Comparison of the effects of melatonin and genistein on radiation-induced nephrotoxicity: Results of an experimental study.
The aim of the present study was to compare the effects of melatonin and genistein on radiation-induced nephrotoxicity (RIN). A total of 70 Swiss Albino mice were divided into 7 groups. Five control groups were defined, which were sham irradiation (C, G1), radiation therapy only (RT, G2), melatonin (M, G3), genistein (G, G4) and polyethylene glycol-400 (G5), respectively. The co-treatment groups were the RT plus melatonin (RT+M, G6) and RT plus genistein (RT+G, G7) groups. Irradiation was applied using a cobalt-60 teletherapy machine (80-cm fixed source-to-surface distance, 2.5-cm depth). Melatonin was administered (100 mg/kg, intraperitoneal injection) 30 min before the single dose of irradiation, whereas genistein was administered (200 mg/kg, subcutaneous injection) 1 day before the single dose of irradiation. All the mice were sacrificed 6 months after irradiation. As an end point, the extent of renal tubular atrophy for each mouse was quantified with image analysis of histological sections of the kidney. Tissue malondialdehyde (MDA) levels were also measured in each animal. In the histopathological examination of the mouse kidneys, there was a statistically significant reduction (P<0.05) in the presence of tubular atrophy between the RT+M and RT+G groups and the RT group. There was a statistically significant increase in MDA levels in the irradiated versus sham groups (RT vs. C; P<0.05); however, MDA levels were significantly decreased by co-treatment with melatonin or genistein vs. RT alone (RT+M and RT+G vs. RT; P<0.05). In conclusion, the present experimental study showed that melatonin and genistein supplementation prior to irradiation-protected mice against RIN, which may have therapeutic implications for radiation-induced injuries.


The effect of muscle hypoperfusion-hyperemia on repetitive vertical jump performance.
Alterations in skeletal muscle blood flow can greatly influence exercise performance. Brief periods of arterial hypoperfusion and subsequent hyperemia (hypoperfusion-hyperemia) have been shown to decrease the rate of skeletal muscle fatigue in a model of repeated, isometric wrist flexion exercise. However, the mechanism by which hypoperfusion-hyperemia influences dynamic motor skills remains unknown. The purpose of this study was to determine the effects of brief hypoperfusion-hyperemia (by femoral cuff occlusion) on repetitive vertical jump performance. Recreationally trained men and women (n = 10, mean +/- SD age, 25 +/- 2 years), performed 2 randomly assigned jumping trials, each consisting of 40 maximal effort vertical jumps. Jump height was videotaped on a Sony digital video recorder and analyzed with the Scion Images program. Trial 1 consisted of 40 vertical jumps without femoral artery occlusion. Trial 2 consisted of 40 vertical jumps preceded by femoral artery cuff occlusion for 90 seconds at 200 mm Hg, followed by 10 seconds of hyperemia before jumping. For both trials, the rate of decline in power output in men and women was approximately 20%. Hypoperfusion-hyperemia had no significant effect on vertical jumping power output, perhaps because additional muscle groups used to jump vertically (e.g., gluteals and arms) were not occluded. These results warrant further research on the effect of hypoperfusion-hyperemia on strength and power measures.


Does body size predict the buzz-pollination frequencies used by bees?
Body size is an important trait linking pollinators and plants. Morphological matching between pollinators and plants is thought to reinforce pollinator fidelity, as the correct fit ensures that both parties benefit from the interaction. We investigated the influence of body size in a specialized pollination system (buzz-pollination) where bees vibrate flowers to release pollen concealed within poricidal stamens. Specifically, we explored how body size influences the frequency of buzz-pollination vibrations. Body size is expected to affect frequency as a result of the physical constraints it places on the indirect flight muscles that control the production of floral vibrations. Larger insects beat their wings less rapidly than smaller-bodied insects when flying, but whether similar scaling relationships exist with floral vibrations has not been widely explored. This is important because the amount of pollen ejected is determined by the frequency of the vibration and the displacement of a bee's thorax. We conducted a field study in three ecogeographic regions (alpine, desert, grassland) and recorded flight and floral vibrations from freely foraging bees from 27 species across four families. We found that floral vibration frequencies were significantly higher than flight frequencies, but never exceeded 400 Hz. Also, only flight frequencies were negatively correlated with body size. As a bee's size increased, its buzz ratio (floral frequency/flight frequency) increased such that only the largest bees were capable of generating floral vibration frequencies that exceeded double that of their flight vibrations. These results indicate size affects the capacity of bees to raise floral vibration frequencies substantially above flight frequencies. This may put smaller bees at a competitive disadvantage because even at the maximum floral vibration frequency of 400 Hz, their inability to achieve comparable thoracic displacements as larger bees would result in generating vibrations with lower amplitudes, and thus less total pollen ejected for the same foraging effort.


Biochemical characterization of the native Kv2.1 potassium channel.
Functional diversity of potassium channels in both prokaryotic and eukaryotic cells suggests multiple levels of regulation. Posttranslational regulation includes differential subunit assembly of homologous pore-forming subunits. In addition, a variety of modulatory subunits may interact with the pore complex either statically or dynamically. Kv2.1 is a delayed rectifier potassium channel isolated by expression cloning. The native polypeptide has not been purified, hence composition of the Kv2.1 channel complexes was not well understood. Here we report a biochemical characterization of Kv2.1 channel complexes from both recombinant cell lines and native rat brain. The channel complexes behave as large macromolecular complexes with an apparent oligomeric size of 650 kDa as judged by gel filtration chromatography. The molecular complexes have distinct biochemical populations detectable by a panel of antibodies. This is indicative of functional heterogeneity. Despite mRNA distribution in a variety of tissues, the native Kv2.1 polypeptides are more abundantly found in brain and have predominantly Kv2.1 subunits but not homologous Kv2.2 subunits. The proteins precipitated by anti-Kv2.1 and their physiological relevance are of interest for further investigation.


A guide for assessing pharmacoepidemiologic studies.
Pharmacoepidemiologic studies are appearing with increasing frequency in clinical journals, describing associations between commonly used drugs and rare adverse clinical events. Before practitioners accept conclusions of causality and alter patterns of practice based on these studies, they should perform two steps: apply a critical appraisal filter to the evidence to determine whether the claims are justified, and explore the consequences of not using a drug associated with an undesired effect. This guide for critically appraising the literature on adverse drug effects emphasizes the need to evaluate the potential biases associated with studies that use nonexperimental designs.


Mortality, readmission, and reoperation after hip fracture in nonagenarians.
Osteoporotic hip fractures are associated with high mortality and morbidity in people of advanced age; however, few studies have investigated the complication rates in nonagenarians. In this study, we applied a competing risk analysis to estimate the mortality, readmission, and reoperation rates after surgery for hip fracture among nonagenarians. A total of 11,184 nonagenarians (aged ≥ 90) who received surgery for hip fracture during the period 1 January 1997 and 31 December 2010 were selected from Taiwan's National Health Insurance (NHI) database. Nonagenarians were followed up until the end of 2012, death, or the date they left the NHI program. Cumulative mortality was estimated using the Kaplan-Meier analysis and risk factors for mortality were investigated using a Cox proportional hazards model. Competing risk analysis was used to estimate cumulative incidence rates and to assess the risk factors for reoperation and readmission. The mortality rates were 29.5% at 1 year, 45.0% at 2 years and 78.1% at 5 years. The cumulative incidence rates of reoperation were 7.3% at 1 year, 9.2% at 2 years and 11.6% at 5 years whereas those of readmission were 18.9% at 1 month and 24.1% at 3 months. Significant risk factors for death included age, male gender, trochanteric fracture, and higher Charlson comorbidity index (CCI) whereas those for reoperation were age, cervical fracture and higher CCI. Furthermore, age, male gender, and higher CCI were risk factors for readmission. The overall 2-years mortality rate among nonagenarians in Taiwan was around 45%, the 2-years reoperation rate was around 9% and the 90-days medical complication rate was around 24%. High complication rates are associated with increased risk for death. Postoperative care to prevent medical complications is likely the most effective strategy to reduce mortality rates among nonagenarians with hip fracture.


First Report of Citrus tristeza virus in National Germplasm of Citrus in Afghanistan.
Rejuvenation of the horticulture industry is a government priority in Afghanistan. With that purpose, European Commission-supported programs specifically focus on greater access to improved and appropriate planting materials to increase the quantity and quality of more competitive horticultural products. Establishment of a biotechnology laboratory was considered essential support to horticulture sector development. This laboratory has begun screening the health status of the Afghan Germplasm National Collection to ensure multiplication of not only the best selected varieties or ecotypes but also to avoid reproduction and distribution of virus-infected fruit trees. Symptom inspection and sample collection for viral diseases was carried out in the citrus orchard during survey activity at the National Collection Experimental Farm in Jalalabad (Nangarhar Province). Ninety-nine variety plots (one row of five plants) were inspected visually and samples from two plants for each plot were collected and analyzed by double-antibody sandwich (DAS)-ELISA. Plants showing vein flecking, yellowing, and plant decline symptoms were observed in several plots. Four accessions were found to be infected by Citrus tristeza virus (CTV): kumquat cv. Margarita (isolates J4 and J8), orange cv. Mahali (J61), mandarin group cv. Fruter (J76), and rough lemon cv. Mahali (J101). Identified isolates have been characterized molecularly. A 655-nt fragment, corresponding to the major coat protein gene, has been amplified from all ELISA-positive samples by reverse transcription (RT)-PCR using CTVF (5'-TAATGGACGACGAACAAAGA-3') and CTVR (5'-CCAAGCTGCCTGACATTAGT-3') primers. Sequence analysis revealed high similarity, ranging from 91.1 to 99.8%, within CTV isolates detected in Jalalabad. In accordance with the phylogenetic groups previously defined (page 8 in: Proceedings of the 15th Conference of the International Organization of Citrus Virologists, 2002), nucleotide sequences of Afghan CTV isolates investigated in the current work cluster in Group 1 (J4 and J8), Group 4 (J61 and J76), and Group 5 (J101). In particular, J4 and J8 isolates show, respectively, identity of 99.4 and 99.2% with reference isolate T36 (GenBank Accession No. M76485) from the United States (Florida). Moreover, in Group 4, isolate J61 and J76 were more similar to ANO-1 isolate (GenBank Accession No. DQ211658) from Egypt (identity of 98.5 and 98.0%, respectively) than to isolate 443-4 (GenBank Accession No. AY791844) from Croatia (97.4 and 97.5%, respectively). Finally, isolate J101 in Group 5, shows identity of 95.6% with isolates C268-2 (GenBank Accession No. AY750770) and C269-6 (GenBank Accession No. AY750775) from Argentina. To our knowledge, our results identified for the first time CTV-infected plants in Afghanistan. The presence of CTV in four accessions of the national citrus collection is of concern for Afghan horticulture. Implementation of the certification schemes is therefore necessary to guarantee the production and the employment of virus-free propagating material.


Host microarray analysis reveals a role for the Salmonella response regulator phoP in human macrophage cell death.
Bacterial pathogens manipulate host cells to promote pathogen survival and dissemination. We used a 22,571 human cDNA microarray to identify host pathways that are affected by the Salmonella enterica subspecies typhimurium phoP gene, a transcription factor required for virulence, by comparing the expression profiles of human monocytic tissue culture cells infected with either the wild-type bacteria or a phoPTn10 mutant strain. Both wild-type and phoPTn10 bacteria induced a common set of genes, many of which are proinflammatory. Differentially expressed genes included those that affect host cell death, suggesting that the phoP regulatory system controls bacterial genes that alter macrophage survival. Subsequent experiments showed that the phoPTn10 mutant strain is defective for killing both cultured and primary human macrophages but is able to replicate intracellularly. These experiments indicate that phoP plays a role in Salmonella-induced human macrophage cell death.


Mitogenic effect of orphan receptor TR3 and its regulation by MEKK1 in lung cancer cells.
TR3, also known as NGFI-B or nur77, is an immediate-early response gene and an orphan member of the steroid/thyroid/retinoid receptor superfamily. We previously reported that TR3 expression was induced by apoptotic stimuli and was required for their apoptotic effect in lung cancer cells. Here, we present evidence that TR3 was also induced by epidermal growth factor (EGF) and serum and was required for their mitogenic effect in lung cancer cells. Ectopic expression of TR3 in both H460 and Calu-6 lung cancer cell lines promoted their cell cycle progression and BrdU incorporation, while inhibition of TR3 expression by the small interfering RNA approach suppressed the mitogenic effect of EGF and serum. Analysis of TR3 mutants showed that both TR3 DNA binding and transactivation were required for its mitogenic effect. In contrast, they were dispensable for its apoptotic activity. Furthermore, confocal microscopy analysis demonstrated that TR3 functioned in the nucleus to induce cell proliferation, whereas it acted on mitochondria to induce apoptosis. In examining the signaling that regulates the mitogenic function of TR3, we observed that coexpression of constitutive-active MEKK1 inhibited TR3 transcriptional activity and TR3-induced proliferation. The inhibitory effect of MEKK1 was mediated through activation of Jun N-terminal kinase, which efficiently phosphorylated TR3, resulting in loss of its DNA binding. Together, our results demonstrate that TR3 is capable of inducing both proliferation and apoptosis in the same cells depending on the stimuli and its cellular localization.


Novel galactose single point method as a measure of residual liver function: example of cefoperazone kinetics in patients with liver cirrhosis.
A novel, simple, clinically useful quantitative liver function test, called the galactose single point (GSP) method, was developed to assess residual liver function by measuring galactose blood concentration 1 hour after galactose was administered (0.5 g/kg). This method was applied to the study of cefoperazone kinetics in patients with hepatic cirrhosis. To study the influence of hepatic cirrhosis on the residual liver function and the correlation between the residual liver function and the pharmacokinetics of cefoperazone, a dose of 1 g of cefoperazone was administered to 11 healthy volunteers and 12 patients with liver cirrhosis. The GSP method, the galactose elimination capacity (GEC) test, and the modified galactose elimination capacity (MGEC) test were done for each volunteer and patient to measure residual liver function. The galactose concentrations were determined enzymatically. Cefoperazone was administered intravenously, and blood and urine samples were collected at appropriate intervals after drug administration. All blood and urine samples were stored at -30 degrees C until high-performance liquid chromatography analysis. Cefoperazone plasma concentrations were much higher in cirrhosis patients than in normal subjects at all times. The elimination half-life, hepatic clearance, mean residence time, and renal clearance of cirrhosis patients differed significantly from those of healthy volunteers. The plasma protein binding was unaltered in both groups. Urinary excretion of cefoperazone was significantly increased in cirrhosis patients (23.95 +/- 5.06% for normal men and 51.09 +/- 11.50% in cirrhosis patients). Hepatic clearance, fraction excreted in urine, and total clearance significantly correlated with GSP, GEC, and MGEC (P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)


Cloning and functional analysis of the naphthomycin biosynthetic gene cluster in Streptomyces sp. CS.
Naphthomycins (NATs) are 29-membered naphthalenic ansamacrolactam antibiotics with antimicrobial and antineoplastic activities. Their biosynthesis starts from 3-amino-5-hydroxy-benzoic acid (AHBA). By PCR amplification with primers for AHBA synthase and amino-dehydroquinate (aDHQ) synthase, a genomic region containing orthologs of these genes was identified in Streptomyces sp. CS. It was confirmed to be involved in naphthomycin biosynthesis by deletion of a large DNA fragment, resulting in abolishment of naphthomycin production. A 106 kb region was sequenced, and 32 complete ORFs were identified, including five polyketide synthase genes, eight genes for AHBA synthesis, and putative genes for modification, regulation, transport or resistance. Targeted inactivation and complementation experiments proved that the halogenase gene nat1 is responsible for the chlorination of C-30 of NATs. The nat1 mutant could also be complemented with asm12, the halogenase gene of ansamitocin biosynthesis. Likewise, an asm12 mutant could be complemented with nat1, suggesting a similar catalytic mechanism for both halogenases. A putative hydroxylase gene, nat2, was also inactivated, whereupon the biosynthesis of NATs was completely abolished with a tetraketide desacetyl-SY4b accumulated, indicating the participation of nat2 in the formation of the naphthalene ring. The information presented here expands our understanding of the biosynthesis of naphthalenic ansamycins, and may pave the way for engineering ansamacrolactams with improved pharmaceutical properties.


The two dimensions of the body representation in women suffering from Anorexia Nervosa.
A core symptom of Anorexia Nervosa (AN) is a severe alteration of body representations. Evidence from somatoperception studies point to a generic disturbances of somatosensory components of body representations. Here we have investigated whether AN patients (N=18) and controls differed in the perception of tactile stimuli differently oriented along the body axes. We tested the hypothesis that patients perceive and represent their body selectively larger in only one dimension. To this aim we used elementary tactile measures for tactile acuity (Von Frey's test and two-point discrimination thresholds - 2PD) and tactile discrimination measures. The rationale is based on the assumption that AN patients have a wider body representation, and that tactile body representation tasks (Tactile Distance task) oriented across the bodies (horizontally) are influenced by distorted body representations compared with tactile stimuli oriented along the bodies (vertically) which should not be influenced by body representations. Results showed that patients judged horizontal tactile stimuli significantly wider than the same stimuli oriented vertically.These results suggest that human brain perceives things differently based on body representations and that the beliefs concerning body size influence the specific somatosensory process of tactile experience.


Autophosphorylation-induced degradation of the Pho85 cyclin Pcl5 is essential for response to amino acid limitation.
Pho85 cyclins (Pcls), activators of the yeast cyclin-dependent kinase (CDK) Pho85, belong together with the p35 activator of mammalian CDK5 to a distinct structural cyclin class. Different Pcls target Pho85 to distinct substrates. Pcl5 targets Pho85 specifically to Gcn4, a yeast transcription factor involved in the response to amino acid starvation, eventually causing the degradation of Gcn4. Pcl5 is itself highly unstable, an instability that was postulated to be important for regulation of Gcn4 degradation. We used hybrids between different Pcls to circumscribe the substrate recognition function to the core cyclin box domain of Pcl5. Furthermore, the cyclin hybrids revealed that Pcl5 degradation is uniquely dependent on two distinct degradation signals: one N-terminal and one C-terminal to the cyclin box domain. Whereas the C-terminal degradation signal is independent of Pho85, the N-terminal degradation signal requires phosphorylation of a specific threonine residue by the Pho85 molecule bound to the cyclin. This latter mode of degradation depends on the SCF ubiquitin ligase. Degradation of Pcl5 after self-catalyzed phosphorylation ensures that activity of the Pho85/Pcl5 complex is self-limiting in vivo. We demonstrate the importance of this mechanism for the regulation of Gcn4 degradation and for cell growth under conditions of amino acid starvation.


Platelet-derived growth factor-alpha receptor activation is required for human cytomegalovirus infection.
Human cytomegalovirus (HCMV) is a ubiquitous human herpesvirus that can cause life-threatening disease in the fetus and the immunocompromised host. Upon attachment to the cell, the virus induces robust inflammatory, interferon- and growth-factor-like signalling. The mechanisms facilitating viral entry and gene expression are not clearly understood. Here we show that platelet-derived growth factor-alpha receptor (PDGFR-alpha) is specifically phosphorylated by both laboratory and clinical isolates of HCMV in various human cell types, resulting in activation of the phosphoinositide-3-kinase (PI(3)K) signalling pathway. Upon stimulation by HCMV, tyrosine-phosphorylated PDGFR-alpha associated with the p85 regulatory subunit of PI(3)K and induced protein kinase B (also known as Akt) phosphorylation, similar to the genuine ligand, PDGF-AA. Cells in which PDGFR-alpha was genetically deleted or functionally blocked were non-permissive to HCMV entry, viral gene expression or infectious virus production. Re-introducing human PDGFRA gene into knockout cells restored susceptibility to viral entry and essential viral gene expression. Blockade of receptor function with a humanized PDGFR-alpha blocking antibody (IMC-3G3) or targeted inhibition of its kinase activity with a small molecule (Gleevec) completely inhibited HCMV viral internalization and gene expression in human epithelial, endothelial and fibroblast cells. Viral entry in cells harbouring endogenous PDGFR-alpha was competitively inhibited by pretreatment with PDGF-AA. We further demonstrate that HCMV glycoprotein B directly interacts with PDGFR-alpha, resulting in receptor tyrosine phosphorylation, and that glycoprotein B neutralizing antibodies inhibit HCMV-induced PDGFR-alpha phosphorylation. Taken together, these data indicate that PDGFR-alpha is a critical receptor required for HCMV infection, and thus a target for novel anti-viral therapies.


Beam breakup integral measurement on high-power laser chains.
We experimentally demonstrate the efficiency of a single-shot method to measure the beam breakup integral (B) accumulated across a high power chain. The technique uses spectrally shaped strongly chirped femtosecond pulses and takes advantage of time-to-spectral coupling generated by nonlinear effects. We performed B measurements on regenerative amplifiers (Ti:sapphire) and on the ALISE 200 J facility currently installed at CEA-CESTA (France).


Imaging photopolarimeter on pioneer saturn.
An imaging photopolarimeter aboard Pioneer 11, including a 2.5-centimeter telescope, was used for 2 weeks continuously in August and September 1979 for imaging, photometry, and polarimetry observations of Saturn, its rings, and Titan. A new ring of optical depth < 2 x 10(-3) was discovered at 2.33 Saturn radii and is provisionally named the F ring; it is separated from the A ring by the provisionally named Pioneer division. A division between the B and C rings, a gap near the center of the Cassini division, and detail in the A, B, and C rings have been seen; the nomenclature of divisions and gaps is redefined. The width of the Encke gap is 876 +/- 35 kilometers. The intensity profile and colors are given for the light transmitted by the rings. A mean particle size less, similar 15 meters is indicated; this estimate is model-dependent. The D ring was not seen in any viewing geometry and its existence is doubtful. A satellite, 1979 S 1, was found at 2.53 +/- 0.01 Saturn radii; the same object was observed approximately 16 hours later by other experiments on Pioneer 11. The equatorial radius of Saturn is 60,000 +/- 500 kilometers, and the ratio of the polar to the equatorial radius is 0.912 +/- 0.006. A sample of polarimetric data is compared with models of the vertical structure of Saturn's atmosphere. The variation of the polarization from the center of the disk to the limb in blue light at 88 degrees phase indicates that the density of cloud particles decreases as a function of altitude with a scale height about one-fourth that of the gas. The pressure level at which an optical depth of 1 is reached in the clouds depends on the single-scattering polarizing properties of the clouds; a value similar to that found for the Jovian clouds yields an optical depth of 1 at about 750 millibars.


Normal-to-abnormal rearrangement of an N-heterocyclic carbene with a silylene transition metal complex.
The synthesis and characterization of the N-heterocyclic carbene (NHC) stabilized dichlorosilylene Group 6 metal complexes {(IPr)SiCl2}W(CO)5 (3-W), {(IPr)SiCl2}2Cr(CO)4 (4-Cr), and {(IPr)SiCl2}2W(CO)4 (4-W) (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) are reported. Treatment of 3-W with CsOH in the presence of IPr leads to the formation of an abnormal-NHC (aNHC) metal complex (aIPrH)W(CO)5 (6-W) (aIPrH = 1,3-bis(2,6-diisopropylphenyl)imidazol-4-ylidene), unveiling an unprecedented normal-to-abnormal transformation route of an NHC. DFT calculations support the proposed mechanism that involves CsOH mediated deprotonation of the IPr-backbone of 3-W to yield a ditopic carbanionic-NHC (dcNHC) complex 5a-W. Subsequent 1,4-migration of the W(CO)5 moiety and hydrolysis of the unmasked SiCl2 rationalize the formation of 6-W. The desired H2O molecule is generated in the initial step on deprotonation of IPr with CsOH. In contrast to the literature precedents, the calculations indicate that the abnormal complex 6-W is 13.5 kcal mol-1 thermodynamically higher in energy than the normal counterpart (IPr)W(CO)5 (8-W). Interestingly, as the aNHC-compounds reported so far are more stable than their normal counterparts, this finding showcases an opposite trend. Moreover, reaction pathways to the synthesized and related complexes have been investigated by DFT calculations.


Chirality enriched carbon nanotubes with tunable wrapping via corona phase exchange purification (CPEP).
Single-walled carbon nanotubes (SWCNTs) have unique photophysical properties and serve as building blocks for biosensors, functional materials and devices. For many applications it is crucial to use chirality-pure SWCNTs, which requires sophisticated processes. Purification procedures such as wrapping by certain polymers, phase separation, density gradient centrifugation or gel chromatography have been developed and yield distinct SWCNT species wrapped by a specific polymer or surfactant. However, many applications require a different organic functionalization (corona) around the SWCNTs instead of the one used for the purification process. Here, we present a novel efficient and straightforward process to gain chirality pure SWCNTs with tunable functionalization. Our approach uses polyfluorene (PFO) polymers to enrich certain chiralities but the polymer is removed again and finally exchanged to any desired organic phase. We demonstrate this concept by dispersing SWCNTs in poly[(9,9-dioctylfluorenyl-2,7-diyl)-alt-co-(6,6'-{2,2'-bipyridine})] (PFO-BPy), which is known to preferentially solubilize (6,5)-SWCNTs. Then PFO-BPy is removed and recycled, while letting the SWCNTs adsorb/agglomerate on sodium chloride (NaCl) crystals, which act as a toluene-stable but water-soluble filler material. In the last step these purified SWCNTs are redispersed in different polymers, surfactants and ssDNA. This corona phase exchange purification (CPEP) approach was also extended to other PFO variants to enrich and functionalize (7,5)-SWCNTs. CPEP purified and functionalized SWCNTs display monodisperse nIR spectra, which are important for fundamental studies and applications that rely on spectral changes. We show this advantage for SWCNT-based nIR fluorescent sensors for the neurotransmitter dopamine and red-shifted sp3 defect peaks . In summary, CPEP makes use of PFO polymers for chirality enrichment but provides access to chirality enriched SWCNTs functionalized in any desired polymer, surfactant or biopolymer.


Do we overemphasize the role of culture in the behavior of racial/ethnic minorities? Evidence of a cultural (mis)attribution bias in American psychology.
Although culture influences all human beings, there is an assumption in American psychology that culture matters more for members of certain groups. This article identifies and provides evidence of the cultural (mis)attribution bias: a tendency to overemphasize the role of culture in the behavior of racial/ethnic minorities, and to underemphasize it in the behavior of Whites. Two studies investigated the presence of this bias with an examination of a decade of peer reviewed research conducted in the United States (N = 434 articles), and an experiment and a survey with psychology professors in the United States (N = 361 psychologists). Archival analyses revealed differences in the composition of samples used in studies examining cultural or noncultural psychological phenomena. We also find evidence to suggest that psychologists in the United States favor cultural explanations over psychological explanations when considering the behavior and cognition of racial/ethnic minorities, whereas the opposite pattern emerged in reference to Whites. The scientific ramifications of this phenomenon, as well as alternatives to overcome it, are discussed in detail. (PsycINFO Database Record


IgE and IgG binding of peptides expressed from fragments of cDNA encoding the major house dust mite allergen Der p I.
Large peptides expressed from cDNA fragments of a clone encoding the mite allergen Der p I were able to bind IgE and IgG in sera from allergic individuals. The binding was found for peptides from sequences throughout the molecule, with at least five regions, comprising residues 1-56, 53-99, 98-140, 166-194, and 188-222. The only limitation was that more than 30 amino acid residues were required for consistent binding. Each of seven sera examined showed a different profile of antibody binding to the peptides. For the most part the pattern of IgE and IgG binding to the peptides for each serum was similar, demonstrating a concordant repertoire. In 5/7 sera, however, IgG bound to some peptides which had little or no IgE binding activity, thus showing more diverse specificities. It is suggested that some divergence of repertoire can develop during the maturation of the B cell response.


Lung fibrosis-associated surfactant protein A1 and C variants induce latent transforming growth factor β1 secretion in lung epithelial cells.
Missense mutations of surfactant proteins are recognized as important causes of inherited lung fibrosis. Here, we study rare and common surfactant protein (SP)-A1 and SP-C variants, either discovered in our familial pulmonary fibrosis cohort or described by others. We show that expression of two SP-A1 (R219W and R242*) and three SP-C (I73T, M71V, and L188Q) variant proteins lead to the secretion of the profibrotic latent transforming growth factor (TGF)-β1 in lung epithelial cell lines. The secreted TGF-β1 is capable of autocrine and paracrine signaling and is dependent upon expression of the latent TGF-β1 binding proteins. The dependence upon unfolded protein response (UPR) mediators for TGF-β1 induction differs for each variant. TGF-β1 secretion induced by the expression of the common SP-A1 R219W variant is nearly completely blocked by silencing the UPR transducers IRE-1α and ATF6. In contrast, the secretion of TGF-β1 induced by two rare SP-C mutant proteins (I73T and M71V), is largely unaffected by UPR silencing or by the addition of the small molecular chaperone 4-phenylbutyric acid, implicating a UPR-independent mechanism for these variants. Blocking TGF-β1 secretion reverses cell death of RLE-6TN cells expressing these SP-A1 and SP-C variants suggesting that anti-TGF-β therapeutics may be beneficial to this molecularly defined subgroup of pulmonary fibrosis patients.


Is This Broken Bone Because of Abuse? Characteristics and Comorbid Diagnoses in Older Adults with Fractures.
To examine the relationship between individual characteristics and potential correlates of elder abuse in older adults who present with fractures. Cross-sectional analysis of deidentified data extracted from medical records. Academic medical center. Individuals aged 65 and with a primary diagnosis of any fracture admitted to an outpatient department or emergency department (ED) in a single southern California medical center over a 36-month period (N = 652). Participant characteristics included demographic characteristics, number of medical visits, and point of service. Corresponding International Classification of Diseases, Ninth Revision (ICD-9) codes, E-codes, and V-codes were extracted to identify cause, location, and type of fracture. The presence of 13 potential correlates of abuse as captured by ICD-9 codes were extracted and summed. Descriptive statistics and regression models were used for analyses. Mean age of participants was 77.2, 58% were female (58%), 60% were white (60%), and 46% had one or more potential correlates of abuse. In bivariate analyses, older age (≥80), dementia, seeking care in the ED (vs inpatient or outpatient clinics), only one visit to a medical facility (vs multiple visits) in the 36-month study period, cause of fracture as something other than a fall, and fractures of the head or face were more likely to have at least one correlate of abuse. In logistic regression, dementia (B = 0.794, standard error (SE) = 0.280); seeking care in the ED (vs outpatient or outpatient clinics) (B = 1.86, SE = 0.302); at least two visits to a medical facility (vs multiple visits) (B = -0.585, SE = 0.343); and fracture of the back (B = 0.730, SE = 0.289), head (B = 1.22, SE = 0.333), and face (B = 1.28, SE = 0.474) were associated with the presence of at least one correlate of abuse. Certain characteristics in older adults with fracture are associated with potential correlates of abuse. Medical practitioners should have a heightened awareness when these signs are present.


Conscientiousness and Effort-Related Cardiac Activity in Response to Piece-Rate Cash Incentives.
Although conscientiousness predicts many aspects of motivation, from delay of gratification to higher achievement, its relationship to responses to monetary incentives is surprisingly inconsistent. Several studies have found null or relationships between conscientiousness and behavioral performance in piece-rate, pay-for-performance tasks, in which people earn money for each unit of work completed. In the present study, we examined the role of conscientiousness in effort-related cardiac activity and behavioral performance during a pay-for-performance task. People worked on a self-paced, piece-rate cognitive task in which they earned 1 cent or 5 cents, manipulated within-person, for each correct response. Conscientiousness predicted greater physiological effort (i.e., shorter pre-ejection period [PEP] reactivity) as incentives increased but had no effect on behavioral performance. The findings suggest that conscientiousness is significantly related to effort for piece-rate tasks, and they reinforce a core idea in motivational intensity theory: effort, performance, and persistence are distinct outcomes that often diverge, so drawing conclusions about effort from performance can be complex.


"Notify your partners--it's the law": HIV providers and mandatory disclosure.
HIV care providers in the United States must counsel clients about disclosure to sexual partners and report anyone who is suspected of noncompliance. This study compared provider attitudes and practices in relation to counseling clients about mandatory disclosure in North Carolina and Alabama, the 2 states with similar HIV epidemiology but different laws for HIV control. Personal interviews were conducted with 20 providers in each state (n = 40). The results were analyzed in a qualitative, cross-comparison method to identify patterns of convergence or difference. Providers in both states believed that clients often failed to notify sexual partners and were secretive if questioned about disclosure. Differences in counseling styles and procedures for each state were noteworthy. Compared to Alabama, North Carolina had harsher penalties for nondisclosure, stricter and more standardized procedures for counseling, and providers expressed greater support for HIV criminalization. Although most North Carolina providers viewed the stricter standards as beneficial for HIV care and control, Alabama providers were likely to view such standards as a barrier to patient care. These results indicated a direct relation between state HIV law, provider attitudes, and counseling procedures for mandatory disclosure.


Co-expression of Argonaute2 Enhances Short Hairpin RNA-induced RNA Interference in Xenopus CNS Neurons In Vivo.
RNA interference (RNAi) is an evolutionarily conserved mechanism for sequence-specific gene silencing. Recent advances in our understanding of RNAi machinery make it possible to reduce protein expression by introducing short hairpin RNA (shRNA) into cells of many systems, however, the efficacy of RNAi-mediated protein knockdown can be quite variable, especially in intact animals, and this limits its application. We built adaptable molecular tools, pSilencer (pSi) and pReporter (pRe) constructs, to evaluate the impact of different promoters, shRNA structures and overexpression of Ago2, the key enzyme in the RNA-induced silencing complex, on the efficiency of RNAi. The magnitude of RNAi knockdown was evaluated in cultured cells and intact animals by comparing fluorescence intensity levels of GFP, the RNAi target, relative to mCherry, which was not targeted. Co-expression of human Ago2 with shRNA significantly enhanced efficiency of GFP knockdown in cell lines and in neurons of intact Xenopus tadpoles. Human H1- and U6-promotors alone or the U6-promotor with an enhancer element were equally effective at driving GFP knockdown. shRNA derived from the microRNA-30 design (shRNA(mir30)) enhanced the efficiency of GFP knockdown. Expressing pSi containing Ago2 with shRNA increased knockdown efficiency of an endogenous neuronal protein, the GluR2 subunit of the AMPA receptor, functionally accessed by recording AMPA receptor-mediated spontaneous synaptic currents in Xenopus CNS neurons. Our data suggest that co-expression of Ago2 and shRNA is a simple method to enhance RNAi in intact animals. While morpholino antisense knockdown is effective in Xenopus and Zebrafish, a principle advantage of the RNAi method is the possibility of spatial and temporal control of protein knockdown by use of cell type specific and regulatable pol II promoters to drive shRNA and Ago2. This should extend the application of RNAi to study gene function of intact brain circuits.


A new computationally efficient CAD system for pulmonary nodule detection in CT imagery.
Early detection of lung nodules is extremely important for the diagnosis and clinical management of lung cancer. In this paper, a novel computer aided detection (CAD) system for the detection of pulmonary nodules in thoracic computed tomography (CT) imagery is presented. The paper describes the architecture of the CAD system and assesses its performance on a publicly available database to serve as a benchmark for future research efforts. Training and tuning of all modules in our CAD system is done using a separate and independent dataset provided courtesy of the University of Texas Medical Branch (UTMB). The publicly available testing dataset is that created by the Lung Image Database Consortium (LIDC). The LIDC data used here is comprised of 84 CT scans containing 143 nodules ranging from 3 to 30mm in effective size that are manually segmented at least by one of the four radiologists. The CAD system uses a fully automated lung segmentation algorithm to define the boundaries of the lung regions. It combines intensity thresholding with morphological processing to detect and segment nodule candidates simultaneously. A set of 245 features is computed for each segmented nodule candidate. A sequential forward selection process is used to determine the optimum subset of features for two distinct classifiers, a Fisher Linear Discriminant (FLD) classifier and a quadratic classifier. A performance comparison between the two classifiers is presented, and based on this, the FLD classifier is selected for the CAD system. With an average of 517.5 nodule candidates per case/scan (517.5+/-72.9), the proposed front-end detector/segmentor is able to detect 92.8% of all the nodules in the LIDC/testing dataset (based on merged ground truth). The mean overlap between the nodule regions delineated by three or more radiologists and the ones segmented by the proposed segmentation algorithm is approximately 63%. Overall, with a specificity of 3 false positives (FPs) per case/patient on average, the CAD system is able to correctly identify 80.4% of the nodules (115/143) using 40 selected features. A 7-fold cross-validation performance analysis using the LIDC database only shows CAD sensitivity of 82.66% with an average of 3 FPs per CT scan/case.


Late mortality during the first year after acute traumatic spinal cord injury: a prospective, population-based study.
Little is known about the possible impact of the system of care on mortality during the first year after acute traumatic spinal cord injury (TSCI). To evaluate late mortality (i.e., >7 days after trauma) during the first year after acute TSCI in 2 European Union (EU) regions, Thessaloniki in Greece and Stockholm in Sweden. This paper is part of the Stockholm Thessaloniki Acute Traumatic Spinal Cord Injury Study (STATSCIS), which is a prospective, population-based study. Incidence cohorts of TSCI cases were identified and followed up in both study regions through STATSCIS. Data from Thessaloniki region were collected through physical examination, medical records review, and interviews with TSCI individuals and the medical teams. Data from Stockholm were retrieved mainly from the Nordic Spinal Cord Injury Registry, as well as from direct contact with all intensive care facilities of the region. The annual case mortality rate after acute TSCI was nearly 20% in Thessaloniki and 0% in Stockholm. The mean time of survival after trauma for the 12 mortality cases of Thessaloniki was 47 days (median = 24, SD +/- 67, range = 8-228). Factors associated with mortality were higher age and presence of comorbid spinal disorders but also the inefficient transfer logistics, initially missed spinal instability, and unsuccessfully treated complications. The annual case mortality rate in Thessaloniki was dramatically higher than in Stockholm. The different approaches to care, one systematic and the other not, is postulated to be an important factor leading to such major discrepancies between the outcomes of these 2 EU regions.


Sampling from four geographically divergent young female populations demonstrates forensic geolocation potential in microbiomes.
Studies of human microbiomes using new sequencing techniques have increasingly demonstrated that their ecologies are partly determined by the lifestyle and habits of individuals. As such, significant forensic information could be obtained from high throughput sequencing of the human microbiome. This approach, combined with multiple analytical techniques demonstrates that bacterial DNA can be used to uniquely identify an individual and to provide information about their life and behavioral patterns. However, the transformation of these findings into actionable forensic information, including the geolocation of the samples, remains limited by incomplete understanding of the effects of confounding factors and the paucity of diverse sequences. We obtained 16S rRNA sequences of stool and oral microbiomes collected from 206 young and healthy females from four globally diverse populations, in addition to supporting metadata, including dietary and medical information. Analysis of these microbiomes revealed detectable geolocation signals between the populations, even for populations living within the same city. Accounting for other lifestyle variables, such as diet and smoking, lessened but does not remove the geolocation signal.


Lesion mapping of social problem solving.
Accumulating neuroscience evidence indicates that human intelligence is supported by a distributed network of frontal and parietal regions that enable complex, goal-directed behaviour. However, the contributions of this network to social aspects of intellectual function remain to be well characterized. Here, we report a human lesion study (n = 144) that investigates the neural bases of social problem solving (measured by the Everyday Problem Solving Inventory) and examine the degree to which individual differences in performance are predicted by a broad spectrum of psychological variables, including psychometric intelligence (measured by the Wechsler Adult Intelligence Scale), emotional intelligence (measured by the Mayer, Salovey, Caruso Emotional Intelligence Test), and personality traits (measured by the Neuroticism-Extraversion-Openness Personality Inventory). Scores for each variable were obtained, followed by voxel-based lesion-symptom mapping. Stepwise regression analyses revealed that working memory, processing speed, and emotional intelligence predict individual differences in everyday problem solving. A targeted analysis of specific everyday problem solving domains (involving friends, home management, consumerism, work, information management, and family) revealed psychological variables that selectively contribute to each. Lesion mapping results indicated that social problem solving, psychometric intelligence, and emotional intelligence are supported by a shared network of frontal, temporal, and parietal regions, including white matter association tracts that bind these areas into a coordinated system. The results support an integrative framework for understanding social intelligence and make specific recommendations for the application of the Everyday Problem Solving Inventory to the study of social problem solving in health and disease.


A Synergistic Anticancer FAK and HDAC Inhibitor Combination Discovered by a Novel Chemical-Genetic High-Content Phenotypic Screen.
We mutated the focal adhesion kinase (FAK) catalytic domain to inhibit binding of the chaperone Cdc37 and ATP, mimicking the actions of a FAK kinase inhibitor. We reexpressed mutant and wild-type FAK in squamous cell carcinoma (SCC) cells from which endogenous FAK had been deleted, genetically fixing one axis of a FAK inhibitor combination high-content phenotypic screen to discover drugs that may synergize with FAK inhibitors. Histone deacetylase (HDAC) inhibitors represented the major class of compounds that potently induced multiparametric phenotypic changes when FAK was rendered kinase-defective or inhibited pharmacologically in SCC cells. Combined FAK and HDAC inhibitors arrest proliferation and induce apoptosis in a subset of cancer cell lines in vitro and efficiently inhibit their growth as tumors in vivo Mechanistically, HDAC inhibitors potentiate inhibitor-induced FAK inactivation and impair FAK-associated nuclear YAP in sensitive cancer cell lines. Here, we report the discovery of a new, clinically actionable, synergistic combination between FAK and HDAC inhibitors.


Pulmonary Infarction due to Paget-Schroetter Syndrome and Nephrotic Syndrome.
BACKGROUND Risk factors for venous thromboembolism can include a combination of genetic, anatomic, and physiologic factors, some of which are modifiable. Patients presenting to the hospital with venous thromboembolism may have multiple risk factors that require testing beyond the initial admission labs and hypercoagulability screening panel. CASE REPORT We describe a right-handed patient who lifts weights for exercise, who presented with pulmonary infarcts and clot in the right superior vena cava/subclavian vein. These were due to a combination of 1) an acquired hypercoagulability from minimal change disease and 2) dynamic anatomic narrowing of the subclavian vein, which is known as Paget-Schroetter syndrome. Despite normal serum levels of antithrombin, protein C and S, his serum albumin was low, which prompted workup for proteinuria. Testing revealed nephrotic range proteinuria as well as dynamic occlusion of the right subclavian vein on magnetic resonance venography only when the patient lifted and externally rotated his arms. CONCLUSIONS This case report highlights the need for a thorough history and physical examination, as well as additional testing in some patients beyond the initial admission laboratory tests and screening panel for hypercoagulability. Tests could include diagnostic imaging testing with provoking maneuvers, which can help elucidate dynamic physiology. Such testing, when appropriate, can help to inform the treatment plan and prevent recurrent thromboses.


Bioassays with terrestrial and aquatic species as monitoring tools of hydrocarbon degradation.
In this study chemical analyses and ecotoxicity tests were applied for the assessment of a heavily hydrocarbon-contaminated soil prior and after the application of a remediation procedure that consisted in the stimulation of soil autochthonous populations of hydrocarbon degraders in static-ventilated biopiles. Terrestrial bioassays were applied in mixtures of test soils and artificial control soil and studied the survival and reproduction of Eisenia fetida and the avoidance response of E. fetida and Folsomia candida. Effects on aquatic organisms were studied by means of acute tests with Vibrio fischeri, Raphidocelis subcapitata, and Daphnia magna performed on aqueous elutriates from test soils. The bioremediation procedure led to a significant reduction in the concentration of hydrocarbons (from 34264 to 3074 mg kg(-1), i.e., 91 % decrease) and toxicity although bioassays were not able to report a percentage decrease of toxicity as high as the percentage reduction. Sublethal tests proved the most sensitive terrestrial bioassays and avoidance tests with earthworms and springtails showed potential as monitoring tools of hydrocarbon remediation due to their high sensitivity and short duration. The concentrations of hydrocarbons in water extracts from test soils were 130 and 100 μg L(-1) before and after remediation, respectively. Similarly to terrestrial tests, most aquatic bioassays detected a significant reduction in toxicity, which was almost negligible at the end of the treatment. D. magna survival was the most affected by soil elutriates although toxicity to the crustacean was associated to the salinity of the samples rather than to the concentration of hydrocarbons. Ecotoxicity tests with aqueous soil elutriates proved less relevant in the assessment of hydrocarbon-contaminated soils due to the low hydrosolubility of hydrocarbons and the influence of the physicochemical parameters of the aquatic medium.


Is disability pension a risk indicator for future need of psychiatric healthcare or suicidal behavior among MS patients- a nationwide register study in Sweden?
Mental disorders and suicidal behavior are common in patients with multiple sclerosis (MS), they also carry a higher risk of disability pension (DP). Our aim was to investigate if DP and other factors are associated with psychiatric disorders and suicidal behavior among MS patients, and whether DP is a stronger risk indicator among certain groups. A prospective population-based cohort study with six-year follow-up (2005-2010), including 11 346 MS patients who in 2004 were aged 16-64 and lived in Sweden. Incidence rate ratios (IRR) with 95 % confidence intervals (CI) were calculated. MS patients on DP had a modestly higher risk of requiring psychiatric healthcare, IRR: 1.36 (95 % CI: 1.18-1.58). MS patients with previous psychiatric healthcare had a higher IRR for both psychiatric healthcare and suicidal behavior; 2.32 (2.18-2.47) and 1.91 (1.59-2.30), respectively. DP moderated the association between sex and psychiatric healthcare, where women on DP displayed higher risk than men, X(2) 4.74 (p = 0.03). The findings suggest that losing one's role in work life aggravates rather than alleviates the burden of MS, as MS patients on DP seem to have a higher need for psychiatric healthcare, especially among women; which calls for extra awareness among clinicians.


Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation.
Hepatocellular adenomas (HCAs) are benign liver tumors that can be assigned to molecular subtypes based on inactivating mutations in hepatocyte nuclear factor 1A, activating mutations in β-catenin, or activation of inflammatory signaling pathways. We aimed to update the classification system for HCA and associate the subtypes with disease risk factors and complications. We analyzed expression levels of 20 genes and sequenced exon regions of 8 genes (HNF1A, IL6ST, CTNNB1, FRK, STAT3, GNAS, JAK1, and TERT) in 607 samples of 533 HCAs from 411 patients, collected from 28 centers mainly in France from 2000 and 2014. We performed gene expression profile, RNA sequence, whole-exome and genome sequence, and immunohistochemical analyses of select samples. Molecular data were associated with risk factors, histopathology, bleeding, and malignant transformation. Symptomatic bleeding occurred in 14% of the patients (85% of cases were female, median age, 38 years); 7% of the nodules were borderline between HCA and hepatocellular carcinoma, and 3% of patients developed hepatocellular carcinoma from HCA. Based on molecular features, we classified HCA into 8 subgroups. One new subgroup, composed of previously unclassified HCA, represented 4% of HCAs overall and was associated with obesity and bleeding. These tumors were characterized by activation of sonic hedgehog signaling, due to focal deletions that fuse the promoter of INHBE with GLI1. Analysis of genetic heterogeneity among multiple HCAs, from different patients, revealed a molecular subtype field effect; multiple tumors had different mutations that deregulated similar pathways. Specific molecular subtypes of HCA associated with various HCA risk factors, including imbalances in estrogen or androgen hormones. Specific molecular subgroup of HCA with β-catenin and sonic hedgehog activation associated with malignant transformation and bleeding, respectively. Using sequencing and gene expression analyses, we identified a subgroup of HCA characterized by fusion of the INHBE and GLI1 genes and activation of sonic hedgehog pathway. Molecular subtypes of HCAs associated with different patients' risk factors for HCA, disease progression, and pathology features of tumors. This classification system might be used to select treatment strategies for patients with HCA.


Facial discrimination in body dysmorphic, obsessive-compulsive and social anxiety disorders.
Body dysmorphic disorder (BDD) is characterized by preoccupation with perceived flaws in one's own appearance. Several risk factors such as aesthetic perceptual sensitivity have been proposed to explain BDD's unique symptomatology. Although research on facial discrimination is limited so far, the few existing studies have produced mixed results. Thus, the purpose of this study was to further examine facial discrimination in BDD. We administered a facial discrimination paradigm, which allows to assess the ability to identify slight to strong facial changes (e.g., hair loss, acne) when presented with an original (unmodified) facial image, relative to a changed (modified) facial image. The experiment was administered in individuals with BDD, social anxiety disorder, obsessive-compulsive disorder, and mentally healthy controls (32 per group, respectively). Overall, groups did not differ with respect to their ability to correctly identify facial aberrations when presented with other people's faces. Our findings do not support the hypothesis of enhanced general aesthetic perceptual sensitivity in individuals with (vs. without) BDD.


Population structure and association analyses of the core collection of hexaploid accessions conserved ex situ in the Japanese gene bank NBRP-Wheat.
In this study, we investigated the genetic diversity and population structure of the core collection of hexaploid wheat accessions in the Japanese wheat gene bank NBRP-Wheat. The core collection, consisting of 188 accessions of Triticum aestivum, T. spelta, T. compactum, T. sphaerococcum, T. macha and T. vavilovii, was intensively genotyped by DArTseq markers and consisted of 20,186 SNPs and 60,077 present and absent variations (PAVs). Polymorphic markers were distributed in all chromosomes, with a tendency for smaller numbers on the D-genome chromosomes. We examined the population structure by Bayesian clustering and principal component analysis with a general linear model. Overall, the core collection was divided into seven clusters. Non-admixture accessions in each cluster indicated that the clusters reflect the geographic distribution of the accessions. Both structure analyses strongly suggested that the cluster consisting of T. spelta and T. macha is out-grouped from other hexaploid wheat accessions. We performed genome-wide association analysis pilot studies for nine quantitative and seven qualitative traits and found marker-trait associations for all traits but one, indicating that the current core collection will be useful for detecting uncharacterized QTLs associated with phenotypes of interest.


Solid olive waste in environmental cleanup: enhanced nitrite ion removal by ZnCl2-activated carbon.
This communication describes how olive solid wastes can be used to prepare activated carbon (AC), with soundly high surface areas, suitable to remove nitrite ions from water. Solid olive wastes, so called Jeft, separated as unwanted bi-products from olive oil mills, have been converted into charcoal. The charcoal was then physically and/or chemically activated using different compounds namely conc. H3PO4 or ZnCl2. Charcoal carbonization was performed under inert atmosphere to avoid loss of heated carbon by oxidation with air. Surface area measurements and SEM micrographs showed that activation using ZnCl2 yields AC with highest surface area and more porous surfaces. The ZnCl2-activated carbon was then used to remove nitrite ions from water by adsorption. Effects of different parameters on value of surface area and adsorption capacity of the AC were investigated. Commercial AC materials were used as reference for comparison. The AC showed higher adsorption capacity toward nitrite than other reported adsorbents. The results suggest that using 5 g of the ZnCl2-activated carbon per liter of heavily nitrite-contaminated water (50 ppm) may bring the contaminant concentration down to the WHO accepted concentration limits within 60 min. This work highlights the future feasibility of using olive waste as feed stocks to produce useful renewable materials while keeping in mind the wisdom "make wastes work in environmental protection".


Differences in physical fitness of male and female recruits in gender-integrated army basic training.
To evaluate gender differences in physical fitness before and after a 4-month gender-integrated basic training (BT) course and to determine whether this program effectively narrowed the differences between male and female soldiers in physical fitness parameters. One hundred and thirty-seven soldiers (109 females and 28 males) successfully completed a 4-month BT course in the Israeli Defense Forces (IDF). The subject's physical fitness was evaluated pre- and post-BT by three laboratory tests [the maximal aerobic capacity (VO2max), the Leonardo Ground Reaction Force Plate, and the Wingate Anaerobic Test (WAnT)] and by the IDF physical fitness test (IDF-PT). Females significantly improved their scores in the IDF-PT and laboratory aerobic tests, whereas males significantly improved only in the IDF-PT. After BT, gender differences narrowed by approximately 4% in all tests except upper body strength. Although fitness improvement after BT was marginally higher in females than males, resulting in a slight narrowing of the gender differences, a significant gender gap in physical fitness still exists after BT. There was only a small overlap in physical abilities at the beginning of BT, which indicated vast differences in physical fitness between the genders. As expected, integrated combat BT improved physical fitness. Although females demonstrated marginally higher improvement in aerobic capacity, basic physiological gender differences were still evident at the end of the training regimen.


Efficacy and Safety of Recurrent Paraesophageal Hernia Repair with Roux-en-Y Gastric Bypass.
Roux-en-Y gastric bypass (RYGB) has been explored as a revisional option to failed paraesophageal hernia (PEH) repair with fundoplication, particularly in patients suffering from obesity. However, few studies have assessed long-term outcomes of RYGB with revisional PEH repair in regard to acid-suppressing medication use. We retrospectively identified 19 patients who underwent revisional PEH repair with RYGB between 2011 and 2018. The median operative time was 232 minutes with a median hospital length of stay of two days. The median length of follow-up was 24 months. Two patients (10.5%) had complications in the first 30 days, and five patients (26.3%) had complications within one year. Of the 12 patients on preoperative acid suppression, 6 (50%) were either off medication or on reduced dose at 12 months. The median BMI decrease was 14.4 kg/m² at 12 months and did not change significantly afterward. Although rates of acid-suppression medication use did not change overall after revisional PEH repair with RYGB, patients experienced successful long-term management of morbid obesity and sustained weight loss. Revisional PEH repair with RYGB is a safe and effective option, with a complication rate comparable with the reported rates after revisional foregut procedures such as revisional Nissen fundoplication.


Nucleation and growth on defect sites: experiment-theory comparison for Pd/MgO(001).
It is well established that nucleation of metal clusters on oxide and halide surfaces is typically dominated by defect sites. Rate equation models of defect nucleation have been developed and applied to these systems. By comparing the models with nucleation density experiments, energies for defect trapping, adsorption, surface diffusion and pair binding have been deduced in favourable cases, notably for Pd deposited on Ar-cleaved MgO(001). However, the defects responsible remain largely unknown. More recently, several types of ab initio calculation have been presented of these energies for Pd and related metals on MgO(001) containing several types of surface defect; these calculated values are surveyed, and some are widely divergent. New rate equation nucleation density predictions are presented using the calculated values. Some calculations, for some defect types, are much closer to experiment than others; the singly charged F(s)(+) centre and the neutral divacancy emerge as candidate defects. In these two cases, the Pd/MgO(001) nucleation density predictions agree well with experiment, and the corresponding surface defects deserve to be taken seriously. Energy and entropy values are discussed in the light of differences in calculated charge redistribution between the metal atoms, clusters and (charged) surface defects, and (assumed or calculated) cluster geometries.


Microfibril assembly by granules of chitin synthetase.
Purified preparations of chitin synthetase (EC 188.8.131.52; UDP-2-acetamido-2-deoxy-D-glucose:chitin 4-beta-acetamidodeoxyglucosyltransferase), capable of forming microfibrils in vitro, were isolated from yeast cells of Mucor rouxii. Chitin synthetase was obtained either by substrate-induced liberation of bound enzyme (54,000 x g pellet) or by isolation of unbound enzyme present in the 54,000 x g supernatant of a cell-free extract. Both preparations contained ellipsoidal granules from about 350 to 1000 A diameter. Many granules exhibited a marked depression. No typical unit membrane profiles appeared in thin sections of glutaraldehyde/OsO4-fixed samples. Upon incubation with substrate and activators, chitin microfibrils were produced. The microfibrils were often found intimately associated with granules. The most common configurations were: a microfibril with a granule at one end, or two microfibrils "arising" from the same granule. These findings lend support to the granule hypothesis for the elaboration of cell wall microfibrils by end-synthesis.


Analysis of archived residual newborn screening blood spots after whole genome amplification.
Deidentified newborn screening bloodspot samples (NBS) represent a valuable potential resource for genomic research if impediments to whole exome sequencing of NBS deoxyribonucleic acid (DNA), including the small amount of genomic DNA in NBS material, can be overcome. For instance, genomic analysis of NBS could be used to define allele frequencies of disease-associated variants in local populations, or to conduct prospective or retrospective studies relating genomic variation to disease emergence in pediatric populations over time. In this study, we compared the recovery of variant calls from exome sequences of amplified NBS genomic DNA to variant calls from exome sequencing of non-amplified NBS DNA from the same individuals. Using a standard alignment-based Genome Analysis Toolkit (GATK), we find 62,000-76,000 additional variants in amplified samples. After application of a unique kmer enumeration and variant detection method (RUFUS), only 38,000-47,000 additional variants are observed in amplified gDNA. This result suggests that roughly half of the amplification-introduced variants identified using GATK may be the result of mapping errors and read misalignment. Our results show that it is possible to obtain informative, high-quality data from exome analysis of whole genome amplified NBS with the important caveat that different data generation and analysis methods can affect variant detection accuracy, and the concordance of variant calls in whole-genome amplified and non-amplified exomes.


Fibrinolytic parameters in patients undergoing total hip replacement: relationship with the development of asymptomatic deep vein thrombosis and diagnostic usefulness of venous occlusion.
It has been suggested that impaired fibrinolytic activity contributes to deep vein thrombosis in orthopedic surgery. Studying the fibrinolytic system following venous occlusion has been proposed as a good method of detecting the risk of this postoperative complication. The objective of this work was to verify whether venous occlusion represents a reliable method of detecting an impaired fibrinolytic response after total hip replacement. Thirty-two consecutive patients undergoing total hip replacement were studied. Citrated blood samples were taken from each patient the day before surgery and on postoperative days 1, 3, and 7, before and after venous occlusion, in order to evaluate plasma levels of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI-1). All patients underwent bilateral phlebography 10 days after surgery. Seven out of 32 patients (21.9%) developed deep venous thrombosis (DVT) according to the venographic test. After surgery, an increase in t-PA antigen levels was detected both in patients who developed DVT and in those who did not, with a significant increase on the first and seventh days after surgery only in the non-DVT group. After 10-min venous occlusion, t-PA antigen levels increased at all postoperative recordings in both groups of patients, but most significantly on days 1 and 7 after surgery. PAI-1 antigen plasma levels, when measured before venous occlusion, increased only in non-DVT patients on the seventh postoperative day. After venous occlusion, a difference was found between the two groups only postoperatively on day 7 with regard to PAI-1 levels. According to our results, no impaired fibrinolytic response was found in DVT patients. In addition, venous stasis seems to give no further information with respect to basal values in the early detection of postoperative thromboembolic complications in orthopedic patients.


Annual summary of vital statistics: 2000.
The birth rate in 2000 (preliminary data) was 14.8 births per 1000 population, an increase of 2% from 1999 (14.5). The fertility rate, births per 1000 women aged 15 to 44 years, increased 3% to 67.6 in 2000, compared with 65.9 in 1999. The 2000 increases in births and the fertility rate were the third consecutive yearly increases, the largest in many years, halting the steady decline in the number of births and fertility rates in the 1990s. Fertility rates for total white, non-Hispanic white, black, and Native American women each increased about 2% in 2000. The fertility rate for black women, which declined 19% from 1990 to 1996, has changed little since 1996. The rate for Hispanic women rose 4% in 2000 to reach the highest level since 1993. Birth rates for women 30 years or older continued to increase. The proportion of births to unmarried women remained about the same at one third, but the number of births rose 3%. The birth rate for teen mothers declined again for the ninth consecutive year. The use of timely prenatal care (83.2%) remained unchanged in 2000, and was essentially unchanged for non-Hispanic white (88.5%), black (74.2%), and Hispanic (74.4%) mothers. The number and rate of multiple births continued their dramatic rise, but all of the increase was confined to twins; for the first time in more than a decade, the number of triplet and higher-order multiple births declined (4%) between 1998 and 1999 (multiple birth information is not available in preliminary 2000 data). The overall increases in multiple births account, in part, for the lack of improvement in the percentage of low birth weight (LBW) births. LBW remained at 7.6% in 2000. The infant mortality rate (IMR) dropped to 6.9 per 1000 live births (preliminary data) in 2000 (the rate was 7.1 in 1999). The ratio of the IMR among black infants to that for white infants was 2.5 in 2000, the same as in 1999. Racial differences in infant mortality remain a major public health concern. The role of low birth weight in infant mortality remains a major issue. Among all of the states, Utah and Maine had the lowest IMRs. State-by-state differences in IMR reflect racial composition, the percentage LBW, and birth weight-specific neonatal mortality rates for each state. The United States continues to rank poorly in international comparisons of infant mortality. Expectation of life at birth reached a record high of 76.9 years for all gender and race groups combined. Death rates in the United States continue to decline. The age-adjusted death rate for suicide declined 4% between 1999 and 2000; homicide declined 7%. Death rates for children 19 years of age or less declined for 3 of the 5 leading causes in 2000; cancer and suicide levels did not change for children as a group. A large proportion of childhood deaths, however, continue to occur as a result of preventable injuries.


Yearly fluctuations of flower landscape in a Mediterranean scrubland: Consequences for floral resource availability.
Species flower production and flowering phenology vary from year to year due to extrinsic factors. Inter-annual variability in flowering patterns may have important consequences for attractiveness to pollinators, and ultimately, plant reproductive output. To understand the consequences of flowering pattern variability, a community approach is necessary because pollinator flower choice is highly dependent on flower context. Our objectives were: 1) To quantify yearly variability in flower density and phenology; 2) To evaluate whether changes in flowering patterns result in significant changes in pollen/nectar composition. We monitored weekly flowering patterns in a Mediterranean scrubland community (23 species) over 8 years. Floral resource availability was estimated based on field measures of pollen and nectar production per flower. We analysed inter-annual variation in flowering phenology (duration and date of peak bloom) and flower production, and inter-annual and monthly variability in flower, pollen and nectar species composition. We also investigated potential phylogenetic effects on inter-annual variability of flowering patterns. We found dramatic variation in yearly flower production both at the species and community levels. There was also substantial variation in flowering phenology. Importantly, yearly fluctuations were far from synchronous across species, and resulted in significant changes in floral resources availability and composition at the community level. Changes were especially pronounced late in the season, at a time when flowers are scarce and pollinator visitation rates are particularly high. We discuss the consequences of our findings for pollinator visitation and plant reproductive success in the current scenario of climate change.


Strategies for engaging patients and families in collaborative care programs for depression and anxiety disorders: A systematic review.
Patients and families are often referred to as important partners in collaborative mental health care (CMHC). However, how to meaningfully engage them as partners remains unclear. We aimed to identify strategies for engaging patients and families in CMHC programs for depression and anxiety disorders. We updated a Cochrane review of CMHC programs for depression and anxiety disorders. Searches were conducted in Cochrane CCDAN and CINAHL, complemented by additional database searches, trial registry searches, and cluster searches for 'sibling' articles. Coding and data extraction of engagement strategies was an iterative process guided by a conceptual framework. We used narrative synthesis and descriptive statistics to report on findings. We found 148 unique CMCH programs, described in 578 articles. Most programs (96%) featured at least one strategy for engaging patients or families. Programs adopted 15 different strategies overall, with a median of two strategies per program (range 0-9 strategies). The most common strategies were patient education (87% of programs) and self-management supports (47% of programs). Personalized care planning, shared decision making, and family or peer supports were identified in fewer than one third of programs. Our search strategy was designed to capture programs evaluated in clinical trials and so other innovative programs not studied in trials were likely missed. Most CMHC programs for depression and anxiety disorders adopted a limited number of strategies to engage patients and families in their care. However, this review identifies numerous strategies that can be used to strengthen the patient- and family-centeredness of collaborative care.


Upregulated inducible co-stimulator (ICOS) and ICOS-ligand in inclusion body myositis muscle: significance for CD8+ T cell cytotoxicity.
Interactions between inducible co-stimulatory molecule (ICOS) and ICOS-ligand (ICOS-L) are crucial for T-cell co-stimulation, effector cell differentiation and memory CD8+ T-cell activation. Because in the muscle of patients with sporadic inclusion body myositis (sIBM) clonally expanded CD8+ T cells invade major histocompatibility complex (MHC) class I-expressing muscle fibres, we investigated ICOS.ICOS-L interactions and correlated their expression with perforin, a marker for cytotoxic effector function by autoinvasive CD8+ T cells. The mRNA from 20 muscle biopsies of sIBM, 20 non-inflammatory or dystrophic controls, two dermatomyositis (DM) and two polymyositis (PM) patients was reverse transcribed and reamplified by semi-quantitative and quantitative reverse transcription-polymerase chain reaction (RT-PCR), using primers for ICOS, ICOS-L and perforin. The glyceraldehyde 3-phosphate dehydrogenase (GAPDH)-normalized ratio of ICOS, ICOS-L and perforin expression was compared with the degree of endomysial inflammation. Protein expression of ICOS, ICOS-L and perforin was confirmed by immunohistochemistry. We demonstrate that ICOS-L mRNA was upregulated in sIBM (arbitrary units, median +/- SEM: 48.6 +/- 14.9) compared with controls (6.2 +/- 17.8, P < 0.05) and significantly correlated with the expression of ICOS (53.9 +/- 16.6 versus 6.7 +/- 8.9 in controls, P < 0.001). By triple labelling immunohistochemistry, the CD8+ T cells in sIBM and PM were found to invade ICOS-L- and MHC class I-co-expressing muscle fibres. Among the autoinvasive CD8+ T cells, however, only a subset of approximately 5-10% were ICOS positive, and thereby perceptive for ICOS.ICOS-L signalling at the immunological synapse. In contrast, in Duchenne muscular dystrophy and DM, although ICOS and ICOS-L mRNA expression was also increased, the majority of ICOS-L- and ICOS-positive cells were in the perimysial regions and connective tissue. The mRNA for perforin was increased in sIBM (28.1 +/- 8.7) compared with controls (4.3 +/- 11.2, P = 0.18), and significantly correlated with mRNA of ICOS, ICOS-L and the degree of endomysial inflammation as assessed in coded haematoxylin/eosin tissue sections. By triple immunohistochemical staining and cell counting, perforin granules were found in 71% of the autoinvasive CD8+ T cells that were also ICOS positive. Our data indicate that in sIBM there is upregulation of ICOS.ICOS-L co-stimulatory signalling in association with enhanced perforin expression by the autoinvasive CD8+ T cells. The findings support previous suggestions that in IBM, the muscle fibres have the capacity for antigen presentation, thereby activating a specific subset among the autoinvasive CD8+ T cells to exert a cytotoxic effect. The observations strengthen the immunopathogenesis of sIBM, and offer the basis for future therapeutic interventions targeting ICOS.ICOS-L co-stimulatory interactions.


Hepatobiliary Cancers, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.
The NCCN Guidelines for Hepatobiliary Cancers focus on the screening, diagnosis, staging, treatment, and management of hepatocellular carcinoma (HCC), gallbladder cancer, and cancer of the bile ducts (intrahepatic and extrahepatic cholangiocarcinoma). Due to the multiple modalities that can be used to treat the disease and the complications that can arise from comorbid liver dysfunction, a multidisciplinary evaluation is essential for determining an optimal treatment strategy. A multidisciplinary team should include hepatologists, diagnostic radiologists, interventional radiologists, surgeons, medical oncologists, and pathologists with hepatobiliary cancer expertise. In addition to surgery, transplant, and intra-arterial therapies, there have been great advances in the systemic treatment of HCC. Until recently, sorafenib was the only systemic therapy option for patients with advanced HCC. In 2020, the combination of atezolizumab and bevacizumab became the first regimen to show superior survival to sorafenib, gaining it FDA approval as a new frontline standard regimen for unresectable or metastatic HCC. This article discusses the NCCN Guidelines recommendations for HCC.


Evidence for a major premutagenic ethyldeoxythymidine-DNA adduct in an in vivo system: N-nitroso-N-ethylurea-treated Salmonella typhimurium.
Mutagenesis induced by N-nitroso-N-ethylurea (NEU) was assayed in four strains of Salmonella typhimurium which are known to be reverted to histidine prototrophy by mutations at A-T base pairs and by extragenic suppression. NEU-induced revertants were characterized for the presence of extragenic suppressors by their sensitivities to the histidine analogue, thiazolealanine. In strains carrying the plasmid, pKM101, only a small percentage of the revertants was due to suppressors, indicating that NEU gives rise to a major premutagenic adenine or thymidine-DNA adduct. In strains without plasmid, mutagenesis was much less efficient and resulted mainly from suppressors. Apparently error-prone DNA-repair plays an important role in mutagenesis via the A or T-DNA adduct in the plasmid-containing strains. Ethylmethanesulfonate (EMS), a mutagen known to form ethyladenines but not ethylthymidines, induced mutagenesis that resulted mainly from suppressors in all strains, and there was little inter-strain difference in the sensitivity to EMS. Since NEU, but not EMS, forms ethylthymidines in appreciable yield, and only NEU induced high percentages of revertants with mutations at A-T base pairs, it appears that at least one ethylthymidine is a major premutagenic adduct in NEU-induced mutagenesis.


Simultaneous detection of Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae in suspected cases of meningitis and septicemia using real-time PCR.
A single-tube 5' nuclease multiplex PCR assay was developed on the ABI 7700 Sequence Detection System (TaqMan) for the detection of Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae from clinical samples of cerebrospinal fluid (CSF), plasma, serum, and whole blood. Capsular transport (ctrA), capsulation (bexA), and pneumolysin (ply) gene targets specific for N. meningitidis, H. influenzae, and S. pneumoniae, respectively, were selected. Using sequence-specific fluorescent-dye-labeled probes and continuous real-time monitoring, accumulation of amplified product was measured. Sensitivity was assessed using clinical samples (CSF, serum, plasma, and whole blood) from culture-confirmed cases for the three organisms. The respective sensitivities (as percentages) for N. meningitidis, H. influenzae, and S. pneumoniae were 88.4, 100, and 91.8. The primer sets were 100% specific for the selected culture isolates. The ctrA primers amplified meningococcal serogroups A, B, C, 29E, W135, X, Y, and Z; the ply primers amplified pneumococcal serotypes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10A, 11A, 12, 14, 15B, 17F, 18C, 19, 20, 22, 23, 24, 31, and 33; and the bexA primers amplified H. influenzae types b and c. Coamplification of two target genes without a loss of sensitivity was demonstrated. The multiplex assay was then used to test a large number (n = 4,113) of culture-negative samples for the three pathogens. Cases of meningococcal, H. influenzae, and pneumococcal disease that had not previously been confirmed by culture were identified with this assay. The ctrA primer set used in the multiplex PCR was found to be more sensitive (P < 0.0001) than the ctrA primers that had been used for meningococcal PCR testing at that time.


Sepsis secondary to complicated skin and soft tissue infection caused by Ignatzschineria indica. First case report in Latin America.
Ignatzschineria is a recently recognized genus associated with larvae infestation Members of this genus are pathogens infrequently implicated in human disease. During the last decade, fewer than 10 cases of infection with Ignatzchineria species have been reported around the world. Bacteria of the genera Ignatzchineria and Wohlfahrtiimonas have been isolated from larvae of the parasitic fly Wohlfahrtia magnifica, which is found in Europe, Asia and North Africa, and is associated with myiasis in several animal species, but rarely in humans. We report the first case of sepsis associated with complicated skin and soft tissue infection caused by I. indica in Latin America. The clinical and molecular findings in our report add information to the accumulating data on emerging pathogens of this type, their geographic distribution, the correlation between the emergence of infectious diseases and social and economic inequalities, as well as the effects of global climate changes on potentially unusual distribution of vectors. We consider that fly larvae should be regarded as a potential source of specific arthropod-borne bacterial systemic infections.


Regeneration of submandibular salivary gland autografted in the rat tongue.
Autologous SMG fragments were implanted in tongues of male rats which were sacrificed 15-20 min, 24 hr, 72 hr, 1 week, or 8 weeks after implantation. The tongues were excised, fixed, and processed for light and electron microscopy. In addition, some rats were injected with [3H]-thymidine 1 hr before sacrifice and the labeling indices (L.I.) of the salivary epithelial and interstitial cells were calculated. Twenty-four hours after implantation, SMG autografts showed massive central necrosis with some acini and ducts surviving at the periphery of the lobules. There was marked infiltration of the autografts with neutrophils and macrophages. Also the basal laminae surrounding the necrotic acini and ducts remained intact. The morphology of the autografts after 72 hr was similar to that after 24 hr except that there was additional necrosis and acini and ducts could no longer be identified in the autografts. By 1 week after implantation, the autografts showed lobular morphogenesis, ductal branching, and revascularization. At this time, the regenerating salivary epithelium appeared undifferentiated with no evidence of secretory granules. The L.I. of interstitial and ductlike structures showed significant increases over control values at 1 week after implantation, and then declined toward control levels by 3 weeks after implantation. By 8 weeks after implantation, there was evidence of acinar and striated ductal cytodifferentiation in two autografts. The results emphasize the potential of SMG autografts to regenerate subsequent to severe tissue necrosis.


Comparative proteomic analysis identifies a role for SUMO in protein quality control.
The small ubiquitin-like modifiers (SUMOs) alter the functions of diverse cellular proteins by covalent posttranslational modification and thus influence many cellular functions, including gene transcription, cell cycle, and DNA repair. Although conjugation by ubiquitin and SUMO-2/3 are largely functionally and mechanistically independent from one another, both appear to increase under conditions of proteasome inhibition. To better understand the relationship between SUMO and protein degradation by the proteasome, we performed a quantitative proteomic analysis of SUMO-2 substrates after short- and long-term inhibition of the proteasome with MG132. Comparisons with changes to the SUMO-2 conjugate subproteome in response to heat stress revealed qualitative and quantitative parallels between both conditions; however, in contrast to heat stress, the MG132-triggered increase in SUMO-2 conjugation depended strictly on protein synthesis, implying that the accumulation of newly synthesized, misfolded proteins destined for degradation by the proteasome triggered the SUMO conjugation response. Furthermore, proteasomal inhibition resulted in the accumulation of conjugated forms of all SUMO paralogs in insoluble protein inclusions and in the accumulation on SUMO-2 substrates of lysine-63-linked polyubiquitin chains, which are not thought to serve as signals for proteasome-mediated degradation. Together, these findings suggest multiple, proteasome-independent roles for SUMOs in the cellular response to the accumulation of misfolded proteins.


The effect of catechol-O-methyltransferase Met/Val functional polymorphism on smoking cessation: retrospective and prospective analyses in a cohort study.
The Met/Val functional polymorphism of the gene-encoding catechol-O-methyltransferase (COMT) is one of the most widely tested variants for association with different phenotypes of addictive behavior, but replication has been inconsistent for smoking status. We investigated the relationship of this COMT single nucleotide polymorphism with smoking cessation in elderly persons in retrospective and prospective analyses. The study is embedded in the population-based Rotterdam Study cohort and included 5,115 persons aged 55 years and more. In the retrospective analyses using logistic regression, current smokers who had smoked 10 or more cigarettes daily for 10 or more years were compared with former smokers. In the prospective analyses, we followed 1,195 current smokers up to 12 years and used Cox proportional hazard model to detect the effect of the COMT single nucleotide polymorphism on self-reported incidence of smoking cessation. The Val/Val genotype of COMT had a consistent association with smoking cessation as compared with the Met/Met+Met/Val genotypes in retrospective [odds ratio=0.79, 95% confidence interval (CI): 0.66-0.96, P=0.02] and prospective analyses (hazard ratio=0.80, 95% CI: 0.63-1.01, P=0.06). In the pooled analyses of prevalent and incident cessation cases that we compared with persisting smokers, the odds ratio was 0.70 (95% CI: 0.55-0.88, P=0.003). No sex difference and no effect of the COMT polymorphism on smoking initiation were observed. Our results suggest that COMT Met/Val polymorphism is strongly associated with smoking cessation. The Met allele is the risk allele that decreases the likelihood of smoking cessation in men and women.


Geometric analysis of ruptured and nonruptured abdominal aortic aneurysms.
The objective of this study was to use parameters to determine the geometric differences between ruptured abdominal aortic aneurysms (AAAs) and nonruptured AAAs. Computed tomography data of 38 ruptured AAAs and 215 electively repaired (nonruptured) AAAs were collected from multiple institutes. We compared the ruptured AAA group and nonruptured AAA group with 1:1 matching by using the Mahalanobis distance, which was calculated using the patient's age, sex, and AAA diameter. We selected the longitudinal AAA image in multiplanar reconstruction view, placed a hypothetical ellipse on the aneurysm's protruded curve, and placed a circle on the portion connecting the aneurysm and the aorta. We then measured the aspect ratio (the vertical diameter divided by the horizontal diameter) and fillet radius (the radius of arc). The aspect ratio was significantly lower in the ruptured group than in the nonruptured group (2.02 ± 0.53 vs 2.60 ± 1.02; P = .002), as was the fillet radius (0.28 ± 0.18 vs 0.81 ± 0.44; P < .001). Receiver operating characteristic analysis revealed that the area under the curve of the aspect ratio was 0.688, and the optimal cutoff point was 2.23, with sensitivity and specificity of 0.55 and 0.76, respectively. The area under the curve of the fillet radius was 0.933, and the optimal cutoff was 0.347, with sensitivity and specificity of 0.97 and 0.87, respectively. The geometric analysis performed in this study revealed that ruptured AAAs had a smaller fillet radius and smaller aspect ratio than nonruptured AAAs did.


Investigating Arousal, Saccade Preparation, and Global Luminance Effects on Microsaccade Behavior.
Microsaccades, small saccadic eye movements occurring during fixation, have been suggested to be modulated by various sensory, cognitive, and affective processes relating to arousal. Although the modulation of fatigue-related arousal on microsaccade behavior has previously been characterized, the influence of other aspects of arousal, such as emotional arousal, is less understood. Moreover, microsaccades are modulated by cognitive processes (e.g., voluntary saccade preparation) that could also be linked to arousal. To investigate the influence of emotional arousal, saccade preparation, and global luminance levels on microsaccade behavior, emotional auditory stimuli were presented prior to the onset of a fixation cue whose color indicated to look either at the peripheral stimulus (pro-saccade) or in the opposite direction of the stimulus (anti-saccade). Microsaccade behavior was found to be significantly modulated by saccade preparation and global luminance level, but not emotional arousal. In the pro- and anti-saccade task, microsaccade rate was lower during anti-saccade preparation as compared to pro-saccade preparation, though microsaccade dynamics were comparable during both trial types. Our results reveal a differential role of arousal linked to emotion, fatigue, saccade preparation, and global luminance level on microsaccade behavior.


Amikacin population pharmacokinetics among paediatric burn patients.
The objectives of this study were to (1) determine the pharmacokinetics of amikacin among children with severe burn and (2) identify influential covariates. Population-based pharmacokinetic modelling was performed in NONMEM 7.2 for hospitalized children who received amikacin at 10-20mg/kg divided two, three, or four times per day as part of early empiric treatment of presumed burn-related sepsis. The analysis included data from 70 patients (6 months to 17 years) with 282 amikacin serum concentrations. Amikacin's mean Cmax was 33.2±9.4μg/mL and the mean Cmin was 3.8±4.6μg/mL. The final covariate model estimated clearance as 5.98L/h/70kg (4.97-6.99, 95% CI), the volume of distribution in the central compartment as 16.7L/70kg (14.0-19.4, 95% CI), the volume of distribution in the peripheral compartment as 40.1L/70kg (15.0-80.4, 95% CI), and the inter-compartmental clearance as 3.38L/h/70kg (2.44-4.32, 95% CI). In multivariate analyses, current weight (P<0.001) was a significant covariate, while age, sex, height, serum creatinine, C-reactive protein, platelet count, the extent and type of burn, and concomitant vancomycin administration did not influence amikacin pharmacokinetics. Children with burn featured elevated amikacin clearance when compared to healthy adult volunteers. However, peak amikacin concentrations are comparable to those attained in other critically-ill children, suggesting that elevated amikacin clearance may not result in sub-therapeutic antibacterial effects. In this study, we found that amikacin displays two-compartment pharmacokinetics, with weight exerting a strong effect upon amikacin clearance. Further pharmacodynamic studies are needed to establish the optimal dosing regimen for amikacin in paediatric burn patients.


Recursive processes in self-affirmation: intervening to close the minority achievement gap.
A 2-year follow-up of a randomized field experiment previously reported in Science is presented. A subtle intervention to lessen minority students' psychological threat related to being negatively stereotyped in school was tested in an experiment conducted three times with three independent cohorts (N = 133, 149, and 134). The intervention, a series of brief but structured writing assignments focusing students on a self-affirming value, reduced the racial achievement gap. Over 2 years, the grade point average (GPA) of African Americans was, on average, raised by 0.24 grade points. Low-achieving African Americans were particularly benefited. Their GPA improved, on average, 0.41 points, and their rate of remediation or grade repetition was less (5% versus 18%). Additionally, treated students' self-perceptions showed long-term benefits. Findings suggest that because initial psychological states and performance determine later outcomes by providing a baseline and initial trajectory for a recursive process, apparently small but early alterations in trajectory can have long-term effects. Implications for psychological theory and educational practice are discussed.


Experimental demonstration of lossy mode resonance generation for transverse-magnetic and transverse-electric polarizations.
This Letter, presents the fabrication of lossy mode resonance (LMR) devices based on titanium dioxide (TiO2)/ poly(sodium 4-styrenesulfonate) (PSS) coatings deposited on side-polished D-shaped optical fibers. TiO2 thin films have been obtained by means of the layer-by-layer (LbL) self-assembly technique. LbL enables us to produce smooth and homogeneous coatings on the polished side of the fiber. This permits us to couple light from the waveguide to the TiO2-coating/external medium region at specific wavelength ranges. The generation of LMRs depends on the coating thickness, so that thicker coatings can produce more resonances. LMRs are sensitive to the external medium refractive index, which allows its utilization as refractometers. The characteristic D-shaped architecture of the devices employed in this Letter enables us to distinguish TE and TM polarizations, which had not been possible before with regular optical fibers due to their cylindrical symmetry. The results presented here show for the first time the experimental demonstration of the generation of LMRs produced by both TM and TE polarizations. More specifically, for these TiO2/PSS thin films, the TM and TM modes of the LMRs show a wavelength shift of 226 nm for the first-order LMR and 56 nm for the second-order LMR.