F1000 Research

Published by F1000Research
Online ISSN: 2046-1402
Publications
Background: Previous studies have shown that gainfully employed individuals with high work demands and low control at work (denoted "job strain") are at increased risk of common mental disorders, including depression. Most existing studies have, however, measured depression using self-rated symptom scales that do not necessarily correspond to clinically diagnosed depression. In addition, a meta-analysis from 2008 indicated publication bias in the field. Methods: This study protocol describes the planned design and analyses of an individual participant data meta-analysis, to examine whether job strain is associated with an increased risk of clinically diagnosed unipolar depression based on hospital treatment registers. The study will be based on data from approximately 120,000 individuals who participated in 14 studies on work environment and health in 4 European countries. The self-reported working conditions data will be merged with national registers on psychiatric hospital treatment, primarily hospital admissions. Study-specific risk estimates for the association between job strain and depression will be calculated using Cox regressions. The study-specific risk estimates will be pooled using random effects meta-analysis. Discussion: The planned analyses will help clarify whether job strain is associated with an increased risk of clinically diagnosed unipolar depression. As the analysis is based on pre-planned study protocols and an individual participant data meta-analysis, the pooled risk estimates will not be influenced by selective reporting and publication bias. However, the results of the planned study may only pertain to severe cases of unipolar depression, because of the outcome measure applied.
 
Impaired base-line proliferation in the hippocampus in the absence of αβ T cells. (A) Representative BrdU immunohistochemistry of the hippocampal dentate gyrus from eight week-old wild-type (A1), TCRα +/− (A2) and TCRα −/− (A3) mice, 24 hours after the first of 3 consecutive BrdU injections. Scale bar, 100 μm. (B) Quantification of BrdU + cells in the dentate gyrus of wild-type (n = 6), TCRα +/− (n = 7) and TCRα −/− (n = 8) mice. All numbers are mean ± SEM. ANOVA, * p < 0.05.  
CD4 + T cells provide a neuro-immunological link in the regulation of adult hippocampal neurogenesis, but the exact mechanisms underlying enhanced neural precursor cell proliferation and the relative contribution of different T helper (Th) cell subsets have remained unclear. Here, we explored the proneurogenic potential of interleukin 17-producing T helper (Th17) cells, a developmentally and functionally distinct Th cell subset that is a key mediator of autoimmune neurodegeneration. We found that base-line proliferation of hippocampal precursor cells in a T cell-deficient mouse model of impaired hippocampal neurogenesis can be restored upon adoptive transfer with homogeneous Th17 populations enriched for myelin-reactive T cell receptors. In these experiments, enhanced proliferation was independent of direct interactions of infiltrating Th17 cells with precursor cells or neighboring cells in the hippocampal neurogenic niche. Complementary studies in immunocompetent mice identified several receptors for Th17 cell-derived cytokines with mRNA expression in hippocampal precursor cells and dentate gyrus tissue, suggesting that Th17 cell activity in peripheral lymphoid tissues might promote hippocampal neurogenesis through secreted cytokines.
 
A new molecular ligand for positron emission tomography (PET) of the human brain, [18F]-T807, is under investigation for the antemortem detection of pathological neurofibrillary aggregates, which are evidence of neurofibrillary tangle (NFT) diseases, also known as tauopathies. Repetitive mild traumatic brain injuries in athletes and battlefield veterans are associated with one such tauopathy, known as chronic traumatic encephalopathy (CTE). In a recent case report, a former NFL player with clinically probable CTE and a concurrent Progressive Supranuclear Palsy (PSP) -like syndrome was studied using [18F]-T807. The interpretation of this player's [18F]-T807 PET imaging was complicated by the overlap of tracer uptake in brain regions involved in CTE and PSP with regions associated with either nonspecific [18F]-T807 ligand binding or "aging-associated" binding of [18F]-T807 to authentic tauopathy known to be associated with aging and disease severity (i.e., NFT in the mesial temporal lobe). The implications of these data for the utility of [18F]-T807 in the pre-mortem detection of CTE are summarized.
 
This article assesses the evidence for the hypothesis that a decline in all types of crime since the early 1990s in the USA was an unintended consequence of removing lead from petrol between 1975 and 1985. It describes ecological and econometric studies that have generally but not always found correlations between lead exposures in childhood and some types of crime 20 years later; a small number of epidemiological studies that have found a dose-response relationship between lead exposure in childhood and self-reported and officially recorded criminal offences in young adulthood; and evidence for the biological plausibility of a causal relationship. The major anomaly in the evidence is that the associations reported in ecological studies are much stronger (explaining 56-90% of the variation in crime rates) than the weaker relationships found in the cohort studies (that typically explain less than 1% of the variance in offending). Suggestions are made for research that will better assess the contribution that reduced lead exposure has made to declining crime rates in the USA.
 
Background: Reports have suggested that academic medicine may be in decline within the UK. Further evidence suggests that rates of subsequent full publication of abstracts presented at major scientific meetings are low and may be declining. We have compared the publication rates of abstracts presented at meetings of the British Society of Gastroenterology (BSG) between 1995 and 2005 and examined factors associated with full paper publication. Methods: Abstracts presented at BSG meetings in 1995 and 2005 were assessed by cross-referencing with multiple databases. Abstract characteristics associated with publication were analysed. Results: There were no differences in overall publication rates, impact factors or time to publication between 1995 and 2005. Overall, basic-science abstracts were twice as likely to achieve full publication than non-basic science. There was a significant fall in the publication rates for case series and audits, and significantly increased rates for fundamental/basic-science abstracts over the study period. There were non-significant increases in publication rates for controlled trials and systematic reviews. In general, publication rates for all predominantly clinically orientated abstracts reduced between the two periods with the most notable fall occurring in nutrition. Conclusions: There was no evidence of a decline in overall abstract publication rates between 1995 and 2005. There seemed to be trend for increased publication rates of abstracts using perceived high-quality study methodologies with a corresponding decrease in those with lower quality methods. The proportion of basic-science abstracts is likely to be a determinant of overall full publication rates following scientific meetings.
 
Curcumin significantly increases chondrocyte death after 24 hours (A) at 50μM and 100μM compared to control indicated by *** (p<0.001). After 48 hours (B) and five days (C), curcumin (25μM) significantly increases chondrocyte death compared to controls. The nitric oxide donor, sodium nitroprusside (SNP) (50mM) also significantly increases chondrocyte death at 24 hours, 48 hours, and five days (p<0.001) compared to control. DMSO at concentrations found in the 100μM curcumin treatment has no effect on chondrocyte death. Results are expressed as the mean number of dead cells per field of view per treatment ± SEM. Data presented are from 5 different animals with 2 technical replicates per animal.  
Effect of curcumin on proteoglycan (PG) release from unstimulated cartilage explants. Control column indicates cartilage discs incubated in the culture medium alone. Values are reported as the mean of three animals per treatment ± SEM. Data are from 3 different animals, with three technical replicates per animal. Significance compared to control is indicated by *** (p<0.001). Sodium nitroprusside (SNP) (50mM) significantly increases PG release compared to control (p<0.001). Curcumin does not alter PG release from the explants compared to control at concentrations of 12μM, 25μM or 50μM. PG loss is expressed as sulfated glycosaminoglycan (GAG) release.  
Effect of curcumin on PG release (A) and prostaglandin E2 (PGE 2 ) (B) from interleukin (IL)-1β-stimulated cartilage explants (dark grey columns) (n=3). Control (light grey column) indicates cartilage discs incubated in the culture medium alone. Values are reported as the mean of three animals per treatment ± SEM. Data are from 3 different animals, with three technical replicates per animal. Significance compared to IL-1β is indicated by * (p<0.05), ** (p<0.01) and *** (p<0.001). IL-1β significantly increases proteoglycan (PG) (p<0.001) and PGE 2 (p<0.001) release compared to control. The non-steroidal anti-inflammatory drug (NSAID) carprofen (100μg/ml) significantly reduces IL-1β-stimulated PG (p<0.01) and PGE 2 (p<0.001) release. Curcumin significantly reduces IL-1β-stimulated PG release at 3μM (p<0.05), 6μM (p<0.01), 12μM (p<0.01), 25μM (p<0.001) and 50μM (p<0.001). IL-1β-stimulated PGE 2 release is also significantly reduced at all curcumin concentrations (p<0.001). PG loss is expressed as sulfated glycosaminoglycan (GAG) release.  
Western blot images and quantifying graphs of matrix metalloproteinase (MMP)-3 in the cartilage explant supernatants from three animals (A, B, and C). The lane on the left of the images shows the molecular weights (MW) of standard markers (Invitrogen, Paisley, Scotland, UK) in kilodaltons (kDa). Graph D shows the relative intensity of bands from all three animals with labeled treatment axes. Values are reported as the mean of three animals per treatment ± SEM. Significance compared to interleukin (IL)-1β is indicated by ** (p<0.01) and *** (p<0.001). All lanes contain equal volumes of protein (50μg protein per lane). Unstimulated cartilage explants release low levels of MMP-3 as shown by the controls in lane 1. Secretion of MMP-3 from explants is significantly increased (p<0.001) by IL-1β (10ng/ml) (Lane 2). The non-steroidal anti-inflammatory drug (NSAID) carprofen (100μg/ml) (Lane 3) significantly reduces IL-1β-stimulated MMP-3 secretion (p<0.01) to near control levels. Curcumin at concentrations of 3μM (Lane 4) and 6μM (Lane 5) does not significantly reduce IL-1β-stimulated MMP-3 release from the explants. However, a significant reduction is observed at 12μM (p<0.01) (Lane 6), 25μM (p<0.01) (Lane 7) and 50μM (p<0.001) (Lane 8) from explants in a dose dependent manner. The extent of reduction differs between animals (one technical replicate was used from each animal).  
Objective: Curcumin (diferuloylmethane) is a phytochemical with potent anti-inflammatory and anti-oxidant properties, and has therapeutic potential for the treatment of a range of inflammatory diseases, including osteoarthritis (OA). The aim of this study was to determine whether non-toxic concentrations of curcumin can reduce interleukin-1beta (IL-1β)-stimulated inflammation and catabolism in an explant model of cartilage inflammation. Methods: Articular cartilage explants and primary chondrocytes were obtained from equine metacarpophalangeal joints. Curcumin was added to monolayer cultured primary chondrocytes and cartilage explants in concentrations ranging from 3μM-100μM. Prostaglandin E 2 (PGE 2) and matrix metalloproteinase (MMP)-3 release into the secretome of IL-1β-stimulated explants was measured using a competitive ELISA and western blotting respectively. Proteoglycan (PG) release in the secretome was measured using the 1,9-dimethylmethylene blue (DMMB) assay. Cytotoxicity was assessed with a live/dead assay in monolayer cultures after 24 hours, 48 hours and five days, and in explants after five days. Results: Curcumin induced chondrocyte death in primary cultures (50μM p<0.001 and 100μM p<0.001) after 24 hours. After 48 hours and five days, curcumin (≥25μM) significantly increased cell death ( p<0.001 both time points). In explants, curcumin toxicity was not observed at concentrations up to and including 25μM after five days. Curcumin (≥3μM) significantly reduced IL-1β-stimulated PG ( p<0.05) and PGE 2 release ( p<0.001) from explants, whilst curcumin (≥12μM) significantly reduced MMP-3 release ( p<0.01). Conclusion: Non-cytotoxic concentrations of curcumin exert anti-catabolic and anti-inflammatory effects in cartilage explants.
 
FHbp, PorA, NadA and NHBA typing analysis of meningococcal serogroup W isolates from Ghana and Burkina Faso. The fHbp variant group is designated according to the classification proposed by Masignani et al. 17 . FHbp sequence ID, PorA subtype, nadA and nhbA allele were determined by sequence query on http://pubmlst.org/neisseria. Each isolate was typed by PCR amplification of each respective gene and sequence analysis using bioinformatics software Simmonics, Mega 5 and Chromas. NadA + IS1301: Strains with NadA encoding gene containing insertion sequence IS1301. NHBA-/stop codon: Strains lacking the NHBA encoding gene or having nhbA with stop codon.  
Primers used for PCR amplification and sequencing of the genes fHbp, porA, nadA snd nhbA. 
Conditions used for PCR amplification of the genes fHbp, porA, nadA and nhbA. 
Neisseria meningitidis is a major cause of bacterial meningitis and a considerable health problem in the 25 countries of the ‘African Meningitis Belt’ that extends from Senegal in West Africa to Ethiopia in the East. Approximately 80% of cases of meningococcal meningitis in Africa have been caused by strains belonging to capsular serogroup A. After the introduction of a serogroup A conjugate polysaccharide vaccine, MenAfriVac ™, that began in December 2010, the incidence of meningitis due to serogroup A has markedly declined in this region. Currently, serogroup W of N. meningitidis accounts for the majority of cases. Vaccines based on sub-capsular antigens, such as Generalized Modules for Membrane Antigens (GMMA), are under investigation for use in Africa. To analyse the antigenic properties of a serogroup W wave of colonisation and disease, we investigated the molecular diversity of the protein vaccine antigens PorA, Neisserial Adhesin A (NadA), Neisserial heparin-binding antigen (NHBA) and factor H binding protein (fHbp) of 31 invasive and carriage serogroup W isolates collected as part of a longitudinal study from Ghana and Burkina Faso between 2003 and 2009. We found that the isolates all expressed fHbp variant 2 ID 22 or 23, differing from each other by only one amino acid, and a single PorA subtype of P1.5,2. Of the isolates, 49% had a functional nhbA gene and 100% had the nadA allele 3, which contained the insertion sequence IS1301 in five isolates. Of the W isolates tested, 41% had high fHbp expression when compared with a reference serogroup B strain, known to be a high expresser of fHbp variant 2. Our results indicate that in this collection of serogroup W isolates, there is limited antigenic diversification over time of vaccine candidate outer membrane proteins (OMP), thus making them promising candidates for inclusion in a protein-based vaccine against meningococcal meningitis for Africa.
 
We analyzed how land-use patterns and changes in urbanization influence reported rabid raccoons in Georgia from 2006 - 2010. Using Geographical Information Systems and rabies surveillance data, multivariate analysis was conducted on 15 land-use variables that included natural topography, agricultural development, and urbanization to model positive raccoon rabies cases while controlling for potential raccoon submission bias associated with higher human population densities. Low intensity residential development was positively associated with reported rabid raccoons while a negative association was found with evergreen forest. Evergreen forests may offer a barrier effect where resources are low and raccoon populations are not supported. Areas with pure stands of upland evergreen forest might be utilized in baiting strategies for oral rabies vaccination programs where fewer or no baits may be needed. Their use as a barrier should be considered carefully in a cost-effective strategy for oral rabies vaccination (ORV) programs to contain the western spread of this important zoonotic disease.
 
Background: During March 2009 a novel Influenza A virus emerged in Mexico. We describe the clinical picture of the pandemic Influenza A (H1N1) Influenza in cancer patients during the 2009 influenza season. Methods: Twelve centers participated in a multicenter retrospective observational study of cancer patients with confirmed infection with the 2009 H1N1 Influenza A virus (influenza-like illness or pneumonia plus positive PCR for the 2009 H1N1 Influenza A virus in respiratory secretions). Clinical data were obtained by retrospective chart review and analyzed. Results: From May to August 2009, data of 65 patients were collected. Median age was 51 years, 57 % of the patients were female. Most patients (47) had onco-hematological cancers and 18 had solid tumors. Cancer treatment mainly consisted of chemotherapy (46), or stem cell transplantation (SCT) (16). Only 19 of 64 patients had received the 2009 seasonal Influenza vaccine. Clinical presentation included pneumonia (43) and upper respiratory tract infection (22). Forty five of 58 ambulatory patients were admitted. Mechanical ventilation was required in 12 patients (18%). Treatment included oseltamivir monotherapy or in combination with amantadine for a median of 7 days. The global 30-day mortality rate was 18%. All 12 deaths were among the non-vaccinated patients. No deaths were observed among the 19 vaccinated patients. Oxygen saturation <96% at presentation was a predictor of mortality (OR 19.5; 95%CI: 2.28 to 165.9). Conclusions: In our cancer patient population, the pandemic 2009 Influenza A (H1N1) virus was associated with high incidence of pneumonia (66%), and 30-day mortality (18.5%). Saturation <96% was significantly associated with death. No deaths were observed among vaccinated patients.
 
mTOR controls metabolism. Mammalian TOR complex 1 (mTORC1) promotes anabolic processes, such as the biosynthesis of proteins, nucleotides and lipids, and inhibits catabolic processes such as autophagy. Aa | mTORC1 phosphorylates (P) the hydrophobic motif (Thr389) in ribosomal S6 kinase (S6K), thereby activating it to subsequently phosphorylate ribosomal protein S6 at the sites indicated to promote ribosome biogenesis. mTORC1 also phosphorylates eIF4E-binding protein (4E-BP) at multiple sites to inhibit it. Inhibition of 4E-BP stimulates translation initiation, especially of 5′ oligopyrimidine tract (termed a 5′ TOP) and pyrimidine-rich translational element (PRTE) containing mRNAs. Ab | mTORC1 stimulates nucleotide and lipid synthesis. mTORC1 promotes the gene expression of key enzymes in the pentose phosphate pathway (PPP), at least in part by activating sterol regulatory element-binding proteins (SREBPs). mTORC1 also stimulates CAD (Gln-dependent carbamoyl-phosphate synthase, Asp carbamoyltransferase, dihydroorotase) by S6K-mediated phosphorylation at Ser1859, which leads to CAD activation and the stimulation of de novo pyrimidine synthesis. Furthermore, mTORC1 promotes lipogenic gene expression by activating S6K or by inhibiting the nuclear translocation of LIPIN1, both of which activate the transcription factor SREBP. Ac | mTORC1 inhibits autophagy by phosphorylating UNC-51-like kinase 1 (ULK1) at Ser758 and ATG14 at multiple sites. During mTORC1 inhibition, AMPK phosphorylates ULK1 at Ser317, and thereby activates ULK1, which phosphorylates Beclin 1 in the vacuolar protein sorting 34 (VPS34)-Beclin 1-ATG14 complex to initiate autophagy. mTORC1 also inhibits autophagy indirectly by blocking lysosome biogenesis, by phosphorylating and inhibiting the nuclear translocation of transcription factor EB (TFEB). B | mTORC2 co-translationally phosphorylates AKT at Thr450 to prevent its ubiquitylation and degradation. mTORC2 also post-translationally phosphorylates ATK at Ser473 to promote lipogenic gene expression by activation of SREBP1c. Moreover, mTORC2 co-translationally phosphorylates IGF2 mRNA-binding protein 1 (IMP1) at Ser181, which stimulates insulin-like growth factor 2 (IGF2) production. The activity of proteins shown in green is promoted by mTOR. The activity of proteins shown in red is inhibited by mTOR. Phosphorylation depicted in yellow is an activation signal and phosphorylation depicted in red is an inhibitory signal. Dashed arrows represent translocation of the protein. mLST8, mammalian lethal with SEC thirteen 8; PDK, phosphoinositide-dependent kinase 1; RAPTOR, regulatory-associated protein of mTOR; RICTOR, rapamycin-insensitive companion of mTOR; SIN1, SAPK-interacting 1. This figure has been reproduced with kind permission from Shimobayashi M, Hall M. Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nature Reviews Molecular Cell Biology 2014;15:155-162. 
Background: As part of a coordinated effort to expand our research activity at the interface of Aging and Energetics a team of investigators at The University of Alabama at Birmingham systematically assayed and catalogued the top research priorities identified in leading publications in that domain, believing the result would be useful to the scientific community at large. Objective: To identify research priorities and opportunities in the domain of aging and energetics as advocated in the 40 most cited papers related to aging and energetics in the last 4 years. Design: The investigators conducted a search for papers on aging and energetics in Scopus, ranked the resulting papers by number of times they were cited, and selected the ten most-cited papers in each of the four years that include 2010 to 2013, inclusive. Results: Ten research categories were identified from the 40 papers. These included: (1) Calorie restriction (CR) longevity response, (2) role of mTOR (mechanistic target of Rapamycin) and related factors in lifespan extension, (3) nutrient effects beyond energy (especially resveratrol, omega-3 fatty acids, and selected amino acids), 4) autophagy and increased longevity and health, (5) aging-associated predictors of chronic disease, (6) use and effects of mesenchymal stem cells (MSCs), (7) telomeres relative to aging and energetics, (8) accretion and effects of body fat, (9) the aging heart, and (10) mitochondria, reactive oxygen species, and cellular energetics. Conclusion: The field is rich with exciting opportunities to build upon our existing knowledge about the relations among aspects of aging and aspects of energetics and to better understand the mechanisms which connect them.
 
Matrix Metallopeptidase 1 (MMP-1) expression has repeatedly been correlated to tumorigenesis and metastasis. Yet, MMP-1 regulation in a metastatic context remains largely unknown. Here we confirm differential MMP-1 expression in mammary carcinoma cells with varied metastatic potentials. We show that MMP-1 expression is regulated by an AP-1 element in its promoter in highly metastatic MDA-MB-231 mammary carcinoma cell derivatives. Fra-1, an AP-1 family transcription factor, differentially binds this element in highly metastatic cells compared to low metastatic cells and is required for MMP-1 expression. Overexpression of Fra-1 also caused increased MMP-1 expression. Fra-1 mRNA levels are unchanged in the cell variants, however its protein levels are higher in the metastatic cells. While there was no change in Fra-1 protein degradation rates, protein synthesis of Fra-1 was increased in the metastatic cell variant. These results demonstrate that Fra-1 and MMP-1 levels are differentially regulated in metastatic cell variants at the level of Fra-1 protein translation. Consistent with the importance of Fra-1 for tumor growth, we found that Fra-1 overexpression was sufficient to increase cell motility and anchorage independent growth. These results suggest that increased Fra-1 translation is critical for regulation of MMP-1 and tumor cell metastasis.
 
The expression level of miR-23b was not significantly changed in patients suffering from idiopathic inflammatory myopathy when compared with healthy controls (
A). No significant difference in expression of miR-23b* was found between myositis patients and controls (
B).
Idiopathic inflammatory myopathies (IIM) belong to a group of autoimmune disorders, primarily characterized by chronic inflammation of human skeletal muscle tissue. The etiology of these diseases is unknown, however, genetic predisposition plays a significant role in disease onset. Beside the known genetic risk located in the MHC complex, the epigenetic modifications including changes in miRNAs expression profiles have been recently implicated recently in many autoimmune diseases. Micro RNA molecules are involved in many physiological processes, including the regulation of the immune response. In our study we have focused on the miR-23b, as it represents a novel promising autoimmunity regulator molecule. Downregulation of miR-23b was recently described in patients with rheumatoid arthritis and systemic lupus erythematosus. We have measured the expression miR-23b peripheral blood mononuclear cells of patients with dermatomyositis and polymyositis. No meaningful difference was found in comparison with healthy controls.
 
Purpose: To present a case who developed Bell’s palsy while using interferon alpha 2a for Behçet uveitis. Methods: A patient with Behçet disease presented with decreased vision in his right eye. Ophthalmic examination, fundus fluorescein angiography and optical coherence tomography were performed. After developing facial paralysis while on interferon therapy, the patient was referred to our neurology service for differential diagnosis and treatment. Results: Examination of right eye revealed panuveitis with branch retinal vein occlusion, so high dose steroids were prescribed. In three days there was no improvement in terms of vitreous inflammation and so steroids were replaced with interferon. At the seventh month, patient experienced a facial paralysis. After eliminating other causes, including viral infections, trauma, cold exposure and neurological evaluation with cranial MRI, the patient was diagnosed to have Bell’s palsy by a neurologist. Interferon was replaced with mycophenolate mofetil and the Bell’s palsy was treated with oral steroids. Conclusion: It is important to be alert to both common and rare complications while treating with interferon.
 
General information on benefit packages in 32 counties. 
The three-dimensional universal coverage model 22 . 
Introduction: Chronic disease has become a major problem affecting the health of the Chinese population. In response to this situation, the New Rural Cooperative Medical Scheme (NRCMS) has begun to provide health cover for outpatients with chronic disease expenses, made possible by the increased risk pool of previous years. We compare the differences between Benefit Packages for Chronic Diseases Outpatients (BPCDO) in order to produce a reference for policy makers. Methods: Information on the various BPCDO was located by searching the official NRCMS website in Chinese, using certain criteria to select the ideal BPCDO. Population coverage, service coverage and cost of coverage were chosen to form the analytical framework for this paper. The diseases were classified according to the World Health Organisation's (WHO) International Classification of Diseases (ICD-10). Results: To avoid “moral hazard”, complex processes have been created. This has resulted in chronic disease patients finding it very difficult to become beneficiaries. Forty-one types of chronic diseases were listed in 32 different BPCDO. We found that different counties have different co-payment rates, deductible lines, ceilings, coverage of drugs and tests, appointed hospitals and reimbursement frequencies. Conclusion: High mortality diseases and diseases with a heavier cost burden should be the priority on the list of reimbursement. The BPCDO scheme should be introduced urgently at the national level. It should include twenty-one types of disease and eight essential factors.
 
The development and growth of the skeleton in the absence of parathyroid-hormone-related protein (PTHrP) is abnormal. The shortening of appendicular bones in PTHrP gene null mice is explained by an effect of PTHrP on endochondral bone growth. Whether or not PTHrP influences intramembranous ossification is less clear. The purpose of this study was to determine the effect of exogenous PTHrP on intramembranous ossification in vitro. Neonatal rat calvarial cells maintained in primary cell culture conditions that permit spontaneous formation of woven bone nodules by intramembranous ossification were studied. The expression of PTHrP, parathyroid hormone 1 receptor (PTH1R), and alkaline phosphatase (AP) by osteogenic cells in developing nodules and the effects of PTHrP (1-36) on nodule development was determined over 3-18 days. PTHrP and PTH1R were detected colonies of osteogenic cells on culture day three, and AP was detected on day six. PTHrP and its receptor were localized in pre-osteoblasts, osteoblasts, and osteocytes, and AP activity was detected in pre-osteoblasts and osteoblasts but not osteocytes. Continuous and intermittent exposure to PTHrP (1-36) decreased the number of mineralized bone nodules and bone sialoprotein (BSP) mRNA and protein, but had no effect on the number of AP-positive osteogenic cell colonies, cell proliferation, apoptosis, or osteopontin (OPN) mRNA. These results demonstrate that osteogenic cells that participate in the formation of woven bone nodules in vitro exhibit PTHrP and PTH1R before they demonstrate AP activity. Exogenous PTHrP (1-36) inhibits the mineralization of woven bone deposited during bone nodule formation in vitro, possibly by reducing the expression of BSP.
 
Sagittal view of a CT Angiogram of the head at the level of lateral ventricle demonstrates mild proliferation of the collateral vessels extending towards the vertex. 
Axial view of CT Angiogram of the head at the level of the Circle of Willis demonstrates mild proliferation of collateral vessels emanating from the distal internal carotid artery, particularly on the left side. In addition, the visualized portion of the distal internal carotid artery and M1 segment of the left middle cerebral artery appear somewhat diminutive in caliber. 
Axial view of CT Angiogram of the head at the level of the Circle of Willis demonstrates mild proliferation of collateral vessels emanating from the distal internal carotid artery, particularly on the left side. In addition, the visualized portion of the distal internal carotid artery and M1 segment of the left middle cerebral artery appear somewhat diminutive in caliber. 
Moyamoya is a rare idiopathic progressive vaso-occlusive disease characterized by irreversible condition of main blood vessels to the brain as they enter into the skull. We present a case of 36 year old African American female presenting to the Out Patient Clinic with headache which were on and off for 4-6 months and did not relieve on routine medical therapy. It was associated with weakness on right side for last few days. The patient was investigated with CT Angiogram, diagnosed as Moyamoya disease and operated. She has been followed up for the last 5 years and the patient has not complained of any headaches or focal neurological symptoms.
 
Background: Kaposi’s sarcoma (KS) is a rare neoplasm of lymphatic endothelial cells. Human herpes virus 8 (HHV-8) is considered to be a necessary, but not sufficient causal agent of KS and additional cofactors remain unknown. In this study we evaluated the expression of human β defensin (HBD)-3 and LL-37 in cutaneous lesions of KS in comparison to the healthy skin of normal subjects. Methods: We performed a quantitative immunohistochemical study of HBD-3 and LL-37 on skin lesions from 18 patients having KS, and on healthy skin from 12 normal controls. Results: HBD-3 and LL-37 were significantly upregulated in epidermal and dermal specimens of all KS patients in comparison to normal skin of healthy controls. The immunostaining score of dermal HBD-3 was significantly higher in nodular lesions (9.6 ± 2.4) versus plaque lesions (4.1 ± 2.2), P = 0.001. Also the immunostaining score of dermal LL-37 was significantly higher in nodular lesions versus plaque lesions (P = 0.001). Conclusions: We have demonstrated for the first time that HBD-3 and LL-37 are significantly upregulated in lesional skin of KS in comparison to the skin of healthy controls. The obtained data suggest a possible involvement of these antimicrobial peptides in the pathogenesis of KS. However, the biological significance of HBD-3 and LL-37 in KS lesions needs further research.
 
Elevated endogenous mouse brain Aβ40 and Aβ42 in mice exposed to nickel nanoparticles (count median diameter 54 nm, at 1 mg/m
3) (
n = 16 per group) versus filtered air (
n = 5 per group) for 3 hours in a nose-only exposure chamber. Data presented as mean + SEM. **
P < 0.01, ***
P < 0.001 (Mann-Whitney test).
Background: Over 20 genetic risk factors have been confirmed to associate with elevated risk for Alzheimer’s disease (AD), but the identification of environmental and/or acquired risk factors has been more elusive. At present, recognized acquired risks for AD include traumatic brain injury, hypercholesterolemia, obesity, hypertension, and type 2 diabetes. Methods: Based on reports associating various inhalants with AD pathology, we investigated the possibility that air pollution might contribute to AD risk by exposing wild-type mice to a standard air pollution modeling system employing nickel nanoparticle-enriched atmosphere for 3 hr. Results: Mice exposed to air pollution showed 72-129% increases in brain levels of both amyloid-β peptides Aβ40 and Aβ42, as well as Aβ42/40 (p <0.01). Conclusions: These effects on elevation of brain Aβ exceed those associated with trisomy 21, a known risk for early onset AD pathology, raising the possibility that clinical importance might be attached. Further work is required to establish the molecular and physiological basis for these phenomena. The rapid, dramatic effect, if verified, would suggest that inhalant exposures should be evaluated for their possible roles in contributing to the environmental risk for common forms of AD.
 
Background: Neuro-inflammatory circuits in the tissue regulate the complex pathophysiology of pain. Protective nociceptive pain serves as an early warning system against noxious environmental stimuli. Tissue-resident mast cells orchestrate the increased thermal sensitivity following injection of basic secretagogue compound 48/80 in the hind paw tissues of ND4 mice. Here we investigated the effects of pre-treatment with TNF-α neutralizing antibody on compound 48/80-provoked thermal hyperalgesia. Methods: We treated ND4 Swiss male mice with intravenous anti-TNF-α antibody or vehicle 30 minutes prior to bilateral, intra-plantar compound 48/80 administration and measured changes in the timing of hind paw withdrawal observed subsequent to mice being placed on a 51oC hotplate. We also assessed changes in tissue swelling, TNF-α gene expression and protein abundance, mast cell degranulation, and neutrophil influx in the hind paw tissue. Findings: We found that TNF-α neutralization significantly blocked thermal hyperalgesia, and reduced early tissue swelling. TNF-α neutralization had no significant effect on mast cell degranulation or neutrophil influx into the tissue, however. Moreover, no changes in TNF-α protein or mRNA levels were detected within 3 hours of administration of compound 48/80. Interpretation: The neutralizing antibodies likely target pre-formed TNF-α including that stored in the granules of tissue-resident mast cells. Pre-formed TNF-α, released upon degranulation, has immediate effects on nociceptive signaling prior to the induction of neutrophil influx. These early effects on nociceptors are abrogated by TNF-α blockade, resulting in compromised nociceptive withdrawal responses to acute, harmful environmental stimuli.
 
Stretcher mutant mouse phenotype. The stretcher mutant is characterized by the stretching and “freezing” of the hind limbs, as illustrated in this photograph. The trait is most apparent when the mice are challenged with some behavioural intervention (e.g. handling for clinical examination). 
Sequence of Ndrg1 allele from stretcher mice. A . Genomic organization of Ndrg1 gene. Exons are represented by filled boxes. The extent of deletion between introns 9 and 14 is indicated; the deleted sequence is indicated by the dotted line and empty boxes. Sequence is shown reversed in comparison to chromosomal orientation. B . Sequence flanking the deletion point. Lower case: sequence from intron 9; upper case: intron 14 sequence; underline: sites for primers to amplify deletion allele. 
Hypothetical structure of wild-type Ndrg1 (upper) and the Ndrg1 str mutant (lower) proteins. Certain residues are indicated for reference. Cyan, amino acids prior to #199; red, residues encoded by exons deleted in the Ndrg1 str mutant; blue, residues 298-end of wild-type Ndrg1. 
Mice affected by a spontaneous mutation which arose within our colony exhibited a neuromuscular phenotype involving tremor and characteristic stretching of the rear limbs. The mutant, named stretcher, was used to breed a backcross cohort for genetic mapping studies. The gene responsible for the mutant phenotype was mapped to a small region on mouse chromosome 15, with a LOD score above 20. Candidate genes within the region included the Ndrg1 gene. Examination of this gene in the mutant mouse strain revealed that exons 10 to 14 had been deleted. Mutations in the human orthologue are known to result in Charcot-Marie-Tooth disease type 4D (CMT4D) a severe early-onset disorder involving Schwann cell dysfunction and extensive demyelination. The stretcher mutant mouse is more severely affected than mice in which the Ndrg1 gene had been knocked out by homologous recombination. Our results demonstrate that the Ndrg1 str mutation provides a new model for CMT4D, and demonstrate that exons 10 to 14 of Ndrg1 encode amino acids crucial to the appropriate function of Ndrg1 in the central nervous system.
 
PP242 inhibits etoposide-induced phosphorylation of Ser/Thr-Gln motifs. A) Western blot analysis of lysates from HeLa cells pretreated with the indicated inhibitors prior to etoposide treatment reveals that PP242 reduces the appearance of multiple phospho-SQ/TQ epitopes recognized by the broadly reactive phospho-VCP/Chk2 antibody. B) Varying concentrations of PP242 from 0.34-1.25 µM block etoposide-induced phosphorylation of proteins recognized by the phospho-SQ/TQ antibody.
A) PP242 treatment increases the eIF4E binding ability of 4E-BP1 and reduces 4E-BP1 phosphorylation.
B) Physiological treatment (serum starvation) modulates HMK-eIF4E binding ability of 4E-BP1 in an mTOR-dependent manner. Western blot using a non-phospho-4E-BP1/2 (Thr46) antibody parallels eIF4E binding.
C) 2DE combined with far-western and western blot analysis to analyze HMK-eIF4E binding forms of 4E-BP1 under control (DMSO) and mTOR inhibitory (Rapamycin and PP242) conditions. Despite fairly equal abundance of spots A-F under control conditions, only "spot A" binds HMK-eIF4E. mTOR inhibition with PP242 potently increases the abundance of eIF4E-binding competent spot A, while rapamycin treatment primarily reduces phosphorylation at Ser65 (spot F).
A) HeLa S3 cells stably expressing 4E-BP1 mutant proteins were subjected to western blotting using anti-HA antibody (upper), and phospho-4E-BP1 (Thr37/46) antibody (middle and lower panels). While phospho-4E-BP1 (Thr37/46) antibodies fail to detect the Thr46Ala single and Thr37/46Ala double point mutant proteins, the Thr37Ala protein is still recognized suggesting that Thr37 is not required for Thr46 phosphorylation. Endogenous 4E-BP1 phosphorylated at Thr37/46 is shown as a control.
B) Untreated and Nocodazole-blocked HeLa S3 cells were subjected to cap-column pull down of eIF4E and associated proteins. eIF4E was eluted with m7-GDP followed by SDS, and fractions were analyzed by western blot using eIF4E and 4E-BP1 antibodies and phospho-4E-BP1 antibodies.
Untreated and nocodazole-blocked HeLa S3 cells lysed, pooled and subjected to 2D-E prior to analysis with phospho-specific and total 4E-BP1 antibodies (left panels). In addition to the standard ordered phosphorylation (Thr37 or Thr46, then "spot B", then Thr70, then "spot E", then Ser65, then "spot G"), 4E-BP1 singly phosphorylated at Thr70 is also observed indicating that this species can exist
in vivo. To facilitate interpretation, the same images have been overlaid with a grid of circles corresponding to spots visible with the total 4E-BP1 antibody (right panels).
A) Western blot analysis of lysates from HeLa cells pretreated with the indicated inhibitors prior to etoposide treatment reveals that PP242 reduces the appearance of multiple phospho-SQ/TQ epitopes recognized by the broadly reactive phospho-VCP/Chk2 antibody.
B) Varying concentrations of PP242 from 0.34–1.25 µM block etoposide-induced phosphorylation of proteins recognized by the phospho-SQ/TQ antibody.
The recent development of mammalian target of rapamycin (mTOR) kinase domain inhibitors and genetic dissection of rapamycin-sensitive and -insensitive mTOR protein complexes (mTORC1 and mTORC2) have revealed that phosphorylation of the mTOR substrate 4E-BP1 on amino acids Thr37 and/or Thr46 represents a rapamycin-insensitive activity of mTORC1. Despite numerous previous reports utilizing serine (Ser)-to-alanine (Ala) and threonine (Thr)-to-Ala phosphorylation site mutants of 4E-BP1 to assess which post-translational modification(s) directly regulate binding to eIF4E, an ambiguous understanding persists. This manuscript demonstrates that the initial, rapamycin-insensitive phosphorylation event at Thr46 is sufficient to prevent eIF4E:4E-BP1 binding. This finding is relevant, particularly as mTOR kinase domain inhibitors continue to be assessed for clinical efficacy, since it clarifies a difference between the action of these second-generation mTOR inhibitors and those of rapamycin analogues.
 
The active site residues in Trypsin, DPP4 and PI-PLC. ( a ) Trypsin (PDBid:1A0J) ( b ) DPP4 (PDBid:1N1M); ( c ) PI-PLC (PDBid:1PTD) ( d ) Superimposing the active site residues using DE- CAAF 35 . The superimposition can be viewed in Superimposeproteins.p1m in Dataset 1. 
PI-PLC inhibition using DPP4 inhibitors. ( a , c ) Time courses of enzyme activity in the presence of varying amounts of inhibitors, respectively LAF-237 and K579. The trace marked LIPOSOMES corresponds to a control in the absence of PI-PLC. ( b , d ) Dose-response effect of inhibitors on PI-PLC activity. Activity was computed as the extent of vesicle aggregation after 10 min enzyme activity. 
The long term side effects of any newly introduced drug is a subject of intense research, and often raging controversies. One such example is the dipeptidyl peptidase-IV (DPP4) inhibitor used for treating type 2 diabetes, which is inconclusively implicated in increased susceptibility to acute pancreatitis. Previously, based on a computational analysis of the spatial and electrostatic properties of active site residues, we have demonstrated that phosphoinositide-specific phospholipase C (PI-PLC) from Bacillus cereus is a prolyl peptidase using in vivo experiments. In the current work, we first report the inhibition of the native activity of PI-PLC by two DPP4 inhibitors - vildagliptin (LAF-237) and K-579. While vildagliptin inhibited PI-PLC at micromolar concentrations, K-579 was a potent inhibitor even at nanomolar concentrations. Subsequently, we queried a comprehensive, non-redundant set of 5000 human proteins (50% similarity cutoff) with known structures using serine protease (SPASE) motifs derived from trypsin and DPP4. A pancreatic lipase and a gastric lipase are among the proteins that are identified as proteins having promiscuous SPASE scaffolds that could interact with DPP4 inhibitors. The presence of such scaffolds in human lipases is expected since they share the same catalytic mechanism with PI-PLC. However our methodology also detects other proteins, often with a completely different enzymatic mechanism, that have significantly congruent domains with the SPASE motifs. The reported elevated levels of serum lipase, although contested, could be rationalized by inhibition of lipases reported here. Also, the methodology presented here can be easily adopted for other drugs, and provide the first line of filtering in the identification of pathways that might be inadvertently affected due to promiscuous scaffolds in proteins.
 
Envelope glycoproteins of Hepatitis C Virus (HCV) play an important role in the virus assembly and initial entry into host cells. Conserved charged residues of the E2 transmembrane (TM) domain were shown to be responsible for the heterodimerization with envelope glycoprotein E1. Despite intensive research on both envelope glycoproteins, the structural information is still not fully understood. Recent findings have revealed that the stem (ST) region of E2 also functions in the initial stage of the viral life cycle. We have previously shown the effect of the conserved charged residues on the TM helix monomer of E2. Here, we extended the model of the TM domain by adding the adjacent ST segment. Explicit molecular dynamics simulations were performed for the E2 amphiphilic segment of the ST region connected to the putative TM domain (residues 683-746). Structural conformation and behavior are studied and compared with the nuclear magnetic resonance (NMR)-derived segment of E2 ( 2KQZ.pdb). We observed that the central helix of the ST region (residues 689 - 703) remained stable as a helix in-plane to the lipid bilayer. Furthermore, the TM domain appeared to provide minimal contribution to the structural stability of the amphipathic region. This study also provides insight into the orientation and positional preferences of the ST segment with respect to the membrane lipid-water interface.
 
( A ) CT scan of the brain showing an area of high density in the front of the pons (arrow) similar to a pontine hemorrhage. ( B ) Brain MRI revealed acute brainstem infarction (arrow). ( C , D ) CT angiography of the head showed a giant aneurysm of the basilar artery (27 mm by 10 mm) (arrow). 
In this article we present an 80 year old female patient with an unruptured giant aneurysm of the basilar artery presenting with posterior circulation ischemic symptoms. Angiography and CT revealed giant basilar aneurysmal dilatation with severe and wide intracranial arteriosclerosis. We described the uniqueness of this case. Giant basilar aneurysm is associated with various complications particularly brain stem infarction. It is emphasized that arteriosclerosis plays an important role in the formation of giant basilar aneurysms.
 
Objective and design: The histone acetylation processes, which are believed to play a critical role in the regulation of many inflammatory genes, are reversible and regulated by histone acetyltransferases (HATs), which promote acetylation, and histone deacetylases (HDACs), which promote deacetylation. We studied the effects of lipopolysaccharide (LPS) on histone acetylation and its role in the regulation of interleukin (IL)-8 expression. Material: A human alveolar epithelial cell line A549 was used in vitro. Methods: Histone H4 acetylation at the IL-8 promoter region was assessed by a chromatin immunoprecipitation (ChIP) assay. The expression and production of IL-8 were evaluated by quantitative polymerase chain reaction and specific immunoassay. Effects of a HDAC inhibitor, trichostatin A (TSA), and a HAT inhibitor, anacardic acid, were assessed. Results: Escherichia coli-derived LPS showed a dose- and time-dependent stimulatory effect on IL-8 protein production and mRNA expression in A549 cells in vitro. LPS showed a significant stimulatory effect on histone H4 acetylation at the IL-8 promoter region by ChIP assay. Pretreatment with TSA showed a dose-dependent stimulatory effect on IL-8 release from A549 cells as compared to LPS alone. Conversely, pretreatment with anacardic acid inhibited IL-8 production and expression in A549 cells. Conclusion: These data suggest that LPS-mediated proinflammatory responses in the lungs might be modulated via changing chromatin remodeling by HAT inhibition.
 
Disinfectant-resistant Candida isolates at 10% (a), 20% (b), 40% (c) and 70% (d) concentration.
Disinfectant-resistant
Candida isolates at 10% (
a), 20% (
b), 40% (
c) and 70% (
d) concentration.
This study was conducted to evaluate the antimicrobial activities of common disinfectants- these are (parachlorometaxylenol) dettol, savlon purit and jik (sodium hypochlorite) on Candida albicans isolated from displaying and cutting tables in five different abattoirs in Port Harcourt (Niger Delta region); the abattoirs include Trans Amadi, Agip, Woji, Rumuokoro, and Rumuodara. This research was carried out between January 2005 and June 2006. Swab samples were collected from abattoirs cutting tables with sterile swab sticks and immediately transferred and cultured in the laboratory on a selective medium Sabouraud Dextrose Agar (SDA). The disinfectants’ concentrations were prepared at 10%, 20%, 40%, and 70%, in triplicates and the mean values calculated. 0.5 Mc Farland turbidity method of standardization and Agar diffusion method were used for disinfectants testing of the isolates. Statistical analysis of the data showed no significant difference in the effectiveness of these disinfectants at (p<0.05). In conclusion, this study has shown that savlon and dettol were the most potent antimicrobial agents at 10% concentration on Candida albicans isolates when compared with purit and jik in this study, hence they are good sanitizing agents to be applied on the abattoirs cutting tables, before meat products can be displayed for sale.
 
Main experimental rack. The designed electromechanical system was composed of three racks. In this figure a scheme of the main rack is presented, containing the four experimentation units. One of the four experimentation units is highlighted with a dashed line. Several electrical holes permitted connection to all electrical components in the main rack (sensors, actuators, linear engines, resistances). One ATP-WB hole permitted access to liquid conductions transporting ATP and Wash Buffer to each experimentation units. Lengths are expressed in mm. 
Final prototype configuration. This picture shows the final configuration of the experiment on board the parabolic aircraft. The three racks presented were, from left to right: storage rack, main rack, fluids and control rack. All principal electric components were placed in a sealed fire-proof cabinet underneath the main rack to protect the equipment from water contact in case of failure of the containment system. 
Net E17βG transport activity. 
Microgravity has been shown to influence the expression of ABC (ATP-Binding Cassette) transporters in bacteria, fungi and mammals, but also to modify the activity of certain cellular components with structural and functional similarities to ABC transporters. Changes in activity of ABC transporters could lead to important metabolic disorders and undesired pharmacological effects during spaceflights. However, no current means exist to study the functionality of these transporters in microgravity. To this end, a Vesicular Transport Assay ® (Solvo Biotechnology, Hungary) was adapted to evaluate multi-drug resistance-associated protein 2 (MRP2) trans-membrane estradiol-17-β-glucuronide (E17βG) transport activity, when activated by adenosine-tri-phosphate (ATP) during parabolic flights. Simple diffusion, ATP-independent transport and benzbromarone inhibition were also evaluated. A high accuracy engineering system was designed to perform, monitor and synchronize all procedures. Samples were analysed using a validated high sensitivity drug detection protocol. Experiments were performed in microgravity during parabolic flights, and compared to 1g on ground results using identical equipment and procedures in all cases. Our results revealed that sufficient equipment accuracy and analytical sensitivity were reached to detect transport activity in both gravitational conditions. Additionally, transport activity levels of on ground samples were within commercial transport standards, proving the validity of the methods and equipment used. MRP2 net transport activity was significantly reduced in microgravity, so was signal detected in simple diffusion samples. Ultra-structural changes induced by gravitational stress upon vesicle membranes or transporters could explain the current results, although alternative explanations are possible. Further research is needed to provide a conclusive answer in this regard. Nevertheless, the present validated technology opens new and interesting research lines in biology and human physiology with the potential for significant benefits for both space and terrestrial medicine.
 
The sequence variants identified in this study. 
Background: Neonatal cholestasis is a common presentation of childhood liver diseases and can be a feature of various conditions including disorders of bile acid biogenesis and transport, various inborn errors of metabolism and perinatal infections. Some inherited metabolic diseases can be easily screened using biochemical assays, however many can only be accurately diagnosed by DNA sequencing. Fluorescent capillary Sanger sequencing (FS) is the gold standard method used by clinical laboratories for genetic diagnosis of many inherited conditions; however, it does have limitations. Recently microarray resequencing (MR) has been introduced into research and clinical practice as an alternative method for genetic diagnosis of heterogeneous conditions. In this report we compared the accuracy of mutation detection for MR with FS in a group of patients with ‘low-normal’ gamma glutamyl transpeptidase (gGT) cholestasis without known molecular diagnoses. Methods: 29 patient DNA samples were tested for mutations in the ATP8B1 and ABCB11 genes using both FS and MR. Other known causes of “low gGT cholestasis” such as ARC syndrome and bile acid biosynthesis disorders were excluded. Results: Mutations were identified in 13/29 samples. In 3/29 samples FS and MR gave discordant results: MR had a false positive rate of 3.4% and a false negative rate of 7%. Conclusions: The major advantage of MR over FS is that multiple genes can be screened in one experiment, allowing rapid and cost-effective diagnoses. However, we have demonstrated that MR technology is limited in sensitivity. We therefore recommend that MR be used as an initial evaluation, with FS deployed when genetic and clinical or histopathological findings are discordant.
 
Severe vitamin deficiency disease is rarely seen in developed countries. We present an atypical case of a young man with scurvy, pellagra, and hypovitaminosis A, caused by longstanding functional abdominal pain that severely limited his ability to eat.
 
We report herein, two cases of massive delayed (2 and 4 days) intra abdominal hemorrhage following ovum pick-up (OPU), in patients at risk for thrombo-embolic events, who concomitantly used therapeutic doses of low molecular weight heparin (LMWH). We discuss the possible mechanisms involved in causing the aforementioned delayed bleeding, and call for re-evaluation of the presently accepted anticoagulant co-treatment regimen. These case reports should direct physicians' attention and keep them alert, while conducting IVF treatment to this subgroup of high risk patients.
 
Chile is recognized worldwide as an emergent economy, with a great power in natural resource exploitation. Nonetheless, despite being one of the most developed countries in Latin America, Chile imports most of the knowledge and technology necessary to drive innovation in the country. The tight budget that the Chilean government assigned to research and development and the absence of a long-term scientific agenda contributed to a limited supply of scientists over the years. In an effort to reverse this scenario, Chile has created several fellowships, such as the Becas Chile Program (BCP) to encourage new generations to pursue graduate studies to ultimately advance research and development in situ. More than 6000 fellows are now being trained abroad, accumulating an incredible potential to transform the Chilean scientific environment as we know it. Chile now faces a greater challenge: it has to offer infrastructure and job openings to the highly skilled professionals in whom it invested. Unfortunately no clear public policies to address this situation have been developed, partially due to the lack of a dedicated institution, such as a Ministry for Science and Technology which could focalize the necessary efforts to promote such policies. Therefore, in the meantime, Chilean scientist have been motivated to create different organizations, such as, Mas Ciencia para Chile and Nexos Chile-USA, to promote constructive discussion of the policies that could be implemented to improve the Chilean scientific situation. We hope that these and other organizations have a real impact on the generation of scientific guidelines that will finally contribute to the development of the country.
 
ABS-Scan workflow. Flowchart depicting various steps involved in ABS-Scan. 
ABS-Scan Sensitivity. (A) The average ΔΔG score per residue distribution from the cognate and decoy protein-ligand complexes of CSAR dataset. (B) The scatter plot displaying the average ΔΔG score for native and the corresponding decoy complexes from the CSAR dataset. (C) Boxplot showing the difference in the % of the residues in the binding site of cognate and decoy complexes having a predicted ΔΔG score ≥ 0.5.
ABS-Scan interactive display. Snapshot explaining the Jmol applet output on the ABScan server. The individual residues are colored in red to blue gradient depending upon the contribution towards the ligand interaction as predicted by ABScan ΔΔG score. Options to visualize the different kinds of interaction-polar, hbonds etc. is also provided.
ABS-Scan energy plots. ( A ) ∆∆ G values reported for each of the alanine mutation performed for the residues present at the binding site. The residues are ordered according to their contribution/ ∆∆ G values. ( B ) The different energy component of autodock interaction score plotted for each of the alanine mutant produced at the binding site. 
Most physiological processes in living systems are fundamentally regulated by protein-ligand interactions. Understanding the process of ligand recognition by proteins is a vital activity in molecular biology and biochemistry. It is well known that the residues present at the binding site of the protein form pockets that provide a conducive environment for recognition of specific ligands. In many cases, the boundaries of these sites are not well defined. Here, we provide a web-server to systematically evaluate important residues in the binding site of the protein that contribute towards the ligand recognition through in silico alanine-scanning mutagenesis experiments. Each of the residues present at the binding site is computationally mutated to alanine. The ligand interaction energy is computed for each mutant and the corresponding ΔΔG values are computed by comparing it to the wild type protein, thus evaluating individual residue contributions towards ligand interaction. The server will thus provide clues to researchers about residues to obtain loss-of-function mutations and to understand drug resistant mutations. This web-tool can be freely accessed through the following address: http://proline.biochem.iisc.ernet.in/abscan/.
 
The success of any type of sexual education programme depends on the knowledge and preparedness for practice by adolescents. A recent study has found that an 'abstinence-only' sexual education programme is effective in reducing sexual activity among adolescents. Knowledge of abstinence-only sexual education and preparedness for practice as an effective tool for promotion of sexual health among Nigerian secondary school adolescents was studied. An analytic descriptive survey design was used for the study. The research population comprised of all public secondary schools in three southern geopolitical zones of the Niger Delta Region of Nigeria. A multistage sampling technique was used to select 2020 senior secondary school (SS1-SS3) students as sample for the study. A partially self-designed and partially adapted questionnaire from an 'abstinence-only versus comprehensive sex education' debate, from debatepedia (http://wiki.idebate.org/), entitled 'Questionnaire on Nigerian Secondary School Adolescents' Perspective on Abstinence-Only Sexual Education (QNSSAPAOSE)' was used in eliciting information from respondents. Hypotheses were formulated and tested. Frequency counts, percentage and Pearson Product Moment Correlation were used in analysing data. A greater proportion of secondary school adolescents in this study lacked knowledge of sexual education. About 80% of the respondents could not define sexual education. The general perspective on abstinence-only sexual education was negative, as revealed by the larger number of respondents who demonstrated unwillingness to practice abstinence-only sexual education. Specifically, of those who responded in favour of abstinence-only sexual education, the youngest group of adolescents (11-13 years) and the male respondents were more likely to accept this type of education than the other groups. Poor knowledge of sexual education could be responsible for unwillingness to practice abstinence-only sexual education. Sexual education should, therefore, be introduced into the secondary school curriculum and taught by well-prepared teachers to enable an informed decision on practice.
 
Gillnet and longline sampling stations within Back Sound and lower Core Sound from March 21 – July 1, 2014. 
Capture locations of spiny dogfish in gillnet sets within Back Sound and lower Core Sound in May 2014. 
Five spiny dogfish were captured in early-mid May during gillnet and longline sampling targeting juvenile coastal sharks in inshore North Carolina waters. Dogfish captures were made within Back Sound and Core Sound, North Carolina. All dogfish were females measuring 849-905 mm total length, well over the size at 50% maturity. Dogfish were caught at stations 1.8-2.7 m in depth, with temperatures 22.9-24.2 °C, 32.8-33.4 ppt salinity, and 6.9-8.0 mg/L dissolved oxygen. These observations are among the latest in the spring for spiny dogfish in the southeastern U.S. and occurred at higher temperatures than previously recorded for this species. It is unclear whether late-occurring spiny dogfish in this area represent a cryptic late-migrating or resident segment of the Northwest Atlantic population.
 
Phylogenetic tree indicating the position of the novel Acaryochloris strain CRS based on full-length 16S rRNA gene sequences. Sequences from other cyanobacteria (35 in total) were obtained from the SILVA database while CRS-specific sequences were obtained through PCR amplification and subsequent sequencing. Phylogeny was calculated using Neighbor-joining methods and Jukes-Cantor substitution models as implemented in MEGA5. Tree stability was assessed using bootstrapping at 10000 replications. Only bootstrap values >50% are displayed within the tree. The scale represents 0.02 substitutions per nucleotide position. The green-sulphur bacterium Chlorobium tepidum TLS was chosen as an outgroup.
In vivo absorption spectra of the three Acaryochloris strains MBIC11017, HICR111A and CRS. All strains were adapted to either visible light (VIS) or near infrared radiation (NIR) prior to measurements. All spectra were normalized to the maximal absorbance of Chl d at 710 nm.
Cyanobacteria in the genus Acaryochloris have largely exchanged Chl a with Chl d, enabling them to harvest near-infrared-radiation (NIR) for oxygenic photosynthesis, a biochemical pathway prone to generate reactive oxygen species (ROS). In this study, ROS production under different light conditions was quantified in three Acaryochloris strains (MBIC11017, HICR111A and the novel strain CRS) using a real-time ethylene detector in conjunction with addition of 2-keto-4-thiomethylbutyric acid, a substrate that is converted to ethylene when reacting with certain types of ROS. In all strains, NIR was found to generate less ROS than visible light (VIS). More ROS was generated if strains MBIC11017 and HICR111A were adapted to NIR and then exposed to VIS, while strain CRS demonstrated the opposite behavior. This is the very first study of ROS generation and suggests that Acaryochloris can avoid a considerable amount of light-induced stress by using NIR instead of VIS for its photosynthesis, adding further evolutionary arguments to their widespread appearance.
 
(continued) 4b2 Derive an Estimate of the Unconfounded Treatment Effect 
Background: Nonrandomized studies typically cannot account for confounding from unmeasured factors. Method: A method is presented that exploits the recently-identified phenomenon of “confounding amplification” to produce, in principle, a quantitative estimate of total residual confounding resulting from both measured and unmeasured factors. Two nested propensity score models are constructed that differ only in the deliberate introduction of an additional variable(s) that substantially predicts treatment exposure. Residual confounding is then estimated by dividing the change in treatment effect estimate between models by the degree of confounding amplification estimated to occur, adjusting for any association between the additional variable(s) and outcome. Results: A hypothetical example is provided to illustrate how the method produces a quantitative estimate of residual confounding if the method’s requirements and assumptions are met. Previously published data is used to illustrate that, whether or not the method routinely provides precise quantitative estimates of residual confounding, the method appears to produce a valuable qualitative estimate of the likely direction and general size of residual confounding. Limitations: Uncertainties exist, including identifying the best approaches for: 1) predicting the amount of confounding amplification, 2) minimizing changes between the nested models unrelated to confounding amplification, 3) assessing the association of the introduced variable(s) with outcome, and 4) deriving confidence intervals for the method’s estimates (although bootstrapping is one plausible approach). Conclusions: To this author’s knowledge, it has not been previously suggested that the phenomenon of confounding amplification, if such amplification is as predictable as suggested by a recent simulation, provides a logical basis for estimating total residual confounding. The method's basic approach is straightforward. The method's routine usefulness, however, has not yet been established, nor has the method been fully validated. Rapid further investigation of this novel method is clearly indicated, given the potential value of its quantitative or qualitative output.
 
Schematic work-and dataflow illustration for the construction of the Uberpheno ontology and the gene annotations.
Files required to connect genes and phenotypes as well as to get the orthology relationship between model organism genes and human genes. These files are especially important for Step 4 in Figure 2.
Current statistics on the data contained in the used cross-product files. HPO and MPO files downloaded from http://code.google.com/p/phenotype-ontologies. Behaviour files downloaded from http://code.google.com/p/behavior-ontology. GO-xp file downloaded from http://obofoundry.org/cgi-bin/detail.cgi?id=biological_process_xp_uber_anatomy.
Phenotype analyses, e.g. investigating metabolic processes, tissue formation, or organism behavior, are an important element of most biological and medical research activities. Biomedical researchers are making increased use of ontological standards and methods to capture the results of such analyses, with one focus being the comparison and analysis of phenotype information between species. We have generated a cross-species phenotype ontology for human, mouse and zebrafish that contains classes from the Human Phenotype Ontology, Mammalian Phenotype Ontology, and generated classes for zebrafish phenotypes. We also provide up-to-date annotation data connecting human genes to phenotype classes from the generated ontology. We have included the data generation pipeline into our continuous integration system ensuring stable and up-to-date releases. This article describes the data generation process and is intended to help interested researchers access both the phenotype annotation data and the associated cross-species phenotype ontology. The resource described here can be used in sophisticated semantic similarity and gene set enrichment analyses for phenotype data across species. The stable releases of this resource can be obtained from http://purl.obolibrary.org/obo/hp/uberpheno/.
 
Out-of-the-box approaches are currently needed to replenish the souring pipelines of pharmaceutical companies across the globe. Here a theme is presented - the use of central nervous system (CNS) drugs as leads for non-CNS targets. The approach is related to the use of existing drugs for new indications. Suitable chemical modifications of the CNS drugs abolish their CNS penetration. These novel analogs may then be screened for activity against non-CNS targets. Careful selection of the appropriate structural modifications remains the key to success.
 
Comparison of telomere-associated sequences (TAS) at the ends of fission yeast chromosomes 1 and 2. ( A ) The October, 2008, versions ( of the nucleotide sequences from the ends of fission yeast chromosomes 1 and 2 were aligned with each other on the basis of restriction map similarities and Pustell DNA matrix alignments using MacVector software ( The left ends of chromosomes 1 and 2 were reverse-complemented so that their sequences would have the same polarity as those of the right ends of chromosomes 1 and 2. The green arrows show the locations and orientations of documented genes (dubious and pseudo genes were omitted). The orange arrows show regions of high sequence similarity between the four chromosome ends. The positions of deletions and an insertion within these highly similar regions in the ends of chromosome 1 (compared to the ends of chromosome 2) are shown by additional orange arrowheads (deletions) or a gap in the orange arrow (insertion). Thin black guide lines are also provided, to facilitate the alignments of similar sequences despite the presence of deletions and an insertion. The far right end of chromosome 2 overlaps for about 4 kb (panel C) with the left end of pNSU21, a clone of a 7992-bp telomeric Hin dIII fragment prepared by Neal Sugawara 1 . Here we have used the reverse-complement of the pNSU21 nucleotide sequence, as determined partially by Neal Sugawara 1 and completely by the Sanger Centre fission yeast sequencing project ( pub2/yeast/sequences/pombe/telomeres). We have employed the reverse complement (and we’ve changed the numbering correspondingly) so that (i) the pNSU21 sequence would have the same orientation as the right end of chromosome 2, and (ii) so that the G-rich strand of 
Identification of two ARS elements in the 8-kb Telomeric HindIII Fragment (THF). (A) Diagram showing overlap between the right end of Chromosome 2 and the THF, which was cloned by Neal Sugawara 1 as pNSU21. (B) Relative positions within the THF of the smaller regions (R1-R7) generated by PCR. (C) AT content in sliding windows of 100 bp (dotted line) and 500 bp (solid line) along the THF. P1-P4 are peaks of unusually high AT content. (D) Results of ARS assays for plasmids containing the sequences in panel B or controls. The results are the averages ± standard deviation of 3 experiments, with triplicate plating in each experiment.
Exonuclease III deletions of Region 1. (A) Intact Region 1 with AT content, expanded from Figure 2. (B) For constructs E1-E6, the thin lines show the portions of R1 that were deleted, and the thick lines show the portions of R1 remaining in each construct. The deletions were constructed using the Promega Erase-A-Base Kit. See Materials and Methods for details. (C) Results of ARS assays for the plasmids containing the deleted versions of Region 1 shown in panel B. Compare with Figure 2D.
Telomeres of the fission yeast, Schizosaccharomyces pombe, are known to replicate in late S phase, but the reasons for this late replication are not fully understood. We have identified two closely-spaced DNA replication origins, 5.5 to 8 kb upstream from the telomere itself. These are the most telomere-proximal of all the replication origins in the fission yeast genome. When located by themselves in circular plasmids, these origins fired in early S phase, but if flanking sequences closer to the telomere were included in the circular plasmid, then replication was restrained to late S phase – except in cells lacking the replication-checkpoint kinase, Cds1. We conclude that checkpoint-dependent late replication of telomere-associated sequences is dependent on nearby cis-acting sequences, not on proximity to the physical end of a linear chromosome.
 
Total number of AK treatments from 1994–2020. Estimated treatment numbers from the period of 1994–2020. Estimated treatment numbers with 95% CI from 2013–2020 is shaded in grey. 
Total cost of AK treatments to Medicare in 2012 Australian dollars from the period of 1994-2020. Estimated costs with 95% CI from 2013-2020 is shaded in grey.
Total number of item 30192 services billed in Australia from 1994 to 2012. Total number of non-melanoma skin cancer treatment for 1997 to 2012 shown in dotted lines.
Objectives: To report the burden and cost of actinic keratosis (AK) treatment in Australia and to forecast the number of AK treatments and the associated costs to 2020. Design and setting: A retrospective study of data obtained from medicare Australia for AK treated by cryotherapy between 1 January 1994 and 31 December 2012, by year and by state or territory. Results: The total number of AK cryotherapy treatments increased from 247,515 in 1994 to 643,622 in 2012, and we estimate that the number of treatments will increase to 831,952 (95% CI 676,919 to 986,987) by 202. The total Medicare Benefits Schedule (MBS) benefits paid out for AK in 2012 was $19.6 million and we forecast that this will increase to $24.7 million by 2020 (without inflation). Conclusion: The number of AK cryotherapy treatments increased by 160% between 1994 and 2012. we forecast that the number of treatments will increase by 30% between 2012 and 2020. The rates of non-melanoma skin cancer (NMSC) and AK appear to be increasing at the same rate. During the period 2010 to 2015 AK is anticipated to increase by 17.8% which follows a similar trend to published data that forecasts an increase in NMSC treatments of 22.3%.
 
Total number of AK treatments from 1994–2020. Estimated treatment numbers from the period of 1994–2020. Estimated treatment numbers with 95% CI from 2013–2020 is shaded in grey. 
Total cost of AK treatments to Medicare in 2012 Australian dollars from the period of 1994-2020. Estimated costs with 95% CI from 2013-2020 is shaded in grey.
Total number of item 30192 services billed in Australia from 1994 to 2012. Total number of non-melanoma skin cancer treatment for 1997 to 2012 shown in dotted lines.
Objectives: To report the burden and cost of actinic keratosis (AK) treatment in Australia and to forecast the number of AK treatments and the associated costs to 2020. Design and setting: A retrospective study of data obtained from medicare Australia for AK treated by cryotherapy between 1 January 1994 and 31 December 2012, by year and by state or territory. Results: The total number of AK cryotherapy treatments increased from 247,515 in 1994 to 643,622 in 2012, and we estimate that the number of treatments will increase to 831,952 (95% CI 676,919 to 986,987) by 2020. The total Medicare Benefits Schedule (MBS) benefits paid out for AK in 2012 was $19.6 million and we forecast that this will increase to $24.7 million by 2020 (without inflation). Conclusion: The number of AK cryotherapy treatments increased by 160% between 1994 and 2012. we forecast that the number of treatments will increase by 30% between 2012 and 2020. The rates of non-melanoma skin cancer (NMSC) and AK appear to be increasing at the same rate. During the period 2010 to 2015 AK is anticipated to increase by 17.8% which follows a similar trend to published data that forecasts an increase in NMSC treatments of 22.3%.
 
We previously demonstrated that Akt differentially modulated a subset of NF-kB target genes during T cell activation. In the current study, we further explored the broader effects of Akt inhibition on T cell gene induction. Global microarray analysis was used to characterize T helper cell transcriptional responses following antigen receptor stimulation in the absence or presence of Akti1/2 (an allosteric inhibitor which targets Akt1 and Akt2), to identify novel targets dependent upon Akt and obtain a more comprehensive view of Akt-sensitive genes in Th2 helper T cells. Pathway analysis of microarray data from a CD4 + Th2 T cell line revealed effects on gene networks involving ribosomal and T cell receptor signaling pathways associated with Akti1/2 treatment. Using real-time PCR analysis, we validated the differential regulation of several genes in these pathways, including Ier3, Il13, Egr1, Ccl1 and Ccl4, among others. Additionally, transcription factor target gene (TFactS) analysis revealed that NF-kB and Myc were the most significantly enriched transcription factors among Akt-dependent genes after T cell receptor and CD28 stimulation. Akt activation elicited increases in the enrichment of NF-kB- and Myc-targeted genes. The present study has identified a diverse set of genes, and possible mechanisms for their regulation, that are dependent on Akt during T cell activation.
 
Factors contributing to opiate toxicity in CKD. 
Pain management in CKD. 
Chronic kidney disease is common and patients with many co-morbid conditions frequently have to undergo surgical procedures and, therefore, require effective pain management. The pharmacokinetics of various analgesic agents are not well studied in patients with chronic kidney disease and the risk of accumulation of the main drug or their metabolites, resulting in serious adverse events, is a common scenario on medical and surgical wards. It is common for these patients to be cared for by 'non-nephrologists' who often prescribe the standard dose of the commonly used analgesics, without taking into consideration the patient's kidney function. It is important to recognize the problems and complications associated with the use of standard doses of analgesics, and highlight the importance of adjusting analgesic dosage based on kidney function to avoid complications while still providing adequate pain relief.
 
Leukemias rarely debut by pleural involvement as the first manifestation of the hematologic malignancy. This complication is most commonly seen in solid tumors such as carcinomas of the breast, lung, gastrointestinal tract and lymphomas. We present a case of a 66 year old male who presented with a pleural leukemic infiltration of his undiagnosed Acute Myeloid Leukemia that was not a complication of the disease extension, but the acute presentation of the illness. Progressive shortness of breath for two weeks, cough, clear sputum and weight loss were the initial complaints. Serum dyscrasia suggested a hematologic abnormality. A chest x-ray performed demonstrated a buildup of fluid with layering in the left pleural cavity. Diagnostic thoracentesis suggested an exudative etiology with cytology remarkable for 62% leukemic myeloblast. The diagnosis was confirmed by bone marrow biopsy with expression of the antigens CD 34+ and CD13+, with unfavorable cytogenetic prognosis and a trisomy 21 chromosomal defect. Chemotherapy was initiated, though no remission achieved with induction chemotherapy. Complications and disease progression precludes in the patient's death. Although rare, due to the unusual presentation of the disease, this case clearly demonstrates the importance of biochemical analysis and cytopathology specimens obtained in pleural fluid.
 
Introduction: Several acute neurological syndromes can be triggered by immune events. Hepatitis E virus (HEV), an emerging infectious disease, can be one of these triggers. Case report: We report the case of a 36-year-old man that presented nausea and a dull abdominal pain for a week and then felt an acute neuralgic pain involving both shoulders that lasted for 8 to 10 hours. Immediately after, the patient presented a severe bilateral muscular weakness of the proximal part of both upper limbs, corresponding to an amyotrophic neuralgia. Two days after the shoulder pain, the patient presented a dysphagia necessitating tube feeding. A blood sample confirmed hepatitis caused by hepatitis E virus (HEV; genotype 3F). Oral feeding resumed progressively after five months. The patient was fully independent for the activities of daily living but was still unable to work after six months. Conclusion: Amyotrophic neuralgia and hepatitis E are both under-diagnosed. It is noteworthy that HEV can trigger amyotrophic neuralgia. Antiviral drugs, oral steroids and intravenous immunoglobulins can be proposed, but the optimal treatment has not yet been determined.
 
Dental caries at time of acute lymphoblastic leukemia diagnosis. 
EORTC Children's Leukemia Group Protocol AR1.
Laboratory results at presentation with fever and severe oral pain.
Oral mucositis is a debilitating manifestation in children undergoing chemotherapy and radiotherapy. Children with mucositis should be properly managed in order to prevent further exacerbation and adverse complications. We hereby present the first report of a severe chemotherapy-induced mucositis, plausibly aggravated by improper dental hygiene leading to shedding of the ventral part of the tongue in a child with pre-B acute lymphoblastic leukemia (ALL). The patient steadily and gradually recovered her oral maneuvers and ability to speak several months later. Her tongue underwent hypertrophy as a compensatory mechanism. We recommend that critical and regular assessment of the oral mucosa and proper dental care and oral hygiene be emphasized in all pediatric patients receiving chemotherapy. Families of affected children need to be educated about the benefits and modes of optimal oral hygiene for their children and the need to seek immediate care for mouth pain and or lesions. Optimal treatment for mucositis needs to be instituted without delay in this high risk pediatric population. Such a preventive and therapeutic approach may prevent associated life threatening oral and systemic complications, promote rapid and complete mucosal healing, alleviate pain and improve quality of life in children with cancer.
 
Schematic showing the joint configurations and details of the practice task. A) Sagittal view of the subject with the wrist secured to the force transducer and the orientation of the forces recorded for all of the experiments. B) When independently changing elbow angle (a. ELBFLEX; b. NEUT; c. ELBEXT) while keeping the same shoulder angle (θ = 95°); and C) When independently changing shoulder angle (a. SHLFLEX; b. NEUT; c. SHLEXT) while keeping the same elbow angle (θ = 95°). Note that the dashed line (b.) in both B and C is the same NEUT condition and was only tested once during the trials and also again after all of the joint positions had been completed. D) Schematic showing the joint configuration (τ = elbow ~95°, shoulder ~95°) for both EXT and FLEX practice protocols. E) Representative data from one subject demonstrating the magnitude and direction of the endpoint force vector from the nociceptive withdrawal response, after practice, from the individual trials (gray-thin lines) and the average responses (black-thick lines) in the (+/-)Y and +X directions. The average responses from the EXT and FLEX trials are also superimposed on panel D. 
Group endpoint force vectors from the Fx (+x) and Fy (-y) before (black) and after (grey) practice for each subject with the A) EXT practice, and the B) FLEX practice. The inset on each panel shows the average for all subjects. No significant differences were noted. 
The nociceptive withdrawal reflex is a protective mechanism to mediate interactions within a potentially dangerous environment. The reflex is formed by action-based sensory encoding during the early post-natal developmental period, and it is unknown if the protective motor function of the nociceptive withdrawal reflex in the human upper-limb is adaptable based on the configuration of the arm or if it can be modified by short-term practice of a similar or opposing motor action. In the present study, nociceptive withdrawal reflexes were evoked by a brief train of electrical stimuli applied to digit II, 1) in five different static arm positions and, 2) before and after motor practice that was opposite (EXT) or similar (FLEX) to the stereotyped withdrawal response, in 10 individuals. Withdrawal responses were quantified by the electromyography (EMG) reflex response in several upper limb muscles, and by the forces and moments recorded at the wrist. EMG onset latencies and response amplitudes were not significantly different across the arm positions or between the EXT and FLEX practice conditions, and the general direction of the withdrawal response was similar across arm positions. In addition, the force vectors were not different after practice in either the practice condition or between EXT and FLEX conditions. We conclude the withdrawal response is insensitive to changes in elbow or shoulder joint angles as well as remaining resistant to short-term adaptations from the practice of motor actions, resulting in a generalized limb withdrawal in each case. It is further hypothesized that the multisensory feedback is weighted differently in each arm position, but integrated to achieve a similar withdrawal response to safeguard against erroneous motor responses that could cause further harm. The results remain consistent with the concept that nociceptive withdrawal reflexes are shaped through long-term and not short-term action based sensory encoding.
 
Photosynthetic gas exchange characteristics. Effect of habitat (H), leaf phenology (L), and their interaction (H × L), on Pn, g s , E, and WUE (mean ± SD, n = 3–5) of the tree species in two habitats. T and Dx represent the two study sites Tianlongshan and Daxiagu, respectively. Measurements were conducted under ambient conditions in 2007 and 2008, and under controlled conditions in 2009. The significance levels (*** = P < 0.001, ** = P < 0.01, * = P < 0.05, and ns = P > 0.05) were based on ANOVA results.  
Characteristics of the tree species examined in this study. For leaf phenology, D represents deciduous and E represents evergreen; For location, T represents Tianlongshan and Dx represents Daxiagu.
Photochemical characteristics. Effects of habitat (H), leaf phenology (L), and their interaction (H × L), on maximal PSII efficiency (Φ(Po)), quantum yield of PSII electron transport (Φ(Eo)), quantum yield of dissipation Φ(Do), and performance index (PI(abs)) (mean ± SD, n = 3–5) of the tree species in two habitats. See Figure 1 for other explanations.  
The purpose of this study was to investigate the eco-physiological adaptation of indigenous woody species to their habitats in karst areas of southwestern China. Two contrasting forest habitats were studied: a degraded habitat in Daxiagu and a well-developed habitat in Tianlongshan, and the eco-physiological characteristics of the trees were measured for three growth seasons. Photosynthetic rate (Pn), stomatal conductance (gs), and transpiration rate (Tr) of the tree species in Daxiagu were 2-3 times higher than those in Tianlongshan under ambient conditions. However, this habitat effect was not significant when measurements were taken under controlled conditions. Under controlled conditions, Pn, gs, and Tr of the deciduous species were markedly higher than those for the evergreen species. Habitat had no significant effect on water use efficiency (WUE) or photochemical characteristics of PSII. The stomatal sensitivity of woody species in the degraded habitat was much higher than that in the well-developed habitat. Similarly, the leaf total nitrogen (N) and phosphorus (P) contents expressed on the basis of either dry mass or leaf area were also much higher in Daxiagu than they were in Tianlongshan. The mass-based leaf total N content of deciduous species was much higher than that of evergreen species, while leaf area-based total N and P contents of evergreens were significantly higher than those of deciduous species. The photosynthetic nitrogen- and phosphorus-use efficiencies (PNUE and PPUE) of deciduous species were much higher than those of evergreens. Further, the PPUE of the woody species in Tianlongshan was much higher than that of the woody species in Daxiagu. The results from three growth seasons imply that the tree species were able to adapt well to their growth habitats. Furthermore, it seems that so-called “temporary drought stress” may not occur, or may not be severe for most woody plants in karst areas of southwestern China.
 
Hemispatial neglect ('neglect') is a disabling condition that can follow damage to the right side of the brain, in which patients show difficulty in responding to or orienting towards objects and events that occur on the left side of space. Symptoms of neglect can manifest in both space- and object-based frames of reference. Although patients can show a combination of these two forms of neglect, they are considered separable and have distinct neurological bases. In recent years considerable evidence has emerged to demonstrate that spatial symptoms of neglect can be reduced by an intervention called prism adaptation. Patients point towards objects viewed through prismatic lenses that shift the visual image to the right. Approximately five minutes of repeated pointing results in a leftward recalibration of pointing and improved performance on standard clinical tests for neglect. The understanding of prism adaptation has also been advanced through studies of healthy participants, in whom adaptation to leftward prismatic shifts results in temporary neglect-like performance. Here we examined the effect of prism adaptation on the performance of healthy participants who completed a computerised test of space- and object-based attention. Participants underwent adaptation to leftward- or rightward-shifting prisms, or performed neutral pointing according to a between-groups design. Significant pointing after-effects were found for both prism groups, indicating successful adaptation. In addition, the results of the computerised test revealed larger reaction-time costs associated with shifts of attention between two objects compared to shifts of attention within the same object, replicating previous work. However there were no differences in the performance of the three groups, indicating that prism adaptation did not influence space- or object-based attention for this task. When combined with existing literature, the results are consistent with the proposal that prism adaptation may only perturb cognitive functions for which normal baseline performance is already biased.
 
Example of crossover between two binary-coded chromosomes. An example of crossover between a set of two binary-coded chromosomes where half the length of chromosome A is exchanged for half the length of chromosome B, resulting in a hybrid set of chromosomes.  
Graphical representation of the surface used for the 3D maximization problem. Visualized in MATLAB 6.5 Using the Command peaks(40). The three maximums of the surface were located at f = 8.1165 (global maximum), 3.5507, and 3.4652.  
Graphical representation of the Rastrigin function used in the comparison of the Nelder-Mead, Hill Climbing, and Random Search algorithms with the adaptive genetic algorithm. Visualized in MATLAB 6.5: f = @(x,y) 10*2 + x.^2 + y.^2 – 10*cos(2*pi*x) – 10*cos(2*pi*y). The global minimum of the Rastrigin function is f (0,0) = 0.  
The fields of molecular biology and neurobiology have advanced rapidly over the last two decades. These advances have resulted in the development of large proteomic and genetic databases that need to be searched for the prediction, early detection and treatment of neuropathologies and other genetic disorders. This need, in turn, has pushed the development of novel computational algorithms that are critical for searching genetic databases. One successful approach has been to use artificial intelligence and pattern recognition algorithms, such as neural networks and optimization algorithms (e.g. genetic algorithms). The focus of this paper is on optimizing the design of genetic algorithms by using an adaptive mutation rate based on the fitness function of passing generations. We propose a novel pseudo-derivative based mutation rate operator designed to allow a genetic algorithm to escape local optima and successfully continue to the global optimum. Once proven successful, this algorithm can be implemented to solve real problems in neurology and bioinformatics. As a first step towards this goal, we tested our algorithm on two 3-dimensional surfaces with multiple local optima, but only one global optimum, as well as on the N-queens problem, an applied problem in which the function that maps the curve is implicit. For all tests, the adaptive mutation rate allowed the genetic algorithm to find the global optimal solution, performing significantly better than other search methods, including genetic algorithms that implement fixed mutation rates.
 
Top-cited authors
Charlotte Soneson
  • University of Zurich
Aaron T L Lun
  • Genentech
Steven Wingett
  • University of Cambridge
Gordon Keith Smyth
  • The Walter and Eliza Hall Institute of Medical Research
Matthew Ritchie
  • The Walter and Eliza Hall Institute of Medical Research