Macropinocytosis of Bevacizumab by Glioblastoma Cells in the Perivascular Niche Affects their Survival.
Purpose: Bevacizumab, a humanized monoclonal antibody to VEGF, is used routinely in the treatment of patients with recurrent glioblastoma (GBM). However, very little is known regarding the effects of bevacizumab on the cells in the perivascular space in tumors.Experimental Design: Established orthotopic xenograft and syngeneic models of GBM were used to determine entry of monoclonal anti-VEGF-A into, and uptake by cells in, the perivascular space. Based on the results, we examined CD133+ cells derived from GBM tumors in vitro Bevacizumab internalization, trafficking, and effects on cell survival were analyzed using multilabel confocal microscopy, immunoblotting, and cytotoxicity assays in the presence/absence of inhibitors.Results: In the GBM mouse models, administered anti-mouse-VEGF-A entered the perivascular tumor niche and was internalized by Sox2+/CD44+ tumor cells. In the perivascular tumor cells, bevacizumab was detected in the recycling compartment or the lysosomes, and increased autophagy was found. Bevacizumab was internalized rapidly by CD133+/Sox2+-GBM cells in vitro through macropinocytosis with a fraction being trafficked to a recycling compartment, independent of FcRn, and a fraction to lysosomes. Bevacizumab treatment of CD133+ GBM cells depleted VEGF-A and induced autophagy thereby improving cell survival. An inhibitor of lysosomal acidification decreased bevacizumab-induced autophagy and increased cell death. Inhibition of macropinocytosis increased cell death, suggesting macropinocytosis of bevacizumab promotes CD133+ cell survival.Conclusions: We demonstrate that bevacizumab is internalized by Sox2+/CD44+-GBM tumor cells residing in the perivascular tumor niche. Macropinocytosis of bevacizumab and trafficking to the lysosomes promotes CD133+ cell survival, as does the autophagy induced by bevacizumab depletion of VEGF-A. Clin Cancer Res; 23(22); 7059-71. ©2017 AACR.


Parenthood and risk of hip fracture: a 10-year follow-up prospective study of middle-aged women and men in China.
This prospective study of Chinese adults demonstrated an inverse J-shaped association of number of children with risk of hip fracture in both men and postmenopausal women aged 50 years or older. Women with 2 or 3 children and men with 4 children had the lowest risk of hip fracture. Women have higher absolute risks of fracture than men, which is believed to reflect differences in oestrogen exposure. The aim of this study was to compare the associations of number of children with risk of hip fracture between men and women aged over 50 years. The China Kadoorie Biobank (CKB) recruited 133,399 women and 110,296 men, aged 50 years or older between 2004 and 2008. During 10-year follow-up, 2068 participants (1394 women and 674 men) suffered a hip fracture. Cox regression analysis was used to estimate sex-specific adjusted hazard ratios (HRs) and 95% CI for incident hip fracture. Over 98% of both subsets of men and women aged 50 or older reported having children. Women who had 2 or 3 children had the lowest risks of hip fracture compared with other groups. Compared with nulliparous women, the adjusted HR for hip fracture were 0.89 (95% CI; 0.72, 1.10) for 1 child, 0.79 (0.70, 0.90) for 2 children, 0.79 (0.72, 0.87) for 3 children, 0.81 (0.72, 0.91) for 4 children, and 0.95 (0.83, 1.10) for those with 5 or more children. The associations of number of children with hip fracture were broadly consistent in men of a similar age. The concordant effects of the number of children with risk of hip fracture between men and women suggest that the lower risks in multiparous women are not due to differences in oestrogen exposure or other biological effects, but may reflect residual confounding by socioeconomic or lifestyle factors.


The epibiotic life of the cosmopolitan diatom Fragilariopsis doliolus on heterotrophic ciliates in the open ocean.
Diatoms are a diverse and ecologically important group of phytoplankton. Although most species are considered free living, several are known to interact with other organisms within the plankton. Detailed imaging and molecular characterization of any such partnership is, however, limited, and an appraisal of the large-scale distribution and ecology of such consortia was never attempted. Here, observation of Tara Oceans samples from the Benguela Current led to the detection of an epibiotic association between a pennate diatom and a tintinnid ciliate. We identified the diatom as Fragilariopsis doliolus that possesses a unique feature to form barrel-shaped chains, associated with seven different genera of tintinnids including five previously undescribed associations. The organisms were commonly found together in the Atlantic and Pacific Ocean basins, and live observations of the interaction have been recorded for the first time. By combining confocal and scanning electron microscopy of individual consortia with the sequencing of high-resolution molecular markers, we analyzed their distribution in the global ocean, revealing morpho-genetically distinct tintinnid haplotypes and biogeographically structured diatom haplotypes. The diatom was among the most abundant in the global ocean. We show that the consortia were particularly prevalent in nutrient-replete conditions, rich in potential predators. These observations support the hypothesis of a mutualistic symbiosis, wherein diatoms acquire increased motility and tintinnids benefit from silicification through increased protection, and highlight that such associations may be more prevalent than currently appreciated.


Topical photodynamic therapy for nevus sebaceous on the face.
Recently, topical photodynamic therapy (PDT) has been tried to treat sebaceous gland disorders. However, only one case of nevus sebaceous treated with PDT has been reported. Our aim was to investigate the outcomes of PDT on nevus sebaceus on the face. A total of 12 patients were treated with topical 20% ALA or methyl aminolevulinate (MAL) after CO(2) laser ablasion. The lesions were irradiated with light emitting diodes (LED) device. The regimen was delivered repeatedly at 1 to 4 week intervals to each patient. Clinical improvement was visually assessed at 1 month after treatment by the lesional responses; No response was defined as less than 25%, mild improvement as 25-50%, moderate improvement as 51-75% and marked improvement as more than 75% decrease of lesional volume. All 12 patients showed mild (3 patients, 25%), moderate (7 patients, 58%), and marked (2 patients, 17%) improvement of the lesions. However, 2 patients showed partial recurrences after completion of treatment. There was no significant side effect.These results suggest that topical PDT may be considered as an effective alternative treatment modality of nevus sebaceous on the face.


Human HL-60 myeloid leukemia cells transport dehydroascorbic acid via the glucose transporters and accumulate reduced ascorbic acid.
The cellular accumulation of vitamin C, a substance critical to human physiology, is mediated by transporters located at the cell membrane, and is regulated in a cell-specific manner. Neoplastic cells may have special needs for vitamin C. Therefore, we investigated the transport of vitamin C in a human myeloid leukemia cell line (HL-60). The HL-60 cells lacked the capacity to transport the reduced form of vitamin C, ascorbic acid, but they showed a remarkable ability to transport the oxidized form of vitamin C, dehydroascorbic acid (DHA). Uptake-accumulation studies indicated that the HL-60 cells accumulated ascorbic acid when provided with DHA. Kinetic analysis showed the presence of two functional activities involved in the uptake of DHA, one with low affinity and one with high affinity. Cytochalasin B and phloretin, which inhibit the passage of glucose through the facilitative glucose transporters, also inhibited the transport of DHA by HL-60 cells. Transport of DHA was completed by D- but not L-hexoses, and was sensitive to D-hexose-dependent counter transport acceleration. These data support the concept that HL-60 myeloid leukemic cells transport DHA through the facilitative hexose transporters (glucose transporters) and accumulate the reduced form of ascorbic acid.


Gene function and expression level influence the insertion/fixation dynamics of distinct transposon families in mammalian introns.
Transposable elements (TEs) represent more than 45% of the human and mouse genomes. Both parasitic and mutualistic features have been shown to apply to the host-TE relationship but a comprehensive scenario of the forces driving TE fixation within mammalian genes is still missing. We show that intronic multispecies conserved sequences (MCSs) have been affecting TE integration frequency over time. We verify that a selective economizing pressure has been acting on TEs to decrease their frequency in highly expressed genes. After correcting for GC content, MCS density and intron size, we identified TE-enriched and TE-depleted gene categories. In addition to developmental regulators and transcription factors, TE-depleted regions encompass loci that might require subtle regulation of transcript levels or precise activation timing, such as growth factors, cytokines, hormones, and genes involved in the immune response. The latter, despite having reduced frequencies of most TE types, are significantly enriched in mammalian-wide interspersed repeats (MIRs). Analysis of orthologous genes indicated that MIR over-representation also occurs in dog and opossum immune response genes, suggesting, given the partially independent origin of MIR sequences in eutheria and metatheria, the evolutionary conservation of a specific function for MIRs located in these loci. Consistently, the core MIR sequence is over-represented in defense response genes compared to the background intronic frequency. Our data indicate that gene function, expression level, and sequence conservation influence TE insertion/fixation in mammalian introns. Moreover, we provide the first report showing that a specific TE family is evolutionarily associated with a gene function category.


Vital needs, human rights, health care law.
Ethics and law are actually dependent and closely interacting, but also in some measure autonomous disciplines. Their balanced interaction is important for the attainment of a common aim and purpose: a good and just society. We now tend to agree that some but not all human rights should be supported by legislation. Some human rights are rooted in vital needs: the denial of a vital need causes death or serious disability. Rights rooted in needs recognized as vital have an exceptional long moral foundation. But "NN has a right to x" can be understood in two ways: either as a right to seek fulfillment of the need with the means and money at his disposal, or as a right to obtain fulfillment of the need. Article 25 of the U.N. declaration of human rights recognizes the right to health care as a human right. Clearly, need for health care in cases of serious illness should be understood in sense: as vital need generating not only (in sense 1)" a weak right to seek, but (in sense 2) a strong right to obtain fulfillment. This amounts to a powerful moral argument for the use of legislation to establish equal access for all to (at least) "basic" health care. Even if this is "no more" than a moral argument, it does have the advantage over legislation that the validity of a moral argument is not restricted by national borders.


Development of a multiplex PCR test for identification of Actinobacillus pleuropneumoniae serovars 1, 7, and 12.
A PCR assay for simultaneous species identification and separation of Actinobacillus pleuropneumoniae serovars 1, 7 and 12 was developed. Primers specific for genes involved in biosynthesis of the capsular polysaccharides (cps genes) of serovars 1, 7, and 12 were combined with a species-specific PCR test based on the omlA gene. The PCR test was evaluated with the serovar reference strains of A. pleuropneumoniae as well as 183 Danish field isolates. For all typable strains, a complete correspondence was found between results obtained with the multiplex PCR test and results from the traditional serotyping methods. Among eight serologically cross-reacting strains designated K1:O7, seven isolates produced amplicons of similar sizes as serovar 1 and one isolate produced amplicons of similar sizes as serovar 7. The species specificity of the assay was evaluated using a collection of 126 strains representing 25 different species within the family Pasteurellaceae including 45 field strains of the phylogenetically affiliated species Actinobacillus lignieresii. All these isolates tested negative for the cps genes by the multiplex PCR test except for 6 isolates of A. lignieresii. Five of these isolates produced an amplicon identical to the cps gene of serovar 7, whereas one isolate produced an amplicon identical to the cps gene of serovar 1. In addition, four isolates of Actinobacillus genomospecies 1 tested positive for the omlA gene but negative for the cps genes. The test represents a convenient and specific method for serotyping A. pleuropneumoniae in diagnostic laboratories.


Clinical development of demethylating agents in hematology.
The term epigenetics refers to the heritable changes in gene expression that are not associated with a change in the actual DNA sequence. Epigenetic dysregulation is linked to the pathogenesis of a number of malignancies and has been studied extensively in myelodysplastic syndromes and acute myeloid leukemia. DNA methylation is frequently altered in cancerous cells and likely results in transcriptional silencing of tumor suppressor genes. Re-expression of these genes by inhibition of the DNA methyltransferases has been successful in the treatment of benign and malignant disease. In this Review, we discuss the clinical development of demethylating agents in hematology, with a focus on azacitidine and decitabine.


Progression of cytomegalovirus retinitis in acquired immunodeficiency syndrome: a case report.
We report an AIDS patient with cytomegalovirus (CMV) retinitis that developed from an early minor lesion and progressed to extended involvement of the retina and severe deterioration of vision due to poor compliance with ganciclovir treatment. A 33-year-old man was known to have acquired immunodeficiency syndrome (AIDS) for eight months. The patient had no complaint of visual symptoms. A routine eye examination revealed his visual acuity to be 6/6 in both eyes. The dilated eye fundus examination using indirect ophthalmoscopy disclosed a localized white yellowish granular lesion in the peripheral retina of the right eye and a completely normal left eye. CMV retinitis with initial manifestation in the right eye was diagnosed. Due to incomplete treatment with ganciclovir, the retinal lesion rapidly enlarged and extended to the posterior pole, with eventual destruction of the nerve fiber layer and optic disc. The visual acuity of right eye dropped from 6/6 to 1/60 within six months. This case report indicates the importance of early, dilated eye fundus examination and recognition of early CMV retinitis in order to salvage visual function in AIDS patients. Completion of the anti-CMV treatment course in halting the progression of CMV retinitis is also emphasized.


Creatine supplementation enhances isometric strength and body composition improvements following strength exercise training in older adults.
We sought to determine whether creatine monohydrate (CrM) supplementation would enhance the increases in strength and fat-free mass that develop during resistance exercise training in older adults. Twenty-eight healthy men and women over the age of 65 years participated in a whole-body resistance exercise program 3 days per week for 14 weeks. The study participants were randomly allocated, in a double-blind fashion, to receive either CrM (5 g/d + 2 g of dextrose; n = 14) or placebo (7 g of dextrose; n = 14). The primary outcome measurements included the following: total body mass, fat-free mass, one-repetition maximum strength for each body part, isometric knee extension, handgrip, and dorsiflexion strength, chair stand performance, 30-m walk test, 14-stair climb performance, muscle fiber type and area, and intramuscular total creatine. Fourteen weeks of resistance exercise training resulted in significant increases in all measurements of strength and functional tasks and muscle fiber area for both groups (p <.05). CrM supplementation resulted in significantly greater increases in fat-free mass and total body mass, as compared with placebo (p <.05). The CrM group also showed a greater increase in isometric knee extension strength in men and women, as compared with placebo (p <.05), and also greater gains in isometric dorsiflexion strength (p <.05), but in men only. There was a significant increase in intramuscular total creatine in the CrM group (p <.05). Finally, there were no significant side effects of treatment or exercise training. This study confirms that supervised heavy resistance exercise training can safely increase muscle strength and functional capacity in older adults. The addition of CrM supplementation to the exercise stimulus enhanced the increase in total and fat-free mass, and gains in several indices of isometric muscle strength.


On the Ground or in the Air? A Methodological Experiment on Crop Residue Cover Measurement in Ethiopia.
Maintaining permanent coverage of the soil using crop residues is an important and commonly recommended practice in conservation agriculture. Measuring this practice is an essential step in improving knowledge about the adoption and impact of conservation agriculture. Different data collection methods can be implemented to capture the field level crop residue coverage for a given plot, each with its own implication on survey budget, implementation speed and respondent and interviewer burden. In this paper, six alternative methods of crop residue coverage measurement are tested among the same sample of rural households in Ethiopia. The relative accuracy of these methods are compared against a benchmark, the line-transect method. The alternative methods compared against the benchmark include: (i) interviewee (respondent) estimation; (ii) enumerator estimation visiting the field; (iii) interviewee with visual-aid without visiting the field; (iv) enumerator with visual-aid visiting the field; (v) field picture collected with a drone and analyzed with image-processing methods and (vi) satellite picture of the field analyzed with remote sensing methods. Results of the methodological experiment show that survey-based methods tend to underestimate field residue cover. When quantitative data on cover are needed, the best estimates are provided by visual-aid protocols. For categorical analysis (i.e., >30% cover or not), visual-aid protocols and remote sensing methods perform equally well. Among survey-based methods, the strongest correlates of measurement errors are total farm size, field size, distance, and slope. Results deliver a ranking of measurement options that can inform survey practitioners and researchers.


Thromboprophylaxis after major orthopedic surgery: Improving compliance with clinical practice guidelines.
Identifying risk factors and strategies for the prevention of deep venous thromboembolism in major orthopedic surgery has allowed the development of Clinical Practice Guidelines (CPGs). Currently, there is a gap between clinical practice and the implementation of the recommendations of CPGs. The purpose of this paper is to report the impact of the implementation of improvement strategies on adherence to venous thromboembolism (VTE) prophylaxis guidelines. We defined 3 quality indicators to assess the adequate use of thromboprophylaxis according to CPGs. We obtained a baseline measurement and identified several barriers for adherence. Six improvement strategies to promote adherence to CPGs were designed and applied. A systematic monitoring of these indicators was performed in real time and a description of the data was completed for patients undergoing primary joint replacement of the hip, knee and shoulder, during February 2012 and August 2014. Data from 773 patients were obtained. In the first trimester, the average of adherence was: 98.3% for medical order in the post-operative note, 60.3% for opportune administration and 67% for adherence to therapy at home. In the trimester, the rates of adherence were 100%, 95.7% and 100% respectively. Combined strategies for improvement of adherence to VTE prophylaxis is associated with higher compliance with clinical practice guidelines.


Masson's Hemangioma of the Urethra: A Case Report.
Intravascular papillary endothelial hyperplasia (IPEH) is an uncommon benign vascular disease characterized by endothelial cell proliferation and papillary formation within the lumen of blood vessels arising from an organizing thrombus. The occurrence of this uncommon lesion is about 2% of all vascular tumors. IPEH mostly occurs in the 5th decade of life, and there is no gender or age predilection. Nevertheless, some studies have suggested that IPEH is more common in women than in men. The clinical features are mostly asymptomatic, and the lesion is typically characterized as a small, firm, slightly elevated mass with red to blue discoloration of the overlying skin. The main diagnosis of the lesion is based on histological examination. The most common locations of IPEH are head and neck, fingers, and trunk. The occurrence of IPEH in the urethra is extremely rare, with only a few cases having been reported in the literature. We describe a 70-year-old woman with a complaint of dysuria and urethral bleeding of 3 days' duration. Clinically, the lesion was a palpable firm mass in the urethra. Urethrocystoscopy illustrated a dark mass, a few millimeters in size, with bleeding. Histologic findings revealed dilated blood vessels with multiple papillary projections into the lumen. Thus, based on these findings, a final diagnosis of Masson's tumor was confirmed. According to clinical and radiographic findings, this lesion is similar to malignant lesions and its accurate diagnosis is based on microscopic findings. Therefore, awareness of the microscopic characteristics of this tumor is very important for clinicians to rule out the presence of malignant vascular lesions and to avoid unnecessarily aggressive therapy.


Ethnopharmacological, chemical, and pharmacological aspects of Halenia elliptica: A comprehensive review.
Traditional Tibetan medicine (TTM) is an old traditional medical system, which is an effective and natural method of improving physical and mental health, and has been widely spread in the western part of China for centuries. Halenia elliptica (H. elliptica) D. Don, known as "Jiadiranguo" (Tibetan medicine name) is one of the most important herbal medicine in TTM that is from the genus Halenia (family: Gentianaceae). The whole herb can be used as a medicine to treat hepatobiliary diseases and xeransis, and possesses many biological and pharmacological activities including heat clearing, bile benefiting, liver soothing, digestion promoting, blood nursing, detoxification activities, and so on. In modern research, H. elliptica can be used to treat acute or chronic hepatitis, especially hepatitis B. In addition, the chemical compounds of the herb have potent antihepatitis B virus (anti-HBV) activity in vitro. As an important TTM, further studies on H. elliptica can lead to the development of new drugs and therapeutics for various diseases, and more attention should be paid on the aspects of how to utilize it better.


Characterization of highly informative cross-species microsatellite panels for the Australian dugong (Dugong dugon) and Florida manatee (Trichechus manatus latirostris) including five novel primers.
The Australian dugong (Dugong dugon) and Florida manatee (Trichechus manatus latirostris) are threatened species of aquatic mammals in the order Sirenia. Sirenian conservation and management actions would benefit from a more complete understanding of genetic diversity and population structure. Generally, species-specific microsatellite markers are employed in conservation genetic studies; however, robust markers can be difficult and costly to isolate. To increase the number of available markers, dugong and manatee microsatellite primers were evaluated for cross-species amplification. Furthermore, one manatee and four dugong novel primers are reported. After polymerase chain reaction optimization, 23 (92%) manatee primers successfully amplified dugong DNA, of which 11 (48%) were polymorphic. Of the 32 dugong primers tested, 27 (84%) yielded product in the manatee, of which 17 (63%) were polymorphic. Dugong and manatee primers were compared and the most informative markers were selected to create robust and informative marker-panels for each species. These cross-species microsatellite marker-panels can be employed to assess other sirenian populations and can provide beneficial information for the protection and management of these unique mammals.


The dimensionality and measurement properties of alcohol outcome expectancies across Hispanic national groups.
This study examines the psychometric properties of alcohol expectancies among Hispanic subgroups. Face-to-face interviews were conducted as part of the 2006 Hispanic Americans Baseline Alcohol Survey (HABLAS), which employed a multistage cluster sample design. A total of 5224 individuals (18+ years of age) representing four Hispanic national groups (Puerto Ricans, Cuban Americans, Mexican Americans, and South/Central Americans) were selected at random from the household population in five metropolitan areas (Miami, New York, Philadelphia, Houston, and Los Angeles). Alcohol expectancies included 18 items covering positive (e.g., laugh more, become more talkative) and negative dimensions (e.g., become aggressive, lose control) when alcohol is consumed. Confirmatory factor models replicated a previously proposed three-factor dimensional structure with a substantial majority of items exhibiting measurement invariance across Hispanic national group and gender. Items covering social extroversion were an exception, showing a lack of invariance for female Cuban and South/Central Americans. Latent mean differences across groups were detected for expectancies concerning emotional fluidity, and the pattern of differences largely mirrored known differences in alcohol consumption patterns. Results suggest that caution should be exercised in interpreting differences in expectancies concerning social extroversion across Hispanic groups, and additional work is needed to identify indices of this construct with invariant measurement properties. However, measures of emotional/behavioral impairment and emotional fluidity expectancies can be validly compared across gender and Hispanic national groups.


Endoscopic optic canal decompression for compressive optic neuropathy.
Compressive optic neuropathy is a rare condition that may be caused by trauma or non-traumatic events. Endoscopic techniques have evolved to provide an easier surgical approach to decompression. The aim of this study was to determine the endoscopic anatomy of the orbital apex and to identify the optimal targets for endoscopic optic nerve decompression. We report five patients with endoscopic optic nerve decompression: two with traumatic optic neuropathies, two with fibrous dysplasias, and one with chordoma. For these lesions, the major treatment concern was removal of the bony structures around the optic nerve. All compressive lesions were removed effectively via an endoscopic endonasal route. Following endoscopic optic nerve decompression, three patients had markedly improved visual acuity and fields of vision, one patient had improved fields of vision without change in visual acuity, and one patient had improved visual acuity alone. There were no operative complications. Adequate exposure of the intracanalicular portion of the optic nerve was essential for effective decompression, and to achieve this, decompression of the roof as well as medial wall of the intracanalicular portion was critical. We conclude that endoscopic optic canal decompression is a minimally invasive, safe, and efficient treatment for compressive optic neuropathy regardless of etiology.


Cardiovascular effects of tricyclic antidepressants.
Overdoses of tricyclic antidepressants (TCAs) leave no doubt that TCA drugs at high concentrations have serious cardiac effects. It has been assumed that, to a lesser extent, these effects will occur at usual therapeutic concentration. Recent prospective, plasma-level-controlled studies have improved our understanding of these drugs and proved these assumptions to be inaccurate. The most common serious cardiovascular complication of most tricyclic drugs is orthostatic hypotension. Tricyclic antidepressants are essentially free of any other serious adverse effects in depressed patients without cardiovascular disease. In patients with preexisting bundle-branch disease, there is a risk of heart block. On the other hand, patients with ventricular arrhythmias are likely to have their arrhythmias improve with TCA therapy. Finally, therapeutic doses of TCA have little adverse effect on left ventricular performance, but at least with imipramine there is a dramatic increase in orthostatic hypotension in those patients with impaired left ventricular function. Understanding these principles, TCA drugs can often be used to benefit depressed patients with overt heart disease.


Twist: a molecular target in cancer therapeutics.
Twist, the basic helix-loop-helix transcription factor, is involved in the process of epithelial to mesenchymal transitions (EMTs), which play an essential role in cancer metastasis. Overexpression of Twist or its promoter methylation is a common scenario in metastatic carcinomas. Twist is activated by a variety of signal transduction pathways, including Akt, signal transducer and activator of transcription 3, mitogen-activated protein kinase, Ras, and Wnt signaling. Activated Twist upregulates N-cadherin and downregulates E-cadherin, which are the hallmarks of EMT. Moreover, Twist plays an important role in some physiological processes involved in metastasis, like angiogenesis, invadopodia, extravasation, and chromosomal instability. Twist also protects cancer cells from apoptotic cell death. In addition, Twist is responsible for the stemness of cancer cells and the generation of drug resistance. Recently, targeting Twist has gained significant interests in cancer therapeutics. The inactivation of Twist by small RNA technology or chemotherapeutic approach has been proved successful. Moreover, several inhibitors which are antagonistic to the upstream or downstream molecules of Twist signaling pathways have also been identified. Development of potential treatment strategies by targeting Twist has a great promise in cancer therapeutics.


Suicide gene therapy for the treatment of high-grade glioma: past lessons, present trends, and future prospects.
Suicide gene therapy has represented an experimental cancer treatment modality for nearly 40 years. Among the various cancers experimentally treated by suicide gene therapy, high-grade gliomas have been the most prominent both in preclinical and clinical settings. Failure of a number of promising suicide gene therapy strategies in the clinic pointed toward a bleak future of this approach for the treatment of high-grade gliomas. Nevertheless, the development of new vectors and suicide genes, better prodrugs, more efficient delivery systems, and new combinatorial strategies represent active research areas that may eventually lead to better efficacy of suicide gene therapy. These trends are evident by the current increasing focus on suicide gene therapy for high-grade glioma treatment both in the laboratory and in the clinic. In this review, we give an overview of different suicide gene therapy approaches for glioma treatment and discuss clinical trials, delivery issues, and immune responses.


First Report of Cylindrocladium pseudonaviculatum Causing Leaf Spot of Pachysandra terminalis.
Cylindrocladium pseudonaviculatum Crous, J.Z., Groenew. & C.F. Hill 2002 was recently reported infecting common boxwood, Buxus sempervirens L., in Connecticut (2). We isolated the pathogen from leaf and stem lesions of B. sempervirens and obtained single-spored cultures on half-strength potato dextrose agar (½PDA). The pathogen was identified as C. pseudonaviculatum by morphological characteristics (1). Colony size reached 71 mm in diameter after 14 days at room temperature on ½PDA, and was fluffy with white aerial hyphae, mars brown, and reverse color chestnut brown at the center fading to pale brown forming concentric bands. Macroconidiophores were solitary or in a group of up to three, comprised a stipe, a sterile elongation, and one to three penicillate fertile branches. The stipe was up to nine septate, 90 to 250 μm long, colorless, smooth, terminating in a naviculate or broadly ellipsoidal vesicle with a pointed or papillate apex, and 27 to 50 × 6.5 to 9 μm. Primary branches were zero- to one-septate, 20 to 36 × 4 to 5 μm; secondary branches were aseptate and 11 to 20 × 3 to 4.5 μm; tertiary branches were rare, each terminal branch producing two to five phialides; phialides were doliiform or reniform, colorless, 12 to 18 μm. Conidia were cylindrical, rounded at both ends, straight, smooth, colorless, two-celled, 48 to 55 × 4.5 to 5.5 μm, and in colorless slimy cylindrical clusters. Microconidiophores were not observed. Chlamydospores were golden to dark brown, thick-walled, and smooth or rough. Microsclerotia were present on ½PDA. Primers T1 and T22 (3) were used to amplify a portion of the β-tubulin gene from isolates Cps-CT-L1 and Cps-CT-S1. Amplified sequences were used in a BLAST search against the GenBank database to demonstrate 100% sequence identity only with other C. pseudonaviculatum strains. Both sequences were deposited in GenBank (Accession Nos. JQ866628 and JQ866629), using corresponding gene data from C. pseudonaviculatum strain STE-U 3399 (GenBank Accession No. AF449455) to distinguish coding from noncoding regions. Healthy plants of Japanese spurge, Pachysandra terminalis, with three plants per 10 cm diameter pot, were inoculated with water alone or a conidial suspension of C. pseudonaviculatum isolate Cps-CT-L1 (ATCC MYA-4891) (1.0 × 106 conidia/plant) with a handheld sprayer until runoff. Plants were kept moist in a plastic bag for 48 h at laboratory temperature and then transferred to the greenhouse. Circular lesions (1- to 4-mm diameter) were evident on leaves after 10 days. All 12 inoculated plants developed lesions, and no lesions were observed on noninoculated plants. Leaves with lesions were surface sterilized in 0.5% NaOCl for 30 s, rinsed twice in sterile water, and lesion margins plated onto water agar or ½PDA. The pathogen was reisolated from at least one leaf per plant. Koch's postulates were performed again with isolate Cps-CT-S1 (ATCC MYA-4890). After 3 weeks, many of the leaves with lesions yellowed and dropped to the soil surface and heavy sporulation of C. pseudonaviculatum and microsclerotia were observed. To our knowledge, this is the first report of C. pseudonaviculatum causing a leaf spot disease on P. terminalis. Pachysandra is a widely grown ground cover suitable for shady, humid environmental conditions that may be conducive for the development of disease. References: (1) P. Crous, et al. Sydowia 54:23, 2002. (2) K. Ivors et al. Plant Disease. 96:X, 2012. (3) K. O'Donnell and E. Cigelnik Mol. Phylogenet. Evol. 7:103, 1997.


Mixed-Methods for Comparing Tobacco Cessation Interventions.
The National Comprehensive Cancer Control Program (NCCCP) and National Tobacco Control Program (NTCP) are both well-positioned to promote the use of population-based tobacco cessation interventions, such as state quitlines and Web-based interventions. This paper outlines the methodology used to conduct a comparative effectiveness research study of traditional and Web-based tobacco cessation and quitline promotion approaches. A mixed-methods study with three components was designed to address the effect of promotional activities on service usage and the comparative effectiveness of population-based smoking cessation activities across multiple states. The cessation intervention component followed 7,902 smokers (4,307 quitline users and 3,595 Web intervention users) to ascertain prevalence of 30-day abstinence rates 7 months after registering for smoking cessation services. User characteristics and quit success was compared across the two modalities. In the promotions component, reach and use of traditional and innovative promotion strategies were assessed for 24 states, including online advertising, state Web sites, social media, mobile applications, and their effects on quitline call volume. The partnership intervention component studied the extent of collaboration among six selected NCCCPs and NTCPs. This study will guide program staff and clinicians with evidence-based recommendations and best practices for implementation of tobacco cessation within their patient and community populations and establish an evidence base that can be used for decision making.


Biochemical and mutational studies of the 5'-3' exonuclease of DNA polymerase I of Escherichia coli.
In order to improve our understanding of the 5'-3' exonuclease reaction catalyzed by Escherichia coli DNA polymerase I, we have constructed expression plasmids and developed purification methods for whole DNA polymerase I and its 5'-3' exonuclease domain that allow the production of large quantities of highly purified material suitable for biophysical and other studies. We have studied the enzymatic properties of the 5'-3' exonuclease, both as an isolated domain and in the context of the whole polymerase, using a variety of model oligonucleotides to explore the enzyme-substrate interaction. The 5'-3' exonuclease is known to be a structure-specific nuclease that cleaves a 5' displaced strand at the junction between single-stranded and duplex regions. Since the isolated domain shows the same structure specificity as the whole polymerase, the correct geometry of substrate binding is achieved without the assistance of the polymerase domain. The 5'-3' exonuclease reaction has a strict requirement for a free 5' end on the displaced strand; however, the upstream template and primer strands are dispensable. Site-directed mutagenesis of the ten carboxylate residues that are highly conserved among bacterial and bacteriophage 5'-3' exonucleases indicates that nine of them are important in the reaction. This finding is discussed in relation to structural and mutational data for related 5' nucleases.


Topiramate for acute affective episodes in bipolar disorder.
Bipolar disorder is a common recurrent illness with high levels of chronicity. Treatment resistance persists despite the use of established medications, such as lithium and valproate. New medications are required for the treatment of refractory cases. Retrospective and open-label trials have suggested that the anticonvulsant topiramate may be efficacious in bipolar disorder. There is a need to clarify the evidence available in the form of randomised controlled trials for its use in bipolar disorder. To review the evidence for the efficacy and acceptability of topiramate in the treatment of acute mood episodes in bipolar disorder. The Cochrane Collaboration Depression, Anxiety and Neurosis (CCDAN) group search strategy was used. The following databases were searched:The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR), September 2003;The Cochrane Controlled Clinical Trials Register (CCCTR), September 2003;EMBASE (1980 to December 2003);MEDLINE (1966 to December 2003);LILACS;PsycLIT;Psyndex.Reference lists of relevant papers and major textbooks of mood disorder. Handsearches (specialist journals and conference proceedings). Authors, other experts in the field and pharmaceutical companies were contacted for knowledge of suitable published or unpublished trials. Randomised controlled trials which compared topiramate with placebo or with active agents in the treatment of any acute mood episodes in bipolar disorder. Participants were patients with bipolar disorder and were males and females of all ages. Data extraction and methodological quality assessment were performed independently by two reviewers. For analysis, relative risk was used for binary efficacy outcomes and the weighted mean difference or standardised mean difference was used for continuously distributed outcomes. One randomised controlled trial met the inclusion criteria for the review, a comparison between topiramate and bupropion sustained release (SR) in the adjunctive treatment of depressed patients with bipolar disorder. However, the trial had several limitations in methodology and in the description of data. Its data regarding efficacy required clarification before it could be analysed according to the protocol of this systematic review. From the limited data available, topiramate had efficacy similar to bupropion SR in the adjunctive treatment of bipolar depression. Both groups of subjects suffered a high drop-out rate. There was no significant difference between the topiramate and the bupropion treated groups in those dropping out for any reason (relative risk 1.60, 95% confidence interval 0.65 to 3.96). There was no significant difference in those withdrawing from the study due to adverse effects (relative risk 1.50, 95% confidence interval 0.51 to 4.43). Although the data on weight loss were not analysed formally, weight loss was marked in the topiramate treated group. Several unpublished trials have been identified and data from these trials may be included in future reviews. There is insufficient evidence on which to base any recommendations regarding the use of topiramate in any phase of bipolar illness, either in monotherapy or as an adjunctive treatment.


Does catch and release affect the mating system and individual reproductive success of wild Atlantic salmon (Salmo salar L.)?
In this study, we documented the breeding system of a wild population of Atlantic salmon (Salmo salar L.) by genetically sampling every returning adult and assessed the determinants of individual fitness. We then quantified the impacts of catch and release (C&R) on mating and reproductive success. Both sexes showed high variance in individual reproductive success, and the estimated standardized variance was higher for males (2.86) than for females (0.73). We found a weak positive relationship between body size and fitness and observed that fitness was positively correlated with the number of mates, especially in males. Mature male parr sired 44% of the analysed offspring. The impact of C&R on the number of offspring was size dependent, as the reproductive success of larger fish was more impaired than smaller ones. Also, there was an interactive negative effect of water temperature and air exposure time on reproductive success of C&R salmon. This study improves our understanding of the complex reproductive biology of the Atlantic salmon and is the first to investigate the impact of C&R on reproductive success. Our study expands the management toolbox of appropriate C&R practices that promote conservation of salmon populations and limit negative impacts on mating and reproductive success.


Desiderata for an authoritative Representation of MeSH in RDF.
The Semantic Web provides a framework for the integration of resources on the web, which facilitates information integration and interoperability. RDF is the main representation format for Linked Open Data (LOD). However, datasets are not always made available in RDF by their producers and the Semantic Web community has had to convert some of these datasets to RDF in order for these datasets to participate in the LOD cloud. As a result, the LOD cloud sometimes contains outdated, partial and even inaccurate RDF datasets. We review the LOD landscape for one of these resources, MeSH, and analyze the characteristics of six existing representations in order to identify desirable features for an authoritative version, for which we create a prototype. We illustrate the suitability of this prototype on three common use cases. NLM intends to release an authoritative representation of MeSH in RDF (beta version) in the Fall of 2014.


Hepatic changes induced by Schrebera alata (Hochst): a preliminary report on the toxicology of II kau kawa.
Schrebera alata is a deciduous fuel tree from which the Samburu people in Northern Kenya obtain bark for medicinal purposes. A pharmacologically active principle that produces analgesic effects can be extracted from the bark with hot water. When administered to rats daily for a period of 6 weeks, the extract of bark (referred to as II kau kawa by the Samburu) caused reduced activities of succinic dehydrogenase, an enzyme that is involved in oxidative processes, and cholinesterase in heart and liver tissues. Histological sections from the liver revealed extensive cellular degeneration and small areas with necrotic lesions. Only that fraction of the bark extracts which contained components less soluble in alcohol produced such lesions within a 2 weeks period. The same fraction is associated with pharmacological activity. Since hepatic injuries occur frequently and the incidence of primary hepatic carcinoma is high in tropical areas, the role of natural toxins as aetiologic factors for cirrhotic conditions must be adequately clarified. It is apparent that bark from S.alata possesses some toxicity and its effects on the liver indicate it can contribute significantly to prevalent hepatocellular damages.


Structural evidence for iron-free citrate and ferric citrate binding to the TonB-dependent outer membrane transporter FecA.
Escherichia coli possesses a TonB-dependent transport system, which exploits the iron-binding capacity of citrate and its natural abundance. Here, we describe three structures of the outer membrane ferric citrate transporter FecA: unliganded and complexed with iron-free or diferric dicitrate. We show the structural mechanism for discrimination between the iron-free and ferric siderophore: the binding of diferric dicitrate, but not iron-free dicitrate alone, causes major conformational rearrangements in the transporter. The structure of FecA bound with iron-free dicitrate represents the first structure of a TonB-dependent transporter bound with an iron-free siderophore. Binding of diferric dicitrate to FecA results in changes in the orientation of the two citrate ions relative to each other and in their interactions with FecA, compared to the binding of iron-free dicitrate. The changes in ligand binding are accompanied by conformational changes in three areas of FecA: two extracellular loops, one plug domain loop and the periplasmic TonB-box motif. The positional and conformational changes in the siderophore and transporter initiate two independent events: ferric citrate transport into the periplasm and transcription induction of the fecABCDE transport genes. From these data, we propose a two-step ligand recognition event: FecA binds iron-free dicitrate in the non-productive state or first step, followed by siderophore displacement to form the transport-competent, diferric dicitrate-bound state in the second step.


How patients use domiciliary oxygen.
Forty-five patients in Southampton who received domiciliary oxygen were visited at home to find out how they used and coped with their oxygen. Generally, the organisation and administration of supplies presented no problems, nearly all the apparatus complied with the drug tariff, and most patients coped well with the equipment. Only two patients were taking oxygen for prescribed periods; the others were taking it when necessary for symptomatic relief. No patient received oxygen for over five hours daily. Most patients thought that they were helped by oxygen, but only four said that it allowed them to increase their level of activity, and the overall benefit seemed slight. This was partly because oxygen was usually limited to one room, so patients used oxygen after rather than during exercise. The amount of oxygen consumed differed widely, ranging from three and a half cylinders a week in three patients to less than one cylinder in six months in 17 patients. The average yearly cost of oxygen per patient ranged from 500 pounds in patients consuming one cylinder or more per week, to 15 pounds in those consuming less than one cylinder in six months. The main cost of domiciliary oxygen is determined by the number of cylinder refills, so patients who use it infrequently are a relatively small drain on resources.


Genetic deletion of the repressor of estrogen receptor activity (REA) enhances the response to estrogen in target tissues in vivo.
We previously identified a coregulator, repressor of estrogen receptor activity (REA), that directly interacts with estrogen receptor (ER) and represses ER transcriptional activity. Decreasing the intracellular level of REA by using small interfering RNA knockdown or antisense RNA approaches in cells in culture resulted in a significant increase in the level of up-regulation of estrogen-stimulated genes. To elucidate the functional activities of REA in vivo, we have used targeted disruption to delete the REA gene in mice. The targeting vector eliminated, by homologous recombination, the REA exon sequences encoding amino acids 12 to 201, which are required for REA repressive activity and for interaction with ER. The viability of heterozygous animals was similar to that of the wild type, whereas homozygous animals did not develop, suggesting a crucial role for REA in early development. Female, but not male, heterozygous animals had an increased body weight relative to age-matched wild-type animals beginning after puberty. REA mRNA and protein levels in uteri of heterozygous animals were half that of the wild type, and studies with heterozygous animals revealed a greater uterine weight gain and epithelial hyperproliferation in response to estradiol (E2) and a substantially greater stimulation by E2 of a number of estrogen up-regulated genes in the uterus. Even more dramatic in REA heterozygous animals was the loss of down regulation by E2 of genes in the uterus that are normally repressed by estrogen in wild-type animals. Mouse embryo fibroblasts derived from heterozygous embryos also displayed a greater transcriptional response to E2. These studies demonstrate that REA is a significant modulator of estrogen responsiveness in vivo: it normally restrains estrogen actions, moderating ER stimulation and enhancing ER repression of E2-regulated genes.


Sex determination by amplification of amelogenin gene from dental pulp tissue by polymerase Chain Reaction.
Forensic odontology necessarily involves the application of dentistry along with various other branches of sciences which deals with proper handling, examination, evaluation, and presentation of dental evidences, that aids to investigate a crime and deliver justice. Sex determination is a part of forensic odontology and an essential priority when traditional identification of the deceased becomes impossible. To determine Sex by analysis of the Amelogenin gene using Polymerase Chain Reaction (PCR) method on Deoxyribose nucleic acid (DNA) isolated from dental pulp, which was exposed to various environmental conditions created artificially to mimic a forensic scenario. This in-vitro study was conducted by subjecting extracted teeth to various conditions imitating a forensic scene, viz. desiccation at room temperatures, immersion in salt water, burial in soil and even exposing to extremes of temperatures. DNA was extracted from dental pulp tissue and sex determination was achieved by amplification of the amelogenin gene through AMEL gene based primers in PCR. Among all the samples used in this study, DNA could be extracted from all, except from those that were subjected to a temperature of 350 °C. DNA amplification and sex determination of the samples were found to be accurate when compared to sex of the individual which was recorded initially, during collection of teeth samples. This study shows teeth to be a potent source of DNA even in extreme environmental conditions, barring high temperatures and determination of sex by PCR amplification of AMEL markers to be quite reliable.


Analysis of depolarizing Mueller matrices through a symmetric decomposition.
A product decomposition of a depolarizing Mueller matrix consisting in the sequence of five factors-a diagonal depolarizer stacked between two retarder and diattenuator pairs-is proposed. This novel "symmetric" decomposition allows for a straightforward interpretation and parameterization of an experimentally determined Mueller matrix in terms of an arrangement of polarization devices and their characteristic parameters: diattenuations, retardances, and axis azimuths. Its application is illustrated on experimentally determined Mueller matrices.


Antigen-activated dendritic cells ameliorate influenza A infections.
Influenza A viruses cause significant morbidity and mortality worldwide. There is a need for alternative or adjunct therapies, as resistance to currently used antiviral drugs is emerging rapidly. We tested ligand epitope antigen presentation system (LEAPS) technology as a new immune-based treatment for influenza virus infection in a mouse model. Influenza-J-LEAPS peptides were synthesized by conjugating the binding ligand derived from the β2-microglobulin chain of the human MHC class I molecule (J-LEAPS) with 15 to 30 amino acid-long peptides derived from influenza virus NP, M, or HA proteins. DCs were stimulated with influenza-J-LEAPS peptides (influenza-J-LEAPS) and injected intravenously into infected mice. Antigen-specific LEAPS-stimulated DCs were effective in reducing influenza virus replication in the lungs and enhancing survival of infected animals. Additionally, they augmented influenza-specific T cell responses in the lungs and reduced the severity of disease by limiting excessive cytokine responses, which are known to contribute to morbidity and mortality following influenza virus infection. Our data demonstrate that influenza-J-LEAPS-pulsed DCs reduce virus replication in the lungs, enhance survival, and modulate the protective immune responses that eliminate the virus while preventing excessive cytokines that could injure the host. This approach shows promise as an adjunct to antiviral treatment of influenza virus infections.


Recovery from acute renal failure predisposes hypertension and secondary renal disease in response to elevated sodium.
Recovery of renal function is a well-characterized feature of models of acute renal failure; however, more recent studies have reported a predisposition to chronic renal disease. This study sought to determine the susceptibility to sodium-dependent hypertension following recovery from ischemic acute renal failure. Following ischemia-reperfusion (I/R) injury, rats were allowed to recover for 35 days on a 0.4% salt diet, then were switched to 4.0% salt diet for an additional 28 days. Blood pressure was significantly increased in postischemic rats switched to high-sodium diet at day 35 (19 +/- 9 mmHg) compared with postischemic rats maintained on low-sodium diet. Plasma renin activity and creatinine clearance were not affected by I/R injury. The ischemic injury combined with transfer to 4.0% salt diet resulted in marked renal hypertrophy characterized by interstitial cellular deposition, tubular dilation, and enhanced rates of albumin excretion. Glomerular structure was altered in post-I/R rats switched to high-sodium diet but not in those maintained on low-sodium diets. When rats were acclimated to high-sodium diet before I/R injury, the early injury was similar to that observed in animals acclimated to low-sodium diet, and these animals progressed rapidly toward chronic kidney disease, as evidenced by advancement of albuminuria. These data suggest that the recovery from acute I/R injury is not complete, compromises Na homeostasis, and predisposes hypertension and secondary renal disease.


Seamless Multi-Projection Revisited.
This paper introduces a novel photometric compensation technique for inter-projector luminance and chrominance variations. Although it sounds as a classical technical issue, to the best of our knowledge there is no existing solution to alleviate the spatial non-uniformity among strongly heterogeneous projectors at perceptually acceptable quality. Primary goal of our method is increasing the perceived seamlessness of the projection system by automatically generating an improved and consistent visual quality. It builds upon the existing research of multi-projection systems, but instead of working with perceptually non-uniform color spaces such as CIEXYZ, the overall computation is carried out using the RLab [10, pp. 243-254] color appearance model which models the color processing in an adaptive, perceptual manner. Besides, we propose an adaptive color gamut acquisition, spatially varying gamut mapping, and optimization framework for edge blending. The paper describes the overall workflow and detailed algorithm of each component, followed by an evaluation validating the proposed method. The experimental results both qualitatively and quantitatively show the proposed method significant improved the visual quality of projected results of a multi-projection display with projectors with severely heterogeneous color processing.


Comparison of Transesophageal and Transthoracic Echocardiographic Measurements of Mechanism and Severity of Mitral Regurgitation in Ischemic Cardiomyopathy (from the Surgical Treatment of Ischemic Heart Failure Trial).
Mitral regurgitation (MR) is common in ischemic heart disease and contributes to symptoms and mortality. This report compares the results of baseline transesophageal echocardiography (TEE) and transthoracic echocardiography (TTE) imaging of the mechanism and severity of functional MR in patients with ischemic cardiomyopathy in the Surgical Treatment for Ischemic Heart Failure (STICH) trial. Independent core laboratories measured both TTE and TEE images on 196 STICH participants. Common measurements to both models included MR grade, mitral valve tenting height and tenting area, and mitral annular diameter. For each parameter, correlations were assessed using Spearman rank correlation coefficients. A modest correlation was present between TEE and TTE for overall MR grade (n = 176, r = 0.52). For mechanism of MR, modest correlations were present for long-axis tenting height (n = 152, r = 0.35), tenting area (n = 128, r = 0.27), and long-axis mitral annulus diameter (n = 123, r = 0.41). For each measurement, there was significant scatter. Potential explanations for the scatter include different orientation of the imaging planes between TEE and TTE, a mean temporal delay of 6 days between TEE and TTE, and statistically significant differences in heart rate and blood pressure and weight between studies. In conclusion, TEE and TTE measurements of MR mechanism and severity correlate only modestly with enough scatter in the data that they are not interchangeable.


Adolescent and Parental Reactions to Puberty in Nigeria and Kenya: A Cross-Cultural and Intergenerational Comparison.
This qualitative study assesses the cross-cultural and intergenerational reactions of young adolescents and parents to puberty in Ile-Ife, Nigeria, and Nairobi, Kenya. Sixty-six boys and girls (aged 11-13 years) and their parents participated in narrative interviews conducted in English or local languages in two urban poor settings in Ile-Ife and Nairobi. All interviews were recorded, transcribed, translated, and uploaded into Atlas.ti software for coding and analysis. Reactions of parents and adolescents to puberty were similar across both sites, with few exceptions. Adolescents' reactions to bodily changes varied from anxiety to pride. Adolescents generally tend to desire greater privacy; trying to hide their developing bodies from others. Most female adolescents emphasized breast development as compared with menstruation as the mark for pubertal initiation, while males emphasized voice changes. Among some ethnic groups in Nairobi, parents and adolescents view male circumcision as the hallmark of adolescence. Parents in both sites reported that with pubertal changes, adolescents tend to become arrogant and engaged in sexual relationships. Parents' reported responses to puberty include: educating adolescents on bodily changes; counseling on sexual relationships; and, provision of sanitary towels to females. Parents' responses are generally focused more on daughters. Approaches used by mothers in educating adolescents varied from the provision of factual information to fear/scare tactics. Compared with their own generation, parents perceive that their own children achieve pubertal development earlier, receive more puberty-related education from mothers, and are more exposed to and influenced by media and information technologies. Adolescents' responses to their pubertal bodily changes include anxiety, shame, and pride. Adolescents desire greater privacy. Parents' reactions were broadly supportive of their children's pubertal transition, but mothers' communication approaches may sometimes be inappropriate in terms of using fear/scare tactics.


[Policies and mental health action plans in OECD: lessons for Quebec?].
The objectives of this research are: 1) to provide a conceptual framework for analyzing mental health policies; 2) to compare mental health policies across a sample of OECD jurisdictions; 3) to describe configurations of mental health policies; 4) to identify practical implications for the Province of Quebec. This research is a comparative synthetic study of mental health policies. The web sites of the Ministries of health of the thirty-four OECD countries and ten Canadian Provinces were searched for mental health policies proposed within the last fifteen years. Twenty one such policies (with an English or French version) were retrieved, covering thirteen OECD countries, six Canadian Provinces and the WHO. Content analysis was performed based on the categories (differentiation, integration, governance) and sub-categories of the aforementioned conceptual framework. Eight policies that together cover the variations encountered between all policies were used to identify typical configurations. A conceptual framework derived from Parsons' Theory of Social Action posits that social action systems must exhibit a level of internal differentiation that corresponds to the heterogeneity of their external environment and also a level of integration that allows them to remain coherent despite the complexity of their environment. Governance mechanisms help them maintain an equilibrium between differentiation and integration.In terms of differentiation, mental health policies exhibit much variation between the needs and the groups that are prioritized (age, gender, ethnicity, culture, etc.), the types of interventions that are proposed (promotion, prevention, treatment, rehabilitation, etc.), the systemic levels at which interventions take place (society, government as a whole, health care system, organizations, programs, individuals), and the level of specification and scientific basis of proposed interventions. In terms of integration, policies promote various mechanisms belonging to four general categories of increasing effectiveness from hierarchical separation of mandates, to exchange of information, to collaborative planning, and to complete structural integration and co-localisation of certain components (ex. dependence and mental health services). In terms of governance, policies present program theories of varying explicitness and scientific bases, and with different emphases on structures, processes or outcomes. Management models also vary in terms of precision, accountability, financing mechanisms, information systems, and the importance of clinical governance and quality improvement.Five configurations of mental health policies are identified (the public health, the professional, the structural technocratic, the functional technocratic, and the political), each comprising typical combinations of the preceding ingredients. The current Quebec mental health policy belongs to the structural technocratic configuration. It specifies fragmented mental health structures with mild integration mechanisms. In the future, it should consider improving its public health aspects (inter-sector work on the determinants of mental health), professional aspects (emphasis on scientific evidence, clinical governance and quality), and functional aspects (integrated specialized community mental health and addiction services). But political factors may prevent it from doing so.


Immune Signatures Following Single Dose Trastuzumab Predict Pathologic Response to PreoperativeTrastuzumab and Chemotherapy in HER2-Positive Early Breast Cancer.
Recent data suggest that intrinsic subtype and immune cell infiltration may predict response to trastuzumab-based therapy. We studied the interaction between these factors, changes in immune signatures following brief exposure to trastuzumab, and achievement of pathologic complete response (pCR) to subsequent preoperative trastuzumab and chemotherapy in HER2-positive breast cancer. In patients enrolled on two multicenter trials (03-311 and 211B), tumor core biopsies were obtained at baseline and after brief exposure to single-agent trastuzumab or nab-paclitaxel. Gene expression profiles were assessed to assign PAM50 subtypes, measure immune cell activation, and were correlated with response. The pCR rate was significantly higher in HER2-enriched tumors in the Discovery, 03-311 (36%, P = 0.043) dataset, as compared with other subtypes, which validated in 211B (50%, P = 0.048). Significant increases in a signature of immune cell admixture (Immune Index) were observed only following brief exposure to trastuzumab in HER2-enriched tumors (Discovery/03-311, P = 0.05; Validation/211B, P = 0.02). Increased Immune Index was predictive of response after brief exposure (03-311, P = 0.03; 211B, P = 0.04), but not at baseline, in addition to increased expression of a CD4(+) follicular helper T-cell signature (03-311, P = 0.05; 211B, P = 0.04). Brief exposure to trastuzumab significantly increased gene expression of the T-cell marker PD-1 in HER2-enriched tumors (Discovery/03-311, P = 0.045) and PD-1 positivity by IHC (Validation/211B, P = 0.035). Correlations between pCR rates, increases in Immune Index and markers of T-cell activity following brief exposure to trastuzumab in HER2-enriched tumors provide novel insights into the interaction between tumor biology, antitumor immunity, and response to treatment, and suggest potential clinically useful biomarkers in HER2(+) breast cancers. Clin Cancer Res; 22(13); 3249-59. ©2016 AACR.


Morphometry of human leukocytes.
In order to establish quantitative models of leukocyte functions, several morphometric parameters on individual white cells are needed. These include the diameter, volume, and membrane area of the cells and their nuclei in the undeformed state. A stereologic method was used to obtain these quantities from transmission electron microscopy of random sections through human white blood cells (neutrophils, lymphocytes, monocytes, and eosinophils). In order to estimate possible artifacts due to preparation of the cells for transmission electron microscopy, a detailed comparison with light microscopy was made. The results show that undeformed white cells in isotonic solution are spherical with many membrane foldings and have a significantly smaller diameter than that measured on blood smears. A method of chemical fixation was employed so that the shrinkage due to fixation of the cells is below the resolution of light microscopic measurements. Further, it was shown that all leukocytes, including lymphocytes, have much more membrane area than is needed to cover their volumes, and this membrane area remains constant when the cell is hypotonically swollen.


Magnesium Oxide Nanoparticles Reinforced Electrospun Alginate-Based Nanofibrous Scaffolds with Improved Physical Properties.
Mechanically robust alginate-based nanofibrous scaffolds were successfully fabricated by electrospinning method to mimic the natural extracellular matrix structure which benefits development and regeneration of tissues. Alginate-based nanofibres were electrospun from an alginate/poly(vinyl alcohol) (PVA) polyelectrolyte complex. SEM images revealed the spinnability of the complex composite nanofibrous scaffolds, showing randomly oriented, ultrafine, and virtually defects-free alginate-based/MgO nanofibrous scaffolds. Here, it is shown that an alginate/PVA complex scaffold, blended with near-spherical MgO nanoparticles (⌀ 45 nm) at a predetermined concentration (10% (w/w)), is electrospinnable to produce a complex composite nanofibrous scaffold with enhanced mechanical stability. For the comparison purpose, chemically cross-linked electrospun alginate-based scaffolds were also fabricated. Tensile test to rupture revealed the significant differences in the tensile strength and elastic modulus among the alginate scaffolds, alginate/MgO scaffolds, and cross-linked alginate scaffolds (P < 0.05). In contrast to cross-linked alginate scaffolds, alginate/MgO scaffolds yielded the highest tensile strength and elastic modulus while preserving the interfibre porosity of the scaffolds. According to the thermogravimetric analysis, MgO reinforced alginate nanofibrous scaffolds exhibited improved thermal stability. These novel alginate-based/MgO scaffolds are economical and versatile and may be further optimised for use as extracellular matrix substitutes for repair and regeneration of tissues.


PHOrming the inflammasome: phosphorylation is a critical switch in inflammasome signalling.
Inflammasomes are protein complexes in the innate immune system that regulate the production of pro-inflammatory cytokines and inflammatory cell death. Inflammasome activation and subsequent cell death often occur within minutes to an hour, so the pathway must be dynamically controlled to prevent excessive inflammation and the development of inflammatory diseases. Phosphorylation is a fundamental post-translational modification that allows rapid control over protein function and the phosphorylation of inflammasome proteins has emerged as a key regulatory step in inflammasome activation. Phosphorylation of inflammasome sensor and adapter proteins regulates their inter- and intra-molecular interactions, subcellular localisation, and function. The control of inflammasome phosphorylation may thus provide a new strategy for the development of anti-inflammatory therapeutics. Herein we describe the current knowledge of how phosphorylation operates as a critical switch for inflammasome signalling.


Listeria monocytogenes virulence factors, including listeriolysin O, are secreted in biologically active extracellular vesicles.
Outer membrane vesicles produced by Gram-negative bacteria have been studied for half a century but the possibility that Gram-positive bacteria secrete extracellular vesicles (EVs) was not pursued until recently due to the assumption that the thick peptidoglycan cell wall would prevent their release to the environment. However, following their discovery in fungi, which also have cell walls, EVs have now been described for a variety of Gram-positive bacteria. EVs purified from Gram-positive bacteria are implicated in virulence, toxin release, and transference to host cells, eliciting immune responses, and spread of antibiotic resistance. Listeria monocytogenes is a Gram-positive bacterium that causes listeriosis. Here we report that L. monocytogenes produces EVs with diameters ranging from 20 to 200 nm, containing the pore-forming toxin listeriolysin O (LLO) and phosphatidylinositol-specific phospholipase C (PI-PLC). Cell-free EV preparations were toxic to mammalian cells, the murine macrophage cell line J774.16, in a LLO-dependent manner, evidencing EV biological activity. The deletion of plcA increased EV toxicity, suggesting PI-PLC reduced LLO activity. Using simultaneous metabolite, protein, and lipid extraction (MPLEx) multiomics we characterized protein, lipid, and metabolite composition of bacterial cells and secreted EVs and found that EVs carry the majority of listerial virulence proteins. Using immunogold EM we detected LLO at several organelles within infected human epithelial cells and with high-resolution fluorescence imaging we show that dynamic lipid structures are released from L. monocytogenes during infection. Our findings demonstrate that L. monocytogenes uses EVs for toxin release and implicate these structures in mammalian cytotoxicity.


Cost and time savings from a rapid access model of care using transient elastography to screen and triage patients with chronic Hepatitis C infection.
Treatment uptake amongst patients with chronic Hepatitis C virus (HCV) in Australia is relatively low. New approaches to assessment have the potential to reduce public waiting lists, improve access to treatment, and to reduce healthcare costs. To describe the costs to the public hospital system and waiting time associated with a novel integrated rapid access to assessment and treatment (RAAT) model of care that utilizes Transient Elastography (TE) as a specialist outpatient-based approach for a streamlined assessment of patients with chronic HCV, compared to conventional outpatient management with liver biopsy (LB). Time from first medical review to treatment plan and costs associated with detection of fibrosis were recorded for patients receiving RAAT during a 3-month period, and for a similar historical cohort managed conventionally with LB. Costs related to medical and multidisciplinary team reviews and the TE/LB test itself were included. Patients receiving RAAT had lower costs (n = 27, median AU$2716) and shorter time to treatment (median = 194 days) than for conventional management (n = 13, median $5005, 420 days; p < 0.01). Differences related to the lower TE test costs and the lower cost of consults between first medical review and establishment of a treatment plan. Based on real world audit data, this evaluation suggests TE, used as part of a new RAAT model of care, is cost saving to the health system in the short-term and reduces waiting times. The analysis reported here was intended to assess the costs related to detection of fibrosis, and is limited by the small sample size and potential selection bias. Future research should undertake a full economic evaluation at a whole of service level, to consider a more comprehensive and longer-term assessment of the costs and benefits associated with HCV management.


A strap strategy for construction of an excited-state intramolecular proton transfer (ESIPT) system with dual fluorescence.
An amine-embedded flexible alkyl strap has been incorporated into an emissive boryl-substituted dithienylpyrrole skeleton as a new entity of excited-state intramolecular proton transfer (ESIPT) chromophores. The π-electron system shows a dual emission, which covers a wide range of the visible region depending on the solvent polarity. The incorporation of the aminoalkyl strap as well as the terminal boryl groups efficiently stabilize the zwitterionic excited-state species resulting from the ESIPT even in an aqueous medium.


Hemispheric asymmetry in cerebrovascular reactivity of the human primary motor cortex: an in vivo study at 7 T.
Current functional MRI (fMRI) approaches assess underlying neuronal activity through monitoring the related local variations in cerebral blood oxygenation, blood volume and blood flow. This vascular response is likely to vary across brain regions and across individuals, depending on the composition of the local vascular bed and on the vascular capacity to dilate. The most widely used technique uses the blood oxygen level dependent (BOLD) fMRI signal, which arises from a complex combination of all of these factors. The model of handedness provides a case where one brain region (dominant motor cortex) is known to have a stronger BOLD response over another (non-dominant motor cortex) during hand motor task performance. We predict that this is accompanied by a higher vascular reactivity in the dominant motor cortex, when compared with the non-dominant motor cortex. Precise measurement of end-tidal CO2 and a novel sinusoidal CO2 respiratory challenge were combined with the high sensitivity and finer spatial resolution available for fMRI at 7 T to measure BOLD cerebrovascular reactivity (CVR) in eight healthy male participants. BOLD CVR was compared between the left (dominant) and right (non-dominant) primary motor cortices of right-handed adults. Hemispheric asymmetry in vascular reactivity was predicted and observed in the primary motor cortex (left CVR = 0.60 ± 0.15%/mm Hg; right CVR = 0.47 ± 0.08%/mm Hg; left CVR > right CVR, P = 0.04), the first reported evidence of such a vascular difference. These findings demonstrate a cerebral vascular asymmetry between the left and right primary motor cortex. The origin of this asymmetry largely arises from the contribution of large draining veins. This work has implications for future motor laterality studies that use BOLD, and it is also suggestive of a vascular plasticity in the human primary motor cortex.


Development of retinoblastoma in the absence of telomerase activity.
The length and stability of telomeres (essential functional structures at the end of eukaryotic chromosomes) have been implicated in the control of cell lifespan. Most somatic cells lack telomerase, the enzyme that synthesizes telomeric DNA, and their telomeres shorten with cell division. Cells immortalized in vitro, on the other hand, express telomerase and maintain their telomeres. Telomerase activity has also been detected in the large majority of tumors from a variety of cancers. These observations have suggested that telomere maintenance is required for unlimited cell proliferation and that telomerase is a marker for cell immortality in vitro and in vivo. We investigated whether telomerase is activated during the development of retinoblastoma. This is a childhood eye cancer associated with a limited number of mutations in an embryonic tissue and thus likely to develop in cells that have long telomeres. The ease of detection of retinoblastoma makes it possible to screen relatively small tumors before extensive proliferation of the malignant cells. We measured telomerase activity in 34 samples of retinoblastoma, four retinoblastoma-derived cell lines, and six cell lines derived from other cancers. Only three of the cell lines from other cancers expressed the retinoblastoma protein. Telomerase activity was assayed by a polymerase chain reaction protocol in extracts prepared from tumors or cell lines. The level of enzyme activity in cell extracts was quantified at several protein concentrations and expressed relative to that in a positive control, after normalization for the amount of protein. Telomere length was measured by Southern blot hybridization of genomic DNA with a telomere-specific probe. Average values of telomere length in telomerase-positive and telomerase-negative tumors and in cell lines were compared by two-sided, two-sample Student's t test. No telomerase activity was detected in 17 (50%) of 34 retinoblastomas. Assays of cell lines derived from other cancers revealed no association between the presence or the level of the enzyme activity and the expression of the retinoblastoma protein. Telomeres were significantly longer in telomerase-negative tumors than in telomerase-positive tumors (P = .0008). Our results indicate that retinoblastoma can develop when telomeres are still relatively long and in the absence of telomerase. Telomerase activity associated with short telomeres is, however, observed in 50% of the retinoblastomas and in retinoblastoma-derived cell lines. Telomerase may not be a marker for acquisition of the malignant phenotype in the case of tumors that are derived from cells with long telomeres and that are associated with a low number of mutations.


Allospecific cytolytic T lymphocytes recognize conformational determinants on hybrid mouse transplantation antigens.
Alloreactive cytolytic T cell (CTL) lines and clones have been used to identify the sites of polymorphism of antigens of the major histocompatibility complex (MHC). Specific CTL were generated against wild-type H-2b products by cells from H-2b mutant mice that had one or a few amino acid changes in either the alpha 1 or alpha 2 domains of the Kb or Db class I molecules. These CTL populations, which might be expected to react with determinants expressed on single MHC domains, were examined for lytic activity on L cells expressing newly constructed hybrid class I molecules. Transformed cell lines expressing native class I molecules or hybrid class I molecules in which the alpha 1 and alpha 2 domains of H-2Kb had been substituted by those domains of H-2Db were lysed by H-2Db-specific CTL. Similarly, all H-2Kb-specific CTL recognized hybrid molecules in which the alpha 1 and alpha 2 domains of H-2Kb were inserted into the H-2Db molecule. In contrast, exchange of the alpha 1 domains of H-2Kb and H-2Db resulted in a total loss of recognition by Kb and Db-specific CTL. These results suggest that the allodeterminants recognized by H-2 mutant CTL are influenced by interactions between the alpha 1 and alpha 2 domains, findings similar to those seen using conventional alloreactive T cells (11). These results were compared to the binding of alloreactive mAbs, including 5 new mAbs specific for the Kb molecules. Finally, it was shown that primary and secondary CTL responses could be generated by direct sensitization against hybrid class I molecules, demonstrating that these molecules express neoantigenic determinants recognized by alloreactive CTL.


Vitamin D Levels in Patients Presenting with Non-Specific Neuromuscular Pain and Fatigue in Ethiopia.
Vitamin D is an important micronutrient impacting multiple physiologic functions including calcium, phosphorus and bone metabolism. Various studies demonstrate low vitamin D levels in non-specific neuromuscular pain disorders and chronic-fatigue-syndromes. This observation was supported by significant improvement of these disorders following Vitamin D supplementation. Several studies demonstrate low serum vitamin D levels in healthy adult Ethiopians despite availability of abundant sunlight. Retrospective medical records review of 62 patients presented to Yehuleshet Specialty Clinic between March 2014-August 2015 with non-specific neuromuscular pain and fatigue. Serum vitamin D levels were obtained at initial clinic visit. The mean (±SD) age was 51.5 ±15.5 years. Two-third (69.4%) of the participants were female. The majority (56.5%) presented with mixed symptoms, including generalized body ache, paresthesia, neck and back pain, while 45.2% reported fatigue. Fifteen (24.2%) participants were on antiepileptic drugs. All patients had initial serum vitamin D levels < 30 ng/ml, among these 62.9% demonstrated severe deficiency (< 12 ng/ml). Thirty (48.4%) participants reported symptomatic improvement after treatment with standard doses of vitamin D and calcium. Age > 50 years, being housewife, use of antiepileptic medications (AEDs), and higher serum parathyroid hormone are associated with severe vitamin D deficiency. This study demonstrated high prevalence of vitamin D deficiency among patients with non-specific neuromuscular pain and fatigue. Vitamin D replacement resulted in significant clinical improvement. It is important to screen vitamin D in individuals with limited sunlight exposure and patients on AEDs when presenting with neuromuscular pain and fatigue.


The Vroman effect in tube geometry: the influence of flow on protein adsorption measurements.
The transient adsorption of fibrinogen from plasma (a manifestation of the Vroman effect), due in large part to displacement by trace proteins such as high-molecular-weight kininogen (HK), factor XII, and plasminogen, has traditionally been studied in nonflowing systems in this laboratory. This paper reports new data on adsorption in tubing geometry under laminar flow. Fibrinogen adsorption from human blood plasma and whole blood diluted to varying exents was measured on glass and polyethylene tubing. The presence of flow did not change the nature of the Vroman effect, except that the processes of adsorption and displacement, which are typically diffusion-limited in static systems, were augmented by convective transport. At the highest applied shear rates of 408 and 510 s-1, the initial adsorption rate of fibrinogen was estimated to be 5.0 X 10(-5) cm/s on both surfaces. The intrinsic rate of displacement of fibrinogen (due to the Vroman effect) at high shear rates was about ten times faster from glass than from polyethylene based on data taken 5 min after the experiment started. The rates of fibrinogen adsorption and displacement were not observed to be significantly augmented by the cellular elements of whole blood at dilutions exceeding 20:1. The consistently observed axial dependence of adsorption in static and flow experiments in tubing geometry was investigated. It was concluded that the effect results, under most conditions, from the creation of a concentration boundary layer during the displacement of the equilibrating buffer by the injected protein solution. The possibility of local depletion due to rapid adsorption during injection or the final displacement of the protein solution was concluded to make lesser contributions to axial variations in measured adsorption.


A randomized clinical trial investigating treatment choice in Chinese men receiving sildenafil citrate and tadalafil for treating erectile dysfunction.
Sildenafil and tadalafil are efficacious and well tolerated in Chinese men with erectile dysfunction (ED). Recent study results indicate that men with ED in China who were naïve to phosphodiesterase inhibitor type 5 (PDE5) therapy prefer tadalafil 20-mg (on-demand) versus sildenafil 100-mg (on-demand). Differences in psychosocial outcomes may help to explain treatment preference in favor of tadalafil. This open-label, randomized, crossover study compared psychosocial outcomes and drug attribute choices between tadalafil and sildenafil in Chinese men with ED naïve to PDE5 inhibitor therapy. Eligible patients were randomized to sequential 20-mg tadalafil/100-mg sildenafil (n = 190) or 100-mg sildenafil/20-mg tadalafil (n = 193) for 8 weeks each and were asked which treatment they preferred to take for the 8-week extension phase. Psychosocial outcomes were assessed using the Psychological and Interpersonal Relationship Scale (PAIRS), Drug Attributes Questionnaire (DRAQ), and Sexual Life Quality Questionnaire (SLQQ). When taking tadalafil versus sildenafil, men had a higher mean endpoint score on the PAIRS Spontaneity Domain (tadalafil = 2.86 vs sildenafil = 2.72; P < 0.001), and a lower mean endpoint score on the Time Concerns Domain (tadalafil = 2.41 vs sildenafil = 2.55; P < 0.001). A numerical increase in the Sexual Self-Confidence Domain was observed when taking tadalafil versus sildenafil (tadalafil = 2.76 vs sildenafil = 2.72; P = 0.102). The most frequently chosen drug attributes explaining treatment preference were able to get an erection long after having drug, and ability to get an erection every time. SLQQ results were comparable between treatment groups. These psychosocial outcomes may explain why more Chinese men preferred tadalafil versus sildenafil for the treatment of ED in this clinical trial.


Self-reported dental coping strategies among fearful adult patients: preliminary enquiry explorations.
This investigation explored strategies to cope with dental treatment used by fearful adult patients undergoing regular dental care and those with phobic avoidance. A newly constructed 20-item questionnaire entitled The Dental Coping Strategy Questionnaire (DCSQ-20) was distributed consecutively to 171 individuals with self- and dentist-reported high dental fear, of whom 77 had dental phobic avoidance and were attending a dental fear clinic and 94 were undergoing regular care at one of three different public dental clinics. The level of dental fear was high in both groups, but significantly higher among avoidant individuals. Several of the DCSQ-20 items showed statistically significant differences between groups. Factor analysis of the DCSQ-20 yielded a four-factor solution explaining 52% of the total variance. The factors were labelled (i) 'self-efficacy statements', (ii) 'self distraction and distancing', (iii) 'catastrophizing', and (iv) 'praying and despair'. The DCSQ-20 displayed sound psychometric properties, and the reliability (Cronbach's alpha) for the factors was between 0.68-0.78. Factors (iii) and (iv) correlated significantly with dental anxiety and were rated significantly higher among individuals with phobic avoidance. In a logistic regression analysis, gender, dental anxiety, and three of the four factors (i, iii, iv) were predictive of regularity vs. phobic avoidance of dental care.


A general model for the origin of allometric scaling laws in biology.
Allometric scaling relations, including the 3/4 power law for metabolic rates, are characteristic of all organisms and are here derived from a general model that describes how essential materials are transported through space-filling fractal networks of branching tubes. The model assumes that the energy dissipated is minimized and that the terminal tubes do not vary with body size. It provides a complete analysis of scaling relations for mammalian circulatory systems that are in agreement with data. More generally, the model predicts structural and functional properties of vertebrate cardiovascular and respiratory systems, plant vascular systems, insect tracheal tubes, and other distribution networks.


Effects of Lactobacillus Plantarum and Lactobacillus Helveticus on Renal Insulin Signaling, Inflammatory Markers, and Glucose Transporters in High-Fructose-Fed Rats.
Background and Objectives: The excess consumption of fructose in the diet may cause metabolic syndrome, which is associated with an increased risk of kidney disease. There is limited data on probiotic treatment in high-fructose-induced metabolic syndrome. The present study aims to investigate whether the supplementation of Lactobacillus plantarum (L. plantarum) and Lactobacillus helveticus (L. helveticus) could provide an improving effect on the renal insulin signaling effectors, inflammatory parameters, and glucose transporters in fructose-fed rats. Materials and Methods: The model of metabolic syndrome in male Wistar rats was produced by fructose, which was given as 20% solution in drinking water for 15 weeks. L. plantarum and L. helveticus supplementations were given by gastric gavage from 10 to 15 weeks of age. Results: High-fructose consumption in rats reduced renal protein expressions of insulin receptor substrate (IRS)-1, protein kinase B (AKT), and endothelial nitric oxide synthase (eNOS), which were improved by L. plantarum and partially by L. helveticus supplementations. Dietary fructose-induced elevations in renal tissue levels of tumor necrosis factor α (TNF-α), interleukin (IL)-1β, IL-6, and IL-10, as well as expression of IL-6 mRNA, were attenuated, especially in L. plantarum treated rats. The increased renal expression of sodium-glucose cotransporter-2 (SGLT2), but not that of glucose transporter type-5 (GLUT5), was suppressed by the treatment with L. plantarum. Conclusion: Suppression in insulin signaling pathway together with the induction of inflammatory markers and upregulation of SGLT2 in fructose-fed rats were improved by L. plantarum supplementation. These findings may offer a new approach to the management of renal dysregulation induced by dietary high-fructose.


Understanding treatment readiness in recently assessed, pre-treatment substance abusers.
The goal of this study was to more fully understand readiness for treatment in a pre-treatment sample of 446 substance abusers. Structural Equation Modeling (SEM) was used to: (1) examine the relationships between readiness factors identified in the Pre-Treatment Readiness Scale; and (2) identify the effects of predisposing, illness, and inhibiting determinants on the factors. As with in-treatment samples, Problem Recognition was found to influence Treatment Readiness, although through a different intervening factor, Desire for Change rather than Desire for Help. A fourth factor, Treatment Reluctance, was also influenced by the Desire for Change factor. Fixed characteristics such as age and gender had minimal influences on readiness factors, as did inhibiting characteristics that reflected recent functioning. Illness characteristics including drug severity and perceived treatment barriers had a more robust influence on readiness factors. This study provides an increased understanding of readiness for treatment among pre-treatment substance abusers and also supported the construct validity of the Pre-Treatment Readiness Scale.


Optical and electronic properties of pyrite nanocrystal thin films: the role of ligands.
Pyrite nanocrystals are currently considered as a promising material for large scale photovoltaic applications due to their non-toxicity and large abundance. While scalable synthetic routes for phase-pure and shape controlled colloidal pyrite nanocrystals have been reported, their use in solar cells has been hampered by the detrimental effects of their surface defects. Here, we report a systematic study of optical and electronic properties of pyrite nanocrystal thin films employing a series of different ligands varying both the anchor and bridging group. The effect of the ligands on the optical and electronic properties is investigated by UV-vis/NIR absorption spectroscopy, current voltage characteristic measurements and surface photovoltage spectroscopy. We find that the optical absorption is mainly determined by the anchor group. The absorption onset in the thin films shifts up to ∼100 meV to the red. This is attributed to changes in the dielectric environment induced by different anchors. The conductivity and photoconductivity, on the other hand, are determined by combined effects of anchor and bridging group, which modify the effective hopping barrier. Employing different ligands, the differential conductance varies over four orders of magnitude. The largest redshift and differential conductance are observed for ammonium sulfides and thiolated aromatic linkers. Pyridine and long chain amines, on the other hand, lead to smaller modifications. Our findings highlight the importance of surface functionalization and interparticle electronic coupling in the use of pyrite nanocrystals for photovoltaic devices.


Fatty acids in arbuscular mycorrhizal fungi are synthesized by the host plant.
Plants form beneficial associations with arbuscular mycorrhizal fungi, which facilitate nutrient acquisition from the soil. In return, the fungi receive organic carbon from the plants. The transcription factor RAM1 (REQUIRED FOR ARBUSCULAR MYCORRHIZATION 1) is crucial for this symbiosis, and we demonstrate that it is required and sufficient for the induction of a lipid biosynthetic pathway that is expressed in plant cells accommodating fungal arbuscules. Lipids are transferred from the plant to mycorrhizal fungi, which are fatty acid auxotrophs, and this lipid export requires the glycerol-3-phosphate acyltransferase RAM2, a direct target of RAM1. Our work shows that in addition to sugars, lipids are a major source of organic carbon delivered to the fungus, and this is necessary for the production of fungal lipids.


Mapping specific protein-protein interactions within the core component of the breast cell DNA synthesome.
We have previously described the isolation and characterization of an intact multiprotein complex for DNA replication, designated the DNA synthesome, from human breast cancer cells and biopsied human breast tumor tissue. The purified DNA synthesome was observed to fully support DNA replication in vitro. We had also proposed a model for the breast cell DNA synthesome, in which DNA polymerases alpha, delta, and epsilon, DNA primase, and replication factor C (RF-C) represent members of the core component, or tightly associated, proteins of the complex. This model was based on the observed fractionation, chromatographic, and sedimentation profiles for these proteins. We report here that poly(ADP-ribose)polymerase (PARP) and DNA ligase 1 are also members of the breast cell DNA synthesome core component. More importantly, in this report we present the results of coimmunoprecipitation studies that were designed to map the protein-protein interactions between several members of the core component of the DNA synthesome. Consistent with our proposed model for the breast cell DNA synthesome, our data indicate that DNA polymerases alpha and delta, DNA primase, RF-C, as well as proliferating cell nuclear antigen (PCNA), tightly associate with each other in the complex, whereas DNA polymerase epsilon, PARP, and several other components were found to interact with the synthesome via a direct contact with only PCNA or DNA polymerase alpha. The association of PARP with the synthesome core suggests that this protein may serve a regulatory function in the complex. Also, the coimmunoprecipitation studies suggest that the three DNA polymerases alpha, delta, and epsilon all participate in the replication of breast cell DNA. To our knowledge this is the first report ever to describe the close physical association of polypeptides constituting the intact human breast cell DNA replication apparatus.


Antiviral activity of SK&F 21681 against herpes simplex virus.
SK&F 21681 (3,10-dimethyl-10-H-s-triazolo[4',3':2,3]-as-triazino-[ 5,6-b]indole) is an inhibitor of the growth of herpes simplex viruses types 1 and 2 at a concentration of 60 micrograms/ml. It inhibits the synthesis of the viral DNA and the formation of virus particles, although the viral polypeptide synthesis is not significantly affected by this compound. Mutants of herpes simplex viruses types 1 and 2 which are able to grow in the presence of SK&F 21681 were isolated. They induced normal levels of thymidine kinase and DNA polymerase activities in the infected cells and did not show resistance to either 9-[2-hydroxyethoxymethyl] guanine or phosphonoacetic acid.