Human retinal progenitor cells grown as neurospheres demonstrate time-dependent changes in neuronal and glial cell fate potential.
The spatiotemporal birth order of the seven major classes of retinal cells is highly conserved among vertebrates. During retinal development, long projection neurons (ganglion cells) are produced first from resident progenitors, followed by the appearance of retinal interneurons, photoreceptors, and Muller glia. This sequence is maintained through the complex orchestration of cell-intrinsic and cell-extrinsic events and factors, including local influences between neighboring cells. Here we asked whether cultures of human prenatal retinal cells might also yield different ratios of cell types based on gestational age and time spent in vitro, thus recapitulating in vivo development. An established chopping technique was used to passage human prenatal retinal cells as neurospheres, avoiding the use of proteases and preserving cell-cell contacts and native microenvironments present in vivo. Retinal neurospheres cultured in this manner demonstrated specific patterns of growth over a limited time period, possibly reflecting trends in normal retinal development. Upon differentiation, immunocytochemical analysis revealed that retinal neurospheres produce predominantly glial cells with increasing gestational age and time in culture. Conversely, the percentage of betaIII tubulin-positive neurons declined over time. This provides information for optimizing culture systems aimed at the study of human retinal development and the generation of specific retinal cell types for therapeutic use or drug testing.


The embodied spaces of children with complex care needs: Effects on the social realities and power negotiations of families.
This paper presents research findings that advance knowledge around the power and agency families with children with complex care needs (CCN). Our conceptual framework uses concepts from geography towards situating the experiences and social realities of family carers within the 'embodied space of care'. The data originate from a longitudinal qualitative study of Canadian families with children with CCN. Findings reveal that interactions and decision-making processes relating to health and everyday life were complex and socially interconnected, and emphasize the need for provisions for family-based decision-making and enhanced social inclusion of families and the importance of the renegotiation of power.


HIV-1 fitness cost associated with escape from the VRC01 class of CD4 binding site neutralizing antibodies.
Broadly neutralizing antibodies (bNAbs) have been isolated from selected HIV-1-infected individuals and shown to bind to conserved sites on the envelope glycoprotein (Env). However, circulating plasma virus in these donors is usually resistant to autologous isolated bNAbs, indicating that during chronic infection, HIV-1 can escape from even broadly cross-reactive antibodies. Here, we evaluate if such viral escape is associated with an impairment of viral replication. Antibodies of the VRC01 class target the functionally conserved CD4 binding site and share a structural mode of gp120 recognition that includes mimicry of the CD4 receptor. We examined naturally occurring VRC01-sensitive and -resistant viral strains, as well as their mutated sensitive or resistant variants, and tested point mutations in the backbone of the VRC01-sensitive isolate YU2. In several cases, VRC01 resistance was associated with a reduced efficiency of CD4-mediated viral entry and diminished viral replication. Several mutations, alone or in combination, in the loop D or β23-V5 region of Env conferred a high level of resistance to VRC01 class antibodies, suggesting a preferred escape pathway. We further mapped the VRC01-induced escape pathway in vivo using Envs from donor 45, from whom antibody VRC01 was isolated. Initial escape mutations, including the addition of a key glycan, occurred in loop D and were associated with impaired viral replication; however, compensatory mutations restored full replicative fitness. These data demonstrate that escape from VRC01 class antibodies can diminish viral replicative fitness, but compensatory changes may explain the limited impact of neutralizing antibodies during the course of natural HIV-1 infection. Some antibodies that arise during natural HIV-1 infection bind to conserved regions on the virus envelope glycoprotein and potently neutralize the majority of diverse HIV-1 strains. The VRC01 class of antibodies blocks the conserved CD4 receptor binding site interaction that is necessary for viral entry, raising the possibility that viral escape from antibody neutralization might exert detrimental effects on viral function. Here, we show that escape from VRC01 class antibodies can be associated with impaired viral entry and replication; however, during the course of natural infection, compensatory mutations restore the ability of the virus to replicate normally.


Determination of amikacin stability at 1% and 3% concentrations in four topical solutions over a 56-day period.
Anecdotally, amikacin has been added to compounded topical preparations for the management of canine bacterial otitis externa. However, the stability of amikacin within these solutions is unknown. The purpose of this study was to determine the stability of amikacin at 10 and 30 mg/mL concentrations in four topical solutions over a 56 day period. We hypothesised that amikacin would maintain chemical stability within the various solutions. Amikacin was formulated to 10 and 30 mg/mL (1% and 3%) concentrations within four topical solutions: tris-EDTA (TrizEDTA Aqueous Flush) (TE); 0.15% chlorhexidine gluconate and tris-EDTA (TrizCHLOR Flush) (TC); 0.9% NaCl (NA); and 0.9% NaCl + 2 mg/mL dexamethasone (ND). Samples were made in duplicate and stored at room temperature (25°C) for 0, 7,14, 21, 28 and 56 days. Amikacin content was quantified, in triplicate, by ultrahigh-performance liquid chromatography tandem mass spectrometry. The recovered amikacin concentrations for the 10 mg/mL solutions ranged from 10 to 13.5 mg/mL (mean 11.5 mg/mL) with the exception of NA sample 2 at Day (D)0 (9.4 mg/mL) and D7 (9.2 mg/mL). The recovered amikacin concentrations for the 30 mg/mL solutions ranged from 30 to 40.2 mg/mL (mean 35.7 mg/mL). No significant difference was seen between the amikacin concentrations at D0 compared to D56 for all solutions except 10 mg/mL TE (P < 0.001). Amikacin maintained stability within TE, TC, NA and ND over 56 days except when formulated at 10 mg/mL within TE.


Dominance of ammonia-oxidizing archaea community induced by land use change from Masson pine to eucalypt plantation in subtropical China.
A considerable proportion of Masson pine forests have been converted into eucalypt plantations in the last 30 years in Guangdong Province, subtropical China, for economic reasons, which may affect the ammonia-oxidizing archaea (AOA) community and the process of ammonia transformation. In order to determine the effects of forest conversion on AOA community, AOA communities in a Masson pine (Pinus massoniana) plantation and a eucalypt (Eucalyptus urophylla) plantation, which was converted from the Masson pine, were compared. Results showed that the land use change from the Masson pine to the eucalypt plantation decreased soil nutrient levels. A significant decrease of the potential nitrification rates (PNR) was also observed after the forest conversion (p < 5 %, n = 6). AOA were the only ammonia oxidizers in both plantations (no ammonia-oxidizing bacteria were detected). The detected AOA are affiliated with the genera Nitrosotalea and Nitrososphaera. A decrease of AOA abundance and an increase of the diversity were evident with the plantation conversion in the surface layer. AOA amoA gene diversity was negatively correlated with organic C and total N, respectively (p < 0.05, n = 12). AOA amoA gene abundance was negatively correlated with NH4 (+) and available P, respectively (p < 0.05, n = 12). However, AOA abundance was positively correlated with PNR, but not significantly (p < 0.05, n = 6), indicating AOA community change was only a partial reason for the decrease of PNR.


An immunoperoxidase monoclonal antibody stain for rapid diagnosis of infectious bursal disease.
Cell smears of chicken-embryo-fibroblast (CEF) cultures and bursa of Fabricius from chickens experimentally infected with six different strains of infectious bursal disease virus (IBDV) were examined for the presence of IBDV by the avidin-biotin-peroxidase complex method of immunoperoxidase (IP) staining using a monoclonal antibody specific for IBDV designated BK70. IBDV of different strains and serotypes were readily detected by the IP method in cell smears prepared from infected CEF cultures and from bursas. Bursal cells were positive for IP stain in most of the infected bursas (87.5%), despite their mild IBD lesions. Positive IP staining of bursal smears was well correlated with the recovery of IBDV from the bursas and with IBD lesions in the bursas. IP stain with a monoclonal antibody (BK70) appeared potentially useful for rapid and definitive diagnosis of IBD.


CALD1, CNN1, and TAGLN identified as potential prognostic molecular markers of bladder cancer by bioinformatics analysis.
Bladder cancer (BC) is one of the most common malignant neoplasms in the genitourinary tract. We employed the GSE13507 data set from the Gene Expression Omnibus (GEO) database in order to identify key genes related to tumorigenesis, progression, and prognosis in BC patients. The data set used in this study included 10 normal bladder mucosae tissue samples and 165 primary BC tissue samples. Differentially expressed genes (DEGs) in the 2 types of samples were identified by GEO2R. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the online website DAVID. The online website STRING was used to construct a protein-protein interaction network. Moreover, the plugins in MCODE and cytoHubba in Cytoscape were employed to find the hub genes and modules in these DEGs. We identified 154 DEGs comprising 135 downregulated genes and 19 upregulated genes. The GO enrichment results were mainly related to the contractile fiber part, extracellular region part, actin cytoskeleton, and extracellular region. The KEGG pathway enrichment results mainly comprised type I diabetes mellitus, asthma, systemic lupus erythematosus, and allograft rejection. A module was identified from the protein-protein interaction network. In total, 15 hub genes were selected and 3 of them comprising CALD1, CNN1, and TAGLN were associated with both overall survival and disease-free survival. CALD1, CNN1, and TAGLN may be potential biomarkers for diagnosis as well as therapeutic targets in BC patients.


Sugar utilization patterns and respiro-fermentative metabolism in the baker's yeast Torulaspora delbrueckii.
The highly osmo- and cryotolerant yeast species Torulaspora delbrueckii is an important case study among the non-Saccharomyces yeast species. The strain T. delbrueckii PYCC 5321, isolated from traditional corn and rye bread dough in northern Portugal, is considered particularly interesting for the baking industry. This paper reports the sugar utilization patterns of this strain, using media with glucose, maltose and sucrose, alone or in mixtures. Kinetics of growth, biomass and ethanol yields, fermentation and respiration rates, hydrolase activities and sugar uptake rates were used to infer the potential applied relevance of this yeast in comparison to a conventional baker's strain of Saccharomyces cerevisiae. The results showed that both maltase and maltose transport in T. delbrueckii were subject to glucose repression and maltose induction, whereas invertase was subject to glucose control but not dependent on sucrose induction. A comparative analysis of specific sugar consumption rates and transport capacities suggests that the transport step limits both glucose and maltose metabolism. Specific rates of CO(2) production and O(2) consumption showed a significantly higher contribution of respiration to the overall metabolism in T. delbrueckii than in S. cerevisiae. This was reflected in the biomass yields from batch cultures and could represent an asset for the large-scale production of the former species. This work contributes to a better understanding of the physiology of a non-conventional yeast species, with a view to the full exploitation of T. delbrueckii by the baking industry.


Giant-cell arteritis without cranial manifestations presenting as fever of unknown origin: a diagnostic value of 18F-FDG PET/CT.
We present a case of 68-year-old female with four months history of fever, fatigue, and weight loss. She was classified as case of fever of unknown origin. The physical examination was normal, the laboratory tests showed anemia, elevation of C-reactive protein, erythrocyte sedimentation rate and fibrinogen. The diagnosis was unclear and 18F-FDG PET/CT was performed. Images showed high glucose uptake in the wall of the ascending and descending aorta, in the walls of the subclavian arteries, abdominal aorta and proximal part of both iliac arteries. The diagnosis of GCA appeared most likely and steroid treatment was initiated. After the therapy, clinical signs disappeared, laboratory parameters normalized and follow-up 18F-FDG PET/CT demonstrated lack of glucose uptake in the vessels' walls. We observed remission. 18F-FDG PET/CT offers a possibility for early detection of inflammation in the vessels and could be used for assessment of therapy response. Performing this nuclear imaging method in a clinical setting, where there is suspicion of large-vessel vasculitis is of great benefit for the final outcome.


A simple and efficient method for processing of cell lysates for two-dimensional gel electrophoresis.
Sample preparation is one of the major issues in 2-DE for the separation of proteins. Although a 100% representation of cellular proteins onto a 2-DE is virtually impossible, maximum representation of cellular proteins compared with the original cell lysate is important in the subsequent analysis. We demonstrate that lysis of cells in urea/thiourea solution with subsequent sonication to disrupt the nucleic acids and concentration of the lysate using centri-con led to enrichment of proteins. The procedure resulted in minimal nucleic acid contamination with better resolution of spots. 2-DE spot patterns of proteins prepared using urea-thiourea solubilization/centri-con method to other protein enrichment methods such as phenol/chloroform/isoamyl alcohol extraction, methanol/ammonium acetate precipitation, acetone precipitation and ethanol precipitation were compared. Urea-thiourea solubilization combined with centri-con method of protein enrichment represented higher number/unique spots particularly in the 50-250 kDa M(r) compared with others. Lysis of cells in urea/thiourea from the beginning of lysate preparation preserves the proteins from protease activity due to denaturation of proteases. Thus, we demonstrate that the centri-con methodology is simple and effective for the preparation of high-quality sample that can be used for a qualitative representation of cellular proteins on a 2-DE for proteomic analysis.


[Ionophore-induced oscillations in erythrocytes. A kinetic model].
The kinetic model for K+, H+, Ca2+ concentrational self-oscillations in erythrocytes induced by A23187 and FCCP ionophores are considered. The model is based on the experimental data available and contains the minimal number of essential variables. The model was analysed by the method based on the graph representation of kinetic equations. The critical graph fragments provoking self-oscillatory trajectories in the system were revealed. It is shown that self-oscillatory behaviour is basically induced by conjugated processes produced by A23187. The parameter domain for self-oscillations is estimated including parameters of Ca2+-induced (through K+-channels) proton transport with FCCP participation. Numerical integration of kinetic equations was performed. The results obtained are in a good qualitative agreement with experimental data.


[Blood flow in the gastric mucosa and components of the kallikrein- kinin system in patients with duodenal ulcer].
The results of study of the blood flow rate in the gastric mucosa by means of intraoperative rheography and content of the main components of kallikrein-kinin system in the systemic and regional blood flow were compared. It was established that increase in the volumetric blood flow rate in patients with a complicated duodenal ulcer disease was caused by activation of the kallikrein-kinin system in the regional blood flow. Blockade of the celiac plexus has a pronounced effect on the state of a kallikrein-kinin system.


Dislodgement of Intracoronary Thrombus During Angiography in a Patient with Unstable Angina Pectoris.
A patient with unstable angina pectoris in whom thrombus release from intracoronary lesion was seen during angiography is described. The event resulted in improvement of vessel patency and resolution of ischemic symptoms. To our knowledge, only two similar cases have been reported in English literature since 1966.


Partial characterization of glutathione S-transferases from wheat (Triticum spp.) and purification of a safener-induced glutathione S-transferase from Triticum tauschii.
Hexaploid wheat (Triticum aestivum L.) has very low constitutive glutathione S-transferase (GST) activity when assayed with the chloroacetamide herbicide dimethenamid as a substrate, which may account for its low tolerance to dimethenamid in the field. Treatment of seeds with the herbicide safener fluxofenim increased the total GST activity extracted from T. aestivum shoots 9-fold when assayed with dimethenamid as a substrate, but had no effect on glutathione levels. Total GST activity in crude protein extracts from T. aestivum, Triticum durum, and Triticum tauschii was separated into several component GST activities by anion-exchange fast-protein liquid chromatography. These activities (isozymes) differed with respect to their activities toward dimethenamid or 1-chloro-2,4-dinitrobenzene as substrates and in their levels of induction by safener treatment. A safener-induced GST isozyme was subsequently purified by anion-exchange and affinity chromatography from etiolated shoots of the diploid wheat species T. tauschii (a progenitor of hexaploid wheat) treated with the herbicide safener cloquintocet-mexyl. The isozyme bound to a dimethenamid-affinity column and had a subunit molecular mass of 26 kD based on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The purified enzyme (designated GST TSI-1) was recognized by an antiserum raised against a mixture of maize (Zea mays) GSTs. Amino acid sequences obtained from protease-digested GST TSI-1 had significant homology with the safener-inducible maize GST V and two auxin-regulated tobacco (Nicotiana tabacum) GST isozymes.


Exploring Alzheimer's disease mouse brain through X-ray phase contrast tomography: From the cell to the organ.
Alzheimer's disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder associated with aberrant production of beta-amyloid (Aβ) peptide depositing in brain as amyloid plaques. While animal models allow investigation of disease progression and therapeutic efficacy, technology to fully dissect the pathological mechanisms of this complex disease at cellular and vascular levels is lacking. X-ray phase contrast tomography (XPCT) is an advanced non-destructive 3D multi-scale direct imaging from the cell through to the whole brain, with exceptional spatial and contrast resolution. We exploit XPCT to simultaneously analyse disease-relevant vascular and neuronal networks in AD mouse brain, without sectioning and staining. The findings clearly show the different typologies and internal structures of Aβ plaques, together with their interaction with patho/physiological cellular and neuro-vascular microenvironment. XPCT enables for the first time a detailed visualization of amyloid-angiopathy at capillary level, which is impossible to achieve with other approaches. XPCT emerges as added-value technology to explore AD mouse brain as a whole, preserving tissue chemistry and structure, enabling the comparison of physiological vs. pathological states at the level of crucial disease targets. In-vivo translation will permit to monitor emerging therapeutic approaches and possibly shed new light on pathological mechanisms of neurodegenerative diseases.


Synthesis of Absorption-Dominant Small Gold Nanorods and Their Plasmonic Properties.
Absorption-dominant small Au nanorods with diameters of less than 10 nm are prepared using a facile seed-mediated growth method. The diameters of the small gold nanorods range from 6 to 9 nm, and their lengths vary from 16 to 45 nm. Their aspect ratios can be tailored from 2.7 to 4.7. As a result, the longitudinal plasmon resonance wavelengths are readily tunable from ∼720 nm to ∼830 nm by changing the seed-to-Au(III) molar ratio in the growth solution. The fractions of the scattering in the total extinction of the small Au nanorods are found to be in the range of 0.005 to 0.025 with finite-difference time-domain simulations, confirming that the extinction values of these small Au nanorods are dominantly contributed to by the light absorption. Moreover, the small Au nanorod sample is coated with a dense silica layer for photothermal therapy with three cell lines. It shows improved photothermal therapy performance compared to a large Au nanorod sample for the same cellular Au contents. Our study suggests that small Au nanorods are promising light absorbers and photothermal therapy agents.


alpha 1-Antitrypsin (AAT) deficiency and ANCA-positive systemic vasculitis: genetic and clinical implications.
A high incidence of alpha 1-antitrypsin (AAT) deficiency has been reported in patients with C-ANCA systemic vasculitis in association with antibodies against proteinase-3 (PR3). To clarify the role of AAT deficiency in the acute vasculitic process as well as in progression of the disease, we studied 84 patients with either C-ANCA or P-ANCA vasculitis with special reference to: (a) the AAT gene, (b) the phenotypic (Pi) variants and (c) the serum levels during both acute illness and remission. The PiZ gene was found in six patients (8% vs. 1.5% controls) irrespective of the type of autoantibodies (C-ANCA vs. P-ANCA). All PiZ patients displayed the ability to raise their AAT serum levels up to the normal range during acute illness. In contrast, 24 patients with the PiM phenotype presented low AAT serum levels during acute illness. In all these patients, the AAT levels returned to normal values during the remission. Low AAT levels were associated with low levels of C-reactive protein (PCR) (P < 0.001), with a less severe renal involvement or a minor risk of death, and, in one tested patient, with a novel point mutation (TCGA-->TCAA) at the enhancer-promoter region of the AAT gene. Low AAT serum levels did not correlate with either type/titre of autoantibody or distribution/severity of the vasculitis process. In the case-control study, high AAT levels emerged as a major determinant of progression towards end-stage renal failure [odds ratio 3 (95% CI 1.1-8.4)]. These results indicate: (a) a high incidence of the PiZ gene of AAT in systemic vasculitis irrespective of the type of autoantibodies; (b) a novel form of AAT deficiency associated with the normal PiM phenotype becoming manifest only during acute illness; (c) dysregulation of the acute-phase response affecting selectively AAT or both AAT and PCR; (d) correlation between low plasma levels of AAT and less severe renal involvement or risk of death.


Thymoquinone Prevents Myocardial and Perivascular Fibrosis Induced by Chronic Lipopolysaccharide Exposure in Male Rats: - Thymoquinone and Cardiac Fibrosis.
Thymoquinone (TQ) is one of the active ingredients of herbal plants such as Nigella sativa L. (NS) which has beneficial effects on the body. The beneficial effects of TQ on the cardiovascular system have reported. This study aimed to investigate the effect of TQ on cardiac fibrosis and permeability, serum and tissue concentration of inflammatory markers and oxidative stress status in chronic lipopolysaccharide exposure in male rats. Seventy male Wistar rats were randomly divided into five groups as follows: (1) control; (2) LPS (1 mg/kg/day); (3-5) LPS + TQ with three doses of 2, 5 and 10 mg/kg (n=14 in each group). After 3 weeks, serum and cardiac levels of IL-1β, TNF-α and nitric oxide (NO) metabolites, and cardiac levels of malondialdehyde (MDA), total thiol groups, catalase (CAT) and superoxide dismutase (SOD) activities, permeability of heart tissue (evaluated by Evans blue dye method) and myocardial fibrosis were determined, histologically. LPS administration induced myocardial and perivascular fibrosis and increased cardiac oxidative stress (MDA), inflammatory markers and heart permeability, while, reduced anti-oxidative enzymes (SOD and CAT) and the total thiol group. Administration of TQ significantly attenuated these observations. TQ improved myocardial and perivascular fibrosis through suppression of chronic inflammation and improving oxidative stress status and can be considered for attenuation of cardiac fibrosis in conditions with chronic low-grade inflammation.


Women who inject drugs in the republic of georgia: in their own words.
This study describes the initiation and maintenance of illicit drug use, risky behaviors, and the substance use treatment experiences of women in Georgia. Qualitative interviews with 55 drug-using women (mean age 36 years; SD = 9.52), were conducted during April-September 2011. Participants presented diverse histories of drug use initiation and substance use, risky behaviors, and drug treatment participation. All participants reported concurrent use of different substances, including home-produced injection preparations. Women described their experiences of both the positive and negative effects (physical and psychological) that they attributed to their use of drugs. Findings enrich our understanding of the environment in which substance use is initiated and maintained in a female population in Georgia, and illustrate the importance of culture and the role of social factors in the development of injection drug use. Results can provide direction for tailoring the development of interventions for substance use disorders, public policy discussions regarding the treatment of women who use drugs, and future research on substance use among women in Georgia and other post-Soviet nations.


Establishing a statewide primary care network: the PrimaryOne experience.
To insure that patients receive the highest quality, cost-effective health care in the future, primary care physicians must become the leaders in the reform. The future of medicine belongs in physicians' hands. Physicians have the opportunity to bring about the greatest reform to the largest industry in the world, and do it in such a fashion that patient care is not compromised. The following article describes the purpose, objectives, organizational structure, accomplishments, philosophy, goals, results, and future of PrimaryOne and its HMO, PrimeONE.


Effects of exchanging carbohydrate or monounsaturated fat with saturated fat on inflammatory and thrombogenic responses in subjects with abdominal obesity: A randomized controlled trial.
Modification of the amount and type of dietary fat has diverse effects on cardiovascular risk. We recruited 54 abdominally obese subjects to participate in a prospective cross-over design, single-blind trial comparing isocaloric 2000 kcal MUFA or carbohydrate-enriched diet with SFA-enriched diet (control). The control diet consisted of 15E% protein, 53E% carbohydrate and 32E% fat (12E% SFA, 13E% MUFA). A total of ∼7E% of MUFA or refined carbohydrate was exchanged with SFA in the MUFA-rich and carbohydrate-rich diets respectively for 6-weeks. Blood samples were collected at fasting upon trial commencement and at week-5 and 6 of each dietary-intervention phase to measure levels of cytokines (IL-6, IL-1β), C-reactive protein (CRP), thrombogenic markers (E-selectin, PAI-1, D-dimer) and lipid subfractions. Radial pulse wave analysis and a 6-h postprandial mixed meal challenge were carried out at week-6 of each dietary intervention. Blood samples were collected at fasting, 15 and 30 min and hourly intervals thereafter till 6 h after a mixed meal challenge (muffin and milkshake) with SFA or MUFA (872.5 kcal, 50 g fat, 88 g carbohydrates) or CARB (881.3 kcal, 20 g fat, 158 g carbohydrates)- enrichment corresponding to the background diets. No significant differences in fasting inflammatory and thrombogenic factors were noted between diets (P > 0.05). CARB meal was found to increase plasma IL-6 whereas MUFA meal elevated plasma D-dimer postprandially compared with SAFA meal (P < 0.05). Comparing the 3 meals, there were similar postprandial elevations in IL-6 and D-dimer and postprandial reductions in PAI-1, augmentation index and pressure (time effect: P < 0.05). CARB diet was found to reduce HDL3 by 7.8% and increase small dense HDL (sdHDL) by 8.6% compared with SFA diet (P < 0.05). SFA diet increased large HDL subfractions compared with both CARB and MUFA diets by 4.9% and 6.6% (P < 0.05), respectively. Overall, the evidence presented in this study suggests that the replacement of SFA with MUFA or refined carbohydrates may not improve inflammatory and thrombogenic markers in abdominally overweight individuals. Indeed increased refined carbohydrates consumption adversely impacts fasting HDL subfractions. This trial was registered under ClinicalTrials.gov. Identifier no. NCT01665482.


Efficacy of frontalis suspension with silicone rods in ptosis patients with poor Bell's phenomenon.
The purpose of the study was to evaluate the efficacy of silicone rods as frontalis sling for correction of ptosis associated with poor Bell's phenomenon in specific situations. A retrospective interventional case series of 25 eyes of 19 patients who underwent frontalis suspension surgery with silicone rods for ptosis correction from May 2006 to April 2011, was performed. Inclusion criteria included severe ptosis with poor Bell's phenomenon. Patient evaluation included clinical history and other relevant parameters of ptosis measurement. Final outcome measurements included postoperative lid height, lagophthalmos, complications, need for reoperation, and patient satisfaction. Mean age at presentation was 25.72 ± 2.2 years. The sex ratio of male: female was 1.11. The causes of ptosis included chronic progressive external ophthalmoplegia (CPEO) in 11 eyes (44%), oculopharyngeal dystrophy in 2 (8%), third cranial nerve palsy in 7 (28%), traumatic in three eyes (12%), and iatrogenic postoperative ptosis (after orbital tumor excision) in two eyes (8%). The postoperative palpebral fissure height and margin reflex distance improved significantly (P = 0.0001). Extrusion of the sling and granuloma formation occurred in two eyes each, and these patients had to undergo sling removal. One patient developed mild exposure keratopathy and was managed conservatively. Silicone is an effective material for use in frontalis suspension in the management of severe ptosis with poor Bell's phenomenon. The elastic nature of silicone rod makes it an ideal suspensory material for patients with CPEO or third nerve palsy.


Hypertension in kidney transplant recipients.
Arterial hypertension is frequently observed in renal transplant recipients. Its pathogenesis is multifactorial in most cases. Calcineurin inhibitors (CNI) can increase peripheral vascular resistance by inducing arteriolar vasoconstriction and can cause extracellular fluid expansion by reducing the glomerular filtration rate (GFR), activating the renin-angiotensin system (RAS), and by inactivating the atrial natriuretic peptide. Glucocorticoids can impair urinary water and salt excretion. Poor graft function can lead to increased extracellular volume and inappropriate production of renin. Native kidneys, older age of the donor and transplant renal artery stenosis (TRAS) may also contribute to the development of hypertension. Arterial hypertension not only can increases the risk for cardiovascular events but can also deteriorate renal allograft function. A number of studies have shown that the higher the levels of blood pressure are, the higher is the risk of graft failure. On the other hand, a good control of blood pressure may prevent many cardiovascular and renal complications. Appropriate lifestyle modification is the first step for treating hypertension. Calcium channel blockers (CCB) and renin-angiotensin system (RAS) inhibitors are the most frequently used antihypertensive agents, but in many cases, a combination of these and other drugs is required to obtain good control of hypertension.


Quantitative brain magnetic resonance imaging in girls with attention-deficit/hyperactivity disorder.
Anatomic studies of boys with attention-deficit/hyperactivity disorder (ADHD) have detected decreased volumes in total and frontal brain, basal ganglia, and cerebellar vermis. We tested these findings in a sample of girls with ADHD. Anatomic brain magnetic resonance images from 50 girls with ADHD, of severity comparable with that in previously studied boys, and 50 healthy female control subjects, aged 5 to 15 years, were obtained with a 1.5-T scanner with contiguous 2-mm coronal slices and 1.5-mm axial slices. We measured volumes of total cerebrum, frontal lobes, caudate nucleus, globus pallidus, cerebellum, and cerebellar vermis. Behavioral measures included structured psychiatric interviews, parent and teacher ratings, and the Wechsler vocabulary and block design subtests. Total brain volume was smaller in girls with ADHD than in control subjects (effect size, 0.40; P =.05). As in our previous study in boys with ADHD, girls with ADHD had significantly smaller volumes in the posterior-inferior cerebellar vermis (lobules VIII-X; effect size, 0.54; P =.04), even when adjusted for total cerebral volume and vocabulary score. Patients and controls did not differ in asymmetry in any region. Morphometric differences correlated significantly with several ratings of ADHD severity and were not predicted by past or present stimulant drug exposure. These results confirm previous findings for boys in the posterior-inferior lobules of the cerebellar vermis. The influence of the cerebellar vermis on prefrontal and striatal circuitry should be explored.


Small molecules showing significant protection of mice against botulinum neurotoxin serotype A.
Botulinum neurotoxin serotype A (BoNTA) causes a life-threatening neuroparalytic disease known as botulism that could afflict large, unprotected populations if the toxin were employed in an act of bioterrorism. Current post-exposure therapy is limited to symptomatic treatment or passive immunization that is effective for treating infant botulism at a cost of US $45,300 per treatment regimen. Antibodies can neutralize the extracellular but not the intracellular BoNTA. Moreover, antibody production, storage, and administration in a mass casualty scenario pose logistical challenges. Alternatively, small-molecule inhibitors of BoNTA endopeptidase (BoNTAe) are sought to antagonize the extracellular or intracellular toxin. While several such molecules reportedly demonstrated efficacy in protecting cells against BoNTA, there is scant information to show that small molecules can significantly protect mammals against BoNTA. Herein we report the development of effective small-molecules BoNTAe inhibitors with promising in vivo pharmacokinetics. One such molecule has an in vivo half-life of 6.5 hours and is devoid of obvious sign of toxicity. Pre-treatment with this molecule at 2 mg/kg protected 100% and 70% of treated mice against BoNTA at 5 times of its median-lethal dose during the periods of 2 and 4 half-lives of the inhibitor, respectively. In contrast, 40% and 0% of untreated mice survived during the respective periods. Similar levels of protection were also observed with two other small molecules. These results demonstrate that small molecules can significantly protect mice against BoNTA and support the pursuit of small-molecule antagonists as a cost-effective alternative or as an adjunct to passive immunity for treating botulism.


Cost-Effectiveness and Budget Impact Analyses of Pneumococcal Vaccination in Indonesia.
As a country with the high number of deaths due to pneumococcal disease, Indonesia has not yet included pneumococcal vaccination into the routine program. This study aimed to analyse the cost-effectiveness and the budget impact of pneumococcal vaccination in Indonesia by developing an age-structured cohort model. In a comparison with no vaccination, the use of two vaccines (PCV10 and PCV13) within two pricing scenarios (UNICEF and government contract price) was taken into account. To estimate the cost-effectiveness value, a 5-year time horizon was applied by extrapolating the outcome of the individual in the modelled cohort until 5 years of age with a 1-month analytical cycle. To estimate the affordability value, a 6-year period (2019-2024) was applied by considering the government's strategic plan on pneumococcal vaccination. In a comparison with no vaccination, the results showed that vaccination would reduce pneumococcal disease by 1,702,548 and 2,268,411 cases when using PCV10 and PCV13, respectively. Vaccination could potentially reduce the highest treatment cost from the payer perspective at $53.6 million and $71.4 million for PCV10 and PCV13, respectively. Applying the UNICEF price, the incremental cost-effectiveness ratio (ICER) from the healthcare perspective would be $218 and $162 per QALY-gained for PCV10 and PCV13, respectively. Applying the government contract price, the ICER would be $987 and $747 per QALY-gained for PCV10 and PCV13, respectively. The result confirmed that PCV13 was more cost-effective than PCV10 with both prices. In particular, introduction cost per child was estimated to be $0.91 and vaccination cost of PCV13 per child (3 doses) was estimated to be $16.61 and $59.54 with UNICEF and government contract prices, respectively. Implementation of nationwide vaccination would require approximately $73.3-$75.0 million (13-14% of routine immunization budget) and $257.4-$263.5 million (45-50% of routine immunization budget) with UNICEF and government contract prices, respectively. Sensitivity analysis showed that vaccine efficacy, mortality rate, and vaccine price were the most influential parameters affecting the ICER. In conclusion, pneumococcal vaccination would be a highly cost-effective intervention to be implemented in Indonesia. Yet, applying PCV13 with UNICEF price would give the best cost-effectiveness and affordability values on the routine immunization budget.


Risk of cancer, tuberculosis and serious infections in patients with ankylosing spondylitis, psoriatic arthritis and psoriasis treated with IL-17 and TNF-α inhibitors: a nationwide nested case-control analysis.
Targeting interleukin (IL)-17 and tumour necrosis factor (TNF)-α is recommended for the management of severe/refractory ankylosing spondylitis (AS), psoriatic arthritis (PsA), and psoriasis (PsO); however, safety data comparing these agents, especially in a large Asian population are unavailable. Patients with AS, PsA and PsO were searched using the Health Insurance Review and Assessment Service database, defined according to the International Classification of Diseases-10 and unique insurance codes for rare diseases. By including patients newly diagnosed with AS, PsA, and PsO between 2010-2020, the outcomes of cancer, tuberculosis (TB) and serious infections following IL-17 and TNF-α inhibitor usage were evaluated. To investigate the association between treatments and outcomes, nested case-control analyses matching patients to controls (maximum of 1:10 ratio) according to index age, sex, index year, and follow-up duration were performed. Among 40322, 4953, and 5347 patients with AS, PsA, and PsO, respectively, three different datasets were generated to evaluate incidence of outcomes. Conditional logistic regression analysis revealed that cyclosporine use (odds ratio [OR] 2.286, p=0.0176) increased cancer, and a higher Charlson Comorbidity Index (CCI) score (OR 1.085, p=0.0406) and IL-17 inhibitor use only (OR 0.126, p=0.0457) showed a positive and negative association with TB, respectively. Serious infections increased in patients with high CCI scores (OR 1.117, p<0.0001), cyclosporine users (OR 1.445, p=0.0098), and medical-aided individuals (OR 1.667, p<0.0001). In this nationwide cohort of IL-17 and TNF-α inhibitor users, both treatments conferred comparable risk of cancer and serious infections, while IL-17 inhibitors may be advantageous for TB.


Incipient Social Groups: An Analysis via In-Vivo Behavioral Tracking.
Social psychology is fundamentally the study of individuals in groups, yet there remain basic unanswered questions about group formation, structure, and change. We argue that the problem is methodological. Until recently, there was no way to track who was interacting with whom with anything approximating valid resolution and scale. In the current study we describe a new method that applies recent advances in image-based tracking to study incipient group formation and evolution with experimental precision and control. In this method, which we term "in vivo behavioral tracking," we track individuals' movements with a high definition video camera mounted atop a large field laboratory. We report results of an initial study that quantifies the composition, structure, and size of the incipient groups. We also apply in-vivo spatial tracking to study participants' tendency to cooperate as a function of their embeddedness in those crowds. We find that participants form groups of seven on average, are more likely to approach others of similar attractiveness and (to a lesser extent) gender, and that participants' gender and attractiveness are both associated with their proximity to the spatial center of groups (such that women and attractive individuals are more likely than men and unattractive individuals to end up in the center of their groups). Furthermore, participants' proximity to others early in the study predicted the effort they exerted in a subsequent cooperative task, suggesting that submergence in a crowd may predict social loafing. We conclude that in vivo behavioral tracking is a uniquely powerful new tool for answering longstanding, fundamental questions about group dynamics.


Spatial-temporal discriminant analysis for ERP-based brain-computer interface.
Linear discriminant analysis (LDA) has been widely adopted to classify event-related potential (ERP) in brain-computer interface (BCI). Good classification performance of the ERP-based BCI usually requires sufficient data recordings for effective training of the LDA classifier, and hence a long system calibration time which however may depress the system practicability and cause the users resistance to the BCI system. In this study, we introduce a spatial-temporal discriminant analysis (STDA) to ERP classification. As a multiway extension of the LDA, the STDA method tries to maximize the discriminant information between target and nontarget classes through finding two projection matrices from spatial and temporal dimensions collaboratively, which reduces effectively the feature dimensionality in the discriminant analysis, and hence decreases significantly the number of required training samples. The proposed STDA method was validated with dataset II of the BCI Competition III and dataset recorded from our own experiments, and compared to the state-of-the-art algorithms for ERP classification. Online experiments were additionally implemented for the validation. The superior classification performance in using few training samples shows that the STDA is effective to reduce the system calibration time and improve the classification accuracy, thereby enhancing the practicability of ERP-based BCI.


The Potential of Seaweeds as a Source of Functional Ingredients of Prebiotic and Antioxidant Value.
Two thirds of the world is covered by oceans, whose upper layer is inhabited by algae. This means that there is a large extension to obtain these photoautotrophic organisms. Algae have undergone a boom in recent years, with consequent discoveries and advances in this field. Algae are not only of high ecological value but also of great economic importance. Possible applications of algae are very diverse and include anti-biofilm activity, production of biofuels, bioremediation, as fertilizer, as fish feed, as food or food ingredients, in pharmacology (since they show antioxidant or contraceptive activities), in cosmeceutical formulation, and in such other applications as filters or for obtaining minerals. In this context, algae as food can be of help to maintain or even improve human health, and there is a growing interest in new products called functional foods, which can promote such a healthy state. Therefore, in this search, one of the main areas of research is the extraction and characterization of new natural ingredients with biological activity (e.g., prebiotic and antioxidant) that can contribute to consumers' well-being. The present review shows the results of a bibliographic survey on the chemical composition of macroalgae, together with a critical discussion about their potential as natural sources of new functional ingredients.


Casting a net: fibres produced by Microcystis sp. in field and laboratory populations.
The reasons for the apparent dominance of the toxic cyanobacterium Microcystis sp., reflected by its massive blooms in many fresh water bodies, are poorly understood. We show that in addition to a large array of secondary metabolites, some of which are toxic to eukaryotes, Microcystis sp. secretes large amounts of fibrous exopolysaccharides that form extremely long fibres several millimetres in length. This phenomenon was detected in field and laboratory cultures of various Microcystis strains. In addition, we have identified and characterized three of the proteins associated with the fibres and the genes encoding them in Microcystis sp. PCC 7806 but were unable to completely delete them from its genome. Phylogenetic analysis of the most abundant one, designated IPF-469, showed its presence only in cyanobacteria. Its closest relatives were detected in Synechocystis sp. PCC 6803 and in Cyanothece sp. strains; in the latter the genomic organization of the IPF-469 was highly conserved. IPF-469 and the other two proteins identified here, a haloperoxidase and a haemolysin-type calcium-binding protein, may be part of the fibres secretion pathway. The biological role of the fibres in Microcystis sp. is discussed.


The role of parental education in the relation between ADHD symptoms and executive functions in children.
Using a population-based sample of 9-year-old children, this study examined whether the relation between symptoms of ADHD and executive functions (EFs) depended on socioeconomic status (SES; indexed by parental education). Parents and teachers rated the children's ADHD symptoms, and parents also indicated their educational level in a questionnaire. The children performed a comprehensive set of EF tasks. Whereas working memory was similarly related to ADHD symptoms in the lower and higher parental education group, the relations of inhibition and mental set-shifting with ADHD symptoms were generally stronger in the higher educational group, a pattern that was supported by several significant group differences in correlations. This suggests that the EF pathway in contemporary multiple pathway models of ADHD etiology may be particularly relevant in higher SES parts of the population.


Current trends in autologous stem-cell transplantation for myeloma in the era of novel therapies.
Since the mid 1990s, high-dose therapy followed by autologous stem-cell transplantation (ASCT) has been considered the standard of care for frontline therapy in younger patients with multiple myeloma (MM). During the past 10 years, thalidomide, bortezomib, and lenalidomide have been widely incorporated to the therapeutic armamentarium for the treatment of this disease. These agents show promise for improving the rate of complete remission both before and after ASCT without increasing toxicity. However, it is not clear whether such therapies are superior if they are used as an alternative to transplantation or whether they may reduce the need for and use of transplantation in patients in whom treatment is indicated. Therefore, the role of ASCT itself is a matter of debate: Should it be used upfront or as salvage treatment at the time of progression in patients initially treated with novel agents? This review presents current trends in ASCT for MM in the era of novel therapies.


Hybrid materials based on conjugated polymers and inorganic semiconductors as photocatalysts: from environmental to energy applications.
Photocatalysts provide a sustainable way to remove pollutants or store energy in the form of solar fuels by processes such as water splitting and CO2 photoreduction (artificial photosynthesis). Research in this topic is an expansive field evidenced by the large number of contributions published in the past few years. Hybrid photocatalysts based on inorganic semiconductors (ISs) and conjugated polymers (CPs) have emerged as novel promising photoactive materials. In addition to the well-known behaviour of ISs in photocatalytic processes, CPs have emerged as an interesting alternative to improve the photocatalytic efficiency due to the possibility of controlling their optoelectronic, textural and morphological properties at the molecular level. Thus, the synergy between ISs and CPs leads to more efficient photocatalysts with enhanced light absorption in the overall solar spectrum, improved photocharge generation and transport, higher stability to photo-corrosion and higher surface areas. Here, we present an overview of the advances in the development of hybrid IS-CP photocatalysts for pollutant degradation and energy conversion through water splitting, CO2 reduction and/or N2 fixation using photo- and photo(electro)catalytic processes.


Binding properties and distribution of insulin-like growth factor binding protein-related protein 3 (IGFBP-rP3/NovH), an additional member of the IGFBP Superfamily.
The protein product of the novH oncogene, a member of the CCN family, is structurally related to the insulin-like growth factor (IGF) binding proteins (IGFBPs). We have characterized aspects of structure, function, and distribution of this protein, which, as IGFBP-related protein 3 (IGFBP-rP3), is a proposed member of the IGFBP Superfamily. Affinity cross-linking experiments performed with baculovirus synthesized recombinant human IGFBP-rP3 established that rhIGFBP-rP3 binds IGF-I, IGF-II, and insulin with low affinity. Specificity of binding was shown by competitive cross-linking experiments; binding to IGF-I and -II was also demonstrated by nondenaturing Western ligand blots. Northern blot analysis indicated the presence of IGFBP-rP3 messenger RNA (mRNA) in a broad range of human tissues. Western immunoblotting studies, using a polyclonal rabbit anti-rhIGFBP-rP3 antibody, demonstrated that IGFBP-rP3 protein is synthesized in vitro by several breast and prostate cancer cell lines: Hs578T, PC3, P69, and LNCaP cells. Western immunoblotting studies of human biological fluids identified that IGFBP-rP3 was present in normal serum, pregnancy serum, serum from patients with growth hormone receptor deficiency, cerebrospinal fluid, amniotic fluid, peritoneal fluid, and follicular fluid, while IGFBP-rP3 fragments were identified in cerebrospinal fluid, amniotic fluid, and prepubertal and pubertal urine samples. Our studies demonstrate that IGFBP-rP3 exhibits IGF binding, albeit at low affinity, and IGFBP-rP3 thus merits inclusion in the IGFBP Superfamily. The low affinity IGF binding suggests that IGFBP-rP3 may act primarily independently of the IGFs. The synthesis of IGFBP-rP3 by several malignant cell lines and its presence in human biological fluids suggest that this protein possesses other interesting roles, potentially in cell growth regulation.


Predictors of nursing home placement among elderly public housing residents.
This study examines risk factors for nursing home placement among elderly residents of public housing. Data on residents of six urban public housing developments for elderly persons (weighted n = 881) were analyzed by using logistic regression procedures to determine the predictors of nursing home placement during a 28-month period. Four baseline indicators of need were identified: greater impairment in instrumental activities of daily living, cognitive disorder, high scores on the General Health Questionnaire, and psychotic disorder. Thus, functional status and mental morbidity are major contributors to nursing home placement in this setting.


The pattern of p14ARF expression in primary and metastatic human endometrial carcinomas: correlation with clinicopathological features and TP53 pathway alterations.
Alterations of p53 pathway (p14(ARF)/MDM2/p53) play a crucial role in the development and progression of various human neoplasms, including endometrial carcinoma (EC). The aim of the current research was to examine the p14(ARF) expression pattern in primary ECs and corresponding metastatic lesions. We studied 47 primary ECs and corresponding metastatic lesions applying immunohistochemistry and investigated the relationship between p14(ARF) overexpression and clinicopathological variables of carcinoma as well as TP53 alterations. Protein expression was predominantly nuclear, present in 32 (68%) of 47 primary cases and in 28 (60%) of 47 metastatic lesions. There were seven p14(ARF)-positive primary tumors showing negative reactivity in the metastatic lesions. On the other hand, 3 cases lacked protein immunoreactivity in the primary ECs but revealed weak nuclear staining in the corresponding metastases. A case of primary cervical adenocarcinoma metastasizing to the lymph nodes showed p14(ARF) expression both in the primary tumor and the corresponding metastases. A trend was found between the p14(ARF) expression in primary tumors and the presence of the neoplasms in the fallopian tube (P = 0.063), but none of the other clinicopathological variables of carcinoma was related to protein immunoreactivity in advanced-stage uterine neoplasms. The p14(ARF) expression in EC metastases was related to the presence of the primary tumor in the fallopian tube (P = 0.036). The p14(ARF) expression was not associated with unfavorable outcome both in the primary tumors (P = 0.302) and in the corresponding metastases (P = 0.217). There was also no relationship between the p14(ARF) expression pattern and TP53 pathway alterations. Altogether, the p14(ARF) protein is expressed in more than half of the primary ECs and metastatic lesions analyzed and is associated with the transtubal dissemination of the primary tumor. The pattern of the p14(ARF) expression is not associated with the alterations of other TP53 pathway members in advanced-stage human ECs.


Natural genetic transformation of Streptococcus mutans growing in biofilms.
Streptococcus mutans is a bacterium that has evolved to be dependent upon a biofilm "lifestyle" for survival and persistence in its natural ecosystem, dental plaque. We initiated this study to identify the genes involved in the development of genetic competence in S. mutans and to assay the natural genetic transformability of biofilm-grown cells. Using genomic analyses, we identified a quorum-sensing peptide pheromone signaling system similar to those previously found in other streptococci. The genetic locus of this system comprises three genes, comC, comD, and comE, that encode a precursor to the peptide competence factor, a histidine kinase, and a response regulator, respectively. We deduced the sequence of comC and its active pheromone product and chemically synthesized the corresponding 21-amino-acid competence-stimulating peptide (CSP). Addition of CSP to noncompetent cells facilitated increased transformation frequencies, with typically 1% of the total cell population transformed. To further confirm the roles of these genes in genetic competence, we inactivated them by insertion-duplication mutagenesis or allelic replacement followed by assays of transformation efficiency. We also demonstrated that biofilm-grown S. mutans cells were transformed at a rate 10- to 600-fold higher than planktonic S. mutans cells. Donor DNA included a suicide plasmid, S. mutans chromosomal DNA harboring a heterologous erythromycin resistance gene, and a replicative plasmid. The cells were optimally transformed during the formation of 8- to 16-h-old biofilms primarily consisting of microcolonies on solid surfaces. We also found that dead cells in the biofilms could act as donors of a chromosomally encoded antibiotic resistance determinant. This work demonstrated that a peptide pheromone system controls genetic competence in S. mutans and that the system functions optimally when the cells are living in actively growing biofilms.


Alveolar ridge preservation with the socket-plug technique utilizing an alloplastic putty bone substitute or a particulate xenograft: a histological pilot study.
Following tooth extraction, ridge preservation procedures are employed to regenerate bone in the extraction socket, limit consequent ridge resorption, and provide a stable base for implant placement. The purpose of this study is to histologically evaluate and compare bone regeneration in extraction sockets grafted with either a putty alloplastic bone substitute or particulate anorganic bovine xenograft utilizing the socket-plug technique. Nineteen patients underwent 20 tooth extractions and ridge preservation following a standardized protocol. Ten sites were grafted with calcium phosphosilicate putty (CPS group) and the remaining 10 with anorganic bovine bone substitute (BO group). Patients were recalled after 4-6 months to evaluate the bone regeneration and to proceed with implant placement. A bone core was obtained during the implant procedure from each site and was used for histologic analysis. Histomorphometry revealed that residual graft values were significantly higher in the BO group (25.60% ± 5.89%) compared to the CPS group (17.40% ± 9.39%) (P < .05). The amount of new bone regenerated was also statistically significant higher in the alloplast group (47.15% ± 8.5%) as compared to the xenograft group (22.2% ± 3.5%) (P < .05). Results suggest that ridge preservation using a putty calcium phosphosilicate alloplastic bone substitute demonstrates more timely graft substitution and increased bone regeneration when compared to an anorganic bovine bone xenograft.


A multifactor complex of eukaryotic initiation factors, eIF1, eIF2, eIF3, eIF5, and initiator tRNA(Met) is an important translation initiation intermediate in vivo.
Translation initiation factor 2 (eIF2) bound to GTP transfers the initiator methionyl tRNA to the 40S ribosomal subunit. The eIF5 stimulates GTP hydrolysis by the eIF2/GTP/Met-tRNA(i)(Met) ternary complex on base-pairing between Met-tRNA(i)(Met) and the start codon. The eIF2, eIF5, and eIF1 all have been implicated in stringent selection of AUG as the start codon. The eIF3 binds to the 40S ribosome and promotes recruitment of the ternary complex; however, physical contact between eIF3 and eIF2 has not been observed. We show that yeast eIF5 can bridge interaction in vitro between eIF3 and eIF2 by binding simultaneously to the amino terminus of eIF3 subunit NIP1 and the amino-terminal half of eIF2beta, dependent on a conserved bipartite motif in the carboxyl terminus of eIF5. Additionally, the amino terminus of NIP1 can bind concurrently to eIF5 and eIF1. These findings suggest the occurrence of an eIF3/eIF1/eIF5/eIF2 multifactor complex, which was observed in cell extracts free of 40S ribosomes and found to contain stoichiometric amounts of tRNA(i)(Met). The multifactor complex was disrupted by the tif5-7A mutation in the bipartite motif of eIF5. Importantly, the tif5-7A mutant is temperature sensitive and displayed a substantial reduction in translation initiation at the restrictive temperature. We propose that the multifactor complex is an important intermediate in translation initiation in vivo.


Effect of Lipid Composition on RNA-Lipid Nanoparticle Properties and Their Sensitivity to Thin-Film Freezing and Drying.
A library of 16 lipid nanoparticle (LNP) formulations with orthogonally varying lipid molar ratios was designed and synthesized, using polyadenylic acid [poly(A)] as a model for mRNA, to explore the effect of lipid composition in LNPs on (i) the initial size of the resultant LNPs and encapsulation efficiency of RNA and (ii) the sensitivity of the LNPs to various conditions including cold storage, freezing (slow vs. rapid) and thawing, and drying. Least Absolute Shrinkage and Selection Operator (LASSO) regression was employed to identify the optimal lipid molar ratios and interactions that favorably affect the physical properties of the LNPs and enhance their stability in various stress conditions. LNPs exhibited distinct responses under each stress condition, highlighting the effect of lipid molar ratios and lipid interactions on the LNP physical properties and stability. We then demonstrated the feasibility of using thin-film freeze-drying to convert poly(A)-LNPs from liquid dispersions to dry powders while maintaining the integrity of the LNPs. Importantly, the residual moisture content in LNP dry powders significantly affected the LNP integrity.Residual moisture content of ≤0.5% or >3-3.5% w/w negatively affected the LNP size and/or RNA encapsulation efficiency, depending on the LNP composition. Finally, we showed that the thin-film freeze-dried LNP powders have desirable aerosol properties for potential pulmonary delivery. We conclude that Design of Experiments can be applied to identify mRNA-LNP formulations with the desired physical properties and stability profiles. Additionally, optimizing the residual moisture content in mRNA-LNP dry powders during freeze-drying is crucial to maintain the physical properties of the LNPs.


Purified JC virus T and T' proteins differentially interact with the retinoblastoma family of tumor suppressor proteins.
The amino termini of polyomavirus T antigens contain LXCXE and J domains, which are necessary for binding and inactivating the retinoblastoma family of tumor suppressors. Both of these motifs are found in the JC virus (JCV) early proteins T'(135), T'(136), and T'(165), leading to the suggestion that these recently discovered proteins complement the cell-cycle-deregulating function of the JCV large T antigen (TAg). To investigate this hypothesis, the three JCV T' proteins were produced in a baculovirus expression system and purified by immunoaffinity chromatography. To facilitate purification, hybridomas that secrete antibodies recognizing amino-terminal epitopes of JCV early proteins were produced. Potential interactions between the early viral proteins and the cellular proteins pRB, p107, and p130 were investigated by incubating purified JCV TAg and T' proteins with extracts of MOLT-4 cells, a human T cell line. The four viral proteins preferentially bound hypophosphorylated species of the cellular proteins and exhibited the highest binding affinity to p107 and the lowest affinity to pRB. TAg and T'(165) bound more pRB and less p107 than did T'(135) and T'(136); T'(165) also bound less p130 than the other three early proteins. Results of these in vitro interactions were compared to those obtained in vivo using POJ cells, a transformed human glial cell line that expresses JCV early proteins, relatively high levels of pRB and p107, and low levels of p130. Most of the pRB in POJ cells is hyperphosphorylated, and only a fraction of the hypophosphorylated form(s) of pRB is bound by the viral proteins. In contrast, only hypophosphorylated p130 is detected in the transformed cells, and most of this protein was found in complex with the viral proteins. Finally, nearly all of the p107 in POJ cells is bound by the JCV proteins.


Potential targets for pancreatic cancer immunotherapeutics.
Pancreatic adenocarcinoma is the fourth leading cause of cancer death with an overall 5-year survival of less than 5%. As there is ample evidence that pancreatic adenocarcinomas elicit antitumor immune responses, identification of pancreatic cancer-associated antigens has spurred the development of vaccination-based strategies for treatment. While promising results have been observed in animal tumor models, most clinical studies have found only limited success. As most trials were performed in patients with advanced pancreatic cancer, the contribution of immune suppressor mechanisms should be taken into account. In this article, we detail recent work in tumor antigen vaccination and the recently identified mechanisms of immune suppression in pancreatic cancer. We offer our perspective on how to increase the clinical efficacy of vaccines for pancreatic cancer.


Fowl typhoid and pullorum disease.
Fowl typhoid (FT) and pullorum disease (PD) are septicaemic diseases, primarily of chickens and turkeys, caused by Gram negative bacteria, Salmonella Gallinarum and S. Pullorum, respectively. Clinical signs in chicks and poults include anorexia, diarrhoea, dehydration, weakness and high mortality. In mature fowl, FT and PD are manifested by decreased egg production, fertility, hatchability and anorexia, and increased mortality. Gross and microscopic lesions due to FT and PD in chicks and poults include hepatitis, splenitis, typhlitis, omphalitis, myocarditis, ventriculitis, pneumonia, synovitis, peritonitis and ophthalmitis. In mature fowl, lesions include oophoritis, salpingitis, orchitis, peritonitis and perihepatitis. Transovarian infection resulting in infection of the egg and subsequently the chick or poult is one of the most important modes of transmission of these two diseases. Salmonella Gallinarum and S. Pullorum can be isolated by use of selective and non-selective media. Salmonella Pullorum produces rapid decarboxylation of ornithine whereas S. Gallinarum does not, an important biochemical difference between the two bacteria. Both FT and PD can be detected serologically by use of a macroscopic tube agglutination test, rapid serum test, stained antigen whole blood test or microagglutination test. Both diseases can be controlled and eradicated by use of serological testing and elimination of positive birds. Vaccines may be used to control the disease and antibiotics for the treatment of FT and PD. Although FT and PD are widely distributed throughout the world, the diseases have been eradicated from commercial poultry in developed countries such as the United States of America, Canada and most countries of Western Europe. Both S. Gallinarum and S. Pullorum are highly adapted to the host species, and therefore are of little public health significance.


The half-life of passively acquired antibody globulin molecules in infants.
By following the titer of passively acquired Rh antibodies in newborn infants, it is calculated that the half-life of the placenta-passing Rh antibody molecule is approximately 30 days. Evidence is offered that this estimate applies not only to placenta-passing Rh antibodies, but also to other placenta-passing antibodies, and not improbably to serum gamma globulin molecules in general. Studies on the fate of free Rh antibodies in erythroblastotic babies show that these antibodies often are eliminated no more rapidly in Rh-positive babies than in Rh-negative babies. On the other hand, incompatible alpha and beta antibodies, as a rule, are quickly neutralized and eliminated from the body of newborn infants. These observations provide one explanation for the lower incidence of erythroblastosis due to A-B sensitization in comparison with cases resulting from Rh sensitization.


Spontaneous fusiform middle cerebral artery aneurysms: characteristics and a proposed mechanism of formation.
The goal of this study was to identify the origins of spontaneous fusiform middle cerebral artery (MCA) aneurysms. One hundred two cases of spontaneous fusiform MCA aneurysms were reviewed, including 40 from the authors' institutions and 62 identified from the literature. The mean age at symptom onset was 38 years, and the male/female ratio was 1.4:1. At presentation, the MCA lumen was stenosed or occluded in 12 patients, focally dilated in 57, and appeared "serpentine" in 33. Most lesions originated from the M1 or M2 segments, and most (80%) presented with nonhemorrhagic symptoms or were discovered incidentally. The presenting clinical features correlated with morphological findings in the aneurysms, which could be observed to progress from a small focal dilation or vessel narrowing to a serpentine channel. Hemorrhage was the most common presentation in small lesions; the incidence of bleeding progressively diminished with larger lesions. Patients with stenoses or occluded vessels most often presented with ischemic symptoms, and occasionally with hemorrhage. Giant focal dilations or serpentine aneurysms were rarely associated with acute bleeding; clinical presentation was most often prompted by mass effect or thromboembolic stroke. Analysis of results after various treatments indicates that for symptomatic lesions, therapies that reverse intraaneurysmal blood flow and augment distal cerebral perfusion are associated with better outcomes than other strategies, including conservative management. Based on the spectrum of clinical, pathological, neuroimaging, and intraoperative findings, dissection is proposed as the underlying cause of these lesions.


Capacity building for mental health services: methodology and lessons learned from the Partners in Recovery initiative.
The Partners in Recovery (PIR) program was implemented by the Australian Government Department of Health. Its overriding aim was to improve the coordination of services for people with severe and persistent mental illness, and who have complex needs that are not being met. The PIR capacity-building project (CBP) was funded to provide capacity building activities to the nationwide network of consortia that were set up in 2013 to deliver PIR over a 3-year period. The purpose of this paper is to describe the design and findings from an evaluation of the PIR CBP. The evaluation involved collecting feedback from consenting PIR staff via an online survey and follow-up semi-structured interviews. CBP activities included: state and national meetings; a web portal; teleconferences; webinars; a support facilitator mentor program; and tailored support from the CBP team. The CBP made a positive contribution to the implementation and delivery of PIR. Staff highly valued activities that employed face-to-face interaction or provided informative knowledge exchange, and were appreciative of CBP staff being responsive and adaptable to their needs. From this evaluation, we recommend the following: identify relevant functions (e.g. prioritise networking), select the right mode of delivery (e.g. establish an online presence) and abide by key principles (e.g. be responsive to staff needs). This information is informing the mental health workforce capacity building activities that our team is currently undertaking.


Solution-processable single-material molecular emitters for organic light-emitting devices.
This tutorial review presents some recent developments in the design, synthesis and implementation of organic solution-processable molecular fluorophores for non-doped electroluminescent [corrected] devices. After a brief presentation of the basic principles of operation and main characteristics of electroluminescent devices, some examples of active emitters representative of the main classes of non-doped molecular electrofluorophores will be discussed. Emphasis is placed on the relationships between the molecular structure and the electronic properties of molecular emitters, in which high photoluminescence efficiency, synthetic accessibility and processability are combined by design with additional functions such as hole and/or electron injection and transport.


Novel management of glioma by molecular therapies, a review article.
The most frequent type of brain tumors is Glioma which commonly appears initially in the neuroglia in the central nervous system. They grow steadily and generally do not outspread to neighboring tissue of the brain. By applying dominant remedial regimens, the patients would have negligible survival rates. Despite the achieved advances in conventional glioma therapy, it proved that a proper medication for glioma is not easily reachable. The glioma penetration nature and accumulate resistance considerably limit the remedial options. Superior explanation of the glioma complex pathobiology and characterization of biological proteogenomic may finally open new approaches for the outlining of extra artificial and impressive combination regimens. This aim could be achieved by exclusively outfitting advanced techniques of neuroimaging, terminating synthesis of DNA via genes that activated via prodrugs, experimental technique of gene therapy via conciliating genes of gliomagenesis, targeting miRNA-mRNA activity of oncogenic, applying stem cell therapy for combining inhibitors of Hedgehog-Gli, adaptive transmission of chimeric immunoreceptors T cells, incorporate inhibitors of regulators of the immune system with conventional remedial modalities and additionally using tumor cell lysates as sources of antigen for efficient evacuation of particular stem cells of tumor via cytotoxic T lymphocytes. Consequently, in this study the authors trying to survey the latest progressions related to the molecular procedures connected with the formation of glial tumors in addition to the radiation, surgery and chemotherapy limitations. Additionally, the novel strategies of molecular remedies and their procedure for the prosperous treatment of glioma will be discussed.


Modeling Learner Heterogeneity: A Mixture Learning Model With Responses and Response Times.
The increased popularity of computer-based testing has enabled researchers to collect various types of process data, including test takers' reaction time to assessment items, also known as response times. In recent studies, the relationship between speed and accuracy in a learning setting was explored to understand students' fluency changes over time in applying the mastered skills in addition to skill mastery. This can be achieved by modeling the changes in response accuracy and response times throughout the learning process. We propose a mixture learning model that utilizes the response times and response accuracy. Such a model accounts for the heterogeneities in learning styles among learners and may provide instructors with valuable information, which can be used to design individualized instructions. A Bayesian modeling framework is developed for parameter estimation and the proposed model is evaluated through a simulation study and is fitted to a real data set collected from a computer-based learning system for spatial rotation skills.


Accuracy of Iliac Screws Insertion in Adult Spinal Deformity Surgery: Relationship Between Misplacement and the Iliac Morphologies.
Retrospective study. To investigate the accuracy of freehand iliac screw insertion and to determine how this can be performed safely. Seventy-seven adult scoliosis patients with an average age of 70.1 years who underwent spinal deformity surgery with spinopelvic fixation using bilateral iliac screws were enrolled. Penetration of the iliac table was assessed using postoperative computed tomography. Screw penetration of the iliac table or screw insertion from the sacroiliac joint was considered misplacement. Screw positioning was classified as the screw being in the proper position (group C), the screw penetrating the outer table (group O), and the screw penetrating the inner table (group I). The iliac opening angle and the distance between the posterior superior iliac spines (PSISs) were measured using preoperative computed tomography. The angle between the sacral slope and the iliac screw, termed as the sagittal screw angle, was measured using postoperative lateral lumbar radiography. Of the 154 iliac screws in 77 patients, 14 screws in 12 patients penetrated the outer table and 12 screws in 11 patients penetrated the inner table. The total proportion of misplacement was 18.8%, although there were no major complications. With regard to iliac morphology, the iliac opening angle was 24.2±4.3 degrees and the distance between the PSISs was 90.6±7.7 mm. The distance between the PSISs correlated negatively with the iliac opening angle. The iliac opening angle was smaller in group O than in group C (P<0.05). The sagittal screw angle in group I was smaller than that in group C (P<0.01). Screw penetration of the outer iliac table possibly occurred in patients with a narrow iliac opening angle. Screw penetration of the inner table occurred when the screw was inserted more cranially than the sacral slope. Therefore, the iliac screw should be inserted approximately parallel to the sacral slope.


Molecular dissection of nucleolin's role in growth and cell proliferation: new insights.
Cells require optimum protein synthetic activity in order to support cell proliferation, maintain homeostatic and metabolic integrity, and repair damage. Since growth depends on protein synthesis through ribosome biogenesis, the control of biosynthesis of ribosomes is necessarily a key element for control of growth. Nucleolin is a major nucleolar protein of exponentially growing eukaryotic cells, which is directly involved in the regulation of ribosome biogenesis and maturation. The highly conserved nucleolin contains three major domains through which it controls the organization of nucleolar chromatin, packaging of pre-RNA, rDNA transcription, and ribosome assembly. Numerous reports have implicated the involvement of nucleolin either directly or indirectly in the regulation of cell proliferation and growth, cytokinesis, replication, embryogenesis, and nucleogenesis. Nucleolin, an RNA binding protein, is also an autoantigen, a transcriptional repressor, and a switch region targeting factor. In addition, nucleolin exhibits autodegradation, DNA and RNA helicase activities, and DNA-dependent ATPase activity. An interesting aspect of nucleolin action is that it is a target for regulation by proteolysis, methylation, ADP-ribosylation, and phosphorylation by CKII, cdc2, PKC-xi, cyclic AMP-dependent protein kinase, and ecto-protein kinase. For these and other reasons, nucleolin is fundamental to the survival and proliferation of cells. Considerable progress has been made in recent years with the identification of new nucleolin binding proteins that may mediate these many nucleolin-dependent functions. Nucleolin also functions as a cell surface receptor, where it acts as a shuttling protein between cytoplasm and nucleus, and thus can even provide a mechanism for extracellular regulation of nuclear events. Exploration of the regulation of this multifaceted protein in a remarkable number of diverse functions is challenging.


Dental Emergencies: A Practical Guide.
Dental disease is a frequent finding on head and neck images, especially in the context of emergencies, and can be a challenge for radiologists who are inexperienced with findings of dental trauma or disease. Dental abnormalities can be subtle and therefore must be included in the systematic approach to these images. Although dedicated dental images are not acquired in most emergency cases, the teeth are included on many different images of the head and neck, and their initial evaluation seldom requires a specific protocol. The high prevalence of craniofacial trauma, sinus infection, and maxillomandibular procedures, among other conditions, frequently requires interpretation of dental images in daily emergency practice. The imaging findings can be categorized into infection, trauma, and complications of procedures, although sometimes these categories can overlap. Such categories can help the radiologist decide which imaging protocol and dynamic maneuvers should be used and are also useful when reading images and proposing differential diagnoses. Familiarity with the imaging findings of dental emergencies improves the radiologist's diagnostic confidence and role in guiding patient care, avoiding progression to life-threatening conditions, and reducing aesthetic problems, dental loss, and related conditions. Information about the imaging protocols is provided, the relevant anatomy of the teeth and related structures is reviewed, and the key imaging findings of dental emergencies are presented.©RSNA, 2019.


[Biochemical modifications of connective tissue induced by the non-saponifiables of avocado and soya-bean oils administered percutaneously in the "Hairless" rat (author's transl)].
A mixture of non-saponifiable fractions of avocado and soya-bean oils was administered percutaneously, for fifteen days, in a 5% dilution in decanol. They resulted in modifications of constituents of connective tissue of the treated skin and in subjacent carrageenan induced granulome. The effect on the granuloma was reduced to an increased total protein content. As for the skin, the effect of the non-saponifiables was different from that induced by the vehicle by an increase of water and lipids and an increased level of soluble proteins, including collagen, as compared to insoluble proteins. The results are in agreement with those obtained using the non-saponifiables taken orally but the effects appear sooner and are localized essentially at skin level.


[Analysis of registries of live births in an urban area of Southern Brazil].
Live births which occurred in the period from April to September of 1994 were analysed, using the two copies of the Birth Declaration-BD-(the white copy coming from the hospital where the child was born and the yellow copy sent by the Legal Registry Office where the birth was registered) received by the Londrina Municipal Health Service. After the "cross matching" of both copies (for each child), household interviews were performed in cases without matched pairs (only a white or only a yellow copy indicating possible unregistered or home deliveries). Results showed that the proportion of births not legally registered was of from 5.3 to 6.6% of the hospital births. Cost, negligence and legitimacy were the main reasons given for not registering births legally. The average time taken to make the registration was 26.5 days (standard deviation of 52 days) and 88.7% of the families did it by the 60th day from the date of the birth. A statistical association was detected between the act of registration and the period within which registration is required (within 60 days from birth) and type of delivery, maternal age and education. The official proportion of home deliveries was 0.5%; however, after the research the value was found to be somewhere between 0.13 and 0.3% of all the registered births--only 36.8% were really born at home. Reasons for home deliveries were: option, "there wasn't a means of transport to take the pregnant woman to hospital" and "there wasn't enough time to get to a hospital".


CNS-endocrine pancreas system. I. The hypothalamus response to insulin deficiency.
The anterior, medial and posterior hypothalamic nuclei in alloxan-diabetic male rats were studied by karyometry. Selective responsiveness of separate nuclei of the medial basal hypothalamus (MBH) and the anterior hypothalamus was revealed. In the MBH cell nuclear-size changes were most prominent in the ventromedial nucleus and less pronounced, but significant, in the arcuate nucleus. In the anterior hypothalamus a significant response was produced by the supraoptic nucleus. The authors do not exclude the possibility that the reaction of the neurosecretory cells of the supraotic nucleus is indirect and reflects disturbed vasopressin balance in alloxan-diabetic rats in response to impairment of water-salt metabolism. The responsiveness of the MBH nuclei is considered as evidence for their involvement, the bentromedial nucleus in particular, in hypothalamic control of the endocrine pancreas. Various means by which insulin-sensitive hypothalamic areas may be implicated in this control are discussed.


Solar heating and cooling.
We have adequate theory and engineering capability to design, install, and use equipment for solar space and water heating. Energy can be delivered at costs that are competitive now with such high-cost energy sources as much fuel-generated, electrical resistance heating. The technology of heating is being improved through collector developments, improved materials, and studies of new ways to carry out the heating processes. Solar cooling is still in the experimental stage. Relatively few experiments have yielded information on solar operation of absorption coolers, on use of night sky radiation in locations with clear skies, on the combination of a solar-operated Rankine engine and a compression cooler, and on open cycle, humidification-dehumidification systems. Many more possibilities for exploration exist. Solar cooling may benefit from collector developments that permit energy delivery at higher temperatures and thus solar operation of additional kinds of cycles. Improved solar cooling capability can open up new applications of solar energy, particularly for larger buildings, and can result in markets for retrofitting existing buildings. Solar energy for buildings can, in the next decade, make a significant contribution to the national energy economy and to the pocketbooks of many individual users. very large-aggregate enterprises in manufacture, sale, and installation of solar energy equipment can result, which can involve a spectrum of large and small businesses. In our view, the technology is here or will soon be at hand; thus the basic decisions as to whether the United States uses this resource will be political in nature.


[Nature, colonization, and utopia in the works of João Daniel].
The article analyzes certain aspects of "Tesouro descoberto no rio Amazonas" (Treasure discovered on the Amazon River), written by João Daniel (1722-76) during his time in the State of Maranhão e Grão-Pará as a Jesuit missionary between 1741 and 1757; the priest was banished to Lisbon two years before the Company of Jesus was expelled from Portuguese America. This unique record of the mid-eighteenth-century Amazon is a compendium on the region's wealth and potential. Most importantly, it put forward a colonization project that was critical of the model then in place; the new proposal was an integrated whole which took environmental conditions, technology, and social relations into account in the organization of local society. In centering his project on the issue of labor, João Daniel revives, as a metaphor, the idea of the Amazon as an earthly paradise-a notion that had characterized seventeenth-century missionary literature but was practically abandoned in the eighteenth century.


[The optimal screening of cervix cancer: combination of polymerase chain reaction technique in real time (Cobas 4800 device) with liquid cytology].
The study was organized to assess the sensitivity of combined technique of diagnostics of pre-cancer and cervix cancer consisted of liquid cytology and detection of clinically significant amount of Human Papillomavirus DNA in cervical samples of cervix. The cervical samples of 62 women were collected to into medium for liquid cytology and Papanikolau's stained in the system B&D TriPath. The results were evaluated according the Bethesda classification. Concurrently with the same material, the polymerase chain reaction technique in real time was applied using the Cobas 4800 device. To specify the cytological diagnosis ASC-US and under L-SIL and H-SIL the immunocitochemical detection of oncomarkers p16INK4a and Ki-67 was implemented using additionally prepared glass of the same material obtained by the liquid cytology technique. The study detected Human Papillomavirus DNA of oncogenic types in 12 cases out of 13 H-SIL (92.3%) < and in 3 cases out of 4 L-SIL (75%). In 31 female patients with ASC-US no clinically significant amount of Human Papillomavirus DNA was detected. This result correlated with the results of immunocitochemical analyses where expression of marker p16INK4a was not present. In 5 out of 9 female patients (55.6%.) aged 21-24 years with cytological diagnosis NILM Human Papillomavirus DNA was detected. The cytological analysis detected in 53 out of 63 female patients the atypical cells of cervix pavement epithelium (85.5%). The combined technique detected pathology in 58 female patients (93.5%). The cytological analysis of Human Papillomavirus was complemented by testing with Cobas 4800 device because this system permits to detect 14 highly oncogenic types of Human Papillomavirus with separate genetic typing of Human Papillomavirus of 16 and 18 types.


Upper airway obstruction in the syndromal craniosynostoses.
This series of consecutive cases details the prevalence and management of upper airway obstruction in the syndromal craniosynostoses (Crouzon, Apert and Pfeiffer syndromes). Upper airway obstruction presents more frequently in Crouzon and Pfeiffer syndrome when presenting early and during the intermediate years. Those patients with Apert syndrome appear relatively free of this problem. Management has been directed toward increasing the size of the nasopharyngeal space by soft tissue alterations (uvulopalatopharyngoplasty, soft palatal split and adenotonsillectomy) with success. Le Fort III advancement osteotomy has been reserved for those more extreme cases, again with objective airway improvement. These techniques have removed the necessity for the progression to tracheostomy in these cases.


TRPM3_miR-204: a complex locus for eye development and disease.
First discovered in a light-sensitive retinal mutant of Drosophila, the transient receptor potential (TRP) superfamily of non-selective cation channels serve as polymodal cellular sensors that participate in diverse physiological processes across the animal kingdom including the perception of light, temperature, pressure, and pain. TRPM3 belongs to the melastatin sub-family of TRP channels and has been shown to function as a spontaneous calcium channel, with permeability to other cations influenced by alternative splicing and/or non-canonical channel activity. Activators of TRPM3 channels include the neurosteroid pregnenolone sulfate, calmodulin, phosphoinositides, and heat, whereas inhibitors include certain drugs, plant-derived metabolites, and G-protein subunits. Activation of TRPM3 channels at the cell membrane elicits a signal transduction cascade of mitogen-activated kinases and stimulus response transcription factors. The mammalian TRPM3 gene hosts a non-coding microRNA gene specifying miR-204 that serves as both a tumor suppressor and a negative regulator of post-transcriptional gene expression during eye development in vertebrates. Ocular co-expression of TRPM3 and miR-204 is upregulated by the paired box 6 transcription factor (PAX6) and mutations in all three corresponding genes underlie inherited forms of eye disease in humans including early-onset cataract, retinal dystrophy, and coloboma. This review outlines the genomic and functional complexity of the TRPM3_miR-204 locus in mammalian eye development and disease.


Modeling infectious diseases dissemination through online role-playing games.
As mathematical modeling of infectious diseases becomes increasingly important for developing public health policies, a novel platform for such studies might be considered. Millions of people worldwide play interactive online role-playing games, forming complex and rich networks among their virtual characters. An unexpected outbreak of an infective communicable disease (unplanned by the game creators) recently occurred in this virtual world. This outbreak holds surprising similarities to real-world epidemics. It is possible that these virtual environments could serve as a platform for studying the dissemination of infectious diseases, and as a testing ground for novel interventions to control emerging communicable diseases.


The moral economy of the pharmaceutical industry: Legitimising prices.
The practices of pharmaceutical companies have been widely criticised by researchers and investigative journalists, yet their conduct has mostly escaped significant moral opprobrium from the wider public, health professionals and governments. This article examines one reason for this by exploring the techniques companies use when seeking to justify and legitimise their conduct - legitimising techniques that help to render their failures to adhere to accepted standards less visible. It explores these techniques by examining four cases involving pricing where the companies' conduct has, nonetheless, been questioned. It is divided into three parts. The first looks at various publicly-stated standards that provide the moral context for the industry's activities. The second examines four cases, each involving pricing, where companies' prices have been challenged as morally unacceptable, each leading to a US Government investigation. These provide a means of exploring how companies seek to justify their actions in order to maintain the appearance of conformity to accepted moral standards. The third considers some reasons why the industry's efforts at legitimation have considerable force. The analysis shows not only the character of the claims made by pharmaceutical companies in defence of their practices - claims about the health benefits of the medicine, access to it, and research and development costs, which are all often exaggerated. It also shows why the companies' legitimising tactics are typically effective.


Indel-correcting DNA barcodes for high-throughput sequencing.
Many large-scale, high-throughput experiments use DNA barcodes, short DNA sequences prepended to DNA libraries, for identification of individuals in pooled biomolecule populations. However, DNA synthesis and sequencing errors confound the correct interpretation of observed barcodes and can lead to significant data loss or spurious results. Widely used error-correcting codes borrowed from computer science (e.g., Hamming, Levenshtein codes) do not properly account for insertions and deletions (indels) in DNA barcodes, even though deletions are the most common type of synthesis error. Here, we present and experimentally validate filled/truncated right end edit (FREE) barcodes, which correct substitution, insertion, and deletion errors, even when these errors alter the barcode length. FREE barcodes are designed with experimental considerations in mind, including balanced guanine-cytosine (GC) content, minimal homopolymer runs, and reduced internal hairpin propensity. We generate and include lists of barcodes with different lengths and error correction levels that may be useful in diverse high-throughput applications, including >106 single-error-correcting 16-mers that strike a balance between decoding accuracy, barcode length, and library size. Moreover, concatenating two or more FREE codes into a single barcode increases the available barcode space combinatorially, generating lists with >1015 error-correcting barcodes. The included software for creating barcode libraries and decoding sequenced barcodes is efficient and designed to be user-friendly for the general biology community.


Allyl methyl disulfide (AMDS) prevents N,N-dimethyl formamide-induced liver damage by suppressing oxidative stress and NLRP3 inflammasome activation.
N,N-dimethylformamide (DMF), a widely consumed industrial solvent with persistent characteristics, can induce occupational liver damage and pose threats to the general population due to the enormous DMF-containing industrial efflux and emission from indoor facilities. This study was performed to explore the roles of allyl methyl disulfide (AMDS) in liver damage induced by DMF and the underlying mechanisms. AMDS was found to effectively suppress the elevation in the liver weight/body weight ratio and serum aminotransferase activities, and reduce the mortality of mice induced by DMF. In addition, AMDS abrogated DMF-elicited increases in malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) levels and decreases in glutathione (GSH) levels in mouse livers. The increase in macrophage number, mRNA expression of M1 macrophage biomarkers, and protein expression of key components in the NF-κB pathway and NLRP3 inflammasome induced by DMF exposure were all suppressed by AMDS in mouse livers. Furthermore, AMDS inhibited DMF-induced cell damage and NF-κB activation in cocultured AML12 hepatocytes and J774A.1 macrophages. However, AMDS per se did not significantly affect the protein level and activity of CYP2E1. Collectively, these results demonstrate that AMDS effectively ameliorates DMF-induced acute liver damage possibly by suppressing oxidative stress and inactivating the NF-κB pathway and NLRP3 inflammasome.