/l (P<0.00). In linear regression analysis with IMT after intervention as dependent variable, PAPPA contributed significantly to the observed variance. The longitudinal change of PAPPA correlated significantly with the change of serum triglycerides. In this cohort of obese children, PAPPA serum levels correlated significantly with other cardiovascular risk factors. The lack of a direct correlation between PAPPA and IMT suggests that the described association of atherosclerotic plaques and increased PAPPA levels might reflect an indirect mechanism of PAPPA with cardiovascular risk factors such as serum lipids rather than a direct effect on the vasculature.


Why Racial Justice Matters in Radiation Oncology.
Recent events have reaffirmed that racism is a pervasive disease plaguing the United States and infiltrating the fabric of this nation. As health care professionals dedicated to understanding and alleviating disease, many radiation oncologists have failed to acknowledge how structural racism affects the health and well-being of the patients we aim to serve. The literature is full of descriptive statistics showing the higher incidence and mortality experienced by the Black population for health conditions ranging from infant mortality to infectious disease, including coronavirus disease 2019 (COVID-19). Acknowledgment that the root of health disparities experienced by Black people in this country are based in racism is essential to moving the nation and the field of radiation oncology forward. With this lens, a brief overview of structural and institutional racism shapes a discussion of what radiation oncologists and the organizations that represent them can do to address this scourge. As members of a technological field, we often harness the power of data to advance human health and approach challenging diseases with optimism that multidisciplinary effort can produce cure. A few principles to mitigate the longstanding issues of Black marginalization within the field have been recommended via the ATIP (Acknowledgment, Transparency, Intentionality, and rePresentation) and LEADS (Learn, Engage, Advocate, Defend, Support) approaches. However, additional introspection is encouraged. Just as individuals, practices, and organizations rallied to determine how best to address the issues related to the COVID-19 pandemic, the same investigational fervor must be applied to the issue of racism to combat this sinister and often deadly disease.


Cancer treatment effects on cognition and depression: The moderating role of physical activity.
Breast cancer survivors report significant cognitive impairments post treatment, particularly following chemotherapy. Depression may also occur post treatment and may partially mediate the effects of cancer treatment on cognition. Additionally, physical activity has been shown to mitigate treatment effects on cognition and depression. This study examined the role of depression in mediating the effects of cancer treatment on cognitive function (perceived cognitive impairment, PCI; perceived cognitive ability, PCA) in breast cancer survivors and explored the role of physical activity in moderating these effects. 317 breast cancer survivors were recruited via Army of Women. Participants were 40-75 years old and had stage 0 (in situ) to IIIc breast cancer and were less than 10 years post treatment. Participants completed a demographic and treatment questionnaire, as well as the International Physical Activity Questionnaire, Functional Assessment of Cancer Therapy-Cognitive Function, and Center for Epidemiologic Studies Depression Scale. Depressive symptoms significantly contributed to cognitive function in all models. Moderate and vigorous levels of physical activity moderated breast cancer treatment effects on depression and cognition. Chemotherapy, tamoxifen, and anastrozole all demonstrated negative effects on cognition. The results from this study support the importance of examining mediating factors in the effects of cancer treatment on cognition, particularly depression, following cancer treatment. Effects of treatment on cognition in breast cancer survivors are partially explained by changes in depressive symptoms, although chemotherapy may impact cognition independent of depression. Importantly, physical activity may reduce the risk of depression and cognitive impairment in breast cancer survivors.


[Bilateral agenesis of internal carotid arteries].
The authors present angiographic and computed tomographic demonstration of bilateral agenesis of internal carotid arteries. The patient was a seventy-six years old man who had been admitted to our hospital because of right hemisparesis and disorientation. In addition to the left chronic subdural hematoma, computed angiotomography showed the dilated basilar artery and dilated posterior communicating arteries. However, the bilateral internal carotid arteries were not recognized. Burr hole and irrigation were performed, then neurological deficits and symptoms were disappeared. Hematoma was 150 ml. Though axial transverse computed tomograms of base of skull demonstrated the absence of bilateral carotid canals. On aortography, the right common carotid artery and vertebral artery were supplied from the innominate artery and the left common carotid artery and vertebral artery were supplied from the left dilated subclavian artery. Bilateral retrograde brachial angiograms demonstrated the internal carotid circulation, which was supplied through bilateral dilated posterior communicating arteries. Basilar artery was also in a large caliber. Bilateral ophthalmic arteries were opacified from external carotid artery via the middle meningeal artery. Ten cases of bilateral agenesis of internal carotid arteries have been reported previously. The findings of angiograms and computed tomograms on the agenesis of bilateral internal carotid arteries were discussed. This anomaly is important on cerebral hemodynamics and embryology.


Elevated Aspergillus-specific antibody levels among HIV infected Ugandans with pulmonary tuberculosis.
The incidence of tuberculosis (TB) is high among human immunodeficiency virus (HIV) infected Ugandans. Recent evidence suggests that Chronic Pulmonary Aspergillosis and Aspergillus sensitisation might be responsible for significant mortality in patients treated for tuberculosis in Uganda. We retrieved and tested paired serum aliquots for 101 HIV-TB co-infected patients at the beginning and week 24 of TB treatment. We tested samples for Aspergillus-specific immunoglobulin G (IgG) and immunoglobulin E (IgE) using ImmunoCAP®; and Aspergillus-specific IgG and total serum IgE using Immulite® immunoassays. We compared antibody levels between baseline and week 24, relating them to selected baseline characteristics. 10% of the patients had elevated Aspergillus-specific IgE (Aspergillus sensitization) and Aspergillus-specific IgG antibodies were elevated in 9% of the patients at the end of TB treatment. There was a significant fall in the Aspergillus-specific IgG antibody levels between baseline and week 24 (P = 0.02). Patients with cluster of differentiation 4 (CD4) T-cell count <100 cells/μl and those who were not on anti-retroviral therapy at baseline had more elevated Aspergillus-specific IgG antibodies (P = 0.01, P = 0.03). The ImmunoCAP® Aspergillus-specific IgG antibody titres were higher at week 24 than baseline with more positives at week 24; even though the difference in means was small. However, this difference was statistically significant (P = 0.02). Pulmonary infiltrates were the commonest x-ray abnormality and only 5% of the patients had pulmonary cavities on chest x-ray at week 24. These results suggest that Aspergillus infection may complicate active pulmonary TB and further studies including fungal culture and thoracic imaging may now be indicated to measure the prevalence of pulmonary aspergillosis complicating tuberculosis. The SOUTH trial was registered prospectively. ClinicalTrials.gov Identifier: NCT01782950 ; Registration date: 4th February 2013; Last verified: 13th April 2015.


Functional and biochemical evidence for G-protein-gated inwardly rectifying K+ (GIRK) channels composed of GIRK2 and GIRK3.
G-protein-gated inwardly rectifying K(+) (GIRK) channels are widely expressed in the brain and are activated by at least eight different neurotransmitters. As K(+) channels, they drive the transmembrane potential toward E(K) when open and thus dampen neuronal excitability. There are four mammalian GIRK subunits (GIRK1-4 or Kir 3.1-4), with GIRK1 being the most unique of the four by possessing a long carboxyl-terminal tail. Early studies suggested that GIRK1 was an integral component of native GIRK channels. However, more recent data indicate that native channels can be either homo- or heterotetrameric complexes composed of several GIRK subunit combinations. The functional implications of subunit composition are poorly understood at present. The purpose of this study was to examine the functional and biochemical properties of GIRK channels formed by the co-assembly of GIRK2 and GIRK3, the most abundant GIRK subunits found in the mammalian brain. To examine the properties of a channel composed of these two subunits, we co-transfected GIRK2 and GIRK3 in CHO-K1 cells and assayed the cells for channel activity by patch clamp. The most significant difference between the putative GIRK2/GIRK3 heteromultimeric channel and GIRK1/GIRKx channels at the single channel level was an approximately 5-fold lower sensitivity to activation by Gbetagamma. Complexes containing only GIRK2 and GIRK3 could be immunoprecipitated from transfected cells and could be purified from native brain tissue. These data indicate that functional GIRK channels composed of GIRK2 and GIRK3 subunits exist in brain.


Factors Leading to Transmission Risk of Acinetobacter baumannii.
To identify patient and healthcare worker factors associated with transmission risk of Acinetobacter baumannii during patient care. Prospective cohort study. ICUs at a tertiary care medical center. Adult ICU patients known to be infected or colonized with A. baumannii. Cultures of skin, respiratory tract, and the perianal area were obtained from participants and evaluated for the presence of A. baumannii. Healthcare worker-patient interactions were observed (up to five interactions/patient) and activities were recorded. Healthcare worker hands/gloves were sampled at room exit (prior to hand hygiene or glove removal) and then evaluated for the presence of A. baumannii. Two hundred fifty-four healthcare worker-patient interactions were observed among 52 patients; A. baumannii was identified from healthcare worker hands or gloves in 77 (30%) interactions. In multivariate analysis, multidrug-resistant A. baumannii (odds ratio, 4.78; 95% CI, 2.14-18.45) and specific healthcare worker activities (touching the bed rail [odds ratio, 2.19; 95% CI, 1.00-4.82], performing a wound dressing [odds ratio, 8.35; 95% CI, 2.07-33.63] and interacting with the endotracheal tube or tracheotomy site [odds ratio, 5.15; 95% CI, 2.10-12.60]), were associated with hand/glove contamination. Healthcare worker hands/gloves are frequently contaminated with A. baumannii after patient care. Patient-level factors were not associated with an increased transmission risk; however, having multidrug-resistant-A. baumannii and specific healthcare worker activities led to an increased contamination risk. Our findings reveal a potential selective advantage possessed by multidrug-resistant-A. baumannii in this environment and suggest possible areas for future research.


Covariation and phenotypic integration in chemical communication displays: biosynthetic constraints and eco-evolutionary implications.
Chemical communication is ubiquitous. The identification of conserved structural elements in visual and acoustic communication is well established, but comparable information on chemical communication displays (CCDs) is lacking. We assessed the phenotypic integration of CCDs in a meta-analysis to characterize patterns of covariation in CCDs and identified functional or biosynthetically constrained modules. Poorly integrated plant CCDs (i.e. low covariation between scent compounds) support the notion that plants often utilize one or few key compounds to repel antagonists or to attract pollinators and enemies of herbivores. Animal CCDs (mostly insect pheromones) were usually more integrated than those of plants (i.e. stronger covariation), suggesting that animals communicate via fixed proportions among compounds. Both plant and animal CCDs were composed of modules, which are groups of strongly covarying compounds. Biosynthetic similarity of compounds revealed biosynthetic constraints in the covariation patterns of plant CCDs. We provide a novel perspective on chemical communication and a basis for future investigations on structural properties of CCDs. This will facilitate identifying modules and biosynthetic constraints that may affect the outcome of selection and thus provide a predictive framework for evolutionary trajectories of CCDs in plants and animals.


Wnt5a cooperates with canonical Wnts to generate midbrain dopaminergic neurons in vivo and in stem cells.
Wnts are a family of secreted proteins that regulate multiple steps of neural development and stem cell differentiation. Two of them, Wnt1 and Wnt5a, activate distinct branches of Wnt signaling and individually regulate different aspects of midbrain dopaminergic (DA) neuron development. However, several of their functions and interactions remain to be elucidated. Here, we report that loss of Wnt1 results in loss of Lmx1a and Ngn2 expression, as well as agenesis of DA neurons in the midbrain floor plate. Remarkably, a few ectopic DA neurons still emerge in the basal plate of Wnt1(-/-) mice, where Lmx1a is ectopically expressed. These results indicate that Wnt1 orchestrates DA specification and neurogenesis in vivo. Analysis of Wnt1(-/-);Wnt5a(-/-) mice revealed a greater loss of Nurr1(+) cells and DA neurons than in single mutants, indicating that Wnt1 and Wnt5a interact genetically and cooperate to promote midbrain DA neuron development in vivo. Our results unravel a functional interaction between Wnt1 and Wnt5a resulting in enhanced DA neurogenesis. Taking advantage of these findings, we have developed an application of Wnts to improve the generation of midbrain DA neurons from neural and embryonic stem cells. We thus show that coordinated Wnt actions promote DA neuron development in vivo and in stem cells and suggest that coordinated Wnt administration can be used to improve DA differentiation of stem cells and the development of stem cell-based therapies for Parkinson's disease.


Depressed antioxidant status in pregnant women on iron supplements: pathologic and clinical correlates.
Iron (Fe) remains a commonly prescribed supplement in pregnancy. Its possible pathologic potential is either uncommonly considered or ignored. We determined the antioxidant status in pregnant women with and without Fe supplements. Fifty-eight apparently healthy pregnant women on Fe supplements were selected for the study from the antenatal clinic of the University College Hospital, Ibadan, Nigeria. Fifty-five aged matched pregnant women who were not on Fe from various parishes of the Christ Apostolic Church, Ibadan (non-drug using Christian sect) were randomly selected as controls. Both groups were classified according to the trimesters of pregnancy. The gestational age in both pregnant women on Fe supplements and non-supplement pregnant women was similar. Fruit and vegetables consumption was higher in the supplement than in the non-supplement group (57.2% vs. 37.3%). Anthropometric indices, weight, height, and BMI, were also similar. But while the weight of the Fe supplement group decreased by nearly 3% in the third trimester, it increased by over 10% (p < 0.00) in the non-supplement group in the same period. Serum Fe level was significantly higher in the supplement than the non-supplement group (p < 0.001). In contrast, the levels of the antioxidants, ascorbic acid, copper (Cu), zinc (Zn), and bilirubin were all significantly decreased (p < 0.05, p < 0.001, p < 0.05, and p < 0.05, respectively). Uric acid level though also lower in the supplement group did not reach statistical significance (p > 0.05), while vitamin E was similar in both groups. There was relative stability of all antioxidants except uric acid, which declined from the first to the last trimester in the non-supplement group. The significantly higher Fe level in the second trimester was sustained in the third trimester though to a lesser degree (p < 0.05) and associated with significant decreases in the following antioxidant levels in the supplement group, ascorbic acid, bilirubin, Cu, and Zn (p < 0.02, p < 0.02, p < 0.02, and p < 0.001, respectively). Uric acid and vitamin E though lower in the supplement group were not significantly different. Remarkably, percentage changes between the first and third trimesters revealed that serum Fe increased by over 116% in the Fe supplement group, while it only increased by over 50% in the non-supplement group. This was associated with 23.50% decrease in ascorbate level (p < 0.003) in the supplement group, while it decreased by only 3.70% in the non-supplement group (p > 0.05). Again vitamin E decreased by 17.22% in the supplement group, while it decreased by only 7.30% in the non-supplement group during the period. Uric acid and bilirubin levels decreased by similar proportions during the period, while Zn decreased by 18.55% in the supplement group and by 14.86% in the non-supplement group. In contrast Cu increased by 7.20% in the supplement group, while it increased by only 2.96 in the non-supplement group. Additionally, all the antioxidants in the supplement group except vitamin E, viz, ascorbic acid, bilirubin, Cu, uric acid, and Zn, were significantly inversely correlated with serum Fe level (r - 0.299, p < 0.05, r - 0.278, p < 0.05, r - 0.383, p < 0.05, and r - 0.0369, p < 0.05). These data imply markedly depressed antioxidant status in the Fe supplement pregnant group with attendant oxidative stress (most probably pro-oxidant Fe-induced). This is associated with molecular and cellular damage as well as a number of pathologic and clinical correlates that underlie the exacerbation of morbidity and mortality in maternal and child populations, particularly in the developing countries. This appears to call for serious caution and prior evaluation of antioxidant and Fe status and during the use of Fe supplements in pregnancy for monitoring and prognostic purposes and to avert or ameliorate oxidative stress-induced pathologies in maternal and fetal systems.


SiReN: Sign-Aware Recommendation Using Graph Neural Networks.
In recent years, many recommender systems using network embedding (NE) such as graph neural networks (GNNs) have been extensively studied in the sense of improving recommendation accuracy. However, such attempts have focused mostly on utilizing only the information of positive user-item interactions with high ratings. Thus, there is a challenge on how to make use of low rating scores for representing users' preferences since low ratings can be still informative in designing NE-based recommender systems. In this study, we present SiReN, a new Sign-aware Recommender system based on GNN models. Specifically, SiReN has three key components: 1) constructing a signed bipartite graph for more precisely representing users' preferences, which is split into two edge-disjoint graphs with positive and negative edges each; 2) generating two embeddings for the partitioned graphs with positive and negative edges via a GNN model and a multilayer perceptron (MLP), respectively, and then using an attention model to obtain the final embeddings; and 3) establishing a sign-aware Bayesian personalized ranking (BPR) loss function in the process of optimization. Through comprehensive experiments, we empirically demonstrate that SiReN consistently outperforms state-of-the-art NE-aided recommendation methods.


Optimizing perioperative decision making: improved information for clinical workflow planning.
Perioperative care is complex and involves multiple interconnected subsystems. Delayed starts, prolonged cases and overtime are common. Surgical procedures account for 40-70% of hospital revenues and 30-40% of total costs. Most planning and scheduling in healthcare is done without modern planning tools, which have potential for improving access by assisting in operations planning support. We identified key planning scenarios of interest to perioperative leaders, in order to examine the feasibility of applying combinatorial optimization software solving some of those planning issues in the operative setting. Perioperative leaders desire a broad range of tools for planning and assessing alternate solutions. Our modeled solutions generated feasible solutions that varied as expected, based on resource and policy assumptions and found better utilization of scarce resources. Combinatorial optimization modeling can effectively evaluate alternatives to support key decisions for planning clinical workflow and improving care efficiency and satisfaction.


The same but different: discussing the literature regarding mental health nurses' difficulty in meeting the physical health needs of service users, regardless of differing education programmes.
In the Western world, there is increasing concern regarding the ability of health care professionals to meet the physical health care needs of those diagnosed with mental illness. This discussion paper seeks to explore some of the issues facing mental health nurses in delivering care to those who have both mental and physical illness. Criticism of the National Health Service for failing to meet the physical health needs of people with serious mental illness has generated a number of political strategies aimed at addressing inequalities between mental and physical health care, a consequence being a change in pre-registration nurse education. It is envisaged that such changes will enable all nurses to deliver safe, effective care to service users, with adult and mental health nurses being more adept at meeting both the mental and physical health needs of those in their care. The impact of three key areas identified within the literature will be considered: the impact of co-existing physical and mental illness; the role of mental health nurses and perceptions of service users re physical health care; and education, training and learning from others in the Western world. In conclusion, the complexities of delivering such care will be addressed.


Site-directed mutations altering the CAAX box of Ste18, the yeast pheromone-response pathway G gamma subunit.
The STE18 gene encodes the gamma subunit of the G protein which functions in the Saccharomyces cerevisiae pheromone-response pathway. The STE18 gene product undergoes a post-translational processing at the carboxyl terminus directed by the CCAAX box motif CCTLM110. A variety of site-directed mutations of this sequence have been constructed to test the role of this motif on Ste18 function. Mutations which change or eliminate the cysteine at position 107 abolish Ste18-dependent mating, and thus the cysteine (C107) is essential for Ste18 function. However, inactivation of the prenyltransferase by disruption of DPR1 has only a minor effect on Ste18-dependent mating. Mutation of cysteine 106 to serine significantly reduces but does not eliminate Ste18 function. Deletion of the C-terminal TLM sequence or modification of the ultimate methionine to lysine, arginine or leucine, all changes which do not affect the CAAX box cysteines, have only minor effects on Ste18-dependent mating. Intriguingly, these latter mutations dramatically compromise Ste18 function in cells which are deleted for Gpa1, the alpha subunit of the G protein. In addition, overexpression of these mutant versions of STE18 causes a dominant negative phenotype and inhibits the constitutive mating response generated by GPA1 deletion in cells which contain a functional STE18 gene. These results suggest that the C terminus of Ste18 and the Gpa1 protein have overlapping roles in some aspect of yeast G protein function such as membrane targeting.


C1019T Polymorphism in the Connexin 37 Gene and Myocardial Infarction Risk in Premature Coronary Artery Disease.
Background: The C1019T polymorphism of the connexin-37 (GJA4) gene is a single-nucleotide polymorphisms involved in atherosclerotic plaque rupture and atherosclerosis predisposition. We examined the association between the C1019T polymorphism of the GJA4 gene and the occurrence of myocardial infarction (MI) in patients with premature coronary artery disease (CAD). Methods: Our study recruited 1000 patients with the final diagnosis of premature CAD and classified them into 2 groups: with a history of MI (n = 461) and without it (n = 539). The polymorphism variants were determined via the PCR-RFLP, and then genotyping was conducted through the high-resolution melting method. From a total of 1000 patients, 554 patients, who had been previously followed-up with a median follow-up time of 45.74 months vis-à-vis long-term major adverse cardiac events, were enrolled in this retrospective cohort phase. Results: The frequencies of the wild, heterozygous, and mutant genotypes of the C1019T polymorphism were 54.0%, 40.6%, and 5.4% in the MI group and 49.2%, 43.2%, and 7.6% in the non-MI group (p value = 0.187). After adjustment for the baseline covariates, no difference was found between the MI and non-MI groups apropos the frequency of the heterozygous genotype (p value = 0.625) and the mutant genotype (p value = 0.452). Regarding the level of human connexin-37, the serum level of this marker was not different between the MI and non-MI groups. Conclusion: The C1019T polymorphism of the GJA4 gene may not be useful for predicting the occurrence of MI in patients with premature CAD. The presence of this polymorphism in such patients may also have a low value for predicting long-term CAD complications.


Genomic sister-disorders of neurodevelopment: an evolutionary approach.
Genomic sister-disorders are defined here as diseases mediated by duplications versus deletions of the same region. Such disorders can provide unique information concerning the genomic underpinnings of human neurodevelopment because effects of diametric variation in gene copy number on cognitive and behavioral phenotypes can be inferred. We describe evidence from the literature on deletions versus duplications for the regions underlying the best-known human neurogenetic sister-disorders, including Williams syndrome, Velocardiofacial syndrome, and Smith-Magenis syndrome, as well as the X-chromosomal conditions Klinefelter and Turner syndromes. These data suggest that diametric copy-number alterations can, like diametric alterations to imprinted genes, generate contrasting phenotypes associated with autistic-spectrum and psychotic-spectrum conditions. Genomically based perturbations to the development of the human social brain are thus apparently mediated to a notable degree by effects of variation in gene copy number. We also conducted the first analyses of positive selection for genes in the regions affected by these disorders. We found evidence consistent with adaptive evolution of protein-coding genes, or selective sweeps, for three of the four sets of sister-syndromes analyzed. These studies of selection facilitate identification of candidate genes for the phenotypes observed and lend a novel evolutionary dimension to the analysis of human cognitive architecture and neurogenetic disorders.


The adenylate cyclase toxin from Bordetella pertussis--a novel promising vehicle for antigen delivery to dendritic cells.
Bordetella pertussis secretes an adenylate cyclase toxin (CyaA or ACT) that targets primarily cells expressing the alphaMbeta2 integrin (CD11b/CD18) receptor. This toxin can deliver its N-terminal catalytic AC domain (400 amino acid residues) into the cytosol directly across the cytoplasmic membrane. Various heterologous CD8+, as well as CD4+ T-cell epitopes have been engineered into genetically detoxified CyaA and the resulting toxoids were successfully used as vectors for delivery of inserted epitopes into antigen-presenting cells. Upon processing and presentation, these recombinant CyaAs trigger specific MHC class I and/or class II-restricted T-cell responses both in vitro and in vivo.


An axis-specific rotational rainbow in the direct scatter of formaldehyde from Au(111) and its influence on trapping probability.
The conversion of translational to rotational motion often plays a major role in the trapping of small molecules at surfaces, a crucial first step for a wide variety chemical processes that occur at gas-surface interfaces. However, to date most quantum-state resolved surface scattering experiments have been performed on diatomic molecules, and little detailed information is available about how the structure of nonlinear polyatomic molecules influences the mechanisms for energy exchange with surfaces. In the current work, we employ a new rotationally resolved 1 + 1' resonance-enhanced multiphoton ionization (REMPI) scheme to measure the rotational distribution in formaldehyde molecules directly scattered from the Au(111) surface at incidence kinetic energies in the range 0.3-1.2 eV. The results indicate a pronounced propensity to excite a-axis rotation (twirling) rather than b- or c-axis rotation (tumbling or cartwheeling), and are consistent with a rotational rainbow scattering model. Classical trajectory calculations suggest that the effect arises-to zeroth order-from the three-dimensional shape of the molecule (steric effects). Analysis suggests that the high degree of rotational excitation has a substantial influence on the trapping probability of formaldehyde at incidence translational energies above 0.5 eV.


Small-scale screening of novel biobased monomers: the curious case of 1,3-cyclopentanediol.
In this work, we report on the small scale polycondensation and consecutive analysis of novel polyesters based on the potentially renewable 1,3-cyclopentanediol (CPdiol). To avoid evaporation of monomers during thin-film polymerization reactions, trimer pre-polyesters have been synthesized from the corresponding acid-chlorides with diol monomers. Polymerization of these trimers was explored by thermogravimetric analysis to identify potential side reactions, and to assess the ideal polymerization temperature. In general we observe that trans-1,3-cyclopentanediol exhibits good thermal stability up to 200 °C, whereas thermal dehydration of the alcohol end-groups occurs upon further heating. In contrast, for cis-1,3-cyclopentanediol, the ester bonds of the cyclopentane end-groups become labile, thereby generating carboxylic acid end-groups, and 3-cyclopentenol already at 180 °C. The thermal dehydration reactions yield double bond end-groups, which in turn facilitate cross-linking through cross-coupling and Diels-Alder reactions, leading to an increase in molecular weight. Despite the limited thermal stability of CPdiol, here we demonstrate that polymerization of CPdiol can successfully be achieved in thin-film polycondensation conditions at 180 °C, yielding molecular weights well above 10 kg mol-1.


Nicotine elevates rat plasma ACTH by a central mechanism.
Nicotine is a potent secretagogue for the release of adrenocorticotropin (ACTH) from the anterior pituitary in vivo. However, the location of its action is unknown; knowledge of this is essential for elucidating its mechanism. Our studies show that cytisine, a peripherally acting nicotinic cholinergic agonist, given i.v. at doses equimolar or greater than nicotine, failed to elevate plasma ACTH levels, whereas nicotine (0.01 and 0.03 mg/kg b.wt.) had significant effects. Nicotine (10(-7)-10(-4) M) had no effect on the secretion of beta-endorphin by anterior pituicytes in vitro, nor did it potentiate the action of corticotropin-releasing factor (10(-9) or 10(-8) M). Intracerebroventricular injection of nicotine (1-20 micrograms) significantly elevated ACTH levels. Moreover, ACTH responses to nicotine delivered into the hypothalamic region of the third ventricle were significantly greater than those elicited by injection into the upper region. Additional studies were conducted to determine the earliest age at which nicotine stimulates ACTH. The response to i.p. nicotine (1 or 2 mg/kg b.wt.) was present but diminished during the postnatal period, whereas maximal responses comparable to mature rats were attained by day 15. To establish whether nicotine has a central effect in younger animals, nicotinic antagonists were tested. Hexamethonium (2 mg/kg b.wt.), a peripherally acting antagonist, was ineffective against nicotine (0.025 and 2.0 mg/kg b.wt.), whereas mecamylamine (2 mg/kg b.wt.), inhibitory at both peripheral and central sites, blocked the ACTH response. Thus, whether administered peripherally or centrally, nicotine activates central mechanisms mediating the release of ACTH; it appears that the target(s) for nicotine are within the hypothalamus or brainstem.


Effect of lipid coating on the interaction between silica nanoparticles and membranes.
Lipid coating is a method highly used to improve the biocompatibility of nanoparticles (NPs), even though its effect on the NP properties is still object of investigation. Herein, silica NPs containing methylene blue, which is a photosensitizer used in a variety of biomedical applications, were coated with a phospholipid bilayer. Regarding the photophysical properties, lipid-coating did not cause significant changes since bare and lipid-coated NPs presented very similar absorption spectra and generated singlet oxygen with similar efficiencies. However, NP interaction with cells and membrane mimics was totally different for bare and lipid-coated NPs. Lipid-coated NPs were distributed through the cell cytoplasm whereas bare NPs were detected only in some vacuolar regions within the cells. Since cellular uptake and cytolocalization are influenced by NP adsorption on cell membranes, the interaction of lipid-coated and bare NPs were studied on a membrane mimic, i.e., Hybrid Bilayer Membranes (HBMs) made of different compositions of negatively charged and neutral lipids. Interactions of bare and lipid-coated NPs with HBMs were analyzed by Surface Plasmon Resonance Imaging. Bare NPs presented high adsorption and aggregation on HBMs independently of the surface charge. Conversely, lipid-coated NPs presented less aggregation on the membrane surface and the adsorption was dependent on the charges of the NPs and of the HBMs. Our results indicated that NPs aggregation on the membrane surface can be modulated by lipid coating, which affects the cytosolic distribution of the NPs.


Step-response analysis of chemotaxis in Caenorhabditis elegans.
The sensorimotor transformation underlying Caenorhabditis elegans chemotaxis has been difficult to measure directly under normal assay conditions. Thus, key features of this transformation remain obscure, such as its time course and dependence on stimulus amplitude. Here, we present a comprehensive characterization of the transformation as obtained by inducing stepwise temporal changes in attractant concentration within the substrate as the worm crawls across it. We found that the step response is complex, with multiple phases and a nonlinear dependence on the sign and amplitude of the stimulus. Nevertheless, the step response could be reduced to a simple kinetic model that predicted the results of chemotaxis assays. Analysis of the model showed that chemotaxis results from the combined effects of approach and avoidance responses to concentration increases and decreases, respectively. Surprisingly, ablation of the ASE chemosensory neurons, known to be necessary for chemotaxis in chemical gradient assays, eliminated avoidance responses but left approach responses intact. These results indicate that the transformation can be dissected into components to which identified neurons can be assigned.


Comparative radiopacity of bonding agents.
The present study was undertaken to determine the content and the constituent elements of inorganic fillers as well as the radiopacity of 15 recently introduced bonding agents and to compare their radiodensities with those of enamel and dentin by using a transmission photodensitometer. The content of inorganic fillers was determined by the ashing method. In addition, x-ray microanalysis was used to identify the constituent elements of the inorganic fillers. In the measurement of the radiopacity, specimens 10 mm in diameter and 0.9 mm in thickness were fabricated from the 15 different bonding agents (n = 3 each) for a total of 45 specimens. Human premolars were longitudinally sectioned into 1.0-mm-thick slices to include both enamel and dentin, then ground to final thickness of 0.9 mm. The optical densities of enamel, dentin, the bonding agents, and an aluminum (Al) step wedge were obtained from radiographic images by transmission photodensitometry. The Al equivalent (mm) for each material was calculated by using the linear regression equation of the log of the normalized optical density and Al thickness (mm) obtained from the step wedge. A linear regression of the logarithm of the normalized optical density and Al thickness (mm) was plotted. The inorganic filler content ranged from 0.0 wt% to 43.5 wt%. Silicon and aluminum were the main constituent elements of the inorganic fillers; however, the resins contained different kinds of inorganic fillers. These elements have high and low atomic numbers. The surface reaction type pre-reacted glass-ionomer (S-PRG)-filled bonding agent (FII) had a filler content of 43.5 wt% and contained B, Si, Sr, Na, F and Al as its elemental constituents. The relative radiopacities expressed as equivalent thickness of Al were ranked ordinally. Fourteen of the 15 adhesive resins had radiopacity values that fell below that value for dentin, whereas the FII resin showed a radiopacity that was equal to or greater than that of dentin but below that of enamel (p < 0.05). The radiopacity of bonding agents depended on their filler content and the presence of heavier atoms of elements in the filler.


Pythium polare, a new heterothallic oomycete causing brown discolouration of Sanionia uncinata in the Arctic and Antarctic.
Pythium polare sp. nov. is a new heterothallic oomycete species isolated from fresh water and moss from various locations in both the Arctic and Antarctic. This water mould is able to infect stems and leaves of Sanionia moss (Sanionia uncinata). Pythium polare causes brown discolouration in in vitro inoculation tests at 5 °C after 5 weeks of inoculation. It is characterized by globose sporangia with various lengths of discharge tubes releasing zoospores and aplerotic oospores with usually one to five antheridia. The sexual structures are only produced in a dual culture of antheridial and oogonial isolates. Phylogenetic analysis, based on ITS sequencing, places all isolated strains of P. polare in a unique new clade, hence it is considered a novel species. Pythium canariense and Pythium violae are the most closely related species of P. polare based both on morphology and the phylogenetic analysis.


The genetic contribution to human T-cell receptor repertoire.
Recent studies in mice have highlighted the importance of polymorphic genetic loci such as the major histocompatibility complex (MHC) or minor lymphocyte-stimulating antigen (Mls) in determining the nature of the peripheral T-cell receptor (TcR) population. As our knowledge of the equivalent process in humans is incomplete, we have utilized a modification of the polymerase chain reaction (PCR) to determine the overall genetic contribution to the normal human TcR variable V beta gene repertoire. These data demonstrate that the normal human T-cell population contains members of all the major TcR V beta families and that there is considerable variation in the relative amounts of specific TcR V beta transcripts between individuals. We have established that the normal peripheral TcR V beta repertoire is more concordant in identical twins than in unrelated individuals. The relative importance of genetic factors in determining the peripheral TcR repertoire is emphasized by these results and suggests that, in humans, the genetic control of immune responsiveness is mediated in part by the peripheral TcR repertoire.