Biotemplating pores with size and shape diversity for Li-oxygen Battery Cathodes.
Synthetic porogens provide an easy way to create porous structures, but their usage is limited due to synthetic difficulties, process complexities and prohibitive costs. Here we investigate the use of bacteria, sustainable and naturally abundant materials, as a pore template. The bacteria require no chemical synthesis, come in variable sizes and shapes, degrade easier and are approximately a million times cheaper than conventional porogens. We fabricate free standing porous multiwalled carbon nanotube (MWCNT) films using cultured, harmless bacteria as porogens, and demonstrate substantial Li-oxygen battery performance improvement by porosity control. Pore volume as well as shape in the cathodes were easily tuned to improve oxygen evolution efficiency by 30% and double the full discharge capacity in repeated cycles compared to the compact MWCNT electrode films. The interconnected pores produced by the templates greatly improve the accessibility of reactants allowing the achievement of 4,942 W/kg (8,649 Wh/kg) at 2 A/ge (1.7 mA/cm2).


A randomised, double-blind, parallel-group study of the safety and efficacy of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional disease-modifying antirheumatic drugs in patients with moderate to severe rheumatoid arthritis (SUMMACTA study).
This study compared the efficacy and safety of subcutaneous (SC) versus intravenous (IV) formulations of tocilizumab in patients with rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs (DMARD). Patients (n=1262) were randomly assigned to receive tocilizumab-SC 162 mg weekly+placebo-IV every 4 weeks or tocilizumab-IV 8 mg/kg every 4 weeks+placebo-SC weekly in combination with traditional DMARD. The primary outcome was to demonstrate the non-inferiority of tocilizumab-SC to tocilizumab-IV with regard to the proportion of patients in each group achieving an American College of Rheumatology (ACR) 20 response at week 24 using a 12% non-inferiority margin (NIM). Secondary outcomes were disease activity score using 28 joints (DAS28), ACR responses, health assessment questionnaire scores and safety assessments. At week 24, 69.4% (95% CI 65.5 to 73.2) of tocilizumab-SC-treated patients versus 73.4% (95% CI 69.6 to 77.1) of tocilizumab-IV-treated patients achieved an ACR20 response (weighted difference between groups -4.0%, 95% CI -9.2 to 1.2); the 12% NIM was met. ACR50/70 responses, DAS28 and physical function improvements were comparable between the tocilizumab-SC and tocilizumab-IV groups. The safety profiles of tocilizumab-SC and tocilizumab-IV were similar, and the most common adverse event was infection. Injection-site reactions (ISR) occurred more frequently in the tocilizumab-SC group than in the tocilizumab-IV (placebo-SC) group. No anaphylaxis was reported over the 24 weeks. Tocilizumab-SC 162 mg weekly demonstrated comparable efficacy to tocilizumab-IV 8 mg/kg. The safety profile of tocilizumab-SC is consistent with the known and well-established safety profile of tocilizumab-IV, with the exception of a higher incidence of ISR, which were more common with tocilizumab-SC administration.


Improved reactivity of a cyclic 13/15 compound by increased steric demand.
Herein we present the synthesis and characterization of the new four-membered Ga/P cycle [tBu2GaP(H)SitBu2Ph]2, which shows a cis/trans isomerization at ambient temperatures via a ring opening mechanism. The sterically demanding substituents on the phosphorus (-SitBu2Ph) and gallium (tBu) atoms lead to an unexpected reactivity towards bulky NHC ligands (IMes and IDipp). The resulting Lewis base stabilized monomeric 13/15 compounds feature an unusual binding mode of the carbene ligand. The ring opened state also enables a masked flp reactivity, which is shown by a reaction with the polar multiple bond in Ph-NCO.


Is there any legal and scientific basis for classifying electronic cigarettes as medications?
The rapid growth in the use of electronic cigarettes has been accompanied by substantial discussions by governments, international organisations, consumers and public health experts about how they might be regulated. In the European Union they are currently regulated under consumer legislation but new legislation will regulate them under the Tobacco Products Directive. However, several countries have sought to regulate them under medicines regulations. These claims have been successfully challenged in 6 court cases in European states. Under European legislation a product may be deemed to be a medicine by function if it is used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis. It is a medicine by presentation if it is presented (e.g. by a manufacturer or distributor) as having properties for treating or preventing disease in human beings. We assess the legal and scientific basis for the claim that electronic cigarettes should be regulated as medicines. We conclude that they are neither medicine by function nor necessarily by presentation The main reason for their existence is as a harm reduction product in which the liking for and/or dependence on nicotine is maintained, and adoption of use is as a substitute for smoking and not as a smoking cessation product. In reality, they are used as consumer products providing pleasure to the user. They are not used to treat nicotine addiction or other disease, but to enable continued use of nicotine. Their use is adjusted individually by each consumer according to his or her perceived pleasure and satisfaction. Gaps in current regulation regarding safety and quality can be met by tailored regulations.


Biomarker-guided interventions of clinically relevant conditions associated with autism spectrum disorders and attention deficit hyperactivity disorder.
Autism spectrum disorders (ASD) and attention-deficit hyperactivity disorder (ADHD) are common and complex neurodevelopmental conditions. Diagnostic criteria for these conditions have traditionally relied solely on behavioral criteria without consideration for potential biomedical underpinnings. Newer evidence, however, reveals that ASDs are associated with: oxidative stress; decreased methylation capacity; limited production of glutathione; mitochondrial dysfunction; intestinal dysbiosis; increased toxic metal burden; immune dysregulation, characterized by a unique inflammatory bowel disease and immune activation of neuroglial cells; and ongoing brain hypoperfusion. Many of these same problems are common features in children with ADHD. These medical conditions, whether co-morbidities or etiopathogenic, would be expected to have synergistically negative effects on the development, cognition, focus, and attention of affected children. It is likely these biological abnormalities contribute significantly to the behavioral symptoms intrinsic in these diagnoses. However, treatment for these underlying medical disorders is clinically justified, even if no clear immediate behavioral improvements are observed. This article reviews the medical literature and discusses the authors clinical experience using various biomarkers for measuring oxidative stress, methylation capacity and transsulfuration, immune function, gastrointestinal problems, and toxic metal burden. These biomarkers provide useful guides for selection, efficacy, and sufficiency of biomedical interventions. The use of these biomarkers is of great importance in young children with ADHD or individuals of any age with ASD, because typically they cannot adequately communicate regarding their symptoms.


Molecular Diagnosis of Orthopedic-Device-Related Infection Directly from Sonication Fluid by Metagenomic Sequencing.
Culture of multiple periprosthetic tissue samples is the current gold standard for microbiological diagnosis of prosthetic joint infections (PJI). Additional diagnostic information may be obtained through culture of sonication fluid from explants. However, current techniques can have relatively low sensitivity, with prior antimicrobial therapy and infection by fastidious organisms influencing results. We assessed if metagenomic sequencing of total DNA extracts obtained direct from sonication fluid can provide an alternative rapid and sensitive tool for diagnosis of PJI. We compared metagenomic sequencing with standard aerobic and anaerobic culture in 97 sonication fluid samples from prosthetic joint and other orthopedic device infections. Reads from Illumina MiSeq sequencing were taxonomically classified using Kraken. Using 50 derivation samples, we determined optimal thresholds for the number and proportion of bacterial reads required to identify an infection and confirmed our findings in 47 independent validation samples. Compared to results from sonication fluid culture, the species-level sensitivity of metagenomic sequencing was 61/69 (88%; 95% confidence interval [CI], 77 to 94%; for derivation samples 35/38 [92%; 95% CI, 79 to 98%]; for validation samples, 26/31 [84%; 95% CI, 66 to 95%]), and genus-level sensitivity was 64/69 (93%; 95% CI, 84 to 98%). Species-level specificity, adjusting for plausible fastidious causes of infection, species found in concurrently obtained tissue samples, and prior antibiotics, was 85/97 (88%; 95% CI, 79 to 93%; for derivation samples, 43/50 [86%; 95% CI, 73 to 94%]; for validation samples, 42/47 [89%; 95% CI, 77 to 96%]). High levels of human DNA contamination were seen despite the use of laboratory methods to remove it. Rigorous laboratory good practice was required to minimize bacterial DNA contamination. We demonstrate that metagenomic sequencing can provide accurate diagnostic information in PJI. Our findings, combined with the increasing availability of portable, random-access sequencing technology, offer the potential to translate metagenomic sequencing into a rapid diagnostic tool in PJI.


Selection and validation of reference genes for functional studies in the Calliphoridae family.
The genera Cochliomyia and Chrysomya contain both obligate and saprophagous flies, which allows the comparison of different feeding habits between closely related species. Among the different strategies for comparing these habits is the use of qPCR to investigate the expression levels of candidate genes involved in feeding behavior. To ensure an accurate measure of the levels of gene expression, it is necessary to normalize the amount of the target gene with the amount of a reference gene having a stable expression across the compared species. Since there is no universal gene that can be used as a reference in functional studies, candidate genes for qPCR data normalization were selected and validated in three Calliphoridae (Diptera) species, Cochliomyia hominivorax Coquerel, Cochliomyia macellaria Fabricius, and Chrysomya albiceps Wiedemann . The expression stability of six genes ( Actin, Gapdh, Rp49, Rps17, α -tubulin, and GstD1) was evaluated among species within the same life stage and between life stages within each species. The expression levels of Actin, Gapdh, and Rp49 were the most stable among the selected genes. These genes can be used as reliable reference genes for functional studies in Calliphoridae using similar experimental settings.


Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment.
Glioblastomas are treated by surgical resection followed by radiotherapy [X-ray therapy (XRT)] and the alkylating chemotherapeutic agent temozolomide. Recently, inactivating mutations in the mismatch repair gene MSH6 were identified in two glioblastomas recurrent post-temozolomide. Because mismatch repair pathway inactivation is a known mediator of alkylator resistance in vitro, these findings suggested that MSH6 inactivation was causally linked to these two recurrences. However, the extent of involvement of MSH6 in glioblastoma is unknown. We sought to determine the overall frequency and clinical relevance of MSH6 alterations in glioblastomas. The MSH6 gene was sequenced in 54 glioblastomas. MSH6 and O(6)-methylguanine methyltransferase (MGMT) immunohistochemistry was systematically scored in a panel of 46 clinically well-characterized glioblastomas, and the corresponding patient response to treatment evaluated. MSH6 mutation was not observed in any pretreatment glioblastoma (0 of 40), whereas 3 of 14 recurrent cases had somatic mutations (P = 0.015). MSH6 protein expression was detected in all pretreatment (17 of 17) cases examined but, notably, expression was lost in 7 of 17 (41%) recurrences from matched post-XRT + temozolomide cases (P = 0.016). Loss of MSH6 was not associated with O(6)-methylguanine methyltransferase status. Measurements of in vivo tumor growth using three-dimensional reconstructed magnetic resonance imaging showed that MSH6-negative glioblastomas had a markedly increased rate of growth while under temozolomide treatment (3.17 versus 0.04 cc/mo for MSH6-positive tumors; P = 0.020). Loss of MSH6 occurs in a subset of post-XRT + temozolomide glioblastoma recurrences and is associated with tumor progression during temozolomide treatment, mirroring the alkylator resistance conferred by MSH6 inactivation in vitro. MSH6 deficiency may therefore contribute to the emergence of recurrent glioblastomas during temozolomide treatment.


The influence of increased peritoneal membrane surface area on dialysis adequacy.
The adequacy of peritoneal dialysis is generally dependant on the choice of peritoneal fluid, the intraperitoneal fill volume and the contact time. Moreover, the peritoneal surface area acts as a major factor in the exchange dynamics of a peritoneal membrane. We designed a mechanism to increase the membrane surface contact area by using an abdominal belt in order to exert enough pressure on the fill volume, to effectively recruit more area in contact for exchange. We studied 12 patients on regular continuous ambulatory peritoneal dialysis (CAPD) at our center from January to October 2008. The age of patients ranged from 44 to 75 years, with a median of 55 years. All the patients were maintained on the same prescription four months before and during the study. Dialysis solutions were 1.36% Deaneal® , two liters, three exchanges and the last fill volume was two liters 7.5% Extraneal® . The belt was applied to all the patients most of the day and all night. We then observed its effect on dialysis adequacy, reflected by various parameters over a period of eight months. The average Kt/V before wearing the belt was 1.89 and improved after applying the belt to 2.3 (P <0.05). Our study suggests that increasing the abdominal pressure by wearing an abdominal belt rendered the filling volume of the PD dialysate to have a better contact with the peritoneal membrane and improved the dialysis adequacy. Studies with larger sample size are required to confirm the results.


Significance of cerebellar tonsillar position on MR.
It has been noted that a low degree of ectopia of the cerebellar tonsils on MR is of questionable significance. We measured the position of the cerebellar tonsils with respect to the inferior aspect of the foramen magnum in 200 normal patients and in 25 patients with a firm diagnosis of Chiari I malformation. In the normal group, the mean position of the tonsils was 1 mm above the foramen magnum with a range from 8 mm above the foramen magnum to 5 mm below. In the patients with Chiari I malformations, the mean position was 13 mm below the foramen magnum with a range from 3 mm below the foramen magnum to 29 mm below. Fourteen percent of normal patients had tonsils extending slightly below the foramen magnum. If 2 mm below the foramen magnum is taken as the lowest extent for tonsils in a normal patient, our sensitivity in predicting symptomatic patients is 100% and our specificity is 98.5% (three false positives). If 3 mm below the foramen magnum is taken as the lowest normal tonsillar position, our sensitivity is 96% and our specificity is 99.5%. MR demonstration of less than 2 mm of tonsillar ectopia is probably of no clinical significance in the absence of syringomyelia.


Dietary patterns and the risk of major adverse cardiovascular events in a global study of high-risk patients with stable coronary heart disease.
To determine whether dietary pattern assessed by a simple self-administered food frequency questionnaire is associated with major adverse cardiovascular events (MACE) in high-risk patients with stable coronary artery disease. A Mediterranean dietary pattern has been associated with lower cardiovascular (CV) mortality. It is less certain whether foods common in western diets are associated with CV risk. At baseline, 15 482 (97.8%) patients (mean age 67 ± 9 years) with stable coronary heart disease from 39 countries who participated in the Stabilisation of atherosclerotic plaque by initiation of darapladib therapy (STABILITY) trial completed a life style questionnaire which included questions on common foods. A Mediterranean diet score (MDS) was calculated for increasing consumption of whole grains, fruits, vegetables, legumes, fish, and alcohol, and for less meat, and a 'Western diet score' (WDS) for increasing consumption of refined grains, sweets and deserts, sugared drinks, and deep fried foods. A multi-variable Cox proportional hazards models assessed associations between MDS or WDS and MACE, defined as CV death, non-fatal myocardial infarction, or non-fatal stroke. After a median follow-up of 3.7 years MACE occurred in 7.3% of 2885 subjects with an MDS ≥15, 10.5% of 4018 subjects with an MDS of 13-14, and 10.8% of 8579 subjects with an MDS ≤12. A one unit increase in MDS >12 was associated with lower MACE after adjusting for all covariates (+1 category HR 0.95, 95% CI 0.91, 0.98, P = 0.002). There was no association between WDS (adjusted model +1 category HR 0.99, 95% CI 0.97, 1.01) and MACE. Greater consumption of healthy foods may be more important for secondary prevention of coronary artery disease than avoidance of less healthy foods typical of Western diets.


SolarView: Low Distortion Radial Embedding with a Focus.
We propose a novel type of low distortion radial embedding which focuses on one specific entity and its closest neighbors. Our embedding preserves near-exact distances to the focus entity and aims to minimize distortion between the other entities. We present an interactive exploration tool SolarView which places the focus entity at the center of a "solar system" and embeds its neighbors guided by concentric circles. SolarView provides an implementation of our novel embedding and several state-of-the-art dimensionality reduction and embedding techniques, which we adapted to our setting in various ways. We experimentally evaluated our embedding and compared it to these state-of-the-art techniques. The results show that our embedding competes with these techniques and achieves low distortion in practice. Our method performs particularly well when the visualization, and hence the embedding, adheres to the solar system design principle of our application. Nonetheless-as with all dimensionality reduction techniques-the distortion may be high. We leverage interaction techniques to give clear visual cues that allow users to accurately judge distortion. We illustrate the use of SolarView by exploring the high-dimensional metric space of bibliographic entity similarities.


Characterisation of [Cu4S], the catalytic site in nitrous oxide reductase, by EPR spectroscopy.
The enzyme nitrous oxide reductase (N(2)OR) has a unique tetranuclear copper centre [Cu(4)S], called Cu(Z), at the catalytic site for the two-electron reduction of N(2)O to N(2). The X- and Q-band EPR spectra have been recorded from two forms of the catalytic site of the enzyme N(2)OR from Paracoccus pantotrophus, namely, a form prepared anaerobically, Cu(Z), that undergoes a one-electron redox cycle and Cu(Z)*, prepared aerobically, which cannot be redox cycled. The spectra of both species are axial with that of Cu(Z) showing a rich hyperfine splitting in the g||-region at X-band. DFT calculations were performed to gain insight into the electronic configuration and ground-state properties of Cu(Z) and to calculate EPR parameters. The results for the oxidation state [Cu(+1)(3)Cu(+2)(1)S](3+) are in good agreement with values obtained from the fitting of experimental spectra, confirming the absolute oxidation state of Cu(Z). The unpaired spin density in this configuration is delocalised over four copper ions, thus, Cu(I) 20.1%, Cu(II) 9.5%, Cu(III) 4.8% and Cu(IV) 9.2%, the mu(4)-sulfide ion and oxygen ligand. The three copper ions carrying the highest spin density plus the sulfide ion lie approximately in the same plane while the fourth copper ion is perpendicular to this plane and carries only 4.8% spin density. It is suggested that the atoms in this plane represent the catalytic core of Cu(Z), allowing electron redistribution within the plane during interaction with the substrate, N(2)O.


Updates on the treatment and outcomes of dual chronic hepatitis C and B virus infection.
Dual hepatitis C virus (HCV)/hepatitis B virus (HBV) infection is found in HBV or HCV endemic areas, and in specific populations exhibiting a high risk of parenteral viral transmission. Clinical observations have revealed that HCV/HBV dually infected patients demonstrate a higher risk of liver disease progression compared with HBV or HCV monoinfected patients. The viral activity responsible for liver disease progression can be determined by examining the viral loads of HCV and HBV and by conducting liver biopsy examinations. Recent trials have confirmed that the combination therapy of peginterferon alpha-2a or 2b and ribavirin for dual hepatitis patients with HCV dominance appears to be as effective and safe as it is in patients with HCV monoinfections. Strikingly, approximately 60% of dually infected patients with inactive hepatitis B before treatment develop HBV reactivation after the clearance of the HCV. The clinical significance of this HBV reactivation and the strategy to prevent and treat this event should be determined. Furthermore, approximately 30% of dually infected patients lost hepatitis B surface antigen (HBsAg) within 5 years after the start of peginterferon-based therapy, and 40% of them harbored occult HBV infection. The underlying mechanisms of their accelerating HBsAg seroclearance and the development of occult HBV await further investigations. Moreover, the optimal treatment strategies for dually infected patients who are seropositive for the hepatitis B e antigen must be explored. Finally, the advent of new direct-acting antiviral-based anti-HCV therapy may change the optimal therapies for patients with dual hepatitis in the near future, which warrants further clinical trials.


Optogenetic activation of parvalbumin and somatostatin interneurons selectively restores theta-nested gamma oscillations and oscillation-induced spike timing-dependent long-term potentiation impaired by amyloid β oligomers.
Abnormal accumulation of amyloid β1-42 oligomers (AβO1-42), a hallmark of Alzheimer's disease, impairs hippocampal theta-nested gamma oscillations and long-term potentiation (LTP) that are believed to underlie learning and memory. Parvalbumin-positive (PV) and somatostatin-positive (SST) interneurons are critically involved in theta-nested gamma oscillogenesis and LTP induction. However, how AβO1-42 affects PV and SST interneuron circuits is unclear. Through optogenetic manipulation of PV and SST interneurons and computational modeling of the hippocampal neural circuits, we dissected the contributions of PV and SST interneuron circuit dysfunctions on AβO1-42-induced impairments of hippocampal theta-nested gamma oscillations and oscillation-induced LTP. Targeted whole-cell patch-clamp recordings and optogenetic manipulations of PV and SST interneurons during in vivo-like, optogenetically induced theta-nested gamma oscillations in vitro revealed that AβO1-42 causes synapse-specific dysfunction in PV and SST interneurons. AβO1-42 selectively disrupted CA1 pyramidal cells (PC)-to-PV interneuron and PV-to-PC synapses to impair theta-nested gamma oscillogenesis. In contrast, while having no effect on PC-to-SST or SST-to-PC synapses, AβO1-42 selectively disrupted SST interneuron-mediated disinhibition to CA1 PC to impair theta-nested gamma oscillation-induced spike timing-dependent LTP (tLTP). Such AβO1-42-induced impairments of gamma oscillogenesis and oscillation-induced tLTP were fully restored by optogenetic activation of PV and SST interneurons, respectively, further supporting synapse-specific dysfunctions in PV and SST interneurons. Finally, computational modeling of hippocampal neural circuits including CA1 PC, PV, and SST interneurons confirmed the experimental observations and further revealed distinct functional roles of PV and SST interneurons in theta-nested gamma oscillations and tLTP induction. Our results reveal that AβO1-42 causes synapse-specific dysfunctions in PV and SST interneurons and that optogenetic modulations of these interneurons present potential therapeutic targets for restoring hippocampal network oscillations and synaptic plasticity impairments in Alzheimer's disease.


Category-related activation for written words in the posterior fusiform is task specific.
Category-related brain activations have been reported in the posterior fusiform gyri when people view pictures of tools and animals, but only a single study has observed this pattern when the stimuli were words, rather than pictures. Here we replicate these category effects with words and provide evidence that distinctive patterns of activation are task specific. The results suggest that category-related activation in the posterior fusiform gyri can be driven either "bottom-up" by visual processing of images or "top-down" by word processing.


Associations between Ischemic Stroke Follow-Up, Socioeconomic Status, and Adherence to Secondary Preventive Drugs in Southern Sweden: Observations from the Swedish Stroke Register (Riksstroke).
Currently, the knowledge that one has on adequate stroke follow-up practices is limited. We report associations between 90-day stroke follow-up, socio-economy and adherence to secondary prevention in southern Sweden. Data on 5,602 patients with ischemic stroke January 1, 2008-December 31, 2010, were obtained from Riksstroke and linked to official registers for information on education, birth country, doctor's follow-ups, and secondary prevention. Primary adherence at 4 months and persistence at 14 months post-stroke were calculated for warfarin, statins, antihypertensive, and antiplatelet drugs. The 90-day follow-up rate was 75%. Patients not receiving a 90-day follow-up had lower age-adjusted OR of persistent drug use at 14 months for antihypertensive agents (OR = 0.74, 95% CI 0.60-0.91) and for antiplatelet drugs (OR = 0.72, 95% CI 0.60-0.87). Drug adherence rates 14 months post-stroke were 85% for antiplatelet drugs, 69% for warfarin, 88% for antihypertensive agents, and 76% for statins. One in three patients discontinued using one or more drug class within 14 months, and nonadherence was associated with activities of daily living dependency at 3 months (age-adjusted OR 0.63, 95% CI 0.57-0.69), but not with age, gender, or educational status. The use of secondary preventive drugs decreases over the first year after stroke and remains suboptimal. Specific reasons for nonadherence warrant further study.


Do specific dietary constituents and supplements affect mental energy? Review of the evidence.
The numbers of marketing claims and food, beverage, and drug products claiming to increase mental energy have risen rapidly, thus increasing the need for scientific specificity in marketing and food label claims. Mental energy is a three-dimensional construct consisting of mood (transient feelings about the presence of fatigue or energy), motivation (determination and enthusiasm), and cognition (sustained attention and vigilance). The present review focuses on four dietary constituents/supplements (Ginkgo biloba, ginseng, glucose, and omega-3 polyunsaturated fatty acids) to illustrate the current state of the literature on dietary constituents and mental energy. The strongest evidence suggests effects of Ginkgo biloba on certain aspects of mood and on attention in healthy subjects, as well as associations between omega-3 polyunsaturated fatty acids and reduced risk of age-related cognitive decline. Limitations of the current data and challenges for future research are discussed.


LENS: web-based lens for enrichment and network studies of human proteins.
Network analysis is a common approach for the study of genetic view of diseases and biological pathways. Typically, when a set of genes are identified to be of interest in relation to a disease, say through a genome wide association study (GWAS) or a different gene expression study, these genes are typically analyzed in the context of their protein-protein interaction (PPI) networks. Further analysis is carried out to compute the enrichment of known pathways and disease-associations in the network. Having tools for such analysis at the fingertips of biologists without the requirement for computer programming or curation of data would accelerate the characterization of genes of interest. Currently available tools do not integrate network and enrichment analysis and their visualizations, and most of them present results in formats not most conducive to human cognition. We developed the tool Lens for Enrichment and Network Studies of human proteins (LENS) that performs network and pathway and diseases enrichment analyses on genes of interest to users. The tool creates a visualization of the network, provides easy to read statistics on network connectivity, and displays Venn diagrams with statistical significance values of the network's association with drugs, diseases, pathways, and GWASs. We used the tool to analyze gene sets related to craniofacial development, autism, and schizophrenia. LENS is a web-based tool that does not require and download or plugins to use. The tool is free and does not require login for use, and is available at http://severus.dbmi.pitt.edu/LENS.


Repurposing Ivermectin for COVID-19: Molecular Aspects and Therapeutic Possibilities.
As of January 2021, SARS-CoV-2 has killed over 2 million individuals across the world. As such, there is an urgent need for vaccines and therapeutics to reduce the burden of COVID-19. Several vaccines, including mRNA, vector-based vaccines, and inactivated vaccines, have been approved for emergency use in various countries. However, the slow roll-out of vaccines and insufficient global supply remains a challenge to turn the tide of the pandemic. Moreover, vaccines are important tools for preventing the disease but therapeutic tools to treat patients are also needed. As such, since the beginning of the pandemic, repurposed FDA-approved drugs have been sought as potential therapeutic options for COVID-19 due to their known safety profiles and potential anti-viral effects. One of these drugs is ivermectin (IVM), an antiparasitic drug created in the 1970s. IVM later exerted antiviral activity against various viruses including SARS-CoV-2. In this review, we delineate the story of how this antiparasitic drug was eventually identified as a potential treatment option for COVID-19. We review SARS-CoV-2 lifecycle, the role of the nucleocapsid protein, the turning points in past research that provided initial 'hints' for IVM's antiviral activity and its molecular mechanism of action- and finally, we culminate with the current clinical findings.


Dynamic proteomic analysis of Aedes aegypti Aag-2 cells infected with Mayaro virus.
Mayaro virus (MAYV) is responsible for a mosquito-borne tropical disease with clinical symptoms similar to dengue or chikungunya virus fevers. In addition to the recent territorial expansion of MAYV, this virus may be responsible for an increasing number of outbreaks. Currently, no vaccine is available. Aedes aegypti is promiscuous in its viral transmission and thus an interesting model to understand MAYV-vector interactions. While the life-cycle of MAYV is known, the mechanisms by which this arbovirus affects mosquito host cells are not clearly understood. After defining the best conditions for cell culture harvesting using the highest virus titer, Ae. aegypti Aag-2 cells were infected with a Brazilian MAYV isolate at a MOI of 1 in order to perform a comparative proteomic analysis of MAYV-infected Aag-2 cells by using a label-free semi-quantitative bottom-up proteomic analysis. Time-course analyses were performed at 12 and 48 h post-infection (hpi). After spectrum alignment between the triplicates of each time point and changes of the relative abundance level calculation, the identified proteins were annotated and using Gene Ontology database and protein pathways were annotated using the Kyoto Encyclopedia of Genes and Genomes. After three reproducible biological replicates, the total proteome analysis allowed for the identification of 5330 peptides and the mapping of 459, 376 and 251 protein groups, at time 0, 12 hpi and 48 hpi, respectively. A total of 161 mosquito proteins were found to be differentially abundant during the time-course, mostly related to host cell processes, including redox metabolism, translation, energy metabolism, and host cell defense. MAYV infection also increased host protein expression implicated in viral replication. To our knowledge, this first proteomic time-course analysis of MAYV-infected mosquito cells sheds light on the molecular basis of the viral infection process and host cell response during the first 48 hpi. Our data highlight several mosquito proteins modulated by the virus, revealing that MAYV manipulates mosquito cell metabolism for its propagation.


Efficacy of Therapeutic Endoscopy for Gastrointestinal Lesion (GI): A network meta-analysis.
Endoscopic therapy can reduce the risks of rebleeding, continued bleeding, need for surgery, and mortality. The objective of this systematic review was to compare the different modalities of endoscopic therapy for GI bleeding. Studies were identified by searching electronic databases MEDLINE. We selected all available clinical studies published after 2000 that assessed efficacy and/or safety of different endoscopic hemostatic techniques in treating GI bleeding. The outcomes evaluated included initial hemostasis, rebleeding rate, and 30-day all-cause mortality. Network meta-analyses were performed to summarize the treatment effects. Total 20 studies involving 1845 patients were evaluated. Ten different treatment categories including mechanic, ablative, injection, and combined therapy were compared in our analysis in terms of their efficacy in stopping bleeding and complications. Band ligation [rate: 0.757; 95% Credible Interval (0.565, 0.887)] and injection therapy [rate: 0.891; 95% CI (0.791, 0.944)] had inferior efficacy in attaining initial hemostasis compared to others. Combined therapy of band ligation and HPC and hemoclip may represent the best options for preventing rebleeding and mortality respectively. No significant difference was found among other treatments in terms of complications. We recommend the application of hemoclips in treating GI bleeding due to its high hemostasis efficacy and low risk of 30-day mortality.


The relationship between event-based prospective memory and ongoing task performance in chimpanzees (Pan troglodytes).
Prospective memory is remembering to do something at a future time. A growing body of research supports that prospective memory may exist in nonhuman animals, but the methods used to test nonhuman prospective memory differ from those used with humans. The current work tests prospective memory in chimpanzees using a method that closely approximates a typical human paradigm. In these experiments, the prospective memory cue was embedded within an ongoing task. Tokens representing food items could be used in one of two ways: in a matching task with pictures of items (the ongoing task) or to request a food item hidden in a different location at the beginning of the trial. Chimpanzees had to disengage from the ongoing task in order to use the appropriate token to obtain a higher preference food item. In Experiment 1, chimpanzees effectively matched tokens to pictures, when appropriate, and disengaged from the ongoing task when the token matched the hidden item. In Experiment 2, performance did not differ when the target item was either hidden or visible. This suggested no effect of cognitive load on either the prospective memory task or the ongoing task, but performance was near ceiling, which may have contributed to this outcome. In Experiment 3, we created a more challenging version of the task. More errors on the matching task occurred before the prospective memory had been carried out, and this difference seemed to be limited to the hidden condition. This finding parallels results from human studies and suggests that working memory load and prospective memory may have a similar relationship in nonhuman primates.


Non-local atomic manipulation on semiconductor surfaces in the STM: the case of chlorobenzene on Si(111)-7×7.
Control over individual atoms with the scanning tunnelling microscope (STM) holds the tantalising prospect of atomic-scale construction, but is limited by its "one atom at a time" serial nature. "Remote control" through non-local STM manipulation-as we have demonstrated in the case of chlorobenzene on Si(111)-7×7-offers a new avenue for future "bottom-up" nanofabrication, since hundreds of chemical reactions may be carried out in parallel. Thus a good understanding of the non-local manipulation process, as provided by recent experiments, is important. Comparison of scanning tunnelling spectroscopy (STS) measurements of the bare Si(111)-7×7 surface and chemisorbed chlorobenzene molecules with the voltage dependence of the non-local STM-induced desorption of chlorobenzene proves particularly instructive. For example, the chlorobenzene LUMO appears at +0.9 V with respect to the Fermi level, whereas non-local manipulation thresholds are found at +2.1 V and +2.7 V. This difference supports a picture in which the voltage thresholds for non-local electron-induced desorption depend principally on the energies of the electronic states of the surface. Furthermore, the demonstration that the non-local process is largely insensitive to surface steps up to five layers in height suggests that either the electron transport in this process is subsurface in character or surface charge transport is responsible but is in some way unaffected by the steps.


The role of telavancin in hospital-acquired pneumonia and ventilator-associated pneumonia.
Hospital-acquired pneumonia (HAP) due to gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) continues to be a major cause of morbid conditions and death. Telavancin is a lipoglycopeptide antibiotic with potent in vitro activity against a range of gram-positive pathogens, including MRSA, methicillin-susceptible S. aureus, and Streptococcus species. In 2 phase 3 clinical trials, telavancin was noninferior to vancomycin in patients with HAP due to gram-positive pathogens. Clinically evaluable patients with S. aureus as the sole pathogen or S. aureus with a vancomycin minimum inhibitory concentration >1 µg/mL, however, had higher cure rates with telavancin than with vancomycin. In patients with bacteremic HAP, telavancin resulted in clearance of blood cultures. It was associated with increased serum creatinine levels and higher mortality rates in patients with moderate to severe renal impairment at baseline; however, on subsequent analysis, the outcomes seemed to have been at least partially affected by the adequacy of empiric gram-negative antimicrobial therapy. Thus, clinicians need to consider the risk-benefit balance when choosing telavancin in patients with severe renal impairment at baseline. Overall, these data support the use of telavancin in the treatment of HAP due to S. aureus, including MRSA and strains with elevated vancomycin minimum inhibitory concentrations, but clinicians should always weigh the risks and benefits of various treatment options.


Macrophage-derived, macrophage migration inhibitory factor (MIF) is necessary to induce disease in the K/BxN serum-induced model of arthritis.
Rheumatoid arthritis (RA) is characterized by the interaction of multiple mediators, among the most important of which are cytokines. In recent years, extensive studies demonstrate a pivotal role for one cytokine, macrophage migration inhibitory factor (MIF), in fundamental events in innate and adaptive immunity. MIF has now been demonstrated to be involved in the pathogenesis of many diseases, but in the case of RA the evidence for a role of MIF is very strong. MIF is abundantly expressed in the sera of RA patients and in RA synovial tissue correlating with disease activity. MIF-deficient mice were used to induce arthritis by serum transfer from K/BxN mice. K/BxN serum transfer arthritis was markedly attenuated in MIF(-) mice, with reduction in clinical index and histological severity as well as decrease in synovial cytokines. Macrophage transfers were done to investigate the specific role of macrophage-derived MIF. We show that adoptive transfer of wild-type macrophages into MIF(-) mice restores the sensitivity of MIF(-) mice to arthritis development, and this affect was associated with a restoration in serum IL-1β and IL-6 production. These results indicate that MIF plays a critical role in inflammation and joint destruction in K/BxN serum-induced arthritis and that the systemic expression of MIF by a subpopulation of macrophages is necessary and sufficient for the full development of arthritis.


Maturation of mammalian 20 S proteasome: purification and characterization of 13 S and 16 S proteasome precursor complexes.
The maturation of the eukaryotic 20 S proteasome complex occurs via 13 S and 16 S precursor complexes in a multistep assembly pathway. These precursor complexes contain alpha-subunits as well as unprocessed beta-subunit proproteins. We have purified and characterized the different proteasome assembly intermediates and analysed their ability to support beta-subunit proprotein processing in vitro. Our data show that 13 S and 16 S proteasome precursor complexes differ not only in size but also in their protein content and behaviour during hydrophobic chromatography. By establishing conditions which allowed us to analyse beta-prosubunit maturation in vitro we demonstrate that the processing of the homologous proproteins of the beta-subunits LMP2 and delta essentially takes place in 16 S precursor complexes. No proprotein processing activity was observed in 13 S precursor complexes. Furthermore, proprotein processing in vitro can be inhibited with a proteasome specific inhibitor, but with different efficiency for LMP2 and delta. A peptide, which represents the sequence of the proprotein processing site HGTT, exhibited no inhibitory effect on the processing of either subunit. These data provide further evidence that proprotein processing occurs via an autocatalytic mechanism. Our experiments also demonstrate that the chaperone protein hsc73 is associated with 16 S but not with 13 S precursor complexes. In support of the specificity of this interaction incubation with ATP leads to the dissociation of hsc73 from 16 S complexes and to the formation of high molecular weight aggregates. Prosubunit processing in isolated 16 S complexes does not, however, result in the formation of proteolytically active 20 S proteasomes which may be due to the fact that not all beta-subunits can be efficiently processed in vitro. In contrast to previous assumptions subunit processing and formation of proteolytic activity do not coincide and final 20 S complex assembly seems to represent in part a separate event which requires additional factors or proteins which are not present or active in the purified 16 S precursor complexes.


Incorporation of organic crystals into the interspace of oriented nanocrystals: morphologies and properties.
Oriented nanocrystals, as seen in biominerals, have both the macroscopic hierarchical morphologies and the nanoscale interspace among the unit crystals. Here we studied the incorporation effects of the specific interspace in the oriented nanocrystals on the morphologies, properties, and applications of organic crystals. Organic crystals, such as 9-vinylcarbazole (VCz), azobenzene (AB), and pyrene (PY), were introduced into the specific interspace of oriented nanocrystals from the melts. The morphologies and properties of the incorporated organic crystals were systematically studied in these model cases. The incorporation of the organic crystals provided the composites with the original oriented nanocrystals. The incorporated organic crystals formed the single-crystalline structures even in the nanoscale interspace. The melts of the organic compounds were crystallized and grown in the interspace of the original materials. The incorporated organic crystals showed the specific phase transition behavior. The freezing points of the organic crystals were raised by the incorporation into the nanospace while the melting points were not changed. The hierarchical morphologies of the organic crystals were obtained after the dissolution of the original materials. The hierarchical morphologies of the original materials were replicated to the organic crystals. The incorporated organic crystal was polymerized without deformation of the hierarchical morphologies. The hierarchical polymer can be applied to the donor material for the generation of a larger amount of the charge-transfer complex with the acceptor molecule than the commercial polymer microparticles. The present work shows the potential use of the nanoscale interspace generated in the oriented nanocrystals.


Synthesis, characterization, and biological evaluation of new Ru(II) polypyridyl photosensitizers for photodynamic therapy.
Two Ru(II) polypyridyl complexes, Ru(DIP)2(bdt) (1) and [Ru(dqpCO2Me)(ptpy)](2+) (2) (DIP = 4,7-diphenyl-1,10-phenanthroline, bdt = 1,2-benzenedithiolate, dqpCO2Me = 4-methylcarboxy-2,6-di(quinolin-8-yl)pyridine), ptpy = 4'-phenyl-2,2':6',2″-terpyridine) have been investigated as photosensitizers (PSs) for photodynamic therapy (PDT). In our experimental settings, the phototoxicity and phototoxic index (PI) of 2 (IC50(light): 25.3 μM, 420 nm, 6.95 J/cm(2); PI >4) and particularly of 1 (IC50(light): 0.62 μM, 420 nm, 6.95 J/cm(2); PI: 80) are considerably superior compared to the two clinically approved PSs porfimer sodium and 5-aminolevulinic acid. Cellular uptake and distribution of these complexes was investigated by confocal microscopy (1) and by inductively coupled plasma mass spectrometry (1 and 2). Their phototoxicity was also determined against the Gram-(+) Staphylococcus aureus and Gram-(-) Escherichia coli for potential antimicrobial PDT (aPDT) applications. Both complexes showed significant aPDT activity (420 nm, 8 J/cm(2)) against Gram-(+) (S. aureus; >6 log10 CFU reduction) and, for 2, also against Gram-(-) E. coli (>4 log10 CFU reduction).


Barriers to Women Entering Surgical Careers: A Global Study into Medical Student Perceptions.
Barriers to female surgeons entering the field are well documented in Australia, the USA and the UK, but how generalizable these problems are to other regions remains unknown. A cross-sectional survey was developed by the International Federation of Medical Students' Associations (IFMSA)'s Global Surgery Working Group assessing medical students' desire to pursue a surgical career at different stages of their medical degree. The questionnaire also included questions on students' perceptions of their education, resources and professional life. The survey was distributed via IFMSA mailing lists, conferences and social media. Univariate analysis was performed, and statistically significant exposures were added to a multivariate model. This model was then tested in male and female medical students, before a further subset analysis by country World Bank income strata. 639 medical students from 75 countries completed the survey. Mentorship [OR 3.42 (CI 2.29-5.12) p = 0.00], the acute element of the surgical specialties [OR 2.22 (CI 1.49-3.29) p = 0.00], academic competitiveness [OR 1.61 (CI 1.07-2.42) p = 0.02] and being from a high or upper-middle-income country (HIC and UMIC) [OR 1.56 (CI 1.021-2.369) p = 0.04] all increased likelihood to be considering a surgical career, whereas perceived access to postgraduate training [OR 0.63 (CI 0.417-0.943) p = 0.03], increased year of study [OR 0.68 (CI 0.57-0.81) p = 0.00] and perceived heavy workload [OR 0.47 (CI 0.31-0.73) p = 0.00] all decreased likelihood to consider a surgical career. Perceived quality of surgical teaching and quality of surgical services in country overall did not affect students' decision to pursue surgery. On subset analysis, perceived poor access to postgraduate training made women 60% less likely to consider a surgical career [OR 0.381 (CI 0.217-0.671) p = 0.00], whilst not showing an effect in the men [OR 1.13 (CI 0.61-2.12) p = 0.70. Concerns about high cost of training halve the likelihood of students from low and low-middle-income countries (LICs and LMICs) considering a surgical career [OR 0.45 (CI 0.25-0.82) p = 0.00] whilst not demonstrating a significant relationship in HIC or UMIC countries. Women from LICs and LMICs were 40% less likely to consider surgical careers than men, when controlling for other factors [OR 0.59 CI (0.342-1.01 p = 0.053]. Perceived poor access to postgraduate training and heavy workload dissuade students worldwide from considering surgical careers. Postgraduate training in particular appears to be most significant for women and cost of training an additional factor in both women and men from LMICs and LICs. Mentorship remains an important and modifiable factor in influencing student's decision to pursue surgery. Quality of surgical education showed no effect on student decision-making.


Trastuzumab Deruxtecan: First Approval.
Trastuzumab deruxtecan (ENHERTU®), a HER2-directed antibody and DNA topoisomerase I inhibitor conjugate, is being developed for the treatment of HER2-expressing solid tumours, including breast cancer, gastric cancer, colorectal cancer and non-small cell lung cancer by Daiichi Sankyo Company Ltd in collaboration with AstraZeneca. Based primarily on the results of the phase 2 DESTINY-Breast01 trial, trastuzumab deruxtecan was recently approved in the USA under accelerated approval for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. This article summarizes the milestones in the development of trastuzumab deruxtecan leading to this first approval.


luxR Homolog-Linked Biosynthetic Gene Clusters in Proteobacteria.
Microbes are a major source of antibiotics, pharmaceuticals, and other bioactive compounds. The production of many specialized microbial metabolites is encoded in biosynthetic gene clusters (BGCs). A challenge associated with natural product discovery is that many BGCs are not expressed under laboratory growth conditions. Here we report a genome-mining approach to discover BGCs with luxR-type quorum sensing (QS) genes, which code for regulatory proteins that control gene expression. Our results show that BGCs linked to genes coding for LuxR-like proteins are widespread in Proteobacteria. In addition, we show that associations between luxR homolog genes and BGCs have evolved independently many times, with functionally diverse gene clusters. Overall, these clusters may provide a source of new natural products for which there is some understanding about how to elicit production. IMPORTANCE Bacteria biosynthesize specialized metabolites with a variety of ecological functions, including defense against other microbes. Genes that code for specialized metabolite biosynthetic enzymes are frequently clustered together. These BGCs are often regulated by a transcription factor encoded within the cluster itself. These pathway-specific regulators respond to a signal or indirectly through other means of environmental sensing. Many specialized metabolites are not produced under laboratory growth conditions, and one reason for this issue is that laboratory growth media lack environmental cues necessary for BGC expression. Here, we report a bioinformatics study that reveals that BGCs are frequently linked to genes coding for LuxR family QS-responsive transcription factors in the phylum Proteobacteria. The products of these luxR homolog-associated gene clusters may serve as a practical source of bioactive metabolites.


A first step towards a mouse model for hepatitis C virus infection containing a human immune system.
Studies of hepatitis C virus (HCV) infection, immunopathogenesis, and resulting liver diseases have been hampered by the lack of a small animal model. We developed humanized mice with human immune system and liver tissues to improve the studies of hepatitis C pathogenesis and treatment. To promote engraftment of human hepatocytes, we expressed a fusion protein of the FK506 binding protein (FKBP) and caspase 8 under the control of the albumin promoter (AFC8), which induces liver cell death, in Balb/C Rag2(-/-) γC-null mice. Co-transplantation of human CD34(+) human hematopoietic stem cells (HSC) and hepatocyte progenitors into the transgenic mice led to efficient engraftment of human leucocytes and hepatocytes. We then infected these humanized mice (AFC8-hu HSC/Hep) with primary HCV isolates and studied HCV-induced immune responses and liver diseases. AFC8-hu HSC/Hep mice supported HCV infection in the liver and generated a human immune T-cell response against HCV. HCV infection induced liver inflammation, hepatitis, and fibrosis, which correlated with activation of stellate cells and expression of human fibrogenic genes. AFC8-hu HSC/Hep mice are a useful model of HCV infection, the immune response, and liver disease, because they contain human immune system and liver cells. These mice become infected with HCV, generate a specific immune response against the virus, and develop liver diseases that include hepatitis and fibrosis. This model might also be used to develop therapeutics for HCV infection.


Anchoring dipalmitoyl phosphoethanolamine to nanoparticles boosts cellular uptake and fluorine-19 magnetic resonance signal.
Magnetic resonance (MR) methods to detect and quantify fluorine ((19)F) nuclei provide the opportunity to study the fate of cellular transplants in vivo. Cells are typically labeled with (19)F nanoparticles, introduced into living organisms and tracked by (19)F MR methods. Background-free imaging and quantification of cell numbers are amongst the strengths of (19)F MR-based cell tracking but challenges pertaining to signal sensitivity and cell detection exist. In this study we aimed to overcome these limitations by manipulating the aminophospholipid composition of (19)F nanoparticles in order to promote their uptake by dendritic cells (DCs). As critical components of biological membranes, phosphatidylethanolamines (PE) were studied. Both microscopy and MR spectroscopy methods revealed a striking (at least one order of magnitude) increase in cytoplasmic uptake of (19)F nanoparticles in DCs following enrichment with 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE). The impact of enriching (19)F nanoparticles with PE on DC migration was also investigated. By manipulating the nanoparticle composition and as a result the cellular uptake we provide here one way of boosting (19)F signal per cell in order to overcome some of the limitations related to (19)F MR signal sensitivity. The boost in signal is ultimately necessary to detect and track cells in vivo.


Can genes play a role in explaining frequent job changes? An examination of gene-environment interaction from human capital theory.
This study examined how a dopamine genetic marker, DRD4 7 Repeat allele, interacted with early life environmental factors (i.e., family socioeconomic status, and neighborhood poverty) to influence job change frequency in adulthood using a national representative sample from the United States. The dopamine gene played a moderating role in the relationship between early life environments and later job change behaviors, which was meditated through educational achievement. In particular, higher family socioeconomic status was associated with higher educational achievement, and thereafter higher frequency of voluntary job changes and lower frequency of involuntary job changes; such relationships were stronger (i.e., more positive or negative) for individuals with more DRD4 7R alleles. In contrast, higher neighborhood poverty was associated with lower educational achievement, and thereafter lower frequency of voluntary job change and higher frequency of involuntary job change; such relationships were again stronger (i.e., more positive or negative) for individuals with more DRD4 7R alleles. The results demonstrated that molecular genetics using DNA information, along with early life environmental factors, can bring new insights to enhance our understanding of job change frequency in individuals' early career development. (PsycINFO Database Record


Are workers from waste sorting industry really protected by wearing Filtering Respiratory Protective Devices? The gap between the myth and reality.
One of the solutions for decreasing the workers' exposure to bioburden is the use of Filtering Respiratory Protective Devices (FRPD). As such it is important to determine whether these devices are fulfilling their protective role. This is the basis of the current study, aimed at characterizing bioburden retained by 120 FRPD (both in interior layers and in exhalation valves) through culture based-methods and molecular tools and also via analysis of antifungal resistance and mycotoxins profile. Our results show that Gram - Bacteria are present at a higher prevalence than total bacteria in both matrixes. Regarding fungal identification, Chrysonilia sitophila presented the highest prevalence on interior layers (55.1% on malt extract agar (MEA) supplemented with chloramphenicol (0.05%); 59.6% on dichloran-glycerol agar (DG18)), whereas on exhalation valves Aspergillus sp. presented the highest prevalence on MEA (6.8%) and C. sitophila on DG18 (36.3%). Among Aspergillus genera, section Fumigati was the one with the highest prevalence in both matrices. Aspergillus sp. was the most prevalent on exhalation valves (75.0% ITRA) in the screening of azole resistance. Fumigati section was the most abundant Aspergillus sp. detected on the interior layers (33.33%, 40 samples out of 120) and on the exhalation valves (1.66%, 2 samples out of 120). The interior layers and exhalation valves from workers with more waste contact showed an increased exposure to bioburden. This study showed that FRPD can have high levels of bioburden, toxigenic fungal strains and Aspergillus sections with reduced susceptibility to the tested azoles and can be used as a passive sampling method since it mimics the results obtained by active methods in previous studies. The gathered information will be useful to prioritize multiple interventions on workers' education or even on FRPD replacement frequency.


A randomised controlled trial evaluating the effect of potassium supplementation on vascular function and the renin-angiotensin-aldosterone system.
There is limited evidence on the effect of potassium supplementation on the vasculature in patients at increased cardiovascular risk. Potassium increases aldosterone and there is a strong association of hyperaldosteronism with poor cardiac outcomes. We aimed to determine whether potassium supplementation has a significant medium-term effect on aldosterone levels and, if so, what the overall effect of this is on vascular function in patients at moderate cardiovascular disease risk. Forty patients at moderate cardiovascular disease risk were included in a randomised placebo-controlled crossover study. Patients were assigned to 64 mmol potassium chloride or placebo for 6 weeks. Vascular function was assessed using pulse-wave analysis including the detection of a change in augmentation index to salbutamol and nitroglycerine-induced vasodilation. There was no change in augmentation index with potassium vs placebo (25.2±1.4 vs. 26.0±1.3%, respectively). Potassium improved brachial systolic blood pressure (131.8±2.2 vs. 137.1±2.4 mm Hg; P=0.013), central systolic blood pressure (123.2±2.3 vs. 128.4±2.3 mm Hg; P=0.011) and central diastolic blood pressure (80.3±1.3 vs. 83.7±1.4 mm Hg; P=0.019). Plasma renin activity and serum aldosterone both increased with potassium (P=0.001 and P=0.048 respectively). We found that potassium supplementation had no effect on endothelial function or pulse-wave analysis. It lowered brachial systolic and central blood pressure. It was associated with increased plasma renin activity and serum aldosterone.


Effects of omega-3 fatty acid supplementation on neurocognitive functioning and mood in deployed U.S. soldiers: a pilot study.
Omega-3 fatty acids (FAs) may have neuroprotective properties for psychological health and cognition. The objective of this study was to evaluate the effectiveness of omega-3 FAs (eicosapentaenoic + docosahexaenoic; Harris-Schacky [HS]-Omega-3 Index) on neuropsychological functioning among U.S. Soldiers deployed to Iraq. This randomized, double-blind, placebo-controlled trial included Soldiers between the ages of 18 and 55 years who were randomly assigned to either the active treatment group (n = 44) or placebo group (n = 34). Active treatment was 2.5 g per day of eicosapentaenoic + docosahexaenoic (Lovaza; GlaxoSmithKline, Research Triangle Park, North Carolina). The placebo was corn oil ethyl esters. HS-Omega-3 Index, a neurocognitive battery (Central Nervous System-Vital Signs, Morrisville, North Carolina), and psychological health scales were assessed at baseline and after 60 days of treatment. Although the results revealed that omega-3 FAs significantly increased the HS-Omega-3 Index (p = 0.001), there were no significant effects on indices psychological health and neurocognitive functioning by treatment group. Nevertheless, there was a significant inverse correlation between the changes in the HS-Omega-3 Index and daytime sleepiness (r = 0.30, p = 0.009). Short-term treatment with 2.5 g of omega-3 FAs did not alter measures of neurocognition or psychological health, but there was evidence of a relationship between omega-3 levels and daytime sleepiness.


Symptomatic treatment of botulism with a clinically approved small molecule.
Botulinum neurotoxins (BoNTs) are potent neuroparalytic toxins that cause mortality through respiratory paralysis. The approved medical countermeasure for BoNT poisoning is infusion of antitoxin immunoglobulins. However, antitoxins have poor therapeutic efficacy in symptomatic patients; thus, there is an urgent need for treatments that reduce the need for artificial ventilation. We report that the US Food and Drug Administration-approved potassium channel blocker 3,4-diaminopyridine (3,4-DAP) reverses respiratory depression and neuromuscular weakness in murine models of acute and chronic botulism. In ex vivo studies, 3,4-DAP restored end-plate potentials and twitch contractions of diaphragms isolated from mice at terminal stages of BoNT serotype A (BoNT/A) botulism. In vivo, human-equivalent doses of 3,4-DAP reversed signs of severe respiratory depression and restored mobility in BoNT/A-intoxicated mice at terminal stages of respiratory collapse. Multiple-dosing administration of 3,4-DAP improved respiration and extended survival at up to 5 LD50 BoNT/A. Finally, 3,4-DAP reduced gastrocnemius muscle paralysis and reversed respiratory depression in sublethal models of serotype A-, B-, and E-induced botulism. These findings make a compelling argument for repurposing 3,4-DAP to symptomatically treat symptoms of muscle paralysis caused by botulism, independent of serotype. Furthermore, they suggest that 3,4-DAP is effective for a range of botulism symptoms at clinically relevant time points.


Human natural anti-alpha-galactosyl IgG. II. The specific recognition of alpha (1----3)-linked galactose residues.
A natural IgG antibody (anti-Gal) with alpha-galactosyl binding specificity has been found in large amounts (0.5 - 1.0% of serum IgG) in all individuals tested. It has been purified by affinity chromatography on a column of melibiose-Sepharose. In addition to its affinity for normal and pathological senescent human red cells, the antibody readily interacts with rabbit red blood cell (RRBC) glycolipids with alpha-galactosyl terminal residues. Two types (glycosidic linkages of 1----3 vs. 1----4) of rabbit red cells glycolipids with terminal alpha-galactosyl residues were tested for antibody binding. The antibody specifically bound to glycolipids with Gal alpha 1----3 terminal residues, and treatment of these glycolipids with alpha-galactosidase abolished binding. Hemagglutination inhibition studies with oligosaccharides of known structure also showed that the antibody binds specifically to glycoconjugates with an alpha 1----3 terminal galactose residue. Anti-Gal did not bind to a human B-active glycolipid, indicating that fucose-linked alpha 1----2 to the penultimate galactose prevents anti-Gal binding. The anti-Gal specificity for RRBC glycolipids also paralleled that of the alpha-galactosyl-specific Bandeiraea simplicifolia lectin. The possible reasons for the occurrence of this unique antibody in human serum are discussed.


Self-organized criticality, plasticity and sensorimotor coupling. Explorations with a neurorobotic model in a behavioural preference task.
During the last two decades, analysis of 1/ƒ noise in cognitive science has led to a considerable progress in the way we understand the organization of our mental life. However, there is still a lack of specific models providing explanations of how 1/ƒ noise is generated in coupled brain-body-environment systems, since existing models and experiments typically target either externally observable behaviour or isolated neuronal systems but do not address the interplay between neuronal mechanisms and sensorimotor dynamics. We present a conceptual model of a minimal neurorobotic agent solving a behavioural task that makes it possible to relate mechanistic (neurodynamic) and behavioural levels of description. The model consists of a simulated robot controlled by a network of Kuramoto oscillators with homeostatic plasticity and the ability to develop behavioural preferences mediated by sensorimotor patterns. With only three oscillators, this simple model displays self-organized criticality in the form of robust 1/ƒ noise and a wide multifractal spectrum. We show that the emergence of self-organized criticality and 1/ƒ noise in our model is the result of three simultaneous conditions: a) non-linear interaction dynamics capable of generating stable collective patterns, b) internal plastic mechanisms modulating the sensorimotor flows, and c) strong sensorimotor coupling with the environment that induces transient metastable neurodynamic regimes. We carry out a number of experiments to show that both synaptic plasticity and strong sensorimotor coupling play a necessary role, as constituents of self-organized criticality, in the generation of 1/ƒ noise. The experiments also shown to be useful to test the robustness of 1/ƒ scaling comparing the results of different techniques. We finally discuss the role of conceptual models as mediators between nomothetic and mechanistic models and how they can inform future experimental research where self-organized critically includes sensorimotor coupling among the essential interaction-dominant process giving rise to 1/ƒ noise.


Interplay between microstructure and magnetism in NiO nanoparticles: breakdown of the antiferromagnetic order.
The possibility of tuning the magnetic behaviour of nanostructured 3d transition metal oxides has opened up the path for extensive research activity in the nanoscale world. In this work we report on how the antiferromagnetism of a bulk material can be broken when reducing its size under a given threshold. We combined X-ray diffraction, high-resolution transmission electron microscopy, extended X-ray absorption fine structure and magnetic measurements in order to describe the influence of the microstructure and morphology on the magnetic behaviour of NiO nanoparticles (NPs) with sizes ranging from 2.5 to 9 nm. The present findings reveal that size effects induce surface spin frustration which competes with the expected antiferromagnetic (AFM) order, typical of bulk NiO, giving rise to a threshold size for the AFM phase to nucleate. Ni(2+) magnetic moments in 2.5 nm NPs seem to be in a spin glass (SG) state, whereas larger NPs are formed by an uncompensated AFM core with a net magnetic moment surrounded by a SG shell. The coupling at the core-shell interface leads to an exchange bias effect manifested at low temperature as horizontal shifts of the hysteresis loop (~1 kOe) and a coercivity enhancement (~0.2 kOe).


Role of reactive oxygen and nitrogen species in etiopathogenesis of rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic disease affecting up to 3% of the population in most countries. The causes of RA have not been completely elucidated. This paper aims to review the role of reactive oxygen and nitrogen species in the etiopathogenesis of RA. Reactive oxygen species (ROS), such as superoxide radical, hydrogen peroxide, hydroxyl radical and hypochlorous acid, as well as reactive nitrogen species (RNS), such as nitric oxide and peroxynitrite, contribute significantly to tissue injury in RA. Several mechanisms are involved in the generation and action of ROS and RNS. Superoxide radical, hydrogen peroxide and nitric oxide do not directly damage the majority of biological molecules. They are however converted into the highly reactive hydroxyl radical, which reacts with almost all molecules in living cells. The resulting chronic inflammation process can be reduced with antioxidant therapy. To date, scavenging, preventive, and enzyme antioxidants are available. The most important mode is scavenging of the hydroxyl radical and of hypochlorous acid. Another important way is to inhibit production of RNS and ROS by neutrophils, monocytes, and macrophages. The control of inflammation in arthritic patients by natural as well as synthetic antioxidants could become a relevant component of antirheumatic prevention and therapy.


Activation of the reward system boosts innate and adaptive immunity.
Positive expectations contribute to the clinical benefits of the placebo effect. Such positive expectations are mediated by the brain's reward system; however, it remains unknown whether and how reward system activation affects the body's physiology and, specifically, immunity. Here we show that activation of the ventral tegmental area (VTA), a key component of the reward system, strengthens immunological host defense. We used 'designer receptors exclusively activated by designer drugs' (DREADDs) to directly activate dopaminergic neurons in the mouse VTA and characterized the subsequent immune response after exposure to bacteria (Escherichia coli), using time-of-flight mass cytometry (CyTOF) and functional assays. We found an increase in innate and adaptive immune responses that were manifested by enhanced antibacterial activity of monocytes and macrophages, reduced in vivo bacterial load and a heightened T cell response in the mouse model of delayed-type hypersensitivity. By chemically ablating the sympathetic nervous system (SNS), we showed that the reward system's effects on immunity are, at least partly, mediated by the SNS. Thus, our findings establish a causal relationship between the activity of the VTA and the immune response to bacterial infection.


Muscarinic agonists reduce tau phosphorylation in non-neuronal cells via GSK-3beta inhibition and in neurons.
Muscarinic agonists alter the metabolism of amyloid precursor protein, leading to an increase in alpha-secretase cleavage and a decreased production of amyloidogenic peptides; suggesting that these compounds might modify the Alzheimer's disease process. A second therapeutic target in AD is the accumulation of stably phosphorylated tau into neurofibrillary tangles; an early event correlating with cognitive impairment. Glycogen synthase kinase-3 (GSK-3beta) phosphorylates tau and is inhibited via protein kinase C (PKC). As certain muscarinic receptors are linked to PKC, we examined the effect of a range of agonists on GSK-3beta phosphorylation of tau. In neurons a nonspecific muscarinic agonist, carbachol, reduced tau phosphorylation. In nonneuronal cells expressing the ml receptor a range of ml agonists reduced transiently-expressed tau phosphorylation and altered its microtubulebinding properties. These findings link the two pathological process of AD-APP metabolism and tau phosphorylation - and suggest that muscarinic and other cholinergic compounds might have disease-modifying properties.


Comet giacobini-zinner: plasma description.
A strong interaction between the solar wind and comet Giacobini-Zinner was observed oh 11 September 1985 with the Los Alamos plasma electron experiment on the International Cometary Explorer (ICE) spacecraft. As ICE approached an intercept point 7800 kilometers behind the nucleus from the south and receded to the north, upstream phenomena due to the comet were observed. Periods of enhanced electron heat flux from the comet as well as almost continuous electron density fluctuations were measured. These effects are related to the strong electron heating observed in the cometary interaction region and to cometary ion pickup by the solar wind, respectively. No evidence for a conventional bow shock was found as ICE entered and exited the regions of strongest interaction of the solar wind with the cometary environment. The outer extent of this strong interaction zone was a transition region in which the solar wind plasma was heated, compressed, and slowed. Inside the inner boundary of the transition region was a sheath that enclosed a cold intermediate coma. In the transition region and sheath, small-scale enhancements in density were observed. These density spikes may be due to an instability associated with cometary ion pickup or to the passage of ICE through cometary ray structures. In the center of the cold intermediate coma a narrow, high-density core of plasma, presumably the developing plasma tail was found. In some ways this tail can be compared to the plasma sheet in Earth's magnetotail and to the current sheet in the tail at Venus. This type of configuration is expected in the double-lobe magnetic topology detected at the comet, possibly caused by the theoretically expected draping of the interplanetary magnetic field around its ionosphere.


Fragmentation of fibronectin by inherent autolytic and matrix metalloproteinase activities.
Fibronectin (FN) purified by gelatin affinity chromatography is unstable and undergoes fragmentation. The cleavage has been ascribed to inherent autolytic protease activities as well as co-purified matrix metalloproteinases (MMP). Understanding the mechanism by which the proteolysis of FN occurs is important, because the FN fragments have biological activities that differ from those of intact FN. Having excluded contributions of other plasma-derived proteases, the present experiments demonstrated that cleavage of FN by MMP-2 to distinct fragments occurred in synergy with inherent FN activities. Limited heat treatment of FN at 56°C for 30 min inactivated the inherent protease activities sharply reducing autolysis of FN in a manner similar to that seen in the presence of serine proteinase inhibitors. Heat treatment did not alter cell attachment to FN, but significantly increased the susceptibility of FN to enzymatic cleavage by MMP-2. The carboxyl-terminal hemopexin-like domain (PEX) of MMP-2 was shown to possess critical exodomain properties required for the interactions of MMP-2 with FN, and FN was cleaved at a significantly reduced rate by an MMP-2 variant with deletion of PEX. Verifying the specificity of interactions, isolated PEX competed FN cleavage by MMP-2 in a concentration-dependent manner. These results have further elucidated the synergistic contributions of inherent autolytic serine protease-like activities and MMP-2 to fragmentation of FN and provide the rationale and basis for modified preparation and handling of FN used in biological research.


Changes in vowel articulation with subthalamic nucleus deep brain stimulation in dysarthric speakers with Parkinson's disease.
Purpose. To investigate changes in vowel articulation with the electrical deep brain stimulation (DBS) of the subthalamic nucleus (STN) in dysarthric speakers with Parkinson's disease (PD). Methods. Eight Quebec-French speakers diagnosed with idiopathic PD who had undergone STN DBS were evaluated ON-stimulation and OFF-stimulation (1 hour after DBS was turned off). Vowel articulation was compared ON-simulation versus OFF-stimulation using acoustic vowel space and formant centralization ratio, calculated with the first (F1) and second formant (F2) of the vowels /i/, /u/, and /a/. The impact of the preceding consonant context on articulation, which represents a measure of coarticulation, was also analyzed as a function of the stimulation state. Results. Maximum vowel articulation increased during ON-stimulation. Analyses also indicate that vowel articulation was modulated by the consonant context but this relationship did not change with STN DBS. Conclusions. Results suggest that STN DBS may improve articulation in dysarthric speakers with PD, in terms of range of movement. Optimization of the electrical parameters for each patient is important and may lead to improvement in speech fine motor control. However, the impact on overall speech intelligibility may still be small. Clinical considerations are discussed and new research avenues are suggested.


Muscle creatine kinase isoenzyme expression in adult human brain.
Previous studies have suggested that MM creatine kinase is a muscle-specific protein and is not present in adult brain tissue. We have isolated a protein from human brain with an apparent molecular weight of 43,000 as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis which is identical to the muscle M creatine kinase isoenzyme subunit at all 30 sequenced amino acid residues and possesses creatine kinase enzymatic activity following nondenaturing agarose-gel electrophoresis. Immunohistochemistry localizes M creatine kinase to discrete areas of adult human brain. Northern blot analysis of both total and poly(A)-selected RNA isolated from brain did not detect M creatine kinase mRNA. However, polymerase chain reaction amplification of cDNA synthesized from human placenta, heart, and brain mRNA detected M creatine kinase message in both heart and brain but not placenta which contains no detectable M creatine kinase protein. N1E115 and NS20Y, mouse neuroblastoma cell lines which have been used as models of neural cell differentiation, were found also to express MM creatine kinase. Moreover, a transiently transfected reporter gene with 4,800 base pairs of M creatine kinase upstream region fused to chloramphenicol acetyltransferase was expressed during differentiation of these neural cell lines. In summary, MM creatine kinase is present in human brain and we suggest the M creatine kinase upstream region is sufficient to modulate M creatine kinase expression in certain neuronal cells and may be regulated independently from other muscle genes.


Impaired prenylation of Rab GTPases in the gunmetal mouse causes defects in bone cell function.
Vesicular trafficking is crucial for bone resorption by osteoclasts, in particular for formation of the ruffled border membrane and for removal of the resultant bone degradation products by transcytosis. These processes are regulated by Rab family GTPases, whose activity is dependent on post-translational prenylation by Rab geranylgeranyl transferase (RGGT). Specific pharmacological inhibition of RGGT inhibits bone resorption in vitro and in vivo, illustrating the importance of Rab prenylation for osteoclast function. The gunmetal (gm/gm) mouse bears a mutation in the catalytic subunit of RGGT, causing a loss of 75% of the activity of this enzyme and hence hypoprenylation of several Rabs in melanocytes, platelets and cytotoxic T cells. We have now found that prenylation of several Rab proteins is also defective in gm/gm osteoclasts. Moreover, while osteoclast formation and cytoskeletal polarization occurs normally, gm/gm osteoclasts exhibit a substantial reduction in resorptive activity in vitro compared with osteoclasts from +/gm mice, which do not have a prenylation defect. Surprisingly, rather than the osteosclerosis that would be expected to result from defective osteoclast function in vivo, gm/gm mice exhibited a slightly lower bone mass than +/gm mice, indicating that defects in other cell types, such as osteoblasts, in which hypoprenylation of Rabs was also detected, may contribute to the phenotype. However, gm/gm mice were partially protected from ovariectomy-induced bone loss, suggesting that levels of Rab prenylation in gm/gm osteoclasts may be sufficient to maintain normal physiological levels of activity, but not pathological levels of bone resorption in vivo.


Droplet-Free Digital Enzyme-Linked Immunosorbent Assay Based on a Tyramide Signal Amplification System.
Digital enzyme-linked immunosorbent assay (ELISA) is a single molecule counting technology and is one of the most sensitive immunoassay methods. The key aspect of this technology is to concentrate enzyme reaction products from a single target molecule in femtoliter droplets. This study presents a novel Digital ELISA that does not require droplets; instead, enzyme reaction products are concentrated using a tyramide signal amplification system. In our method, tyramide substrate reacts with horseradish peroxidase (HRP) labeled with an immunocomplex on beads, and the substrate is converted into short-lived radical intermediates. By adjusting the bead concentration in the HRP-tyramide reaction and conducting the reaction using freely moving beads, tyramide radicals are deposited only on beads labeled with HRP and there is no diffusion to other beads. Consequently, the fluorescence signal is localized on a portion of the beads, making it possible to count the number of labeled beads digitally. The performance of our method was demonstrated by detecting hepatitis B surface antigen with a limit of detection of 0.09 mIU/mL (139 aM) and a dynamic range of over 4 orders of magnitude. The obtained limit of detection represents a >20-fold higher sensitivity than conventional ELISA. Our method has potential applications in simple in vitro diagnostic systems for detecting ultralow concentrations of protein biomarkers.


Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa.
Two-thirds of the world's HIV-infected people live in sub-Saharan Africa, and more than 1.5 million of them die annually. As access to antiretroviral treatment has expanded within the region; early pessimism concerning the delivery of antiretroviral treatment using a large-scale public health approach has, at least in the short term, proved to be broadly unfounded. Immunological and virological responses to ART are similar to responses in patients treated in high-income countries. Despite this, however, early mortality rates in sub-Saharan Africa are very high; between 8 and 26% of patients die in the first year of antiretroviral treatment, with most deaths occurring in the first few months. Patients typically access antiretroviral treatment with advanced symptomatic disease, and mortality is strongly associated with baseline CD4 cell count less than 50 cells/mul and WHO stage 4 disease (AIDS). Although data are limited, leading causes of death appear to be tuberculosis, acute sepsis, cryptococcal meningitis, malignancy and wasting syndrome. Mortality rates are likely to depend not only on the care delivered by antiretroviral treatment programmes, but more fundamentally on how advanced disease is at programme enrollment and the quality of preceding healthcare. In addition to improving delivery of antiretroviral treatment and providing it free of charge to the patient, strategies to reduce mortality must include earlier diagnosis of HIV infection, strengthening of longitudinal HIV care and timely initiation of antiretroviral treatment. Health systems delays in antiretroviral treatment initiation must be minimized, especially in patients who present with advanced immunodeficiency.


Diagnostic Ability of Retinal Vessel Diameter Measurements in Open-Angle Glaucoma.
To determine the diagnostic ability of retinal vessel diameter (RVD) measurements and the factors related to retinal vascular diameters in patients with open-angle glaucoma (OAG). This retrospective observational study included 145 patients with OAG (63 with high-tension and 82 with low-tension glaucoma) and 60 healthy controls. The central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) were measured using the IVAN software version 1.3. Receiver operating characteristic (ROC) curves were obtained for the average retinal nerve fiber layer (RNFL) thickness and RVD indices including CRAE, CRVE, and CRAE/CRVE ratio. Areas under the ROC curves (AUCs), 95% confidence intervals (CIs), and sensitivities at a fixed specificity (>90% and >80%) were calculated. Factors related to CRAE were analyzed by simple and multiple linear regression analyses. Among the RVD indices, the CRAE had the largest AUC for discriminating glaucomatous changes between eyes with glaucoma and those without (0.803; 95% CI, 0.742-0.855). The AUC of CRAE did not significantly differ from that of average RNFL thickness (P = 0.134). However, CRAE showed lower sensitivity than average RNFL thickness at a specificity greater than 90%. Factors significantly associated with CRAE in both simple and multiple linear regression analyses were age, spherical equivalent, average RNFL thickness, presence of diabetes mellitus, and a glaucoma diagnosis (all P ≤ 0.05). The diagnostic ability of CRAE for detecting OAG was good, which was not much worse than that of average RNFL thickness. This finding suggests the potential usefulness of RVD for glaucoma detection.


Influence of additives on thermoresponsive polymers in aqueous media: a case study of poly(N-isopropylacrylamide).
Thermoresponsive polymers (TRPs) in different solvent media have been studied over a long period and are important from both scientific and technical points of view. Despite numerous studies on the behavior of TRPs with various additives, the interactions of additives with TRPs are still poorly understood. Moreover, despite the vast available literature regarding the biomolecular interactions between various TRPs and naturally occurring additives, it is not possible to provide a unifying declaration about the behavior of different additives, in particular at the phase transition temperature of the polymer. However, potential reviews that describe the behavior of additives as stimuli upon the phase transition of TRPs are also absent. A lack of sufficient knowledge regarding the responses of TRPs to additives as stimuli has hindered the expansion of the wide spectrum of applications of these polymers. Therefore, it was proposed to review the responses of TRPs in the presence of various additives in aqueous media. In-depth knowledge acquired via a literature survey has drawn our attention towards filling this gap by analyzing the interactions of TRPs with different additives. In this perspective, we have systematically examined the stability, aggregation, and phase transition behaviours of various polymers in the presence of different additives. The perspective on the influence of additives as stimuli on the behavior of TRPs in an aqueous medium will provide new reliable information about intramolecular interactions between interior polymer segments as well as intermolecular interactions between TRPs and additive molecules, which will be helpful for industrialists in the preparation of new polymeric materials for drug-delivery systems.


Gastric Cancer Consensus conference recommends Helicobacter pylori screening and treatment in asymptomatic persons from high-risk populations to prevent gastric cancer.
Gastric adenocarcinoma remains a common cause of death worldwide, and there is convincing evidence that this cancer is causally linked to Helicobacter pylori. The first Asian-Pacific Gastric Cancer Consensus brought together leading authorities in the field including the authors, and systematically reviewed all of the available evidence for the role of H. pylori, diet and other risk factors in this malignancy. The consensus conference boldly recommended population-based screening and treatment for H. pylori in particularly high-risk population settings. The evidence for these recommendations is summarized in this report, and the global and U.S. implications are considered.


Effects of strenuous maternal exercise on fetal organ weights and skeletal muscle development in rats.
The purpose of the present study was to observe the effects of strenuous maternal aerobic exercise throughout gestation on fetal outcome in the rat. The strenuous exercise intensity consisted of a treadmill speed of 30 m.min-1 on a 10 degrees incline, for 120 min.day-1, 5 days.week-1. The rats were conditioned to run on a motor-driven treadmill by following a progressive two-week exercise program, so that by the end of the two weeks the rats were capable of running comfortably at this strenuous intensity in the non-pregnant state. Following the two-week running programme, the rats were paired by weight and randomly assigned to either a pregnant group that continued the running program throughout gestation (pregnant runner), or a pregnant group that did not continue the running program throughout pregnancy (pregnant control). At birth the neonates born to the pregnant running group did not differ in average neonatal body weight values, number per litter or total litter weight values when compared to controls, nor were superficial gross abnormalities observed in neonates born to the pregnant control or pregnant running groups. The strenuous maternal exercise intensity did not alter neonatal organ weight values (brain, heart, liver, lung, kidney), nor neonatal skeletal muscle (gastrocnemius, sternomastoid, diaphragm) when compared to control values. It is suggested that maternal exercise of this intensity throughout gestation does not affect fetal outcome in the rat, and may be due to the animals accustomization to the strenuous exercise protocol prior to pregnancy.


The number of people with glaucoma worldwide in 2010 and 2020.
To estimate the number of people with open angle (OAG) and angle closure glaucoma (ACG) in 2010 and 2020. A review of published data with use of prevalence models. Data from population based studies of age specific prevalence of OAG and ACG that satisfied standard definitions were used to construct prevalence models for OAG and ACG by age, sex, and ethnicity, weighting data proportional to sample size of each study. Models were combined with UN world population projections for 2010 and 2020 to derive the estimated number with glaucoma. There will be 60.5 million people with OAG and ACG in 2010, increasing to 79.6 million by 2020, and of these, 74% will have OAG. Women will comprise 55% of OAG, 70% of ACG, and 59% of all glaucoma in 2010. Asians will represent 47% of those with glaucoma and 87% of those with ACG. Bilateral blindness will be present in 4.5 million people with OAG and 3.9 million people with ACG in 2010, rising to 5.9 and 5.3 million people in 2020, respectively. Glaucoma is the second leading cause of blindness worldwide, disproportionately affecting women and Asians.


Two novel 14-Epi-analogues of 1,25-dihydroxyvitamin D3 inhibit the growth of human breast cancer cells in vitro and in vivo.
The biological activity of two novel 14-epi-analogues of 1,25(OH)2D3, 19-nor-14-epi-23-yne-1,25(OH)2D3 (TX 522) and 19-nor-14,20-bisepi-23-yne-1,25(OH)2D3 (TX 527), is described. Both analogues were at least 10 times more potent than 1,25(OH)2D3 in inhibiting in vitro cell proliferation and had much lower in vivo calcemic effects than 1,25(OH)2D3. Treatment with 1,25(OH)2D3, TX 522, or TX 527 in vitro was accompanied by an accumulation of cells in the G1 phase of the cell cycle. Protein levels of cyclin C and cyclin D1 in in vitro cultures of MCF-7 cells were down-regulated to 50 and 30%, respectively, of control levels at 72 and 120 h after stimulation. Protein levels of p21 and p27 at 72 h were significantly enhanced by 1,25(OH)2D3 and TX 522 but surprisingly not by TX 527. The inability of TX 527 to up-regulate p21 seemed to be cell type specific because p21 was induced in other cell types. Diminished phosphorylation of the retinoblastoma protein after treatment with 1,25(OH)2D3, TX 522, or TX 527 may ultimately contribute to the growth inhibition caused by these compounds. According to the data presented, the induction of apoptosis seemed not to be a major mechanism responsible for the growth-inhibitory effect of 1,25(OH)2D3 and analogues. Both 14-epianalogues significantly retarded tumor progression (40% reduced compared with control mice) in an in vivo model of MCF-7 breast cancer cells established in nude mice. In conclusion, these novel analogues have the eligible profile to be tested as therapeutic agents for the treatment of hyperproliferative diseases such as breast cancer.


Cell-free expression and in meso crystallisation of an integral membrane kinase for structure determination.
Membrane proteins are key elements in cell physiology and drug targeting, but getting a high-resolution structure by crystallographic means is still enormously challenging. Novel strategies are in big demand to facilitate the structure determination process that will ultimately hasten the day when sequence information alone can provide a three-dimensional model. Cell-free or in vitro expression enables rapid access to large quantities of high-quality membrane proteins suitable for an array of applications. Despite its impressive efficiency, to date only two membrane proteins produced by the in vitro approach have yielded crystal structures. Here, we have analysed synergies of cell-free expression and crystallisation in lipid mesophases for generating an X-ray structure of the integral membrane enzyme diacylglycerol kinase to 2.28-Å resolution. The quality of cellular and cell-free-expressed kinase samples has been evaluated systematically by comparing (1) spectroscopic properties, (2) purity and oligomer formation, (3) lipid content and (4) functionality. DgkA is the first membrane enzyme crystallised based on cell-free expression. The study provides a basic standard for the crystallisation of cell-free-expressed membrane proteins and the methods detailed here should prove generally useful and contribute to accelerating the pace at which membrane protein structures are solved.


Ambiguity in practice? Carers' roles in personalised social care in England.
Carers play an ambiguous role within the personalisation paradigm currently shaping adult social care practice in England. Although carers have rights to assessments and support in their own right, these rights sit uneasily alongside the practices of assessment, support planning and personal budget (PB) allocation for older and disabled people. This paper reports how 14 dyads of older and learning disabled people with cognitive and/or communication impairments and their carers viewed the roles - desired and actual - played by carers in PBs. Interviews with carers and with older and disabled people were conducted during 2012 as part of a wider study into carers' roles in assessment, support planning and managing PBs. The interviews complemented a survey of reported practice in two English regions - interviews with adult social care services senior managers and focus groups with front-line care managers. Talking Mats(©) were used to support interviews with some service users. Interviews were transcribed and data analysed using the Framework approach. The interviews indicated that carers played important roles in service users' assessments and support planning, but were less likely to report receiving assessments or support of their own. While carers had the potential to benefit from PBs and support arrangements for service users, this did not reflect practice that aimed to enhance choice and control for carers. The paper draws on Twigg's typology of service conceptualisations of family carers and concludes that, despite the important social rights won by carers in England, current practice continues to regard carers primarily as a resource or a co-worker, rather than a co-client.