Coffee Consumption and Incident Kidney Disease: Results From the Atherosclerosis Risk in Communities (ARIC) Study.
Moderate coffee consumption has been suggested to be associated with lower risk for chronic conditions such as diabetes, a major precursor to chronic kidney disease (CKD). However, the association between coffee and CKD has not been fully established. STUDY DESIGN: Prospective cohort study. 14,209 participants aged 45 to 64 years from the Atherosclerosis Risk in Communities (ARIC) Study. Coffee consumption (cups per day) was assessed at visits 1 (1987-1989) and 3 (1993-1995) using food frequency questionnaires. Incident CKD defined as estimated glomerular filtration rate < 60mL/min/1.73m2 accompanied by ≥25% estimated glomerular filtration rate decline, CKD-related hospitalization or death, or end-stage renal disease. There were 3,845 cases of incident CKD over a median of 24 years of follow-up. Men, whites, current smokers, and participants without comorbid conditions were more likely to consume higher amounts of coffee per day. After adjustment for demographic, clinical, and dietary factors, higher categories of coffee consumption were associated with lower risk for incident CKD compared with those who never consumed coffee (HR for <1 cup per day, 0.90 [95% CI, 0.82-0.99]; 1-<2 cups per day, 0.90 [95% CI, 0.82-0.99]; 2-<3 cups per day, 0.87 [95% CI, 0.77-0.97]; and ≥3 cups per day, 0.84 [95% CI, 0.75-0.94]). In continuous analysis, for each additional cup of coffee consumed per day, risk for incident CKD was lower by 3% (HR, 0.97; 95% CI, 0.95-0.99; P<0.001). Self-reported coffee consumption and observational design. Participants who drank higher amounts of coffee had lower risk for incident CKD after adjusting for covariates. Coffee consumers may not be at adverse risk for kidney disease.


Cedrol, a Sesquiterpene Alcohol, Enhances the Anticancer Efficacy of Temozolomide in Attenuating Drug Resistance via Regulation of the DNA Damage Response and MGMT Expression.
Glioblastoma (GBM) is a common and aggressive brain tumor with a median survival of 12-15 months. Temozolomide (TMZ) is a first-line chemotherapeutic agent used in GBM therapy, but the occurrence of drug resistance limits its antitumor activity. The natural compound cedrol has remarkable antitumor activity and is derived from Cedrus atlantica. In this study, we investigated the combined effect of TMZ and cedrol in GBM cells in vitro and in vivo. The TMZ and cedrol combination treatment resulted in consistently higher suppression of cell proliferation via regulation of the AKT and MAPK signaling pathways in GBM cells. The combination treatment induced cell cycle arrest, cell apoptosis, and DNA damage better than either drug alone. Furthermore, cedrol reduced the expression of proteins associated with drug resistance, including O6-methlyguanine-DNA-methyltransferase (MGMT), multidrug resistance protein 1 (MDR1), and CD133 in TMZ-treated GBM cells. In the animal study, the combination treatment significantly suppressed tumor growth through the induction of cell apoptosis and decreased TMZ drug resistance. Moreover, cedrol-treated mice exhibited no significant differences in body weight and improved TMZ-induced liver damage. These results imply that cedrol may be a potential novel agent for combination treatment with TMZ for GBM therapy that deserves further investigation.


Radiatively Limited Dephasing and Exciton Dynamics in MoSe2 Monolayers Revealed with Four-Wave Mixing Microscopy.
By implementing four-wave mixing (FWM) microspectroscopy, we measure coherence and population dynamics of the exciton transitions in monolayers of MoSe2. We reveal their dephasing times T2 and radiative lifetime T1 in a subpicosecond (ps) range, approaching T2 = 2T1 and thus indicating radiatively limited dephasing at a temperature of 6 K. We elucidate the dephasing mechanisms by varying the temperature and by probing various locations on the flake exhibiting a different local disorder. At the nanosecond range, we observe the residual FWM produced by the incoherent excitons, which initially disperse toward the dark states but then relax back to the optically active states within the light cone. By introducing polarization-resolved excitation, we infer intervalley exciton dynamics, revealing an initial polarization degree of around 30%, constant during the initial subpicosecond decay, followed by the depolarization on a picosecond time scale. The FWM hyperspectral imaging reveals the doped and undoped areas of the sample, allowing us to investigate the neutral exciton, the charged one, or both transitions at the same time. In the latter, we observe the exciton-trion beating in the coherence evolution indicating their coherent coupling.


The length of time necessary to break even after converting to digital mammography.
The cost differences between film-based mammography (FBM) and digital mammography (DM) were estimated after discussions with hospital personnel and industry representatives. Human resource costs were not included. The fixed cost of FBM per machine was estimated to be $50,000 and the variable cost $4.60 per examination. The fixed cost of DM per machine was estimated to be $102,000 and the variable cost $0.10 per examination. The total number of examinations required to break even was therefore 11,556. At a rate of 15 examinations per machine per day and with 251 working days per year, it would take 3.1 years to break even. In the first year after the break-even point had been attained, $16,943 would be saved for every 3765 examinations performed. Extrapolating to the USA as a whole, in which 23 million mammographic examinations are performed each year, suggests that the annual savings from going filmless would be more than $103 million.


Three probable cases of Loa loa encephalopathy following ivermectin treatment for onchocerciasis.
Over the past nine years, more than 12 million people exposed to Onchocerca volvulus infection have received at least one dose of ivermectin, almost all without serious adverse reactions. Since 1991, however, several cases with neurologic manifestations, including coma, have been reported after ivermectin treatment of persons infected with O. volvulus who also had concomitant Loa loa infection with very high microfilaremia (> 50,000 microfilariae/ml of blood). In 1995, four criteria were established to define probable cases of Loa encephalopathy temporally related to treatment with ivermectin (PLERI). The present paper describes three PLERI cases recorded in Cameroon and compares them with two others reported previously. Disorders of consciousness began 3-4 days after treatment. The objective neurologic signs were variable. The conditions improved favorably in three patients who benefited from early hospitalization and good nursing; their disorders of consciousness lasted only 2-3 days; the results of clinical examination became normal after one month and electroencephalographic abnormalities disappeared after 5-7 months. Conversely, late diagnosis and delay in proper management in two others probably led to worsening of the condition and to fatal outcome related to the usual complications of coma. In addition to these cases, patients w with high Loa microfilaremia also developed milder neurologic manifestations causing functional impairment lasting for at least one week after treatment. Before launching mass ivermectin distribution programs to control onchocerciasis in central Africa, communities in which the intensity of concomitant L. loa microfilaremia is high need to be identified, and specific educational measures and monitoring strategies should be developed and applied before they are treated.


A Genetic Transformation Method for Cadmium Hyperaccumulator Sedum plumbizincicola and Non-hyperaccumulating Ecotype of Sedum alfredii.
The present study demonstrates the development of an Agrobacterium-mediated genetic transformation method for species of the Sedum genus, which includes the Cd/Zn hyperaccumulator Sedum plumbizincicola and the non-hyperaccumulating ecotype of S. alfredii. Multiple shoots were induced from stem nodes of two Sedum plants using Murashige and Skoog (MS) medium containing 0.1 mg/L cytokinin 6-benzyladenine (6-BA) and 1.0 mg/L auxin 1-naphthaleneacetic acid (NAA). The shoot primordia were used as direct targets for Agrobacterium infection. Selection on hygromycin was highly effective in generating Agrobacterium-transformed explants. This callus-free procedure allowed us to obtain transgenic plantlets after rooting hygromycin-resistant shoots on phytohormone-free MS medium containing the antibiotic. The presence and expression of the reporter genes gusA and GFP in transgenic plants were confirmed by a real-time polymerase chain reaction, histochemical GUS assays, and confocal microscopy. This reliable method for genetic transformation of Sedum plants will help us to understand gene functions and the molecular mechanisms underlying Cd hypertolerance and hyperaccumulation in these species.


A proposal for reform of the structure and financing of primary care graduate medical education.
Accessible, high-quality, cost-effective health care systems are anchored in primary care, yet decreasing production from graduate medical education (GME) jeopardizes the primary care workforce and the nation's health. The GME Initiative recommends Congress (1) invigorates primary care physician (PCP) supply through GME benchmarking and enforcement by creating a workforce that is at least 40% PCPs, holding teaching hospitals accountable, and increasing the primary care residency position cap, (2) establishes a GME system supported by all insurers-public and private-and implements a fixed floor funding of direct GME (DME) at $100,000 per resident per year for residencies that produce graduates who truly go on to practice primary care, (3) reallocates some indirect GME (IME) to support primary care residency education, including enhanced PCP education outside hospitals, including teaching health centers, (4) restores funding for the 1997 full-time equivalent (FTE) PCP residency slots cut for training outside the teaching hospital, (5) allows states expanding Medicaid through the Patient Protection and Affordable Care Act (ACA) to increase PCP education capacity through Medicaid DME and/or IME at the enhanced Federal Medical Assistance Percentage (FMAP).


A new approach for quantitative phosphoproteomic dissection of signaling pathways applied to T cell receptor activation.
Reversible protein phosphorylation plays a pivotal role in the regulation of cellular signaling pathways. Current approaches in phosphoproteomics focus on analysis of the global phosphoproteome in a single cellular state or of receptor stimulation time course experiments, often with a restricted number of time points. Although these studies have provided some insights into newly discovered phosphorylation sites that may be involved in pathways, they alone do not provide enough information to make precise predictions of the placement of individual phosphorylation events within a signaling pathway. Protein disruption and site-directed mutagenesis are essential to clearly define the precise biological roles of the hundreds of newly discovered phosphorylation sites uncovered in modern proteomics experiments. We have combined genetic analysis with quantitative proteomic methods and recently developed visual analysis tools to dissect the tyrosine phosphoproteome of isogenic Zap-70 tyrosine kinase null and reconstituted Jurkat T cells. In our approach, label-free quantitation using normalization to copurified phosphopeptide standards is applied to assemble high density temporal data within a single cell type, either Zap-70 null or reconstituted cells, providing a list of candidate phosphorylation sites that change in abundance after T cell stimulation. Stable isotopic labeling of amino acids in cell culture (SILAC) ratios are then used to compare Zap-70 null and reconstituted cells across a time course of receptor stimulation, providing direct information about the placement of newly observed phosphorylation sites relative to Zap-70. These methods are adaptable to any cell culture signaling system in which isogenic wild type and mutant cells have been or can be derived using any available phosphopeptide enrichment strategy.


Topographic maps in human frontal cortex revealed in memory-guided saccade and spatial working-memory tasks.
We used fMRI at 3 Tesla and improved spatial resolution (2 x 2 x 2 mm(3)) to investigate topographic organization in human frontal cortex using memory-guided response tasks performed at 8 or 12 peripheral locations arranged clockwise around a central fixation point. The tasks required the location of a peripheral target to be remembered for several seconds after which the subjects either made a saccade to the remembered location (memory-guided saccade task) or judged whether a test stimulus appeared in the same or a slightly different location by button press (spatial working-memory task). With these tasks, we found two topographic maps in each hemisphere, one in the superior branch of precentral cortex and caudalmost part of the superior frontal sulcus, in the region of the human frontal eye field, and a second in the inferior branch of precentral cortex and caudalmost part of the inferior frontal sulcus, both of which greatly overlapped with activations evoked by visually guided saccades. In each map, activated voxels coded for saccade directions and memorized locations predominantly in the contralateral hemifield with neighboring saccade directions and memorized locations represented in adjacent locations of the map. Particular saccade directions or memorized locations were often represented in multiple locations of the map. The topographic activation patterns showed individual variability from subject to subject but were reproducible within subjects. Notably, only saccade-related activation, but no topographic organization, was found in the region of the human supplementary eye field in dorsomedial prefrontal cortex. Together these results show that topographic organization can be revealed outside sensory cortical areas using more complex behavioral tasks.


Bacterial evolution and silicon.
This review examines the possible role of silicon in molecular evolution. It is possible silicon participated in early molecular evolution by providing a stable mineral surface or gel structure where the assembly and replication of primitive genetic information occurred. However, as molecular evolution proceeded, silicon was not required in the evolution of C-based organisms. Silicon can be accumulated by diatoms and other living organisms such as silicoflagellates, some xanthophytes, radiolarians and actinopods and plants such as grasses, ferns, horseradish, some trees and flowers, some sponges, insects and invertebrates and bacteria and fungi. Silicon also has a role in synthesis of DNA, DNA polymerase and thymidylate kinase activity in diatoms. It is not unreasonable to examine the role of silicon in early molecular evolution as it may have been part of a micro-environment in which assembly of genetic information occurred.


Effectiveness of Platelet Rich Plasma and Bone Graft in the Treatment of Intrabony Defects: A Clinico-radiographic Study.
Periodontal disease is characterized by the presence of gingival inflammation, periodontal pocket formation, loss of connective tissue attachment and alveolar bone around the affected tooth. Different modalities have been employed in the treatment and regeneration of periodontal defects which include the use of bone grafts, PRP and other growth factors.The purpose of this prospective, randomized controlled study was to compare the regenerative efficacy of PRP and bonegraft in intrabony periodontal defects. This randomized control trial was carried out in the Department of Periodontics & Oral Implantology, Kalinga Institute of Dental Sciences and Hospital, KIIT University, Bhubaneswar. The study sample included 20 periodontal infrabony defects in 20 patients, 12 males and 8 females. The patients were aged between 25 -45 years(with mean age of 35 years). The 20 sites selected for the study were was randomly divided into 2 groups of 10 sites each. Group A: PRP alone, Group B: Bone Graft. Statistical analysis was done usingpaired 't' tests and ANOVA that revealed a significant reduction ingingival index, plaque index, probing pocket depth and gain in clinical attachment level at various time intervalswithin both the groups. Radiographic evaluation revealed statistically significant defect fill (p<0.001) at the end of 6months within both the groups. However, there was astatistically significant difference seen in group B radiographically, when compared to group A. Both the groups showed promising results in enhancing periodontal regeneration; however the resultswith bonegraftwere comparatively better, although not statistically significant when compared to PRP alone.


The Use of Family Rituals in Eating Behaviors in Hispanic Mothers.
Food rituals often abruptly change when Hispanic families migrate to the United States. This report describes changes in rituals of food procurement, preparation, and presentation (food-PPP) in Hispanic women following migration to the United States. Focus groups and face-to-face interviews were conducted with 13 low-income, overweight/obese Hispanic women 27 to 40 years of age. Content analysis was used to analyze cultural and contextual sources for food-PPP. Changes in rituals and traditions in food-PPP occurred, including materials and ingredients for traditional meals. Food rituals may play a role in healthful eating and could, therefore, serve as leverage points for interventions designed to promote healthy eating behaviors.


Searching for "environmentally-benign" antifouling biocides.
As the result of the ecological impacts from the use of tributyltins (TBT) in shipping, environmental legislation for the registration of chemicals for use in the environment has grown to a monumental challenge requiring product dossiers to include information on the environmental fate and behavior of any chemicals. Specifically, persistence, bioaccumulation and toxicity, collectively known as PBT, are properties of concern in the assessment of chemicals. However, existing measurements of PBT properties are a cumbersome and expensive process, and thus not applied in the early stages of the product discovery and development. Inexpensive methods for preliminary PBT screening would minimize risks arising with the subsequent registration of products. In this article, we evaluated the PBT properties of compounds reported to possess anti-fouling properties using QSAR (quantitative structure-activity relationship) prediction programs such as BIOWIN™ (a biodegradation probability program), KOWWIN™ (log octanol-water partition coefficient calculation program) and ECOSAR™ (Ecological Structure Activity Relationship Programme). The analyses identified some small (Mr < 400) synthetic and natural products as potential candidates for environmentally benign biocides. We aim to demonstrate that while these methods of estimation have limitations, when applied with discretion, they are powerful tools useful in the early stages of research for compound selection for further development as anti-foulants.


A bending mode analysis for growing microtubules: evidence for a velocity-dependent rigidity.
Microtubules are dynamic protein polymers that continuously switch between elongation and rapid shrinkage. They have an exceptional bending stiffness that contributes significantly to the mechanical properties of eukaryotic cells. Measurements of the persistence length of microtubules have been published since 10 years but the reported values vary over an order of magnitude without an available explanation. To precisely measure the rigidity of microtubules in their native growing state, we adapted a previously developed bending mode analysis of thermally driven shape fluctuations to the case of an elongating filament that is clamped at one end. Microtubule shapes were quantified using automated image processing, allowing for the characterization of up to five bending modes. When taken together with three other less precise measurements, our rigidity data suggest that fast-growing microtubules are less stiff than slow-growing microtubules. This would imply that care should be taken in interpreting rigidity measurements on stabilized microtubules whose growth history is not known. In addition, time analysis of bending modes showed that higher order modes relax more slowly than expected from simple hydrodynamics, possibly by the effects of internal friction within the microtubule.


Lifetime imaging of a fluorescent protein sensor reveals surprising stability of ER thiol redox.
Interfering with disulfide bond formation impedes protein folding and promotes endoplasmic reticulum (ER) stress. Due to limitations in measurement techniques, the relationships of altered thiol redox and ER stress have been difficult to assess. We report that fluorescent lifetime measurements circumvented the crippling dimness of an ER-tuned fluorescent redox-responsive probe (roGFPiE), faithfully tracking the activity of the major ER-localized protein disulfide isomerase, PDI. In vivo lifetime imaging by time-correlated single-photon counting (TCSPC) recorded subtle changes in ER redox poise induced by exposure of mammalian cells to a reducing environment but revealed an unanticipated stability of redox to fluctuations in unfolded protein load. By contrast, TCSPC of roGFPiE uncovered a hitherto unsuspected reductive shift in the mammalian ER upon loss of luminal calcium, whether induced by pharmacological inhibition of calcium reuptake into the ER or by physiological activation of release channels. These findings recommend fluorescent lifetime imaging as a sensitive method to track ER redox homeostasis in mammalian cells.


Optimization for the production of surfactin with a new synergistic antifungal activity.
Two of our long term efforts are to discover compounds with synergistic antifungal activity from metabolites of marine derived microbes and to optimize the production of the interesting compounds produced by microorganisms. In this respect, new applications or mechanisms of already known compounds with a high production yield could be continually identified. Surfactin is a well-known lipopeptide biosurfactant with a broad spectrum of antimicrobial and antiviral activity; however, there is less knowledge on surfactin's antifungal activity. In this study, we investigated the synergistic antifungal activity of C(15)-surfactin and the optimization of its production by the response surface method. Using a synergistic antifungal screening model, we found that the combination of C(15)-surfactin and ketoconazole (KTC) showed synergistic antifungal effect on Candida albicans SC5314 when the concentrations of C(15)-surfactin and KTC were 6.25 µg/mL and 0.004 µg/mL, respectively. These concentrations were lower than their own efficient antifungal concentrations, which are >100 µg/mL and 0.016 µg/mL, respectively. The production of C(15)-surfactin from Bacillus amyloliquefaciens was optimized by the response surface methodology in shaker flask cultivation. The Plackett-Burman design found sucrose, ammonium nitrate and NaH(2)PO(4) x 2H(2)O to have significant effects on C(15)-surfactin production. The optimum values of the tested variables were 21.17 g/L sucrose, 2.50 g/L ammonium nitrate and 11.56 g/L NaH(2)PO(4)·2H(2)O. A production of 134.2 mg/L, which were in agreement with the prediction, was observed in a verification experiment. In comparison to the production of original level (88.6 mg/L), a 1.52-fold increase had been obtained. This work first found that C(15)-surfactin was an efficient synergistic antifungal agent, and demonstrated that response surface methodology was an effective method to improve the production of C(15)-surfactin.


Adolescents risky MP3-player listening and its psychosocial correlates.
Analogue to occupational noise-induced hearing loss, MP3-induced hearing loss may be evolving into a significant social and public health problem. To inform prevention strategies and interventions, this study investigated correlates of adolescents' risky MP3-player listening behavior primarily informed by protection motivation theory. We invited 1687 adolescents (12- to 19-year old) of Dutch secondary schools to complete questionnaires about their MP3-player listening, sociodemographic characteristics and presumed psychosocial determinants of MP3-player listening. Of all participants, 90% reported listening to music through earphones on MP3 players; 28.6% were categorized as listeners at risk for hearing loss due to estimated exposure of 89 dBA for ≥1 hour per day. Compared with listeners not at risk for hearing loss, listeners at risk were more likely not to live with both parents, to experience rewards of listening to high-volume levels, to report a high habit strength related to risky MP3 listening, and were less likely to be motivated to protect their hearing. Habit strength was the strongest correlate of risky listening behavior, suggesting that voluntary behavior change among adolescents might be difficult to achieve and that a multiple strategy approach may be needed to prevent MP3-induced hearing loss.


Incidence of hip and other osteoporotic fractures in elderly men and women: Dubbo Osteoporosis Epidemiology Study.
In this prospective 12-year study in men and women 60 years of age and older, there was a 4-6% per year reduction in the incidence rate of overall osteoporotic fractures, but the study was unable to exclude any change in the hip fracture incidence rate. Approximately one-half of hip fractures occurred before 80 years in men and two-thirds before 85 years in women. The age distribution of hip fractures underlines the need for earlier intervention in osteoporosis. Although hip fracture is the major osteoporotic fracture in terms of health outcomes, quality of life, and costs, there is a paucity of long-term data on secular changes in men and women within a defined community. This long-term prospective population-based study over 12 years from 1989 to 2000 specifically examined the age distribution and secular changes in the incidence rates of hip and other osteoporotic fractures in men and women 60 years of age and older in a predominantly white population in Dubbo, Australia. Hip and all other clinical fractures were ascertained by reviewing all radiography reports from the two area radiology services, ensuring complete ascertainment of all clinical osteoporotic fractures. Among the 1055 symptomatic atraumatic fractures (after excluding pathological fractures), there was a significant reduction in the overall fracture incidence rate in women (4% per year; p = 0.0003) and men (6% per year; p = 0.0004) over the 12 years. There were 229 hip fractures (175 in women and 54 in men) within 39,357 person-years of observation. The overall rate +/- SE of hip fracture was 759 +/- 57 per 100,000 person-years in women and 329 +/- 45 per 100,000 person-years in men, with an exponential increase with age. With advancing age, the incidence rate of hip fractures in men approached that in women; the female:male ratio fell from 4.5 (95% CI: 1.3-15.7) to 1.5 (0.9-2.5) and 1.9 (1.2-2.8) in the 60-69, 70-79, and 80+ year age groups, respectively. In women, the absolute number of fractures and incidence rate continuously increased with age; however, in men, the absolute number of hip fractures peaked at 80-84 years of age and then decreased. Most importantly, despite the continuing increase with age, almost one-half (48%) of the hip fractures occurred before the age of 80 years in men, and 66% of hip fractures occurred before the age of 85 years in women. The overall hip fracture incidence is comparable with other white (except Sweden) and Asian groups as well as two other Australian studies. This study could not exclude a change in hip fracture incidence rate, even in those 80 years of age and over among whom the incidence of hip fractures was the highest. The incidence data highlight the fact that a large proportion of hip fractures occurs in those under 80 years of age, particularly in men. This age distribution underlines the need for earlier intervention in osteoporosis in women and particularly in men to achieve the most cost-effective outcomes.


Combined aerobic exercise and enzyme replacement therapy rejuvenates the mitochondrial-lysosomal axis and alleviates autophagic blockage in Pompe disease.
A unifying feature in the pathogenesis of aging, neurodegenerative disease, and lysosomal storage disorders is the progressive deposition of macromolecular debris impervious to enzyme catalysis by cellular waste disposal mechanisms (e.g., lipofuscin). Aerobic exercise training (AET) has pleiotropic effects and stimulates mitochondrial biogenesis, antioxidant defense systems, and autophagic flux in multiple organs and tissues. Our aim was to explore the therapeutic potential of AET as an ancillary therapy to mitigate autophagic buildup and oxidative damage and rejuvenate the mitochondrial-lysosomal axis in Pompe disease (GSD II/PD). Fourteen weeks of combined recombinant acid α-glucosidase (rhGAA) and AET polytherapy attenuated mitochondrial swelling, fortified antioxidant defense systems, reduced oxidative damage, and augmented glycogen clearance and removal of autophagic debris/lipofuscin in fast-twitch skeletal muscle of GAA-KO mice. Ancillary AET potently augmented the pool of PI4KA transcripts and exerted a mild restorative effect on Syt VII and VAMP-5/myobrevin, collectively suggesting improved endosomal transport and Ca(2+)- mediated lysosomal exocytosis. Compared with traditional rhGAA monotherapy, AET and rhGAA polytherapy effectively mitigated buildup of protein carbonyls, autophagic debris/lipofuscin, and P62/SQSTM1, while enhancing MnSOD expression, nuclear translocation of Nrf-2, muscle mass, and motor function in GAA-KO mice. Combined AET and rhGAA therapy reactivates cellular clearance pathways, mitigates mitochondrial senescence, and strengthens antioxidant defense systems in GSD II/PD. Aerobic exercise training (or pharmacologic targeting of contractile-activity-induced pathways) may have therapeutic potential for mitochondrial-lysosomal axis rejuvenation in lysosomal storage disorders and related conditions (e.g., aging and neurodegenerative disease).


Study of effective optical thickness in photopolymer for application.
The impact of the effective optical thickness of a photopolymer on its holographic performance was studied. To overcome the attenuation of gratings for a better uniformity, a multilayer approach was introduced, by adjusting concentrations of dye along the depth of photopolymer to compensate the attenuation of recording light due to absorption. Multilayer photopolymers with thicknesses over 500 μm were designed, fabricated, and characterized experimentally, exhibiting better Bragg selectivity. More holograms were stored in multilayer material by angular multiplexing, and the cumulative grating strength was enhanced, leading towards larger holographic storage capacity.


Tunable clustering of magnetic nanoparticles in microgels: enhanced magnetic relaxivity by modulation of network architecture.
In the present work we used microgels as colloidal containers for the loading of hydrophobic magnetic nanoparticles using the solvent exchange method. We varied systematically two parameters: (i) the crosslinking degree of microgels (1-4.5 mol% crosslinker) and (ii) loading of hydrophobic magnetite nanoparticles (d = 7 nm) in microgels (2-10 wt%). The experimental data show that the interplay between these two parameters provides efficient control over the clustering of magnetic nanoparticles in the microgel structure. Transverse magnetization relaxation measurements indicate that the formation of nanoparticle clusters in microgels induces non-linear enhancement of the relaxivity with the increase of nanoparticle loading in microgels. The results suggest that the modulation of the microgel network architecture can be efficiently applied to trigger self-assembly processes inside microgels and design hybrid colloids with unusual morphologies and properties.


The antimycotic ciclopirox olamine induces HIF-1alpha stability, VEGF expression, and angiogenesis.
The heterodimeric hypoxia-inducible factor (HIF)-1 is a master regulator of oxygen homeostasis. Protein stability and transactivation function of the alpha subunit are controlled by iron- and oxygen-dependent hydroxylation of proline and asparagine residues. The anti-mycotic ciclopirox olamine (CPX) is a lipophilic bidentate iron chelator that stabilizes HIF-1alpha under normoxic conditions at lower concentrations than other iron chelators, probably by inhibiting HIF-1alpha hydroxylation. As shown by the inhibition of iron-dependent quenching of FITC-labeled deferoxamine (DFX) fluorescence, CPX appears to have an even higher affinity for iron than DFX. Initial observations that treatment with 1% CPX, but not with placebo, occasionally caused reddening of wound margins in a mouse skin wound model prompted us to investigate the capability of CPX to induce angiogenesis. CPX-induced HIF-1-mediated reporter gene activity and endogenous HIF-1 target gene expression, including elevation of transcription, mRNA, and protein levels of the vascular endothelial growth factor (VEGF). In the chick chorioallantoic membrane assay, inert polymer disks containing CPX but not the solvent alone induced angiogenesis. In summary, these results suggest that CPX induces angiogenesis in vivo via HIF-1 and VEGF induction. Therefore, CPX might serve as an alternative to recombinant VEGF treatment or to VEGF gene therapy for therapeutic angiogenesis.


Health-related quality of life--from the perspective of mothers and fathers of adult children suffering from long-term mental disorders.
There is a lack of studies on mothers' and fathers' experiences of Health-Related Quality of Life (HRQOL) associated with caregiving of adult children suffering from mental disorder. A cross-sectional study was therefore carried out with 108 mothers and 43 fathers. Data were collected by means of the Short Form Health Survey (SF-36), the Hospital Anxiety and Depression Scale (HADS), the Family Involvement and Alienation Questionnaire (FIAQ) and the Burden Assessment Scale (BAS). Mothers' HRQOL was affected more than fathers' and lower compared to Swedish age related norms. HRQOL was predominantly related to ratings on HADS and BAS.


Primary Health Care: Potential Home for Family-Focused Preventive Interventions.
Family-focused prevention programs have been shown to effectively reduce a range of negative behavioral health outcomes but have had limited reach. Three key barriers must be overcome to expand the reach of family-focused prevention programs and thereby achieve a significant public health impact. These barriers are (1) current social norms and perceptions of parenting programs; (2) concerns about the expertise and legitimacy of sponsoring organizations to offer parenting advice; and (3) a paucity of stable, sustainable funding mechanisms. Primary healthcare settings are well positioned to overcome these barriers. Recent changes within health care make primary care settings an increasingly favorable home for family-focused prevention and suggest possibilities for sustainable funding of family-focused prevention programs. This paper discusses the existing advantages of primary care settings and lays out a plan to move toward realizing the potential public health impact of family-focused prevention through widespread implementation in primary healthcare settings.


PaCATB, a secreted catalase protecting Podospora anserina against exogenous oxidative stress.
A differential mass spectrometry analysis of secreted proteins from juvenile and senescent Podospora anserina cultures revealed age-related differences in protein profiles. Among other proteins with decreased abundance in the secretome of senescent cultures a catalase, termed PaCATB, was identified. Genetic modulation of the abundance of PaCATB identified differential effects on the phenotype of the corresponding strains. Deletion of PaCatB resulted in decreased resistance, over-expression in increased resistance against hydrogen peroxide. While the lifespan of the genetically modified strains was found to be unaffected under standard growth conditions, increased exogenous hydrogen peroxide stress in the growth medium markedly reduced the lifespan of the PaCatB deletion strain but extended the lifespan of PaCatB over-expressors. Overall our data identify a component of the secretome of P. anserina as a new effective factor to cope with environmental stress, stress that under natural conditions is constantly applied on organisms and influences aging processes.


Longitudinal Analysis of Serum Cytokine Levels and Gut Microbial Abundance Links IL-17/IL-22 With Clostridia and Insulin Sensitivity in Humans.
Recent studies using mouse models suggest that interaction between the gut microbiome and IL-17/IL-22-producing cells plays a role in the development of metabolic diseases. We investigated this relationship in humans using data from the prediabetes study of the Integrated Human Microbiome Project (iHMP). Specifically, we addressed the hypothesis that early in the onset of metabolic diseases there is a decline in serum levels of IL-17/IL-22, with concomitant changes in the gut microbiome. Clustering iHMP study participants on the basis of longitudinal IL-17/IL-22 profiles identified discrete groups. Individuals distinguished by low levels of IL-17/IL-22 were linked to established markers of metabolic disease, including insulin sensitivity. These individuals also displayed gut microbiome dysbiosis, characterized by decreased diversity, and IL-17/IL-22-related declines in the phylum Firmicutes, class Clostridia, and order Clostridiales This ancillary analysis of the iHMP data therefore supports a link between the gut microbiome, IL-17/IL-22, and the onset of metabolic diseases. This raises the possibility for novel, microbiome-related therapeutic targets that may effectively alleviate metabolic diseases in humans as they do in animal models.


Antibacterial and wound healing properties of methanolic extracts of some Nigerian medicinal plants.
This study was conducted to evaluate methanolic extracts of Ageratum conyzoides, Anthocleista djalonensis, Napoleona imperialis, Ocimum gratissimum, and Psidium guajava for antibacterial and wound healing properties. Antibacterial properties of the extracts were studied against eleven wound isolates (Staphylococcus aureus (four strains), E. coli (two strains), Pseudomonas aeruginosa (one strain), Proteus spp. (three strains), and Shigella spp. (one strain)) using the well diffusion method. Wound healing properties of Ageratum conyzoides, Anthocleista djalonensis, Napoleonaea imperialis, and Ocimum gratissimum were determined using the excision wound model. Extract of Napoleona imperialis inhibited growth of all the test bacterial strains while Psidium guajava and Anthocleista djalonensis extracts prevented growth of 81.8 and 72.7% of the test organisms, respectively. Ageratum conyzoides and Ocimum gratissimum extracts did not inhibit growth of any of the test organisms. More than 90% wound healing was recorded in the extract and cicatrin powder treated groups by 14 days post surgery, where as 72% healing was observed in the distilled water-treated group. The percentage healing in the distilled water-treated group was significantly different (P<0.001) from those of extract and antibiotic-treated groups.


The neural basis of predicate-argument structure.
Neural correlates exist for a basic component of logical formulae, PREDICATE(x). Vision and audition research in primates and humans shows two independent neural pathways; one locates objects in body-centered space, the other attributes properties, such as colour, to objects. In vision these are the dorsal and ventral pathways. In audition, similarly separable "where" and "what" pathways exist. PREDICATE(x) is a schematic representation of the brain's integration of the two processes of delivery by the senses of the location of an arbitrary referent object, mapped in parietal cortex, and analysis of the properties of the referent by perceptual subsystems. The brain computes actions using a few "deictic" variables pointing to objects. Parallels exist between such nonlinguistic variables and linguistic deictic devices. Indexicality and reference have linguistic and nonlinguistic (e.g., visual) versions, sharing the concept of attention. The individual variables of logical formulae are interpreted as corresponding to these mental variables. In computing action, the deictic variables are linked with "semantic" information about the objects, corresponding to logical predicates. Mental scene descriptions are necessary for practical tasks of primates, and preexist language phylogenetically. The type of scene descriptions used by nonhuman primates would be reused for more complex cognitive, ultimately linguistic, purposes. The provision by the brain's sensory/perceptual systems of about four variables for temporary assignment to objects, and the separate processes of perceptual categorization of the objects so identified, constitute a pre-adaptive platform on which an early system for the linguistic description of scenes developed.


Putting theory into practice: a cluster randomized trial with a small number of clusters.
Many of the difficulties encountered in the design, organization and analysis of cluster randomized trials arise from the dual nature of such trials; that is, they focus on both the cluster and the individual. A trial now in progress to compare three methods of promoting secondary prevention of coronary heart disease in primary care includes only 21 general practices, but 2142 patients, and thus contains the problems of both small and large samples. With only seven practices in each arm, the trial demanded carefully restricted randomization, may be difficult to analyse, and risks loss of power if one practice should drop out. At the same time, the large number of patients makes for an expensive and administratively complex study. The simultaneous demands of clarity and thoroughness point to an analysis at both cluster and individual level. With two different approaches, however, there may be difficulties of presentation, even if the results agree, and additional problems of interpretation if they do not. Finally, practical considerations may conflict with theoretical demands. Since the trial contained a service element, all patients with heart disease had to be included, even though it would have been more efficient to take only a sample of patients from some practices.


Depressive symptomatology and fall risk among community-dwelling older adults.
Falls are common among older adults and may be related to depressive symptoms (DS). With advancing age, there is an onset of chronic conditions, sensory impairments, and activity limitations that are associated with falls and with depressive disorders. Prior cross-sectional studies have observed significant associations between DS and subsequent falls as well as between fractures and subsequent clinical depression and DS. The directionality of these observed relationship between falls and DS is in need of elaboration given that cross-sectional study designs can yield biased estimates of the DS-falls relationship. Using 2006-2010 Health and Retirement Study data, cross-lagged panel structural equation models were used to evaluate associations between falls and DS among 7233 community-dwelling adults ages ≥65. Structural coefficients between falls and DS (in 2006→2008, 2008→2010) were estimated. A good-fitting model was found: Controlling for baseline (2006) physical functioning, vision, chronic conditions, and social support and neighborhood social cohesion, falls were not associated with subsequent DS, but a 0.5 standard deviation increase in 2006 DS was associated with a 30% increase in fall risk two years later. This DS-falls relationship was no longer significant when use of psychiatric medications, which was positively associated with falls, was included in the model. Using sophisticated methods and a large U.S. sample, we found larger magnitudes of effect in the DS-falls relationship than in prior studies-highlighting the risk of falls for older adults with DS. Medical providers might assess older individuals for DS as well as use of psychotropic medications as part of a broadened falls prevention approach. National guidelines for fall risk assessments as well as quality indicators for fall prevention should include assessment for clinical depression.


Endometrial cancer: recent developments in evaluation and treatment.
Endometrial carcinoma is the most common gynecologic malignancy in the United States. Most cases are diagnosed at an early stage. However, the outcome for women diagnosed with advanced-stage disease remains poor. The etiology of most endometrial carcinomas stems from the effects of excess estrogen, whether this comes from exogenous or endogenous sources. Differences in epidemiology and presentation suggest the existence of two forms of endometrial cancer: those related to and those unrelated to hormonal stimulation. Most women with endometrial cancer present with abnormal uterine bleeding; endometrial sampling is essential to exclude endometrial carcinoma in such patients. Endometrial cancer is surgically staged, and staging usually includes a hysterectomy and bilateral salpingooophorectomy. Lymphadenectomy also should be performed in selective cases to better assess disease spread and to evaluate the need for adjuvant therapy. Adjuvant treatment may include the use of radiation, progestins, or cytotoxic chemotherapeutic agents. Several clinical trials are underway to compare these treatment modalities, as well as to determine the optimal combination of active chemotherapeutic agents, such as doxorubicin, platinum agents, and paclitaxel (Taxol).


Media reporting of health interventions: signs of improvement, but major problems persist.
Studies have persistently shown deficiencies in medical reporting by the mainstream media. We have been monitoring the accuracy and comprehensiveness of medical news reporting in Australia since mid 2004. This analysis of more than 1200 stories in the Australian media compares different types of media outlets and examines reporting trends over time. Between March 2004 and June 2008 1230 news stories were rated on a national medical news monitoring web site, Media Doctor Australia. These covered a variety of health interventions ranging from drugs, diagnostic tests and surgery to dietary and complementary therapies. Each story was independently assessed by two reviewers using ten criteria. Scores were expressed as percentages of total assessable items deemed satisfactory according to a coding guide. Analysis of variance was used to compare mean scores and Fishers exact test to compare proportions. Trends over time were analysed using un-weighted linear regression analysis. Broadsheet newspapers had the highest average satisfactory scores: 58% (95% CI 56-60%), compared with tabloid newspapers and online news outlets, 48% (95% CI 44-52) and 48% (95% CI 46-50) respectively. The lowest scores were assigned to stories broadcast by human interest/current affairs television programmes (average score 33% (95% CI 28-38)). While there was a non- significant increase in average scores for all outlets, a significant improvement was seen in the online news media: a rise of 5.1% (95%CI 1.32, 8.97; P 0.009). Statistically significant improvements were seen in coverage of the potential harms of interventions, the availability of treatment or diagnostic options, and accurate quantification of benefits. Although the overall quality of medical reporting in the general media remains poor, this study showed modest improvements in some areas. However, the most striking finding was the continuing very poor coverage of health news by commercial current affairs television programs.


PROSPECT: a practical method for formulating evidence-based expert recommendations for the management of postoperative pain.
Many patients still suffer severe acute pain in the postoperative period. Although guidelines for treating acute pain are widely published and promoted, most do not consider procedure-specific differences in pain experienced or in techniques that may be most effective and appropriate for different surgical settings. The procedure-specific postoperative pain management (PROSPECT) Working Group provides procedure-specific recommendations for postoperative pain management together with supporting evidence from systematic literature reviews and related procedures at http://www.postoppain.org The methodology for PROSPECT reviews was developed and refined by discussion of the Working Group, and it adapts existing methods for formulation of consensus recommendations to the specific requirements of PROSPECT. To formulate PROSPECT recommendations, we use a methodology that takes into account study quality and source and level of evidence, and we use recognized methods for achieving group consensus, thus reducing potential bias. The new methodology is first applied in full for the 2006 update of the PROSPECT review of postoperative pain management for laparoscopic cholecystectomy. Transparency in PROSPECT processes allows the users to be fully aware of any limitations of the evidence and recommendations, thereby allowing for appropriate decisions in their own practice setting.


Fos is phosphorylated by p34cdc2, cAMP-dependent protein kinase and protein kinase C at multiple sites clustered within regulatory regions.
The proto-oncogene c-fos encodes a nuclear protein (Fos) that functions in transcriptional regulation in response to extracellular signals. Fos is extensively modified in the nucleus by serine and threonine phosphorylation. It has been suggested that phosphorylation may play an important role in regulating Fos function in normal and transformed cells. As a first step in addressing this issue, we have used purified Fos as a substrate for several serine-threonine protein kinases, including cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and p34cdc2. Each of these kinases phosphorylated Fos at several unique sites. These sites were located within two regions that were previously shown to reduce the transcriptional activity of Fos in vitro. Several of the sites modified in vitro were also shown to be phosphorylated in serum-stimulated fibroblasts. These findings demonstrate that Fos is a target for several protein kinases involved in signal transduction and suggest that phosphorylation could regulate the transcriptional properties of Fos.


Proteomics for breast cancer urine biomarkers.
Although the survival of breast cancer (BC) patients has increased over the last two decades due to improved screening programs and postoperative adjuvant systemic therapies, many patients die from metastatic relapse. Current biomarkers used in the clinic are not useful for the early detection of BC, or monitoring its progression, and have limited value in predicting response to treatment. The development of proteomic techniques has sparked new searches for novel protein markers for many diseases including BC. Proteomic techniques allow for a high-throughput analysis of samples with the visualization and quantification of thousands of potential protein and peptide markers. Human urine is one of the most interesting and useful biofluids for routine testing and provides an excellent resource for the discovery of novel biomarkers, with the advantage over tissue biopsy samples due to the ease and less invasive nature of collection. In this review, we summarize the results from studies where urine was used as a source for BC biomarker research and discuss urine sample preparation, its advantage, challenges, and limitation. We focus on the gel-based proteomic approaches as well as the recent development of quantitative techniques in BC urine biomarker detection. Finally, the future use of modern proteomic techniques in BC biomarker identification will be discussed.


Age-dependent maturation of Toll-like receptor-mediated cytokine responses in Gambian infants.
The global burden of neonatal and infant mortality due to infection is staggering, particularly in resource-poor settings. Early childhood vaccination is one of the major interventions that can reduce this burden, but there are specific limitations to inducing effective immunity in early life, including impaired neonatal leukocyte production of Th1-polarizing cytokines to many stimuli. Characterizing the ontogeny of Toll-like receptor (TLR)-mediated innate immune responses in infants may shed light on susceptibility to infection in this vulnerable age group, and provide insights into TLR agonists as candidate adjuvants for improved neonatal vaccines. As little is known about the leukocyte responses of infants in resource-poor settings, we characterized production of Th1-, Th2-, and anti-inflammatory-cytokines in response to agonists of TLRs 1-9 in whole blood from 120 Gambian infants ranging from newborns (cord blood) to 12 months of age. Most of the TLR agonists induced TNFα, IL-1β, IL-6, and IL-10 in cord blood. The greatest TNFα responses were observed for TLR4, -5, and -8 agonists, the highest being the thiazoloquinoline CLO75 (TLR7/8) that also uniquely induced cord blood IFNγ production. For most agonists, TLR-mediated TNFα and IFNγ responses increased from birth to 1 month of age. TLR8 agonists also induced the greatest production of the Th1-polarizing cytokines TNFα and IFNγ throughout the first year of life, although the relative responses to the single TLR8 agonist and the combined TLR7/8 agonist changed with age. In contrast, IL-1β, IL-6, and IL-10 responses to most agonists were robust at birth and remained stable through 12 months of age. These observations provide fresh insights into the ontogeny of innate immunity in African children, and may inform development of age-specific adjuvanted vaccine formulations important for global health.


Lessons from the design, development and implementation of a three-dimensional (3D) neonatal resuscitation training smartphone application: Life-saving Instruction for Emergencies (LIFE app).
Neonatal mortality remains disproportionately high in sub-Saharan Africa partly due to insufficient numbers of adequately trained and skilled front-line health workers. Opportunities for improving neonatal care may result from upskilling frontline health workers using innovative technological approaches. This practice paper describes the key steps involved in the design, development and implementation of an innovative smartphone-based training application using an agile, human-centred design approach. The Life-saving Instruction for Emergencies (LIFE) app is a three-dimension (3D) scenario-based mobile app for smartphones and is free to download. Two clinical modules are currently included with further scenarios planned. Whilst the focus of the practice paper is on the lessons learned during the design and development process, we also share key learning related to project management and sustainability plans, which we hope will help researchers working on similar projects.


Helium Ion Microscopy (HIM) for the imaging of biological samples at sub-nanometer resolution.
Scanning Electron Microscopy (SEM) has long been the standard in imaging the sub-micrometer surface ultrastructure of both hard and soft materials. In the case of biological samples, it has provided great insights into their physical architecture. However, three of the fundamental challenges in the SEM imaging of soft materials are that of limited imaging resolution at high magnification, charging caused by the insulating properties of most biological samples and the loss of subtle surface features by heavy metal coating. These challenges have recently been overcome with the development of the Helium Ion Microscope (HIM), which boasts advances in charge reduction, minimized sample damage, high surface contrast without the need for metal coating, increased depth of field, and 5 angstrom imaging resolution. We demonstrate the advantages of HIM for imaging biological surfaces as well as compare and contrast the effects of sample preparation techniques and their consequences on sub-nanometer ultrastructure.


Development of structured support groups for HIV-positive women in South Africa.
Women living with HIV in a stigmatising community need support to cope with their HIV status. In a process of action research, a structured support group programme was designed to meet the needs of women to cope with their diagnosis and interpersonal relationships. The emphasis was on identifying their needs and developing programme material to address those needs through group participation and interaction. The programme was pilot-tested at two sites located in two townships in Tshwane, South Africa. Feedback after each session made it possible to adjust the programme to the needs of the participants. In a formative evaluation, audio-taped sessions, process notes of facilitators, and experiences of the participants were used to identify therapeutic elements, the value of the groups and the problems in the implementation process. Women reported benefit from participation in the support groups. A 10-session structured programme to be used in support groups addressing the most important needs of HIV-positive women was developed.


Mediators of the development and prevention of violent behavior.
The purpose of this investigation was to determine if the Aban Aya Youth Project, a culturally grounded intervention, produced differences in changes over time in core intervening variables (i.e., communal value orientation, empathy, violence avoidance efficacy beliefs) and whether these variables mediated intervention effects on the development of youth violent behavior. Fifth grade cohorts at 12 schools were randomly assigned to one of two intervention conditions or an attention placebo control condition and followed longitudinally through eighth grade. A total of 668 students (49% male) participated in the study. Mediation analyses suggested that both program conditions (as compared to the control condition) led to steeper increases over time in empathy which, in turn were related to reductions in the likelihood of violent behavior over time. No other significant program effects were detected, although changes over time in violence avoidance efficacy were associated with reduced likelihood of violent behavior. Findings are discussed in terms of theory development, program development and points of refinement of the Aban Aya Youth Project and implications for future research.


Oxygen-dependent cleavage of the p75 neurotrophin receptor triggers stabilization of HIF-1α.
Homeostatic control of oxygen availability allows cells to survive oxygen deprivation. Although the transcription factor hypoxia-inducible factor 1α (HIF-1α) is the main regulator of the hypoxic response, the upstream mechanisms required for its stabilization remain elusive. Here, we show that p75 neurotrophin receptor (p75(NTR)) undergoes hypoxia-induced γ-secretase-dependent cleavage to provide a positive feed-forward mechanism required for oxygen-dependent HIF-1α stabilization. The intracellular domain of p75(NTR) directly interacts with the evolutionarily conserved zinc finger domains of the E3 RING ubiquitin ligase Siah2 (seven in absentia homolog 2), which regulates HIF-1α degradation. p75(NTR) stabilizes Siah2 by decreasing its auto-ubiquitination. Genetic loss of p75(NTR) dramatically decreases Siah2 abundance, HIF-1α stabilization, and induction of HIF-1α target genes in hypoxia. p75(NTR-/-) mice show reduced HIF-1α stabilization, vascular endothelial growth factor (VEGF) expression, and neoangiogenesis after retinal hypoxia. Thus, hypoxia-induced intramembrane proteolysis of p75(NTR) constitutes an apical oxygen-dependent mechanism to control the magnitude of the hypoxic response.


A self-organized anisotropic liquid-crystal plasmonic metamaterial.
A composite material that leads to self organization of mesogen-coated gold nanospheres is synthesized and shows enhanced anisotropic optical properties due to synergistic effects of the mesogens intrinsic birefringence and its ability to drive the self-assembly process into highly anisotropic architectures with densely packed nanospheres. Such nanoengineered matter sustains a response beyond that achievable by its individual constituents, i.e., a metamaterial.


Expression of multiple forms of 3'-end variant CCK2 receptor mRNAs in human pancreatic adenocarcinomas.
Two main types of receptors for gastrin and cholecystokinin (CCK) have been cloned and identified. CCK1 (CCK-A) receptors are expressed in the pancreas, the gallbladder, and parts of the brain, while CCK2 (CCK-B/gastrin) receptors (CCK2R) are expressed in gastric glands and in most of the brain. A splice variant of the CCK2R designated CCKRi4sv (CCK-C), which is constitutively expressed in human pancreatic cancer cells, has also been described. The purpose of the present investigation was to study CCK2R, CCK2i4svR, and gastrin mRNA expression in human pancreatic adenocarcinoma on the assumption that co-expression of CCK2R and gastrin or constitutive CCK2i4svR mRNA expression plays a pivotal role in the progression of pancreatic cancer. PCR amplification using CCK2R specific primer-pairs, followed by ethidium-bromide stained agarose gel electrophoresis revealed the expression of wild-type CCK2R mRNA in 12 of 17 biopsy specimens. A CCK2R intron 4 specific nested PCR assay revealed that CCK2i4svR mRNA was expressed in only one of the biopsy specimen. The authenticity of PCR amplicons was confirmed by cloning of selected amplicons and DNA sequence analysis. Moreover, we found that hitherto undescribed multiple forms of 3'-end variant CCK2R mRNAs with various deletions in the retained intron 4 and exon 5, tentatively generating truncated proteins, were expressed in the pancreatic adenocarcinomas. Cloning and DNA sequencing of selected amplicons revealed that CCK2R and multiple CCK2i4svR-like mRNAs are expressed in human pancreatic adenocarcinoma. The originally described CCK2i4svR mRNA was only expressed in one of 17 tumours and appears to be rarely expressed in pancreatic adenocarcinoma. We report that CCK2R- and gastrin mRNA co-expression may play a role in a portion, but not in all of these tumours, and that aberrant splicing takes places in these tissues generating multiple forms of 3'-end variant CCK2R mRNAs.


Early versus deferred endovenous ablation of superficial venous reflux in patients with venous ulceration: the EVRA RCT.
Venous ulceration is a common and costly health-care issue worldwide, with poor healing rates greatly affecting patient quality of life. Compression bandaging has been shown to improve healing rates and reduce recurrence, but does not address the underlying cause, which is often superficial venous reflux. Surgical correction of the reflux reduces ulcer recurrence; however, the effect of early endovenous ablation of superficial venous reflux on ulcer healing is unclear. To determine the clinical effectiveness and cost-effectiveness of compression therapy with early endovenous ablation of superficial venous reflux compared with compression therapy with deferred endovenous ablation in patients with venous ulceration. A pragmatic, two-arm, multicentre, parallel-group, open randomised controlled trial with a health economic evaluation. Secondary care vascular centres in England. Patients aged ≥ 18 years with a venous leg ulcer of between 6 weeks' and 6 months' duration and an ankle-brachial pressure index of ≥ 0.8 who could tolerate compression and were deemed suitable for endovenous ablation of superficial venous reflux. Participants were randomised 1 : 1 to either early ablation (compression therapy and superficial endovenous ablation within 2 weeks of randomisation) or deferred ablation (compression therapy followed by endovenous ablation once the ulcer had healed). The primary outcome measure was time from randomisation to ulcer healing, confirmed by blinded assessment. Secondary outcomes included 24-week ulcer healing rates, ulcer-free time, clinical success (in addition to quality of life), costs and quality-adjusted life-years (QALYs). All analyses were performed on an intention-to-treat basis. A total of 450 participants were recruited (224 to early and 226 to deferred superficial endovenous ablation). Baseline characteristics were similar between the two groups. Time to ulcer healing was shorter in participants randomised to early superficial endovenous ablation than in those randomised to deferred ablation [hazard ratio 1.38, 95% confidence interval (CI) 1.13 to 1.68; p = 0.001]. Median time to ulcer healing was 56 (95% CI 49 to 66) days in the early ablation group and 82 (95% CI 69 to 92) days in the deferred ablation group. The ulcer healing rate at 24 weeks was 85.6% in the early ablation group, compared with 76.3% in the deferred ablation group. Median ulcer-free time was 306 [interquartile range (IQR) 240-328] days in the early ablation group and 278 (IQR 175-324) days in the deferred endovenous ablation group (p = 0.002). The most common complications of superficial endovenous ablation were pain and deep-vein thrombosis. Differences in repeated measures of Aberdeen Varicose Vein Questionnaire scores (p < 0.001), EuroQol-5 Dimensions index values (p = 0.03) and Short Form questionnaire-36 items body pain (p = 0.05) over the follow-up period were observed, in favour of early ablation. The mean difference in total costs between the early ablation and deferred ablation groups was £163 [standard error (SE) £318; p = 0.607]; however, there was a substantial and statistically significant gain in QALY over 1 year [mean difference between groups 0.041 (SE 0.017) QALYs; p = 0.017]. The incremental cost-effectiveness ratio of early ablation at 1 year was £3976 per QALY, with a high probability (89%) of being more cost-effective than deferred ablation at conventional UK decision-making thresholds (currently £20,000 per QALY). Sensitivity analyses using alternative statistical models give qualitatively similar results. Only 7% of screened patients were recruited, treatment regimens varied significantly and technical success was assessed only in the early ablation group. Early endovenous ablation of superficial venous reflux, in addition to compression therapy and wound dressings, reduces the time to healing of venous leg ulcers, increases ulcer-free time and is highly likely to be cost-effective. Longer-term follow-up is ongoing and will determine if early ablation will affect recurrence rates in the medium and long term. Current Controlled Trials ISRCTN02335796. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 24. See the NIHR Journals Library website for further project information.


Gene encoding a deubiquitinating enzyme is mutated in artesunate- and chloroquine-resistant rodent malaria parasites.
Artemisinin- and artesunate-resistant Plasmodium chabaudi mutants, AS-ART and AS-ATN, were previously selected from chloroquine-resistant clones AS-30CQ and AS-15CQ respectively. Now, a genetic cross between AS-ART and the artemisinin-sensitive clone AJ has been analysed by Linkage Group Selection. A genetic linkage group on chromosome 2 was selected under artemisinin treatment. Within this locus, we identified two different mutations in a gene encoding a deubiquitinating enzyme. A distinct mutation occurred in each of the clones AS-30CQ and AS-ATN, relative to their respective progenitors in the AS lineage. The mutations occurred independently in different clones under drug selection with chloroquine (high concentration) or artesunate. Each mutation maps to a critical residue in a homologous human deubiquitinating protein structure. Although one mutation could theoretically account for the resistance of AS-ATN to artemisinin derivates, the other cannot account solely for the resistance of AS-ART, relative to the responses of its sensitive progenitor AS-30CQ. Two lines of Plasmodium falciparum with decreased susceptibility to artemisinin were also selected. Their drug-response phenotype was not genetically stable. No mutations in the UBP-1 gene encoding the P. falciparum orthologue of the deubiquitinating enzyme were observed. The possible significance of these mutations in parasite responses to chloroquine or artemisinin is discussed.


Somatostatin: electron microscope immunohistochemical localization in secretory neurons of rat hypothalamus.
Somatostatin, the hypothalamic hormone which inhibits the secretion of growth hormone by the pituitary, has been localized in the rat hypothalamus by using electron microscope immunohistochemistry. Somatostatin occurs in secretory granules (80 to 110 nm in diameter) of a few neurons located in the hypothalamic periventricular nucleus. These observations establish the identity of neurosecretory neurons involved in the regulation of adenohypophyseal secretion.


Quantitative analysis of chromosome conformation capture assays (3C-qPCR).
Chromosome conformation capture (3C) technology is a pioneering methodology that allows in vivo genomic organization to be explored at a scale encompassing a few tens to a few hundred kilobase-pairs. Understanding the folding of the genome at this scale is particularly important in mammals where dispersed regulatory elements, like enhancers or insulators, are involved in gene regulation. 3C technology involves formaldehyde fixation of cells, followed by a polymerase chain reaction (PCR)-based analysis of the frequency with which pairs of selected DNA fragments are crosslinked in the population of cells. Accurate measurements of crosslinking frequencies require the best quantification techniques. We recently adapted the real-time TaqMan PCR technology to the analysis of 3C assays, resulting in a method that more accurately determines crosslinking frequencies than current semiquantitative 3C strategies that rely on measuring the intensity of ethidium bromide-stained PCR products separated by gel electrophoresis. Here, we provide a detailed protocol for this method, which we have named 3C-qPCR. Once preliminary controls and optimizations have been performed, the whole procedure (3C assays and quantitative analyses) can be completed in 7-9 days.


Critical roles of RNA helicase DDX3 and its interactions with eIF4E/PABP1 in stress granule assembly and stress response.
Upon environmental insults, SGs (stress granules) aid cell survival by serving as sites of translational silencing. RNA helicase DDX3 was reported to associate with SGs. However, its role in SG physiology remains undefined. We have demonstrated previously that DDX3 acts as an eIF4E (eukaryotic initiation factor 4E)-inhibitory protein to suppress translation. In the present study, we indentified the SG marker PABP1 [poly(A)-binding protein 1] as another direct interaction partner of DDX3. We established various stimuli as novel stressors that direct DDX3 with eIF4E and PABP1 into SGs, but not to processing bodies. Interestingly, down-regulation of DDX3 interfered with SG assembly, led to nuclear accumulation of PABP1 and reduced cell viability following stress. Conversely, supplementation with a shRNA (short hairpin RNA)-resistant DDX3 restored SG formation, the translocation of PABP1 into SGs and cell survival. Notably, the SG-inducing capacity of DDX3 is independent of its ATPase and helicase activities, but mapped to the eIF4E-binding region. Moreover, the eIF4E-binding-defective mutant DDX3 was impaired in its SG-inducing ability and protective effect on cell survival under adverse conditions. All together, the present study has characterized DDX3 as a pivotal SG-nucleating factor and illustrates co-ordinative roles for DDX3, eIF4E and PABP1 in integrating environmental stress with translational regulation.


Muscarinic receptors, protein kinase C isozymes and proliferation of astroglial cells: effects of ethanol.
Activation of cholinergic muscarinic receptors (primarily the M3 subtype) causes proliferation of astroglial cells and this effect is inhibited by low concentrations (10-50 mM) of ethanol. Investigations on the signal transduction pathways activated by muscarinic receptors in a human astrocytoma cell line (1321N1) have focused on protein kinases C (PKC). Among PKC isozymes expressed in this cell line (alpha, epsilon, zeta), the atypical PKCzeta appears to play a primary role in the mitogenic action of muscarinic agonists. We investigated whether activation of these PKC isozymes may be affected by ethanol at concentrations that can inhibit muscarinic receptor-induced proliferation. Carbachol caused an increase in phorbol ester binding and translocation of PKCepsilon, however, these were inhibited only by 100-200 mM ethanol. On the other hand, translocation of the atypical PKCzeta to the perinuclear area by carbachol was inhibited by ethanol in a dose-dependent manner (10-100 mM). These results suggest that activation of PKCzeta may represent a relevant target for the inhibitory effect of ethanol on muscarinic receptor-induced glial cell proliferation.


Interferon-alpha influences tryptophan metabolism without inducing psychiatric side effects.
Interferon-alpha (IFN-alpha) treatment is often associated with psychiatric side effects and has been found to lower the amount of tryptophan (TRP) available to the brain. The alterations in tryptophan metabolism might underlie the psychiatric side effects during treatment with IFN-alpha. In this study, 43 oncology patients treated with IFN-alpha were included. In order to study de novo depressions, depressed patients at baseline were excluded. Psychiatric evaluation comprising clinical judgment combined with a structured psychiatric interview and observer-based and self-report rating scales was performed at baseline and at 4 weeks, 8 weeks and 6 months after the start of treatment with IFN-alpha, and in the case of emerging psychopathology. Blood samples were drawn at the same evaluation times and assessed for concentrations of TRP, large neutral amino acids, kynurenine, 5-hydroxyindole acetic acid, neopterin and biopterin. During treatment with IFN-alpha, several alterations in laboratory parameters occurred that were consistent with an increased degradation of peripheral TRP. Psychometric ratings revealed hardly any psychiatric changes. No consistent associations were found between changes in the laboratory assessments determined and the diverse psychiatric measures. In this study, IFN-alpha was found to alter TRP metabolism without inducing psychiatric side effects. Therefore, a possible relationship between TRP metabolism and depression was not substantiated by this study.


Protein S1 counteracts the inhibitory effect of the extended Shine-Dalgarno sequence on translation.
There are two major components of Escherichia coli ribosomes directly involved in selection and binding of mRNA during initiation of protein synthesis-the highly conserved 3' end of 16S rRNA (aSD) complementary to the Shine-Dalgarno (SD) domain of mRNA, and the ribosomal protein S1. A contribution of the SD-aSD and S1-mRNA interactions to translation yield in vivo has been evaluated in a genetic system developed to compare efficiencies of various ribosome-binding sites (RBS) in driving beta-galactosidase synthesis from the single-copy (chromosomal) lacZ gene. The in vivo experiments have been supplemented by in vitro toeprinting and gel-mobility shift assays. A shortening of a potential SD-aSD duplex from 10 to 8 and to 6 bp increased the beta-galactosidase yield (four- and sixfold, respectively) suggesting that an extended SD-aSD duplex adversely affects translation, most likely due to its redundant stability causing ribosome stalling at the initiation step. Translation yields were significantly increased upon insertion of the A/U-rich S1 binding targets upstream of the SD region, but the longest SD remained relatively less efficient. In contrast to complete 30S ribosomes, the S1-depleted 30S particles have been able to form an extended SD-aSD duplex, but not the true ternary initiation complex. Taken together, the in vivo and in vitro data allow us to conclude that S1 plays two roles in translation initiation: It forms an essential part of the mRNA-binding track even when mRNA bears a long SD sequence, and through the binding to the 5' untranslated region, it can ensure a substantial enhancing effect on translation.


Feasibility and accuracy of computer-assisted individual drill guide template for minimally invasive lumbar pedicle screw placement trajectory.
To discuss the feasibility and accuracy of a specific computer-assisted individual drill guide template (CIDGT) for minimally invasive lumbar pedicle screw placement trajectory (MI-LPT) through a bovine cadaveric experimental study. A 3-D reconstruction model, including lumbar vertebras (L1-L5), was generated, and the optimal MI-LPTs were determined. A drill guide template with a surface made of the antitemplate of the vertebral surface, including the spinous process and the entry point vertebral surface, was created by reverse engineering and rapid prototyping techniques. Then, MI-LPTs were determined by the drill guide templates, and the trajectories made by K-wires were observed by postoperative CT scan. General Hospital of Shenyang Military Area Command of Chinese PLA. In total, 150 K-wires for MI-LPTs were successfully inserted into L1-L5. The required mean time and fluoroscopy times between fixation of the template to the spinous process, entry point vertebral surface, and insertion of the K-wires for minimally invasive lumbar pedicle screw placement trajectories into each vertebra were 79.4 ± 15.0 s and 2.1 ± 0.8 times. There were no significant differences between the preoperative plan and postoperative assessment in the distance from the puncture to the midline and inclination angles according to the different levels (P > 0.05, respectively). The mean deviation between the preoperative plan and postoperative assessment in the distance from the puncture to the midline and inclination angles were 0.8 ± 0.5 mm and 0.9 ± 0.5°, respectively. The potential use of the novel CIDGT, which was based on the unique morphology of the lumbar vertebra to place minimally invasive lumbar pedicle screws, is promising and could prevent too much radiation exposure intraoperatively.


Clinical characteristics of central European and North American samples of pregnant women screened for opioid agonist treatment.
Little comparable information is available regarding clinical characteristics of opioid-dependent women from different countries. In the present study, women from the USA, Canada and a Central European country, Austria, screened for participation in the Maternal Opioid Treatment Human Experimental Research study, were compared with respect to their demographic and addiction histories. Pregnant women (n = 1,074) were screened for study participation using uniformed clinical criteria and instruments. The screening results were compared with regard to exclusion, demographics, drug use, and psychosocial and treatment histories. Compared to the screened US and Canadian women, Austrian women were more likely to be younger (p < 0.001), white (p < 0.001), had significantly lower levels of educational attainment (p < 0.001), were less likely to use opioids daily (p < 0.001) and more likely to have been prescribed buprenorphine (p < 0.001). Compared to both rural and urban US groups, the Austrian group was less likely to have legal issues (p < 0.001) and was younger when first prescribed agonist medication (p < 0.001). The differences between North American and European groups may offer unique insights concerning treatment and pregnancy outcomes for opioid-dependent pregnant women.


Evidence of association of APOE with age-related macular degeneration: a pooled analysis of 15 studies.
Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in high-income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low-density cholesterol modulation. Potential interaction between APOE and sex, and smoking status has been reported. We present a pooled analysis (n = 21,160) demonstrating associations between late AMD and APOε4 (odds ratio [OR] = 0.72 per haplotype; confidence interval [CI]: 0.65-0.74; P = 4.41×10(-11) ) and APOε2 (OR = 1.83 for homozygote carriers; CI: 1.04-3.23; P = 0.04), following adjustment for age group and sex within each study and smoking status. No evidence of interaction between APOE and sex or smoking was found. Ever smokers had significant increased risk relative to never smokers for both neovascular (OR = 1.54; CI: 1.38-1.72; P = 2.8×10(-15) ) and atrophic (OR = 1.38; CI: 1.18-1.61; P = 3.37×10(-5) ) AMD but not early AMD (OR = 0.94; CI: 0.86-1.03; P = 0.16), implicating smoking as a major contributing factor to disease progression from early signs to the visually disabling late forms. Extended haplotype analysis incorporating rs405509 did not identify additional risks beyond ε2 and ε4 haplotypes. Our expanded analysis substantially improves our understanding of the association between the APOE locus and AMD. It further provides evidence supporting the role of cholesterol modulation, and low-density cholesterol specifically, in AMD disease etiology.


Screening for Occult Cancer in Unprovoked Venous Thromboembolism.
Venous thromboembolism may be the earliest sign of cancer. Currently, there is a great diversity in practices regarding screening for occult cancer in a person who has an unprovoked venous thromboembolism. We sought to assess the efficacy of a screening strategy for occult cancer that included comprehensive computed tomography (CT) of the abdomen and pelvis in patients who had a first unprovoked venous thromboembolism. We conducted a multicenter, open-label, randomized, controlled trial in Canada. Patients were randomly assigned to undergo limited occult-cancer screening (basic blood testing, chest radiography, and screening for breast, cervical, and prostate cancer) or limited occult-cancer screening in combination with CT. The primary outcome measure was confirmed cancer that was missed by the screening strategy and detected by the end of the 1-year follow-up period. Of the 854 patients who underwent randomization, 33 (3.9%) had a new diagnosis of occult cancer between randomization and the 1-year follow-up: 14 of the 431 patients (3.2%) in the limited-screening group and 19 of the 423 patients (4.5%) in the limited-screening-plus-CT group (P=0.28). In the primary outcome analysis, 4 occult cancers (29%) were missed by the limited screening strategy, whereas 5 (26%) were missed by the strategy of limited screening plus CT (P=1.0). There was no significant difference between the two study groups in the mean time to a cancer diagnosis (4.2 months in the limited-screening group and 4.0 months in the limited-screening-plus-CT group, P=0.88) or in cancer-related mortality (1.4% and 0.9%, P=0.75). The prevalence of occult cancer was low among patients with a first unprovoked venous thromboembolism. Routine screening with CT of the abdomen and pelvis did not provide a clinically significant benefit. (Funded by the Heart and Stroke Foundation of Canada; SOME ClinicalTrials.gov number, NCT00773448.).


Effects of conventional and problem-based medical curricula on problem solving.
This study examined the reasoning processes of beginning, intermediate, and senior students in two medical schools with different curricular formats. One school had a conventional curriculum (CC) where basic science was taught one and a half years before the clinical training, and the other had a problem-based learning curriculum (PBLC) where basic science was taught in the context of clinical problems and general problem-solving heuristics were specifically taught. The students were asked to give diagnostic explanations of a clinical case, both before and after being exposed to relevant basic science information. Two distinct modes of reasoning were identified, each reflecting a curriculum type. A predominantly "backward-directed" hypothetico-deductive mode of reasoning was found in the explanations of the PBLC students, and a "more forward-directed" pattern of reasoning was found in the explanations of the CC students. Students in the PBLC produced extensive elaborations using relevant biomedical information, which was relatively absent from the CC students' explanations. However, these elaborations were accompanied by a tendency to generate errors. These results have important implications regarding the strengths and weaknesses of the two types of curricula.


Calpain inhibitors prevent neuronal cell death and ameliorate motor disturbances after compression-induced spinal cord injury in rats.
Traumatic spinal cord injury (SCI) results in widespread neuronal cell death. Recent studies have suggested that activated calpain mediates neuronal cell death in the central nervous system. We conducted a study to determine whether calpain mediates neuronal cell death in the motor neurons of the spinal cord after SCI, and whether postinjury administration of the calpain inhibitors N-acetyl- Leu-Leu-Met-CHO (ALLM) and calpain inhibitor III (CI III) (MDL28170) reduces the motor disturbances in rats with a model of SCI. Adult male Wistar rats were subjected to SCI by application of a 20-g weight impactor probe to the spinal cord at T12 for 20 min. The rats were divided into three groups according to whether they were injected intravenously with 0.05-2.5 mg/kg ALLM, 10 mg/kg CI III, or 0.1% DMSO as a control every 24 h for 1 week after SCI. Calpain was activated in the spinal cord at 8 h, 24 h, and 5 days after SCI, and administration of ALLM inhibited its activation. ALLM, as compared to the DMSO vehicle alone, also significantly reduced the number of motor neurons in spinal-cord lesions that were positively labeled at 24 h after SCI with the terminal deoxynucleotidyl transferase-uridine nucleotide end-labeling (TUNEL) technique. Additionally, both the inclined plane test and footprint analysis showed markedly better motor activity after 4 weeks in rats injected with ALLM or CI III than in rats given vehicle only. These results suggest that activation of calpain plays a critical role in the neuronal cell death that follows SCI, and that calpain inhibitors may have benefit in treating the motor disturbances that follow SCI.


Promising techniques for breast cancer detection, diagnosis, and staging using non-ionizing radiation imaging techniques.
Traditional imaging for the diagnosis and staging of breast cancer has relied on the tissue morphology of cancers in the background of normal patterns of fibroglandular breast tissue. X-ray mammography and ultrasound have been the primary modalities for the diagnosis and the work-up of breast cancer. New modalities have been validated including magnetic resonance imaging (MRI) and positron emission tomography (PET). New pulse sequences in MRI combined with contrast enhancement kinetic perfusion curves have greatly enhanced detection of mammographically occult cancers. New modalities on the horizon include optical imaging, exploiting again the differential perfusion properties of cancers in a background of normal glandular tissue. Even more specificity can be ach eved with the addition of ductal or intravenous introduction of optical probes specific to tumor associated antigens such as the HER-2/neu receptor in aggressive breast cancers. Quantum dots and other fluorescent dyes coupled to peptides or other probes will greatly enhance our ability to detect cancers earlier and without ionizing radiation.


Assessment of the impact of lifting device use on low back pain and musculoskeletal injury claims among nurses.
The aims of this study were: (1) to evaluate the effect of manually lifting patients on the occurrence of low back pain (LBP) among nurses, and (2) to estimate the impact of lifting device use on the prevention of LBP and musculoskeletal disorder (MSD) injury claims. A literature search of PubMed, Embase and Web of Science identified studies with a quantitative assessment of the effect of manually lifting patients on LBP occurrence and studies on the impact of introducing lifting devices on LBP and MSD injury claims. A Markov decision analysis model was constructed for a health impact assessment of patient lifting device use in healthcare settings. The best scenario, based on observational and experimental studies, showed a maximum reduction in LBP prevalence from 41.9% to 40.5% and in MSD injury claims from 5.8 to 5.6 per 100 work-years. Complete elimination of manually lifting patients would reduce the LBP prevalence to 31.4% and MSD injury claims to 4.3 per 100 work-years. These results were sensitive to the strengths of the association between manually patient lifting and LBP as well as the prevalence of manual lifting of patients. A realistic variant of the baseline scenario requires well over 25 000 healthcare workers to demonstrate effectiveness. This study indicates that good implementation of lifting devices is required to noticeably reduce LBP and injury claims. This health impact assessment may guide intervention studies as well as implementation of programmes to reduce manual lifting of patients in healthcare settings.


A virus causes cancer by inducing massive chromosomal instability through cell fusion.
Chromosomal instability (CIN) underlies malignant properties of many solid cancers and their ability to escape therapy, and it might itself cause cancer [1, 2]. CIN is sustained by deficiencies in proteins, such as the tumor suppressor p53 [3-5], that police genome integrity, but the primary cause of CIN in sporadic cancers remains uncertain [6, 7]. The primary suspects are mutations that deregulate telomere maintenance, or mitosis, yet such mutations have not been identified in the majority of sporadic cancers [6]. Alternatively, CIN could be caused by a transient event that destabilizes the genome without permanently affecting mechanisms of mitosis or proliferation [5, 8]. Here, we show that an otherwise harmless virus rapidly causes massive chromosomal instability by fusing cells whose cell cycle is deregulated by oncogenes. This synergy between fusion and oncogenes "randomizes" normal diploid human fibroblasts so extensively that each analyzed cell has a unique karyotype, and some produce aggressive, highly aneuploid, heterogeneous, and transplantable epithelial cancers in mice. Because many viruses are fusogenic, this study suggests that viruses, including those that have not been linked to carcinogenesis, can cause chromosomal instability and, consequently, cancer by fusing cells.


USBombus, a database of contemporary survey data for North American Bumble Bees (Hymenoptera, Apidae, Bombus) distributed in the United States.
Bumble bees (Hymenoptera: Apidae, Bombus) are pollinators of wild and economically important flowering plants. However, at least four bumble bee species have declined significantly in population abundance and geographic range relative to historic estimates, and one species is possibly extinct. While a wealth of historic data is now available for many of the North American species found to be in decline in online databases, systematic survey data of stable species is still not publically available. The availability of contemporary survey data is critically important for the future monitoring of wild bumble bee populations. Without such data, the ability to ascertain the conservation status of bumble bees in the United States will remain challenging. This paper describes USBombus, a large database that represents the outcomes of one of the largest standardized surveys of bumble bee pollinators (Hymenoptera, Apidae, Bombus) globally. The motivation to collect live bumble bees across the United States was to examine the decline and conservation status of Bombus affinis, B. occidentalis, B. pensylvanicus, and B. terricola. Prior to our national survey of bumble bees in the United States from 2007 to 2010, there have only been regional accounts of bumble bee abundance and richness. In addition to surveying declining bumble bees, we also collected and documented a diversity of co-occuring bumble bees. However we have not yet completely reported their distribution and diversity onto a public online platform. Now, for the first time, we report the geographic distribution of bumble bees reported to be in decline (Cameron et al. 2011), as well as bumble bees that appeared to be stable on a large geographic scale in the United States (not in decline). In this database we report a total of 17,930 adult occurrence records across 397 locations and 39 species of Bombus detected in our national survey. We summarize their abundance and distribution across the United States and association to different ecoregions. The geospatial coverage of the dataset extends across 41 of the 50 US states, and from 0 to 3500 m a.s.l. Authors and respective field crews spent a total of 512 hours surveying bumble bees from 2007 to 2010. The dataset was developed using SQL server 2008 r2. For each specimen, the following information is generally provided: species, name, sex, caste, temporal and geospatial details, Cartesian coordinates, data collector(s), and when available, host plants. This database has already proven useful for a variety of studies on bumble bee ecology and conservation. However it is not publicly available. Considering the value of pollinators in agriculture and wild ecosystems, this large database of bumble bees will likely prove useful for investigations of the effects of anthropogenic activities on pollinator community composition and conservation status.


Chromosomal localization of the human genes for lipocortin I and lipocortin II.
The human genes which code for Lipocortin I and Lipocortin II, proteins that inhibit phospholipase A2 (PLA2) activity, have been regionally localized in the human genome by chromosomal in situ hybridization and segregation analysis in somatic cell hybrids using cDNA clones for Lipocortin I and II. Lipocortin I, the 35 kd substrate for the epidermal growth factor (EGF) receptor/kinase, maps to chromosome region 9q11- greater than q22. The Lipocortin II cDNA probe detects at least four independently segregating loci which map to human chromosome regions 4q21-q31.1, 9pter-q34 proximal to c-abl, 10q proximal to 10q24 and 15q21-q22 proximal to the 15q22 translocation breakpoint characteristic of acute promyelocytic leukemia (APL). Thus, Lipocortin I and one locus detected by Lipocortin II cDNA are syntenic on chromosome 9; one Lipocortin II locus is perhaps not far from the genes for EGF and IL-2 on 4q; and another of the Lipocortin II loci is on 15q, perhaps not far from the APL breakpoint.


Development of an efficient phenolic sensor based on facile Ag2O/Sb2O3 nanoparticles for environmental safety.
The facile hydrothermal method was used to prepare low-dimensional doped Ag2O/Sb2O3 nanoparticles (NPs) at low temperature in alkaline medium. The calcined NPs were characterized in detail by FTIR, UV/vis, FESEM, XPS, EDS, and XRD. A thin layer of Ag2O/Sb2O3 NPs was deposited onto a glassy carbon electrode (GCE) using Nafion (5% Nafion suspension in ethanol) conducting binder, which formed the working electrode of the selective 3-methoxyphenol electrochemical sensor probe. The proposed chemical sensor exhibits high sensitivity, long-term stability, and enhanced electrochemical responses towards 3-methoxyphenol. Response to 3-methoxyphenol is linear over the concentration range (LDR) of 0.09 nM to 0.09 mM. The analytical parameters of the sensor such as sensitivity, stability, response time, linearity, LDR, robustness, selectivity etc. were evaluated by an electrochemical approach. The sensor probe fabricated with Ag2O/Sb2O3 NPs seems to be a promising candidate for effective and reliable electrochemical detection of hazardous and carcinogenic chemicals in the environment and health care fields in large scales.


Unravelling redox processes of Li7MnN4 upon electrochemical Li extraction-insertion using operando XAS.
A large data set of XAS (X-ray Absorption Spectroscopy) Manganese K-edge spectra has been collected operando and studied upon the electrochemical oxidation of the promising Li-ion battery anode material Li7MnN4. Using chemometric tools such as PCA (Principal Component Analysis) and MCR-ALS (Multivariate Curve resolution - Alternating Least Squares), three independent environment spectra were insulated. Based on the faradaic yield and well-chosen comparison of absorption spectrum energies within the frame of the coordination charge model, these environments were ascribed to unusual oxidation states allowed by nitride chemistry at a low potential (∼1.2 V vs. Li+/Li), i.e. Mn5+ (3d2), Mn6+ (3d1) and Mn7+ (3d0). Also, their relative amounts are discussed with regard to the long-range structural variation which can be simply described by two successive biphasic domains followed by a solid-solution behaviour. Gathering this long-range and local structure information provides a complete picture of the redox mechanisms occurring in Li7MnN4.