Because of the low prevalence of Human T Lymphotropic Virus type I (HTLV-I) in comparison with Khorasan Province, considering HTLV-I as an etiology of spastic paraparesia, it may be neglected in evaluation of spastic paraparesis in the other regions of Iran. Some reports of spastic paraparetic patients due to HTLV-I infection in West Azarbaijan, caused us to reconsider the importance of HTLV-I epidemiology in the other areas of the country.All spastic paraparetic patients who referred to Motahari and Imam Khomeini educational hospitals of Urmia from September 2004 to September 2007 were assessed for HTLV-I infection antibodies.In our 3 years study, 11 cases were diagnosed as Human T Lymphotropic Virus type I Associated Myelopathy/Tropical Spastic Paraparesis .The mean age of patients at the time of diagnosis was 45.8 years. Dorsal and cervical MRI of all patients was normal. Serum Enzyme-Linked Immuno-Sorbent Assay (ELISA) and Western blot (WB) for anti HTLV-I antibody in all patients was positive. Four patients underwent for lumbar puncture in which were normal in respect of cells and biochemistry, but positive for anti-HLTLV-I antibodies.HAM/TSP detection in West Azarbaijan in spite of its long distance from Khorasan Province shows the importance of anti-HTLV-I Ab assay in the blood and CSF of every spastic paraparetic patient all over the country. During the past 25 years, Human T Lymphotropic Virus type I (HTLV-I) epidemiology has been studied many times getting more advanced day by day. Geographical distribution of virus in the world was previously demonstrated. Although several studies showed the high prevalence of HTLV-I in Japan southwest, however the prevalence of virus in adjacent countries like Korea, China, Eastern Russia and Khorasan in Iran is low. HTLV-I cAll patients presented with spastic paraparesia and referred to Motrahari and Imam Khomeini hospitals in Urmia, from September 2004 to September 2007 were assessed for anti HTLV-I Ab.All patients after systemic and neurologic examinations underwent dorsal and cervical Magnetic Resonance Imaging (MRI). After ruling out of compressive lesions all patients’ blood were tested for anti HTLV-I Ab with ELISA and WB methods. Only four patients allowed us to do lumbar puncture for Cerebro- spinal Fluid (CSF) analysis . The results are presented in Eleven patients  were diagnosed as HAM/TSP. The mean age for diagnosis was 45.8 years and for beginning of symptoms based on history was 36.3 years old. Three patients had a history of blood transfusion . Three patients were under treatment for primary progressive multiple sclerosis. All patients underwent dorsal and cervical MRI which were normal.Using ELISA and WB methods showed anti-HTLVI Ab in all patients. Only four patients underwent lumbar puncture in which all were normal for cell and biochemistry but positive for anti-HTLV-I antibodies.Epidemiologic studies have been done over the past 25 year's demonestrating worldwide distribution of HTLV-I with different prevalence rates. Because of wide distribution of HTLV-I infection all over the world, doing epidemiological studies in every region (even non-endemic areas) is essential. In some nonendemic areas such as rural West African and SoutA positive blood result for HTLV-I by ELISA in all patients indicates the high sensitivity of this test and repeatedly, proving the fact that ELISA is the best screening test in HTLV-I assay. Normal dorsal and cervical MRI in patients who referred to us with spastic paraparesia, reinforces the suspicion for viral and infectious etiologies such as HTLV-I. The presence of upper motor neuron signs with less severity in upper limbs is an interesting finding in which should be considered in HAM/TSP.Reporting 11 HAM/TSP patients in West Azarbaijan during a three years interval indicates the distribution of HTLV-I in Iran that remind us of the necessity for evaluation of any patient who refer with spastic paraparesia or spastic tetraparesia for HTLV-I.Regarding the possibility of HTLV-I transmission by blood transfusion, assessing the patients with the history of blood transfusion in past decades should be considered. Finally we are emphasizing that HAM/TSP should be considered in patients with subjective complains such as urinary incontinence or frequency, distal paresthesia, dysesthesia, muscle stiffness and gait disturbances.


Recently, numerous interdisciplinary approaches that include integration of bioinformatics, epigenetics, and molecular and cellular biology have started to shed light on the complex dynamics that regulate cellular processes such as cell “stemness,” reprogramming, and differentiation. From the sequencing of the first complete genomes to the recent high-throughput genomic and proteomic approaches, a huge amount of information has been generated to improve our understanding of how the eukaryotic genome works to activate and coordinate specific programs of gene expression.The focus of this review is to provide an overview of the epigenetic regulatory mechanisms controlling crucial cellular fate decisions, in particular during differentiation and reprogramming. A special emphasis has been given to skeletal myogenesis, as it provides an amenable model for in vitro and in vivo studies.A system approach and skeletal myogenesis” provide an overview of the most common approaches currently used to address transcriptional regulation. They discuss deep sequencing and microarray-based methods, cell-based high throughput assays, and the generation of in situ gene expression databases as potent tools to dissect complex networks of gene expression. Using skeletal muscle as a paradigm, they highlight the main discoveries obtained through the different methods and underline the advantages of an integrated approach to obtain a full picture of cellular differentiation. Y. Ito et al. in “Epigenetic alterations in muscular disorders,” Dr. C. Lanzuolo discusses how altered epigenetic mechanisms contribute to human pathology and in particular to the development and progression of neuromuscular disorders. Muscular dystrophies arise from either mutations of proteins that play a role in the integrity of the sarcolemma—the plasma membrane that wraps the myofibers in skeletal muscles—or are due to a dysfunction within the cell nucleus. Dr. C. Lanzuolo focuses on the so-called nuclear muscular dystrophies and she analyzes the possible contribution of an important group of epigenetic modifiers, the polycomb-group (PcG) complexes, to the pathogenesis of these diseases. The dissection of the aberrant epigenetic profiles associated to several human pathologies has contributed to the design of experimental therapies with epigenetic drugs.An increasing number of studies suggest an epigenetic component in the development of many human diseases. In the review article “Tackling skeletal muscle cells epigenome in the next-generation sequencing era” by R. Fittipaldi and G. Caretti points to the significance of genome-wide study of the epigenetic modifications and the transcription factors that are activated during skeletal muscle differentiation. The authors discuss on the new genome-wide technologies to monitor the epigenetic landscape that characterizes myoblast-to-myotube transition in order to obtain innovative information on molecular mechanisms orchestrating biological processes, such myogenic differentiation.The review “myogenin is discussed in “Turning on myogenin in muscle: A paradigm for understanding mechanisms of tissue-specific gene expression” by H. Faralli and F. J. Dilworth. Transcription factors, cofactors, and epigenetic modifications contribute to regulate muscle-specific gene expression during development. In particular, the authors highlight the fact that a tissue-specific factors such as MyoD cooperate with more ubiquitously expressed proteins  to establish a transcriptionally permissive environment to ensure proper spatiotemporal myogenin expression.The fine regulation of a myogenic gene such as Predictive models of gene regulation from high-throughput epigenomics data” describes a computational framework using integrative tools and machine learning algorithms that facilitate the systematic analysis of high-throughput sequencing epigenetic data for integrative studies. Their analysis shows a different epigenetic code of expression for intron-less and intron-containing genes, with more prominent differences for genes with low GC content (LGC) in their promoter, showing for instance that at the promoter regions of LGC intron-less genes, H3K36me3 and H3K4me1 are the most informative marks while in polyadenylation sites of expressed genes, the H3K36me3 signal is much weaker than in intron-containing genes. Based on epigenetic data, their model predicts very strongly gene expression between two conditions; therefore, this approach can be applied to study gene expression in different developmental stages, disease states, or treatments.The current challenge of epigenetics is how to analyse and extract biological knowledge from the large volumes of data produced with new high-throughput technologies. In this regard, the paper of S. Althammer et al., “The stability of the induced epigenetic programs”, M. J. Barrero discusses the epigenetic changes that occur during differentiation and the way back upon cellular reprogramming emphasizing on the thin regulation of pluripotent and lineage-specific genes expression to ensure a correct differentiation during development and in adult life.Of tremendous relevance for its therapeutic potential, is the possibility to manipulate cell identity. In the review titled “The epigenetic regulation of B lymphocyte differentiation, transdifferentiation, and reprogramming” by B. Barneda-Zahonero et al. reviews the hierarchical network of transcription factors that mediate the epigenetic signature regulating the transcriptome during B cell development. B lymphocytes are highly specialized terminally differentiated cells responsible for generating high-affinity antibodies, providing the humoral immunity against pathogens. Every day the human body generates millions of B lymphocytes from precursor hematopoietic stem cells by a differentiation process that is a tightly regulated. This multistep differentiation process, vital to immunity, combines the successive expression of specific transcriptional factors and associated epigenetic changes to restrict the developmental potential of lymphoid progenitors to the B cell pathway by repressing B-lineage-inappropriate genes, while simultaneously promoting B cell development by activating B-lymphoid-specific genes. “Lucia LatellaLucia LatellaDaniela PalaciosDaniela PalaciosSonia ForcalesSonia ForcalesPier Lorenzo PuriPier Lorenzo Puri


Selenoproteins are proteins that contain the amino acid selenocysteine (Sec) and the first release of the database included annotations for eight species. Since the release of SelenoDB 1.0 many new animal genomes have been sequenced. The annotations of selenoproteins in new genomes usually contain many errors in major databases. For this reason, we have now fully annotated selenoprotein genes in 58 animal genomes. We provide manually curated annotations for human selenoproteins, whereas we use an automatic annotation pipeline to annotate selenoprotein genes in other animal genomes. In addition, we annotate the homologous genes containing cysteine (Cys) instead of Sec. Finally, we have surveyed genetic variation in the annotated genes in humans. We use exon capture and resequencing approaches to identify single-nucleotide polymorphisms in more than 50 human populations around the world. We thus present a detailed view of the genetic divergence of Sec- and Cys-containing genes in animals and their diversity in humans. The addition of these datasets into the second release of the database provides a valuable resource for addressing medical and evolutionary questions in selenium biology.SelenoDB ( Selenoproteins are proteins that contain the amino acid selenocysteine (Sec) as one of their constituent residues. Sec, the 21st amino acid in the genetic code, is analogous to the amino acid cysteine (Cys) in its molecular structure with an atom of selenium replacing that of sulfur in Cys. An in-frame UGA (stop) codon in conjugation of a SElenoCysteine Insertion Sequence (SECIS) element, an RNA secondary structure in the mRNA of selenoproteins, codes for a Sec residue instead of terminating protein synthesis , which we contributed to produce . Thus, wSaccharo-myces cerevisiae genome. This yeast genome lacks selenoproteins but contains selenoprotein homologs with Cys in the place of Sec.Using Selenoprofiles , we presSelenoprofiles is a homology-based annotation pipeline, specially designed for the detection of selenoprotein genes in target genome sequences. It produces accurate gene predictions using a set of manually curated profiles, one for each known protein family. Each profile is built from a multiple amino acid sequence alignment of representative members of the family, including the Sec residue. Unlike other gene prediction pipelines, Selenoprofiles is able to correctly predict selenoprotein genes. The genome sequence is scanned using the psi-blast program  with a pWe have annotated 23 selenoprotein families  in SelenSecO-phosphoseryl-tRNA (PSTK), Selenocysteine synthase (SecS) and the associated protein 43 (SECp43) genes are annotated for the first time in SelenoDB.In addition, we have annotated the structure of five additional gene families associated with the Sec insertion machinery  Table 2Table 2. . glutathione peroxidase) but not the subfamily (e.g. glutathione peroxidase 1) of a predicted protein because this entails phylogenetic analysis with a species of reference. That is, a species where all the members of a protein family are reliably assigned to subfamilies. This is the case only for the selenoprotein families annotated in the human genome . In such cases, we chose not to assign a subfamily based on the reference human proteins.The SECIS element is a RNA stem–loop found in the selenoprotein mRNAs, essential for Sec insertion. In eukaryotes, it resides in the 3′-UTR (untranslated region) and can be classified in two classes, type I and type II with the latter possessing an additional helix and a short apical loop. The structure adopts a kink-turn motif through the non-canonical base pairs AG-GA in the quartet, the most conserved region in eukaryotic SECIS elements . ComputaSelenoDB 2.0 includes intra-specific diversity data for the first time and, in doing so, gives what is currently the best view of human variation in selenoprotein genes, Cys-containing homologs and genes involved in the Sec insertion machinery. We include SNP data from 928 human samples from the CEPH HGDP panel . These sTo obtain the human data, we used an Agilent custom array (Agilent Technologies) to target all exons plus 200 bp of the surrounding introns and 2000 bp upstream (to include promoter regions) of genes in Human sequences were mapped to the human reference genome (hg19) using BWA  yieldingThe initial GATK output was put through a comprehensive set of filters to remove sites that: (i) had a coverage below 8x in more than 50% of samples; (ii) had an average coverage above 100x; (iii) were indels or SNPs within 5 bp of an indel; (iv) were trialellic sites; (v) had a GATK SNP quality <20 and (vi) a strand bias (SB) >10. We additionally filtered out human SNPs that did not have one-to-one human to chimpanzee correspondence in the Ensembl EPO 6 primate alignments ,46 or weThe majority of search, display and sequence manipulation features found in SelenoDB 1.0  remain iWith the release of SelenoDB 2.0, we have provided a comprehensive annotation of selenoprotein genes across animal genomes. Two features provided for human selenoproteins in this release are the annotation of alternative transcripts and a worldwide catalog of genetic variation. It would be of interest to selenium researchers to have the annotation of alternative transcripts in other species as well as a sample of the genetic diversity of selenoproteins in non-human species.The Max Planck Society; the Plan Nacional and the Instituto Nacional de BIoinformatica (Spain) (to R.G.); National Institutes of Health grants (to V.N.G.) Funding for open access charge: Max Planck Society.Conflict of interest statement. None declared.


Social factors affect the risk of very preterm birth and may affect subsequent outcomes in those born preterm. We assessed the influence of neighbourhood socio-economic characteristics on the risk and outcomes of singleton very preterm birth (<32 weeks of gestation) in two European regions with different health systems.Live births (n=1118) from a population-based cohort of very preterm infants in 2003 in Trent (UK) and Ile-de-France (France) regions were geocoded to their neighbourhood census tracts. Odds ratios for very preterm singleton birth by neighbourhood characteristics  were computed using infants enumerated in the census as a control population. The impact of neighbourhood variables was further assessed by pregnancy and delivery characteristics and short term infant outcomes.Risk of very preterm singleton birth was higher in more deprived neighbourhoods in both regions (OR between 2.5 and 1.5 in the most versus least deprived quartiles). No consistent associations were found between neighbourhood deprivation and maternal characteristics or health outcomes for very preterm births, although infants in more deprived neighbourhoods were less likely to be breastfed at discharge.Neighbourhood deprivation had a strong consistent impact on the risk of singleton very preterm birth in two European regions, but did not appear to be associated with maternal characteristics or infant outcomes. Differences in breastfeeding at discharge suggest that socio-economic factors may affect long term outcomes. Preterm birth is related to individual social factors, including maternal education, occupation and ethnicity ,2, as weMechanisms underlying the association between the risk of very preterm birth and social factors are not well understood . AttemptWide variations in very preterm births rates exist in Europe  . ResearcCross-national comparisons of the impact of social factors on the risks and outcomes of very preterm birth have been limited because of the difficulties of defining comparable populations as well as the lack of socioeconomic information in studies on these infants. International variations in procedures for recording births and deaths at early gestational ages  as well We investigated the influence of neighbourhood socio-economic status on the risk of very preterm singleton birth in two French and English regions with different very preterm rates and health systems using data from the population-based MOSAIC study collected with a common protocol and standardized inclusion and validation criteria. A second aim was to study whether the clinical characteristics of pregnancy, very preterm delivery, in-hospital mortality and short term infant health outcomes varied by neighbourhood of residence.Data were available for very preterm infants born between 22+0 to 31+6 weeks from the former Trent health region (UK) and Ile-de-France (France), two regions participating in the population-based MOSAIC study . The oveData were collected on all very preterm births from 01/01/2003 to 31/12/2003 in Trent and from 01/02/2003 to 31/08/2003 in Ile-de-France. Information on maternal and infant’s characteristics were abstracted from medical records using a common protocol. Infants were followed until discharge from hospital (to home or long-term care) or death. Inclusions in the study were cross-checked with birth registers in each maternity unit. After excluding fetal deaths before onset of labour and infants born or resident outside the study regions, 667 infants in Trent (534 singletons) and 809 in Ile-de-France (584 singletons) were available for analysis.th percentile for gestational age), bronchopulmonary dysplasia and neurological morbidity . We also included breast milk feeding at discharge. Definitions have been published previously [Information on characteristics of the very preterm delivery included gestational age, small for gestational age, multiplicity (singleton or twin), indicated delivery (caesarean section before labour) and pregnancy complications: hypertension ; antepartum haemorrhage without hypertension; preterm premature rupture of membranes (PPROM) without hypertension or haemorrhage; and preterm labour without hypertension, haemorrhage or PPROM. Infant outcome measures included in-hospital mortality, mechanical ventilation (>1 day), long hospital stay  and the IRIS-2000 in Ile-de-France (between 1800 to 5000 inhabitants and a median surface of 70.0 Km2).No data were routinely available on maternal socio-economic factors from medical records and so information on the location of mother’s place of residence was collected. Subsequent analysis on the effects of social factors on very preterm birth and health outcomes were carried out in Ile-de-France and the Trent region, as both countries could provide census data on small geographic areas using similar data collection methodology. These data were thus used to characterize neighbourhoods of residence for very preterm infants. Very preterm infants were geocoded to the smallest geographic units for which census data were available based on their mothers’ place of residence: super output areas in Trent  in Trent and from 01/01/1999 to 03/08/1999  in Ile-de-France).Sensitivity analyses were carried out to test that the census accurately reflected the birth cohort’s place of residence, using birth registries for the whole 2003 year in Trent and from one of the districts in 1999 in Ile-de-France.Analyses were restricted to singleton very preterm births as we could not differentiate births by multiplicity in the denominator from the census data. Rates of very preterm singleton births were similar in the two regions (80.9% in Trent and 80.2% in Ile-de-France). Multiples are only 3% of all births and tend to have different characteristics from total births, including older more affluent mothers. Furthermore, the sample was small (133 twins in the Trent region and 225 twins in Ile-de-France) and this sample was inadequate for twin specific analysis which are necessary as maternal complications and outcomes differ for twins.We studied four neighbourhood socio-economic characteristics Table  (unemploWe first compared singleton very preterm infants with census infants by neighbourhood characteristics quartiles within each region. Odds ratios (OR) with 95% confidence intervals were calculated for the risk of very preterm birth; we tested for trends across deprivation quartiles and for interactions between neighbourhood characteristics and region. While we could not exclude multiple births from the census data, these constitute a small fraction of all births and the census population provides a good approximation of the characteristics of the singleton population.Then pregnancy and delivery characteristics and infant outcomes for very preterm singleton births were compared across the four socio-economic neighbourhood characteristics. Adjusted odds ratios (aOR) were calculated, controlling for maternal age, small for gestational age and sex, using logistic regression models. The small number of infants with brain lesions did not make it possible to calculate aOR for this outcome. We tested whether the association between pregnancy and delivery characteristics and infant outcomes varied by each neighbourhood characteristic between the two regions. Interactions were considered significant if p<0.05. Analyses were undertaken to investigate all four neighbourhood deprivation characteristics. Here associations are shown for unemployment rates alone to simplify the presentation of results.Data were analysed using STATA 9 software .Table In both regions, the percentage of very preterm singletons increased with a higher rate of unemployment, a higher proportion of manual workers and non-home owners or a low educational level when compared to infants in the census Table . More thTable After adjustment for maternal age, gestational age, small for gestational age and sex, breastfeeding at discharge was lower in neighbourhoods with the highest unemployment rates (Trent: OR=0.2 (95% CI: 0.1-0.4); Ile-de-France: OR=0.4 (95% CI: 0.2-0.8)). The interaction between hypertension during pregnancy and region was not significant after adjustment. (interaction test p<0.07)  are that we were unable to exclude very preterm infants and multiples from the census population, as gestational age and multiplicity are not available in the census data; but these represent a small proportion of all live births and would thus have a very minor impact on the birth population deprivation quartiles. Infants who died in the first days of life will most likely not be included in the census, although these infants are a very small proportion of total births.Our results were robust despite differences in the definitions used to report census data on socio-economic characteristics in England and France. The magnitudes of the risk of very preterm births for singletons in most deprived versus least deprived neighbourhoods were quite similar for Trent and Ile-de-France, and slightly higher than those reported previously in Europe ,9 using We found no systematic differences between pregnancy and delivery characteristics of very preterm births and neighbourhood of residence in the two regions. This finding corroborates previous studies which found no socio-demographic gradient for spontaneous delivery or PPROM for very preterm births in Australia  and no aVery preterm outcomes varied between the two regions, but they did not vary by neighbourhood socio-economic characteristics within each region, with the exception of breastfeeding. Similar results have been shown recently for survival, respiratory support, length of stay among very preterm infants  and the Despite the absence of an association between neighbourhood socio-economic status and infant mortality and morbidity, the total burden of mortality and respiratory and neurological morbidity will be greater in deprived areas because of their higher rates of preterm birth. In addition, the total burden of these socio-economic differences may be greater in England, where rates of very preterm births are higher, than in France . The neoIn conclusion, trends in the risk of very preterm birth according to area-level socio-economic characteristics were robust in two European regions with different health care systems and rates of very preterm birth leading to a greater health burden in deprived areas despite the absence of socio-economic disparities in mortality and short-term morbidity. Planning for neonatal care provision, social support services for families and follow-up programmes needs to consider the socio-spatial distribution of very preterm children. Extending the methodology used in this paper to other countries with access to area-based census data would make it possible to test whether these trends are similar in other settings.1. Socio-economic disparities are associated with adverse obstetric and birth outcomes and an increased burden of neonatal care2. Neonatal mortality and neonatal care for very preterm infants do not vary across area deprivation levels in the UK3. Very preterm birth rates vary widely between European countries.1. Area deprivation more than doubled the risk of singleton very preterm birth, in two European regions with different health systems and differing rates of very preterm birth.2. There were not consistent associations across the two regions in pregnancy complications and delivery characteristics by neighbourhood deprivation.3. Area deprivation did not affect the outcomes to discharge from hospital for very preterm singletons with the exception of breastfeeding.The authors declare that they have no competing interests.Analysis and interpretation of the data were carried out by MB, LS and JZ. MB wrote the first draft of the paper and all authors participated in revisions and approved the final manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2393/13/97/prepubAdjusted odds ratio for maternal and infant's outcomes among very preterm singletons by neighbourhood unemployment rate quartiles.Click here for file


EGFR mutation status appears to be the strongest predictor for the selection of NSCLC patients to first-line treatment with EGFR tyrosine kinase inhibitors vs chemotherapy. Use of other biomarkers remains investigational.Non-small-cell lung cancer (NSCLC) remains by far the major cause of cancer-related death in the Western world in both men and women. The majority of patients will be diagnosed with metastatic disease, and chemotherapy doublets remain the cornerstone of treatment for these patients. However, chemotherapy has a minimal impact on long-term survival and prognosis remains poor for these patients. Further improvement in treatment is likely to require incorporation of novel targeted therapies. Among these agents, inhibitors of the epidermal growth factor receptor (EGFR) have demonstrated significant activity in the first-, second- or third-line treatment of NSCLC. The purpose of current paper is to present the evidence for using several proposed molecular biomarkers as a tool for selection of NSCLC patients for anti-EGFR treatment. According to current data,  Chemotherapy has been the backbone of treatment for patients with advanced non-small-cell lung cancer (NSCLC) for the last decades; however, it has clearly reached a plateau of activity, and thus further improvements will require integration of novel therapies. Among the targeted agents, epidermal growth factor receptor (EGFR) inhibitors gefitinib and erlotinib are now established as an option for first-, second- or third-line treatment  as well as reference lists of original and review articles. A consensus was reached among all authors for the manuscript.P=0.03) and ISEL trials  in NSCLC specimens, with patient sensitivity to EGFR TKI treatment has been studied extensively with both positive ( placebo . HoweverP<0.001). The Iressa NSCLC Trial Evaluating Response and Survival versus Taxotere (INTEREST) trial was a non-inferiority phase III trial that compared gefitinib with docetaxel as second-line treatment , which makes this marker unlikely to be used in practice for patient selection. Placebo-controlled phase III trials with EGFR TKIs in the second- or third-line setting were the only studies indicating some predictive value of lack of protein expression in selecting patients who do not benefit from these agents, although its predictive discrimination did not meet the expectations of a clinically useful test .EGFR gene copy number, assessed by fluorescence in situ hybridisation (FISH), has been tested extensively as a predictive factor for response and survival benefit from TKI treatment. The original classification of FISH positivity includes both gene amplification (rare in NSCLC) and high polysomy  and predictive of greater survival benefit in erlotinib-treated patients (P=0.005). In the ISEL trial, high EGFR copy was associated with a survival benefit in patients receiving gefitinib compared with placebo , whereas no benefit was observed in patients with FISH-negative tumours . In the IPASS study, EGFR FISH positivity was associated with higher response rate and a borderline PFS benefit from gefitinib when compared with platinum-based chemotherapy . Discovery of these mutations in tumours from NSCLC patients was immediately linked with response to gefitinib  and higher RR when treated with gefitinib when compared with docetaxel  than in the overall population , and in the population with wild-type EGFR , indicating that EGFR mutations have a positive prognostic role. There was no OS difference between treatment groups according to EGFR mutation status . The predictive role of EGFR mutation was also demonstrated by the noteworthy differences in PFS observed in patients with EGFR mutation-positive or -negative tumours when treated with gefitinib (9.5 vs 1.5 months). In patients without EGFR TK mutations, PFS was significantly superior in the group treated with chemotherapy compared with gefitinib . This trend was more apparent in the chemotherapy group  than in the cetuximab group , confirming the prognostic role of EGFR mutations n repeat is situated in intron 1 of the gene. In vitro as well as in vivo data indicate that EGFR transcriptional activity may be influenced by the number of CA repeats , D770_(ins SVQ) and D770_(ins G) N771T (One of the mechanisms of primary and acquired resistance in patients who receive TKI treatment is insertion point mutations in exon 20 of the G) N771T . NeverthVirtually all patients responding to TKI treatment will inevitably develop resistance to these agents. A point mutation in the tyrosine kinase domain (T790M) is found in approximately half of patients at the time of acquired resistance to EGFR TKI therapy . This muRAS mutations result in EGFR-independent activation of MAPK and are mutually exclusive with EGFR mutations  and was shown to associate with outcome in a clinical trial of erlotinib and bevacizumab (P=0.0006) and also when applied in a blinded test to patients treated with erlotinib alone in the phase II first-line monotherapy trial, ECOG 3503 , not confirmed in other studies. High vs late (second and third line) settings. The role of EGFR mutations was confirmed in three phase III trials specially designed for the population of patients treated in the first-line setting  on data derived from large randomised phase III trials. On the other hand, it should be noted that molecular analyses derived from placebo-controlled studies (BR.21 and ISEL) were retrospective, not preplanned and restricted to patient subsets with available samples and thus likely to be biased  derive a survival benefit from treatment with erlotinib compared with placebo, although the effect of erlotinib was much greater in patients with EGFR-mutated tumours (EGFR mutations, although the smaller benefit in patients with EGFR wild-type tumours should be taken into account in pharmacoeconomic analyses to guide reimbursement decisions. It is likely that a combination of markers, such as K-RAS mutations or other as yet unidentified markers, will be used in future to identify patients who will not benefit from EGFR TKI therapy.Another important issue is whether treatment with EGFR TKIs should be denied to patients with tumours showing wild-type EGFR mutations. A study from the Spanish Lung Cancer Group reported the screening of >2000 NSCLC patients and found mutations in 350 patients (16.6% EGFR mutation testing, in particular IHC with antibodies constructed against abnormal EGFR proteins as a result of gene mutations, should facilitate large-scale testing (An important concern is the feasibility of large-scale screening of NSCLC patients for EGFR inhibitors came in parallel to the clinical trials testing these agents. This knowledge should serve as a lesson in the current development of other agents in NSCLC, where many trials do not meet their end points because of a questionable clinical benefit in unselected populations. Rational drug development, based on profound understanding of tumour biology, a drug's mechanism of action and clinical implications of patient selection, is hoped to impact on the current poor treatment outcomes of NSCLC patients.The evolution of our knowledge of biomarkers to guide treatment in NSCLC patients treated with


We previously showed the existence of selective pressure against protein aggregation by the enrichment of aggregation-opposing ‘gatekeeper’ residues at strategic places along the sequence of proteins. Here we analyzed the relationship between protein lifetime and protein aggregation by combining experimentally determined turnover rates, expression data, structural data and chaperone interaction data on a set of more than 500 proteins. We find that selective pressure on protein sequences against aggregation is not homogeneous but that short-living proteins on average have a higher aggregation propensity and fewer chaperone interactions than long-living proteins. We also find that short-living proteins are more often associated to deposition diseases. These findings suggest that the efficient degradation of high-turnover proteins is sufficient to preclude aggregation, but also that factors that inhibit proteasomal activity, such as physiological ageing, will primarily affect the aggregation of short-living proteins. In order to carry out their biological function, proteins need to fold into well-defined three-dimensional structures. Protein aggregation is a process whereby proteins misfold into inactive and often toxic higher order structures, which is implied in about 30 human diseases such as Alzheimer's disease, Parkinson's disease and systemic amyloidosis. In earlier work it has been shown that although protein aggregation is an intrinsic property of polypeptide chains that cannot be entirely avoided, evolution has optimized protein sequences to minimize the risk of aggregation in a proteome. Here we show that this pressure is not uniform, but that proteins with a short lifetime have on average a higher aggregation propensity than long-living proteins. In addition, we show that high turnover proteins also make fewer interactions with chaperones. Taken together, these observations suggest that under normal physiological conditions the aggregation propensity of short-lived proteins does not represent a significant treat for the biochemistry of the cell. Presumably the strong dependence of these proteins on proteasomal degradation is sufficient to preclude the accumulation of aggregates. As proteasomal activity declines with age this would also explain why we observe a higher association of high turnover proteins with age-dependent aggregation-related diseases. Biological networks are fine-tuned to respond to narrow changes in protein concentration. The ability of a cell to maintain metabolic and signal transduction fluxes is therefore highly dependent on a tight regulation of its proteostatic network i) short-living proteins on average are predicted to have longer and more severe aggregating regions than long-living proteins, and ii) the evolutionary enrichment of aggregation breaking gatekeeper residues is less pronounced in short-living proteins, suggesting that they experience milder selective pressure to minimize aggregation. Further, we also found significantly less interactions between short-living proteins and molecular chaperones in the IntAct database In order to determine the relationship between protein lifetime and protein aggregation we here combine experimental lifetime measured for 611 proteins The current study focuses on short-stretch mediated protein aggregation, where specific segments of a polypeptide chain assemble into an intermolecular beta-sheet and thus nucleate aggregation. Since current knowledge in the field suggests that the short-stretch mediated protein aggregation covers the majority of disease-associated protein deposition, and no reliable prediction methods exist for alternative protein aggregation mechanisms, we feel justified to ignore alternative aggregation mechanisms such as 3D domain swapping and native protein aggregation. Like all current protein aggregation prediction algorithms, TANGO calculates intrinsic aggregation propensity of an input polypeptide sequence and returns short stretches predicted to have a high propensity to nucleate protein aggregation through the formation of intermolecular beta-sheets. These regions constitute the intrinsic aggregation propensity of the sequence in the absence of globular structure. Since these aggregation prone regions are nearly always part of the hydrophobic core when the protein resides in its native conformation, the aggregating stretches identified computationally need to become exposed by  unfolding of the protein before they can actually nucleate protein aggregation. So, although three dimensional relationships that existed in the folded state are no longer relevant during assembly into an intermolecular beta-sheet, they are highly relevant to determine if a particular region is likely to become exposed in the first place. In order to estimate the likelihood that a given short polypeptide segment may become exposed by  protein unfolding, we employ the FoldX force field, which calculates the contribution of each amino acid to the thermodynamic stability of the three dimensional structure of the protein, thus allowing to determine if an aggregation prone region is in a stable or less stable part of the structure.Trans-membrane (TM) and extracellular proteins in the experimental dataset were excluded from the analysis. As hydrophobic trans-membrane regions of the TM proteins are not under selective pressure against aggregation they should not be considered for the analysis of the relation between protein lifetime and aggregation tendency. Since this study analyses the relation between proteasomal degradation and aggregation, extracellular proteins that are degraded by lysosomes are also deleted. We selected these proteins using the keywords “Membrane” (KW-472) and “Extracellular matrix” (KW-0272). This resulted in a dataset of 191 short-living (PSI ≤ 2) and 420 long-living (PSI ≥ 5) proteins.Yen et al. developed a global stability analysis, a high throughput approach for proteome-scale protein-turnover analysis, resulting in a protein stability index (PSI) for 8000 human proteins The statistical mechanics algorithm TANGO Our dataset was composed of 532 HG-U133_Plus_2 type microarray experiments extracted from GEO (Gene Expression Omnibus) Structures were selected according to the following criteria: (1) 100% sequence identity with the sequence of interest, (2) crystal structure, (3) resolution at least 3 Ä. All modeling was performed using the FoldX 2.8 force field and tool suite Comparison of the distributions for each parameter tested in the analysis of short versus long-living proteins was performed using Mann-Whitney and Kolmogorov-Smirnov tests.i) the average aggregation propensity of the protein , ii) the number of aggregating segments in the protein, iii) the length of aggregating segments, and iv) the aggregation propensity of each aggregating segment. The correlation with the experimentally determined biological lifetime of the protein was tested for each individual parameter and significant differences were found  for 8000 human proteins re found : Short-lre found , which ire found , but by re found  and aggrre found . As prevre found . In viewre found . Howeverre found , we see An alternative explanation for the lower sensitivity of fast turnover proteins to the evolutionary pressure against protein aggregation could be that these proteins possess native structures with inherently superior thermodynamic stability to those of proteins from the long lifetime group. Given the significant structural coverage of our dataset, i.e. there are high resolution crystallographic structures available for 127 proteins in our dataset of 611 , we can gatekeeper residues, a term used to indicate amino acids that counteract aggregation It has been well established that evolutionary pressure against protein aggregation has resulted in the enrichment at the flanks of aggregation prone segments of et al., we divided this set of proteins into four categories according to their PSI turnover scores: short half-life (PSI < 2), medium half-life (2 ≤ PSI<3), long half-life (3 ≤ PSI<4) and extra-long half-life (PSI ≥ 4) N/PSIT – SUMN/SUMTPSI. PSIx is the number of proteins in a given set x, belonging to a given PSI category and SUMx the total number of proteins in a given set x. X points to the total set (T) or the (non-) chaperone-binding proteins (N). Comparison of the chaperone enrichment in short-living versus long-living proteins shows that in our limited dataset, proteins that interact with molecular chaperones are significantly enriched in the group of long-living proteins folding and disaggregation and eventually shuttle substrates to the degradation machinery proteins . Given wWe investigated which of the proteins in our dataset are involved in a human disease associated with protein deposition and found 16 proteins with known PSI score . InteresProtein aggregation is triggered by short polypeptide stretches within a protein sequence that assemble into intermolecular beta-sheets when they become exposed to the solvent Given the high burden of protein aggregation on the proteome, and even if aggregation propensity cannot be avoided altogether, selective pressure to minimize the aggregation propensity of protein sequences is still to be expected. Indeed, it was found that aggregation-opposing residues are enriched at specific sites along the sequence of proteins et alSelective pressure against aggregation is not homogeneous. We previously showed that enrichment of gatekeeper residues is more pronounced at the flanks of strongly aggregating sequences Moreover, a search of the IntAct database On the other hand, it is known that the efficiency of the proteasomal system erodes as a result of physiological ageing Text S1Supplementary data. Table 1. Comparison between the aggregation parameters for short-living and long-living proteins. The analysed population is the group of short-living protein, the reference population are the long-living proteins. ++ and − indicate that the population has a distribution significantly (p<0.001) shifted to respectively higher or lower values than the reference population in the performed statistical test, idem for + and − where p<0.01. Table 2. Lifetime data for disease-associated proteins. We show the lifetime values of the proteins from the Yen dataset Table 3. Overview of the protein set used. From the Yen dataset http://www.pdb.org) Table 4. Overview of the chaperone set. This table contains the chaperones used in the IntAct (DOC)Click here for additional data file.


Whereas rejection of donor cells bearing mismatched MHC alleles has been ascribed to direct activation of T cells by the altered MHC-peptide structures, the factors that initiate rejection of MHC-matched donor cells remain elusive. Our recent study identified these factors . We founThe discovery that natural antibodies initiate the rejection of allogeneic tumors led us to assess the impact of these antibodies on tumors that arise in the autologous setting. The effects of tumor-binding IgG during autologous tumor initiation and progression have been a source of controversy for many years. On the one hand, circulating antibodies against p53 are associated with poor prognosis and metastases in a variety of human cancers (reviewed in ). Moreovin vivo in the autologous tumor setting led us to a broad study of the interactions between various DC subsets and IC. The findings showed that while BMDC and splenic DC can efficiently process IC, tumor-associated DC are not able to internalize and process IC unless exposed to additional stimuli such as TNFα and CD40 ligand. Intratumoral injection of tumor-binding IgG in combination with such stimuli induced remarkably potent anti-tumor immunity that resulted in eradication of established tumor nodules and distant metastases through recruitment and activation of tumor-reactive T cells. This treatment proved effective in a number of mouse tumor models and despite its potency, no autoimmune disease or other serious toxicity was detected.Nonetheless, in our study injections of allogeneic tumor-binding IgG into syngeneic tumor-bearing mice had little or no treatment effect. The discrepancy between the capacity of IC to induce DC activation in vitro, and the inability to apply this principle In subsequent studies, we used mass spectroscopy to identify the antigens on B16 melanoma recognized by the alloantibodies, and found no relationship between these antigens and those recognized by tumor-infiltrating T cells in successfully treated mice. For example, although none of the antibodies were directed against TRP-2 or gp100, large numbers of activated CD8 T cells recognizing these proteins were found in tumors injected with the alloantibodies. In agreement with this finding, Zhu et al. recently demonstrated a synergistic effect between anti-gp75 antibodies and CD8 T cells that recognize gp100 [


The integration of large-scale wind power adds a significant uncertainty to power system planning and operating. The wind forecast error is decreased with the forecast horizon, particularly when it is from one day to several hours ahead. Integrating intraday unit commitment (UC) adjustment process based on updated ultra-short term wind forecast information is one way to improve the dispatching results. A novel three-stage UC decision method, in which the day-ahead UC decisions are determined in the first stage, the intraday UC adjustment decisions of subfast start units are determined in the second stage, and the UC decisions of fast-start units and dispatching decisions are determined in the third stage is presented. Accordingly, a three-stage birandom UC model is presented, in which the intraday hours-ahead forecasted wind power is formulated as a birandom variable, and the intraday UC adjustment event is formulated as a birandom event. The equilibrium chance constraint is employed to ensure the reliability requirement. A birandom simulation based hybrid genetic algorithm is designed to solve the proposed model. Some computational results indicate that the proposed model provides UC decisions with lower expected total costs. With growing concern about energy and the environment, wind power as the most visible renewable energy generation has been vigorously developed across the world. However, the growth of integrated wind power also brings many dispatching and control challenges due to the nature of wind energy and the characteristics of wind plants. High wind power uncertainties due to unsatisfactory forecast accuracy usually generate additional integration costs, which may be reduced by employing adaptive scheduling policies and developing more appropriate models. Unit commitment (UC) has always been regarded as one of the most crucial processes in system scheduling and the crucial basis for dispatching. How to address the wind power uncertainty in unit commitment has attracted much more concern in recent decades.Increasing the system reserve level explicitly had been presented when wind uncertainty addressing problem appeared. Soder presented a methodology to estimate the requirements of kinds of reserves  by linking with the predefined probability of too low frequency and predefined rate of load shedding in , consideUncertain programming has been more widely applied in UC modeling to cope with high wind power uncertainties. In particular, stochastic UC (SUC) has been widely studied and applied , 5. The Besides applying advanced modeling methods, much valuable work has been conducted on building adaptive UC policies to cope with wind uncertainty. By using any of the kinds of forecast methods, the wind power forecast accuracy is increased with the forecast horizon shortening, which shows a clear trend when it is from day ahead to several hours ahead. Some studies on UC policy and modeling have been conducted based on this feature, and some positive effects have been shown up. Tuohy et al. , 16 presIntegrating intraday adjustment event into day-ahead UC calculation as well as obtaining a UC decision with the lowest total costs including adjustment cost is another method. In , the intThe largest challenge of modeling the three-stage UC described above is how to formulate the unrealized next-day hours-ahead forecasted wind power output, which would be used as an input for the intraday UC adjustment stage. When making day-ahead scheduling decisions, the available information about wind power output is its day-ahead forecast value and the statistical forecast error or an uncertain wind forecast result which includes both. The only available information about intraday forecasted wind power in day-ahead scheduling is the statistical forecast error. It can be found that the day-ahead forecasted wind power and intraday hours-ahead forecasted wind power, which are seemingly unable to connect with each other, could build up mathematical relationship based on the possible actual wind power as a medium. The actual wind power output can be formulated as a random variable according to day-ahead forecast data. Considering the random characteristic of intraday wind power forecast errors, the intraday hours-ahead forecasted wind power could also be expressed as a random variable, which takes the value of the stochastic actual wind power output with stochastic hours-ahead forecast errors. It means that the intraday hours-ahead forecasted wind power and intraday UC adjustment event are both with twofold randomness when being considered in day-ahead scheduling. There do exist many scenes of such twofold phenomena in practical situations. In order to build mathematical models that are closer to such actual situations, a so-called birandom variable was proposed by operations research scholars . The birTo solve the UC problems, many methods have been studied, including Lagrangian relaxation algorithm (LR) , dynamicIn this paper, an equilibrium chance-constrained three-stage birandom programming UC (ECTBUC) model which integrates expected stochastic intraday UC adjustment event is proposed. The remainder of this paper is organized as follows. A three-stage decision method is employed for the proposed UC problem. An additional middle stage is contained to modify UC schedule of subfast start units several hours earlier when the reliability requirement cannot be satisfied, estimated using the updated wind realization and the hours-ahead wind power forecasting. Therefore, in the UC policy proposed in this paper, the first stage is making day-ahead UC decisions of nonfast start units considering the stochastic intraday UC adjustment event; the second stage is estimating the reliability level according to the ultra-short-term wind power forecasting and making UC adjustment decisions of the subfast start units when the reliability level was estimated unsatisfactory; the third stage is making UC decisions of fast start units and the dispatching decisions. The timeline of the proposed policy is shown in In the policy proposed in this paper, the intraday UC adjustment event should be integrated in the day-ahead UC decision-making process. Due to the fact that the intraday UC adjustment decision should be determined several hours earlier because of the minimum uptime/downtime of subfast start units, the intraday hours-ahead wind power forecasting results should be applied in day-ahead UC modeling. How to model the intraday ultra-short-term forecasted wind power output which cannot be realized when making the day-ahead UC decisions is the key.t is wtdaf and the day-ahead forecast error Ftdaf according to statistical analyzing; then the actual wind power output, Fthaf, then, based on each realized actual wind power output wt, the hours-ahead forecasted wind power output σtdaf indicates the standard deviation of day-ahead wind forecast during time interval t and σthaf indicates the stranded deviation of hours-ahead wind forecast during time interval t. How to deal with the wind power uncertainty in practical application will be introduced in detail in As mentioned in ug,ts1, binary variables indicating the status of unit g during time interval t determined in day-ahead UC) are the first-stage decisions, the intraday UC adjustment decisions  are the second-stage decisions, and the economic dispatch decisions  are the third-stage decisions. The commitment of fast start units  is decided in the third stage, as suggested in [In this paper, we develop an equilibrium chance-constrained three-stage birandom unit commitment formulation, which contains an additional middle stage to modify UC schedule of subfast units several hours earlier. In our formulation, the day-ahead UC decisions  is startup/shutdown cost function of unit g; Fg(·) is power production cost function of unit g; CL is unserved energy price; pgt is generation output of unit g during time interval t; and Udt is unserved energy during time interval t.In our formulation, the reliability constraints are considered in the intraday UC adjustment stage and dispatching stage. To avoid frequent startup/shutdown in intraday operating, only the necessary startup adjustment is permitted, which means no shutdown decisions can be determined in the intraday UC adjustment process, except for a startup adjustment scheduled in the former intraday UC adjustment process. In this model, the only uncertainty considered is the wind power output. The objective function is the expected total cost, which includes the expected startup/shutdown cost according to the final UC decisions modified by intraday UC adjustment event, the expected generation cost, and the expected load shedding cost. The proposed model is formulated as follows:In the objective formulation , the staGfast is subset of fast start units; MUg is minimum uptimes of unit g; MDg is minimum downtimes of unit g; ygts1 is startup flag of unit g at time interval t determined in the first-stage decision; and zgts1 is shutdown flag of unit g at time interval t determined in the first-stage decision.The first-stage constraints includeTo obtain more economic and flexible UC decisions, only some necessary startup/shutdown constraints for nonfast start units are considered in the first stage. Startup and shutdown flags are summarized in  and 3),,3), respα is minimum reliability requirement; ygts2 is startup flag of unit g at time interval t determined in the second-stage decision; zgts2 is shutdown flag of unit g at time interval t determined in the second-stage decision; vt is adjustment flag indicating the UC decisions during time interval t should be adjusted; and qgt is flag indicating unit g is scheduled to start up in the second-stage decision.The second-stage constraints includeg hours according to the day-ahead UC decisions. To avoid frequent startup/shutdown of subfast start units, constraint (Constraints  and 12)12) are bnstraint  is builtnstraint –11). If. Ifg houg; g; rampgup is ramp-up limit of unit g; rampgdown is ramp-down limit of unit g; and wt is wind power output during time interval t.The third-stage constraints includeConstraint  expresseGA is a traditional method to solve UC problem and is considered as one of the most effective methods to solve mathematical programming in an uncertain environment, especially in a birandom environment. In , 19, 21,(a) Wind Scenarios Generation. Similar to the solving methods of most stochastic UC and birandom programming models, simulation technique is applied. Both the actual wind scenarios and intraday hours-ahead forecasted wind scenarios should be generated as the input of the problem. The wind forecast error distribution feature in the time dimension visibly affects the proposed model. Generating representative actual wind and hours-ahead forecast wind scenarios is the basis for obtaining expected results. Similar to stochastic models, more scenarios can cover much wider uncertainties, however, the computational problems will also show up. In this paper, the initial actual wind scenarios and hours-ahead forecasted wind scenarios are generated using auto regressive moving average  approac(b) Hybrid Genetic Algorithm. In the proposed method, GA is employed to solve the master problem which determines the day-ahead UC decisions, and MILP method is used to solve the subproblem of UCED under each hours-ahead forecasted wind power-actual wind power scenario group. As a result, most of the constraints are considered in solving sub-UCED problem. The minimum on/off hours constraints of conventional units and the reliability constraints are both considered in the master problem solving. The minimum on/off hours of conventional units could be met directly by integer coding in GA algorithm. The reliability constraints are considered by feasibility checking as follows.(1)Chromosome Definition. The chromosomes consist of concatenated positive/negative integers that represent the duration of the “ON/OFF” cycles for each unit during the scheduling period [g period . Positiv(2)Initialization. To improve the quality of initial population, parts of initial individuals are generated by solving UCED problems with one or more wind scenarios using MILP method. And to increase the diversity of the population, other parts of initial individuals satisfying the unit minimum uptime and downtime constraints are randomly generated.(3)Fitness Function. Each individual is evaluated by a fitness function as follows:F represents the expected total costs according to the current UC decision and A is a system-dependent constant used to avoid getting too small fitness values.(4)Selection. The selection is based on the roulette-wheel mechanism, so that the chromosome owning a higher fitness value should therefore have a higher chance to be selected.(5)Crossover. To enhance the exchanges of good genes between different chromosomes, a hybrid crossover composed of two crossover operators is used. One operator selects one or two crossing units in the parent chromosomes and exchanges their whole schedules. The other operator randomly selects one or two ON/OFF cycles of randomly selected units and exchanges them and then adjusts the durations of remaining cycles with the least adjusting time to ensure that the sum of durations of selected units is equal to scheduling period.(6)Mutation. Similar to the crossover operators used, a hybrid mutation composed of two mutation operators is applied. One mutation operator changes the whole schedules of selected unit of the parent chromosomes using randomly generated durations of ON/OFF cycles. The other mutation operator changes the cycling duration of one randomly selected position of the selected unit and makes corresponding adjustments to the other ON/OFF cycles of the selected units with the least adjustment times.(7)Elitism. To avoid the destruction through a genetic operator during the evolution process, the best individual of each generation is directly copied to the next.(8)Local Search. To improve the local search ability of the GA algorithm, a local search algorithm proposed in [posed in  is appli(c) Feasibility Checking and UC Decision Evaluation. For each day-ahead UC decision produced by the crossover and mutation operation, the intraday UC adjustment scheduling and economic dispatching should be carried out under each possible hour-ahead forecasted and actual wind scenario group to check their feasibility (the chance constraints) and evaluate their fitness value. This is in practice a birandom simulation. There are two kinds of chance constraints in the proposed model. One is the constraint ((1)i = 0 and N′ = 0.Set (2)i = i + 1 and j = 0.Set (3)j = j + 1. Carry out IUC-ED (intraday UC adjustment-economic dispatching) scheduling assuming the hours-ahead forecasted wind scenario sjhaf-actual wind scenario siaw group (sjhaf − siaw) is realized, and then calculate the total costs Fij and the total hours satisfying Ud ≤ 0  (Tj(Ud ≤ 0)).Set (4)j < Nhaf, repeat step (3).If (5)F(i) when the scenario siaw being realized, according to F(i) pij represents the probability of sjhaf if siaw is realized; Fij represents the total costs when sjhaf − siaw scenario group is realized.where (6)Ud ≤ 0} according to i < Naw, repeat step (2) to step (6).If (8)N′/Naw ≥ α, return the current UC decision being feasible, and then calculate the expected total costs according to (If rding to , or else pi represents the probability of the siaw scenario realization; F represents the expected total costs according to the current UC decision.where nstraint  which enThe proposed approach is implemented on a revised 10-unit system presented in  first toIn the genetic algorithm, 10 actual wind scenarios and 5 hours-ahead forecasted wind scenarios for each actual wind scenario are generated. The pop size is 20. The probability of crossover was set as 0.7, and probability of mutation was set as 0.2. The initial individuals include 10 UC decisions obtained at each actual wind scenario, 5 UC decisions obtained at randomly grouped 2 actual wind scenarios, 1 UC result obtained with all the 10 actual wind scenarios, 1 UC result considering the day-ahead forecasted wind as a perfect forecasting, and randomly generated 3 UC schedules meeting the minimum uptimes/downtimes of units. The maximum number of generation is 100. The cost of load shedding is assumed to be 3000$/MWh. To compare with the proposed model, the traditional two-stage stochastic UC was also implemented on the test system.The UCED and two-stage SUC problems in all case studies have been solved using CPLEX 12 under Matlab. An AMD Core computer at 3.01 GHz and 4 GB of RAM has been used.The proposed approach is implemented on a revised IEEE118 bus system with 33 conventional units to test its validity. The load and day-ahead forecasted wind power output data are shown in The main contribution of the proposed UC policy and model is integrating intraday UC adjustment process, on the theoretical basis that the wind forecast accuracy is increased with the forecast length shortening. Another two wind forecast error curves shown in The operation costs of power systems with wind power integration can be reduced by applying the proposed three-stage UC policy and the corresponding birandom UC model.The improvement level of hours-ahead wind power forecast accuracy compared with day-ahead forecast accuracy greatly influences the benefit of applying the proposed UC policy and model. When the day-ahead forecast accuracy is low, the operation costs will not be so high if hours-ahead forecast accuracy is higher, when using the proposed policy and model. However, if the trend of forecast error decreasing with the forecast horizon is not so clear, the cost saving effect of using the proposed model will be reduced.When the day-ahead wind forecast accuracy cannot be satisfactorily improved, improving the ultra-short-term wind forecast accuracy can further reduce the operation costs if using the proposed approach.Solving the proposed birandom UC model needs much longer time. But, in practice, the computation performance may be improved by using a parallel algorithm, because the fitness calculation and feasibility checking of individuals are independent of each other.This paper presents a novel three-stage UC policy and a corresponding equilibrium chance-constrained three-stage birandom UC model for the power systems with wind power uncertainty. The main contribution of this paper is to integrate hours-ahead UC adjustment stage into traditional two-stage UC, based on the feature of wind power forecast accuracy that can be increased if the forecast length is shorter. A birandom simulation based hybrid genetic algorithm is designed to solve the proposed model. The following conclusions can be indicated by numerical results.


Palm-print based individual identification is regarded as an effectual method for identifying persons with high confidence. Palm-print with larger inner surface of hand contains many features such as principle lines, ridges, minutiae points, singular points, and textures. Feature based pattern matching has faced the challenge that the spatial positional variations occur between the training and test samples. To perform effective palm-print features matching, Rabin-Karp Palm-Print Pattern Matching (RPPM) method is proposed in this paper. With the objective of improving the accuracy of pattern matching, double hashing is employed in RPPM method. Multiple patterns of features are matched using the Aho-Corasick Multiple Feature matching procedure by locating the position of the features with finite set of bit values as an input text, improving the cumulative accuracy on hashing. Finally, a time efficient bit parallel ordering presents an efficient variation on matching the palm-print features of test and training samples with minimal time. Experiment is conducted on the factors such as pattern matching efficiency rate, time taken on multiple palm-print feature matching efficiency, and cumulative accuracy on hashing.  Biometrics has been receiving a mushroom growth with the increase in the civilian, military, and forensic applications, which involves with the significant identification of persons on the basis of biological or behavioral characteristics. Nowadays, a plethora of biometrics-based methodologies is available, and among them palm-print identification has received greater attention. Singular Value Decomposition (SVD)  based miMultimodal Sparse Representation (MSR)  method rOne of the major problems faced in person identification based on palm-print images is the individual identification with high confidence. The significance of the problem lies in the effective feature matching using palm-print images. To address the problem related to feature  matching higher accuracy, in this work, Rabin-Karp Palm-Print Pattern Matching (RPPM) method is presented. The problems related to the existing method are that though reliability of palm-print matching was robust to noise and occlusion, effective palm-print features matching was not addressed. In order to address an effective palm-print features matching Aho-Corasick Multiple Feature matching procedure is applied in the proposed RPPM method.The contributions of our palm-print feature matching algorithm are summarized as follows. First, we learn different angle of position using double hashing with finite set of bit values as an input text and avoid the hash collision to improve the accuracy of pattern matching. The value of palm-print pattern with different features is evaluated using the double hashing, which motivates us to exploit different angle of position and use it for palm-print feature matching. Second, multiple patterns of features between the test and training samples are matched simultaneously using the Aho-Corasick Multiple Feature matching procedure. It is different from the widely used multiple feature matching, where the Aho-Corasick Multiple Feature matching procedure locates the position of the features with finite set of bit values as an input text. The finite set of bit values learnt from multiple features makes our palm-print feature matching more effective but involves lengthy search process which is double the time of the actual single palm-print feature matching. Third, with an efficient bit parallel ordering, a high level time efficient method is constructed on matching the palm-print features of test and training samples with minimal time.This paper is organized as follows: Latent palm-prints include certain amount of significant critical evidential measure for applications related to forensic as it is probably estimated that about 30 percent of the latents obtained through crime scenes are those of palm-prints. Minutiae propagation algorithm introduced in  providedSegmentation and enhancement of palm-prints in  were desSeveral research works for palm-print recognition has been performed with the aid of 2D palm images. Though higher amount of accuracy can be achieved using 2D palm-print recognition, much 3D palm structural information is lost. 3D palm-print classification using global features was introduced in  with theA hybrid biometric cryptosystem introduced in  solved tk-nearest neighbor is used in [To minimize the vulnerabilities related to palm-print, biometric template security model was introduced in . Descrip used in  addressiMore specifically, the recognition of palm-print is based on either low resolution or high resolution of images. Minutiae cylindrical code applied in  providedBased on the aforementioned methods and techniques, we design an efficient pattern matching procedure for palm-print images using Rabin-Karp Palm-Print Pattern Matching algorithm.Biometric palm-print image pattern matching uses Rabin-Karp Palm-Print Pattern Matching (RPPM) method which is constructed with the help of double hashing method with different angle of position. RPPM method is applied for multiple features matching using Aho-Corasick procedure and time efficient feature matching using bit parallel ordering. The concept of bit pattern matching with features such as principle lines, ridges, minutiae points, and textures is performed simultaneously in RPPM method. The pattern matching with the features is clearly shown in As shown in I” uses the double hashing procedure to retrieve the result with collision-free hash values on different angle of test and training sample position. The modifications in the position and direction are also easily matched by Rabin-Karp through double hashing. Multiple feature matching is done effectively using Aho-Corasick procedure. The feature bit matching of the palm-print image uses the Time Effective Bit Parallel Ordering method to perform the matching nonlinearly to reduce the time complexity.The RPPM forming several palm-print images “The overall structural diagram of RPPM method is shown in As illustrated in Subsequently, feature based pattern matching is carried out using the Aho-Corasick Multiple Feature. The objective behind the application of Aho-Corasick Multiple Feature is to present multiple features while performing pattern matching. To perform multiple pattern matching, Aho-Corasick Multiple Feature is applied to the RPPM method. With the search being linear using Aho-Corasick Multiple Feature, resulting in time complexity, Time Effective Bit Parallel Ordering method is employed for the fast matching of the palm-print features.The goal of the RPPM method is to identify the consistent and diverse features in palm-print by performing the double hashing procedure. Double hashing procedure in RPPM resolves the hash collisions with different values in hash table. The double hashing for RPPM method is formularized ash1 and h2 are used widely for efficient identification of the matched features with “i” and “j” representing the pixels of palm-print images that are tested. To fetch the accurate results without collisions, “k1” and “k2” is the alternate keys  used with the aid of “T” that represents the hash table for palm-print feature matching.In , two hasIf the palm-print features are not matched with the single hash value, then the other hashing is carried out with different hash key.i” and “j” probe pixels of palm-print image are analyzed through the double hash key values in Rabin-Karp Palm-Print Method. Rabin-Karp Palm-Print uses the double hash function and is represented in As a result, “h1” and “h2” are placed for removing the collision resolution on the palm-print biometric individual identification. The sequence of bits for different series of palm-print image features is generated and placed in the table to perform the matching. The training samples used in the table are probe sequences to test the palm-print image features.The double hashing table produces the sample form of hash key used for the palm-print feature matching. The hash keys “n,” with the different feature pattern “f” producing the best case of result on matching multiple features simultaneously. The probe sequence of bits for different image performs different separation to match the specific features. The different set of bits helps to recognize , to test and train samples, and to produce more accurate biometric results for individuals. The probe sequence of bits on the double hashing table is shown in Once the relevant features are identified using double hashing procedure, the next step is to perform the efficient pattern matching for multiple features. Let us assume a palm-print image of length “fi” to match the palm-print feature pattern accurately. Each row in the double hash table identifies the hash key values “1” and “2” for that specific probe sequence of bits whereas the column path indicates the sequence of key value “1” and “2” and probe sequence bit, respectively. Followed by this, the matching process is formulized as follows:Aho-Corasick procedure automates the transition of pattern matching of features without any backtracking process. Aho-Corasick is constructed with the double hashing table using RPPM method. This procedure finds the right function “The features uses the Aho-Corasick data structure for matching multiple features with the hash key values. In this way multiple feature matching operation is carried out with explicit value in RPPM method.In Aho-Corasick, the linear form of multiple features is carried out in RPPM method, but the time complexity arises on matching the palm-print features in a linear fashion. To reduce the time complexity in our proposed work, Time Effective Bit Parallel Ordering method is designed.RPPM method easily constructs a nonlinear automaton to improve the matching of the test and training sample image bit in a parallel fashion. Bit parallel ordering technique in RPPM method is favorable to cut down the time taken on matching the features. Bit parallel ordering of the probe in RPPM method produces the suitable bisection for matching different combination of features in an effective manner and is formulized as Bit Parallel Ordering “BPO” of features for matching nonlinearity mainly depends on the ordering format. The “mintim” denotes the minimum time taken on matching multiple palm-print features simultaneously. The ordering of the bit palm-print image feature is formulized asI” and the pixels are denoted as “i” and “j” in order to perform feature matching. The features are matched with the ordered bits of varying size of “n” images. The length varied features which are not matched are removed, to perform the accurate matching with the double hashing table.The time factor on ordering the bit before performing the palm-print feature matching is provided in . Here, tRabin-Karp Palm-Print Pattern Matching (RPPM) method uses MATLAB coding to perform palm-print matching. Initially, the features of the palm-print with the positional angles are mentioned for effective processing. CASIA database consists of 5.502 palm-print images of both left and right palms with 8-bit gray level JPEG files confined from 312 users as depicted in The pattern matching efficiency rate, time taken on multiple palm-print feature matching efficiency, cumulative accuracy on hashing, and false positive rate on matching the patterns are the factors used for experimenting evaluation. The proposed method is compared against the existing methods such as Singular Value Decomposition (SVD)  based miThe pattern matching efficiency rate in RPPM is the amount of patterns efficiency matched using the double hashing procedure. The pattern efficiency rate is measured in terms of percentage and is the ratio of difference between the number of features matched and features provided as input to the total number of features provided. Consider fmatched” and features provided as input “fi,” where “n” denotes the total features provided as input. The higher pattern matching efficiency proves the efficacy of the method. The time taken on multiple palm-print feature matching is the amount of time taken to perform the feature matching for multiple palm-print features using the bit ordering. It is measured in terms of milliseconds (ms). Consider From , the patThe cumulative accuracy on hashing using RPPM method is the difference between the measured features to the actual features. Consider The false positive rate on matching the patterns refers to the measure of good features falsely identified as bad features. It is measured in terms of percentage (%). Consider The false positive on matching the patterns is the ratio of difference between the good features and bad features to good features. Low false positive rate on matching the patterns confers the efficiency of the method.The Rabin-Karp Palm-Print Pattern Matching (RPPM) method is compared against the existing Singular Value Decomposition (SVD)  based miComparatively, from The convergence plot for 21 images is depicted in The Time Effective Bit Parallel Ordering method in RPPM effectively constructs a nonlinear automaton in a parallel manner for the test and training sample images by producing suitable bisection and therefore reducing the time taken on multiple palm-print feature matching by 20–26% compared to SVD .Moreover, the length varied features of test and training sample images that are not matched are removed using RPPM and as a result the time taken is reduced on multiple palm-print feature matching by 19–44% compared to MSR .The Rabin-Karp Palm-Print Pattern Matching (RPPM) method is compared with the two existing methods in terms of cumulative accuracy on hashing in this section and is depicted in From Convergence characteristics of measure of false positive rate for 35 test images with varying principle lines, ridges, minutiae points, and textures are considered and compared with two other methods and are shown in The targeting results of false positive rate on matching the patterns using RPPM method are compared with two state-of-the-art methods , 2. In FThe conventional palm-print based person identification usually designed for providing high quality pattern matching using differing features like principle lines, ridges, minutiae points, singular points, and textures with high confidence may not give satisfactory result for accuracy during pattern matching. To improve the accuracy of palm-print features matching and reduce the time taken on multiple palm-print features matching efficiency on palm-print images, Rabin-Karp Palm-Print Pattern Matching (RPPM) method based on Double Hashing procedure and enhancing multiple feature matching using Aho-Corasick Multiple Feature matching procedure has been implemented. The three-step model, feature identification using Double hashing procedure, multiple feature pattern matching using Aho-Corasick procedure, and fast matching of multiple features using time effective Bit Parallel Ordering method introduced in RPPM resulted in significant improvement over the state-of-the-art methods in terms of pattern matching efficiency, time on multiple palm-print feature matching efficiency, cumulative accuracy on hashing, and false positive on matching the patterns.


In India, TB and HIV co-infection remains as a serious public health problem. From 2006 onwards, the intensified TB-HIV collaborative activities are being jointly implemented by National AIDS Control Programme (NACP) and Revised National TB Control programme (RNTCP) at high HIV burden states.To determine (a) the predictors of outcome among a cohort of HIV-TB co-infected patients after two years after initiation of ART treatment. (b) prognostic significance of time difference between the initiation of ATT and ART in HIV-TB co-infected patients.Patients registered at sixteen ART centres in Karnataka, from October through December 2009 formed the study cohort and were followed till December 2011.A total of 604 HIV-TB patients were registered. Follow-up (a) at the end of one year had shown 63.6% (377)patients with unfavorable TB treatment outcomes (b) at the end of second year, 55.6% (336)patients were alive on ART treatment. The variables male, smear negative TB, CD4 count less than 50cells per cumm and unfavorable TB outcome were significantly associated with unfavorable ART treatment outcome.The programmes need to review the existing strategies and strengthen HIV-TB collaborative activities for timely treatment initiation with intensive monitoring of HIV-TB patients on treatment. In high TB burden countries like India, tuberculosis and HIV pose to be a serious public health problem. HIV augments the progression of latent TB to active TB, relapse and death . CertainThough, systems are in place to provide ART services for diagnosed HIV-TB patients, there is a substantial gap in the knowledge about socio-demographic and clinical factors associated with poor treatment outcomes. The relevance to bridge this gap is extremely important as it drives the programme to adopt suitable strategies that vouch for better treatment outcomes. Hence, we conducted this study to determine the outcomes and explore the predictors for outcome among a cohort of HIV-TB co-infected patients registered at ART centers.Though, many prospective studies have evaluated the optimal time for initiating ART in HIV-TB co-infected patients and have demonstrated reduced mortality among early ART initiators; there laA retrospective cohort study was conducted in the state of Karnataka, south India. The state of Karnataka is one of the high HIV burden state in the country with adult HIV prevalence exceeding 1% in some districts of the state.. Patients with early ART, delayed ART and TB diagnosed while on ART had a mortality risk of 19.3, 12.0 and 17.6 per 100 person years respectively. The interval between the initiation of ART and the initiation of TB therapy did not have a significant impact on all-cause mortality in the multivariate cox regression model. Smear negative TB and CD4 count less than 50 cells per cumm are significantly associated with all-cause mortality among HIV-TB co-infected patients. . The studFirst, although the timing of initiation of ART was not associated with treatment outcome and mortality rate; the proportion of patients who died after two years was twice among patients where ART was started after ATT treatment compared to those who were on ART treatment before ATT. It perhaps indicates that there would have been a delay in the diagnosis of HIV and the patients could be reluctant to seek health care till they develop the symptoms of tuberculosis while being the late presenters to the health system. Currently, the TB services are mostly decentralized and integrated into the general health system while HIV services remain largely centralized. The gap in infrastructure between the TB and HIV programme might have led to suboptimal linkages.Second, HIV-TB patient with unfavorable TB outcome has six times risk of having an unfavorable ART outcome and nine times risk for all-cause mortality at the end of two years. It was also significantly associated with the time interval between initiation of ART and ATT. In biological perspective, development of TB is associated with increased HIV-1 replication. Both HIV-1 load and heterogeneity appear to be affected by tuberculosis infection. UnfavoraWe presume the shortcomings can be addressed in following ways (a) intensifying community awareness regarding early health care seeking behavior among people with symptoms of HIV/AIDS and TB. (b) accessibility issues in terms of diagnosis and treatment have to be addressed which might prevent patients presenting ‘too late’. Mechanisms should be in place to provide access to HIV testing and ART services at the TB treatment sites itself to avoid delay in ART initiation. (c) appropriate newer TB diagnostic tools to be made to reduce the diagnostic and treatment delays linked to smear negative pulmonary TB and through simpler and more efficient TB diagnostic tools for use in resource limited settings. Even for smear positive TB and HIV co-infected patients sputum smear microscopy is not a sensitive tool to diagnose TB and the HIV patients should be provided an access to a culture based diagnosis preferably liquid culture technology or equivalent technology. (d) the health care settings frequented by high numbers of HIV-infected persons, it becomes necessary to implement airborne infection control measures. Simple administrative and environmental measures aimed at reducing exposure of HIV-infected patients to M. tuberculosis bacilli will be worthwhile.(e) WHO recommended isoniazid preventive therapy (IPT) should be implemented as a policy for prevention of incident TB among HIV infected patients. These above measures may decrease the transmission of TB and help the programme to ensure timely detection of TB and initiation of ATT.Third, earlier trials have shown that early ART initiation (less than 2 weeks of ATT) improved survival in HIV-TB co-infected patients.13]14] [14] 13][ [14] 13]Operationally, we have defined early ART with a cut-off of 60 days, although previous studies have used different cut-offs such as 90 days. The compFourth, among those who were initiated on ART before starting on ATT, a significant proportion of patients (51%) had ART started within 60 days before ATT initiation. Such cases could be due to unmasking of latent TB i.e., TB-IRIS. Luetkemeyer et al. demonstrated increased risk of TB IRIS among those with very low CD4 cell counts of less than 50 cells per cumm thus necessitating screening thoroughly for TB before starting ART among patients with low CD4 count. Fifth, an important assumption of survival analysis is that the censored patients are considered to have survival prospects similar to the participants who continued to be followed up. We found that the patients who were lost to follow up were similar (p>0.05) to those who could be followed up in terms of their CD4 count, type of TB, category of TB and timing of initiation of ATT and ART which are the possible factors determining treatment outcomes as reported in this study. (data not shown) Thus, we can confidently opine that the participants who were drop out in the study did so due to reasons unrelated to the study and had similar survival prospects compared to those who could be followed up and thus satisfies the assumption of non-informative censoring.The strengths of this study is that a large cohort of HIV-TB co-infected patients were studied, deaths were ascertained, the loss to follow up was minimal and the data was from a programme setting which reflected the operational reality on the ground.The following were the limitations of the study (a) observational nature of the data and the retrospective collection of data (b) other associated co-morbid factors for death in patients were not studied (c) the average CD4 count of cohort at different points of time were taken into consideration as the CD4 cell counts for quite a number of patients were not done or not recorded (d) only those TB-HIV co-infected patients who were registered at the ART centers were studied; there would have been a number of HIV-TB co-infected patients who were diagnosed and did not access the ART services during this period. (e) there is ample scope in this study to follow up the cohort of patients for next two years as there is sparse evidence of such findings under programmatic settings.The programmes needs to urgently review the existing strategies and strengthen HIV-TB collaborative activities for timely treatment initiation with intensive monitoring of HIV-TB patients on treatment.