dataesr/scientific-paragraphs-categorization huggingface dataset:
GE-Based Risk Score in CLL. Using Maxstat R function and Benjamini-Hochberg multiple testing correction  [18] , 22 probe sets were found to have prognostic value for OS (adjusted  value < 0. 05) in two independent cohorts of patients with previously-untreated CLL (GSE22762,  = 107 and  = 44  [15] ) (Table  1 ). These 22 probe sets were probed for 20 unique genes and were used to build a GE-based risk score as reported  [20]. Figures  1(a ) and 1(b) show expression of the 22 prognostic probe sets and GE-based risk score from patients' tumor samples of the training cohort (ranked according to increasing GE-based risk score). When used as a continuous variable, GE-based risk score had a prognostic value in the two cohorts of patients with CLL (P ≤ 10-4, data not shown). Patients of the training cohort ( = 107) were ranked according to increased prognostic score and, for a given score value X, the difference in survival of patients with a GE-based risk score ≤X or >X was computed.
None of these genes were included in the current 20 prognostic genes. Using univariate analyses, GE-based risk score, ADAM29, AKAP12, DMD, LPL, NRIP1, SET10, SPG20, TCF7, TCL1A, TPM1, ZAP70 gene expression, PS8, and Del17p were prognostic ( < 0. 05, Karyotype investigations revealed the association of CLL with del13q14, trisomy 12, del11q22-q23, and del17p13  [1]. Del13q14 is the most frequent alteration that occurs in 50%-60% of cases  [1] ; trisomy 12 and de11q22-q23 occur in approximately 15% of CLL cases  [1]  and del17p13 occurs in 5%-10% of untreated CLL patients  [28]. Using a cohort of 109 patients with previously untreated CLL (GSE25571)  [17] , we investigated the association between the GE-based risk score and chromosomal abnormalities. GE-based risk score is significantly higher in patients with del17p13 (Supplementary Figure  S1 ; Supplementary Material is available online at http://dx.
Results Anti-apoptotic proteins are frequently expressed in localized SCLC specimens. To investigate the frequency of anti-apoptotic proteins in SCLC, we first assessed whether anti-apoptotic proteins such as Bcl-2, Bcl-X L and Mcl-1 were overexpressed in a tissue microarray including 29 localized SCLC that had been surgically removed (Supplementary Figure  1 ). Bcl-2, Bcl-X L and Mcl-1 were expressed at high levels in 17 (60%), 24 (85%) and 20 specimens (70%). To assess whether overexpression of these proteins might be related to gene amplification, we extracted in silico microarray data from a public database including 40 SCLC samples and 23 cell lines. 19 In this study, no copy number alteration was found for BCL2 and BCL-XL gene. By contrast, MCL1 gene amplification was observed in 57% of samples.
These data demonstrate that S44563 potently triggers apoptosis in Bcl-2-dependent H146 cells. S44563 has a differential effect on three distinct SCLC cell lines. To examine the sensitivity of SCLC cell lines to S44563, we assessed the impact of S44563 on cell viability by means of a cell proliferation assay (Figure  1e ) and a clonogenic survival assay (Supplementary Figure  3 ). S44563 was particularly effective on Bcl-2-overexpressing H146 cells, less so on H69 cells and had no major effect on Mcl-1-expressing H196 cells, which resisted micromolar concentrations of S44563. Addition of the caspase inhibitor Z-VAD-FMK strongly reduced the negative effect of S44563 on the viability of H146 cells (Supplementary Figure  4 ). To determine whether the effect on cell survival was mediated by apoptosis induction, we assessed the generation of cleaved caspase-3 and the dissipation of the mitochondrial inner transmembrane potential.
Consistent with the in vitro activity of S44563 against SCLC cells, S44563 showed a    6a ). No weight loss was observed over the time course of the experiment (Supplementary Figure  6b ), suggesting that S44563 can mediate anticancer effects at an acceptable level of toxicity. S44563 sensitizes SCLC cell lines to radiation. To determine the radiosensitivity of SCLC cells, we performed a clonogenic survival assay using IR at different doses. SCLC cells exhibited different sensitivity to radiation. Surviving fraction at 2 Gy (SF2) values ranges from 0. 35 to 0. 86 (data not shown). In this assay, 100 nmol/l of S44563 radiosensitized H69 and H146 cells, yet had no effect on H196 cells. For this latter cell line, a 100 times higher concentration of S44563 (10 mM) was required to mediate radiosensitization (Figure  3a ).
All treatments appeared to be well tolerated, with no evidence of treatment-related weight loss (data not shown). Moreover, we did not observe any S44563mediated increase in radiation-induced endothelial damage and fibrosis-like lesions (21) suggesting that the combination of radiation and S44563 is safe (Supplementary Figure  7 ). S44563 plus chemoradiotherapy prolongs survival in mice bearing H146 xenografts. Because the standard of care of localized SCLC is radiochemotherapy, that is, the association of IR and cisplatin-based chemotherapy, we assessed the potential value of adding S44563 to chemoradiotherapy. The triple combination resulted in more frequent complete response of H146 xenografts and decreased median tumor growth, as compared with IR alone and all other groups including S44563 alone or IR þ cisplatin alone (Supplementary Table  3 ).
To test this hypothesis, mice bearing H69 xenografts were treated as above (with concomitant IR and S44563) or sequentially, when S44563 was administered only during the 5 days following the completion of radiotherapy. On day 49, mean tumor volume was significantly reduced in the sequential group (465 mm 3 ) as compared with the concomitant group (704 mm 3 ) and radiation alone (1261 mm 3 ) (P ¼ 0. 04, two-way ANOVA test) (Figure  6b ). To characterize the mechanisms through which S44563 induces radiosensitization, we determined its transcriptional effects at 24 h, as measured at the concentration of S44563 that would kill 50% of the cells at 48 h (100 nmol/l for H146 and 1 mmol/l for H69 cells) by microarray experiments. At 24 h, S44563 did not cause any consistent upregulation or the downregulation of genes involved in DNA reparation or checkpoint control (data not shown).
BCL2L1 and BCL2L2 gene amplifications have been reported in previous studies,  11  although others showed that low-level gains of the BCL2 gene are present in 40% of cases in an array including 62 SCLC samples and high-level gains are observed in only 8% of the tumors. 22 These results are consistent with publicly accessible data banks revealing MCL1 gene amplification in 57% of samples but no copy number alteration for the genes encoding BCL2 and BCL2L1. Thus, Bcl-2 and Bcl-X L overexpression could result from alternative mechanisms such as activation of their promoters by transcriptional factors. Furthermore, chemotherapy induces Bcl-2 and Bcl-X L expression, perhaps explaining in part the acquisition of resistance to cisplatinbased regimens. Here, we showed that radiation itself resulted in the enhanced expression of Bcl-X L at the mRNA and protein levels, both in vitro and in vivo through transcriptional event.
50 Stained nuclei were analyzed for DNA-propidium iodide fluorescence using a Becton Dickinson (Rungis, France) FACSCaliburs flow cytometer. Microarrays studies and multiplex PCR. For transcriptome analysis, 10 6 cells were seeded in T25 flasks, allowed to grow for 24 h and then left untreated or treated with 2 Gy radiation. After 24 h, cells were harvested, lysed for the extraction of RNA and processed to analyze gene expression, as previously reported. 50 Raw data have been submitted to ArrayExpress (accession numer: E-MTAB-966). For PCR analysis, 10 6 cells were seeded in T25 flasks, allowed to grow for 24 h and then left untreated or treated 6 Gy radiation and harvested either 2 or 24 h after the treatment. Apoptosis TaqMan Low Density Array (TLDA) custom-designed format from Applied-Biosystems (Villebon-sur-Yvette, France) were used as duplicates for each gene expression per sample using the Applied Biosystems 7900HT Real-Time PCR system.
The results of each plate were analyzed using ABI PRISM software to calculate the C T value of each well and compare these values in studied gene wells with endogenous control wells. Analysis of protein expression. Protein samples of SCLC cells were prepared in lysis buffer, according to standard established protocols. 49 Extracted proteins were separated by 12% SDS-PAGE and subjected to immunoblots using mouse monoclonal IgG1 antibodies specific for active caspase-8 (Cell Signalling Technology, Leiden, Netherlands), or glyceraldehyde-3-phosphate dehydrogenase (GAPDH; Millipore, Guyancourt, France) and rabbit polyclonal antibodies against caspase-3, active caspase-9 (Cell Signalling Technology). To fractionate cytoplasmic and nuclear proteins, cells were washed and incubated on ice for 10 min in buffer A (10 mM HEPES pH 7.
Acknowledgements. GK is supported by the  Ligue Nationale contre le Cancer (Equipes labellisee) ,  Agence Nationale pour la Recherche, European Commission (ChemoRes) ,  Fondation pour la Recherche Medicale (FRM) ,  Institut National du Cancer (INCa) ,  Fondation de France ,  Canceropole Ile-de-France ,  Fondation Bettencourt-Schueller  and the  LabEx Immuno-Oncology. ED is supported by the  Assocciation pour la Recherche contre le Cancer (ARC) ,  Electricitede France (EDF) ,  Canceropole Ile-de France. This manuscript has been supported by  Institut de Recherche Servier.
Sequenced viruses and viromes Part of the challenge in the bioinformatics analysis of NGS data for virus identification is that this step largely relies on the identification of homologies with already known agents (see below). The growing availability in public databases of genomic sequences for a wide diversity of viruses is therefore a key element in a successful diagnostic. More than 3500 reference sequences of virus  (and viroid)  genomes are now available at NCBI (see http://www. ncbi. nlm. nih. gov/genome) and 623 plant virus genomes are also available in Comprehensive Phytopathogen Genomics Resource  (Hamilton et al. , 2011). Besides targeted sequencing efforts in individual hosts that allow the characterization of individual agents, a wide range of novel viruses have been identified in metagenomic efforts aimed at the characterization of virus populations in various environments like feces  (Minot et al.
, 2012; Reyes et al. , 2010) , or fresh  (Djikeng et al. , 2009; Rosario et al. , 2009)  or saline aquatic environments  (Williamson et al. , 2008). These projects have already greatly expanded the viral genes and genomes catalogs and will continue to do so at an increasing pace in the coming years, contributing to an improved ability to identify viral sequences among NGS data. Nevertheless, the recent discovery and sequencing of giant viruses (∼2 Mb) with only 7% of their genes with matches in databases also shows the limitations of our current knowledge  (Philippe et al. , 2013).
For de novo assembly, the (meta)genome is reconstructed by matching all the generated sequences to each other. This is considered the current gold standard for bacteria or virus genome sequencing. It is also the only feasible approach to characterize novel viral agents for which no reference genome is available. Each NGS platform developed its own bioinformatic tool, such as the Consensus Assessment of Sequence and Variation (CASAVA -Illumina) or the GS De Novo Assembler, Reference mapper and Variant Analyzer (Roche). In parallel, many softwares were developed specifically for de novo assembly or alignment (for more information, see http://en. wikipedia. org/wiki/List of sequence alignment software#Genomics analysis). The annotation of the generated contigs or of the remaining singletons is relatively straightforward and generally based on the use of well-known homology search programs such as Blast (in its various BlastN, BlastX, BlastP and TBlast versions) or Blat  (Kent, 2002).
This is a very straightforward process when the reads or contigs belong to a well annotated species or a relatively close relative. However, problems increase when the sequences belong to agents that are more and more distant from the viruses present in international databases. Although automated algorithms are now routinely used, there is frequently no or little manual assessment of accuracy  (Foster et al. , 2012). For shotgun metagenomic sequencing, another strong limitation is the large number of contigs and singletons which have to be annotated de novo. This has an important impact on computing time which is likely to increase as sequence databases continue their exponential growth. The use of dedicated databases or of subsections of GenBank partially solves this problem while creating other potential misidentification pitfalls.
The other problematic situation concerns the ability (or inability) to identify sequences from a virus that has no close homolog in databases. This situation is far from theoretical since, for example, a large fraction of the genes identified in marine viral metagenomes, in particular when it comes from phages or Archeae have no clear counterpart in GenBank. The recent discovery of Pandora virus, containing only 7% of the genes homologous to existing genes, is another striking example  (Philippe et al. , 2013). In such situations, other strategies that do not rely on homology, such as frequency analysis techniques  (Palacios et al. , 2010; Trifonov and Rabadan, 2010) , may possibly offer an interesting option but need additional evaluation and testing. The (meta)genome of a sample can be characterized by identifying its genomic variations or specificities as compared to a reference genome or gene catalog.
On the other hand, the detection of novel agents not represented in the databases necessitated de novo assembly of contigs, which could only be achieved at higher viral titers. Almost no corresponding data is currently available for plant viruses, with the exception of the work of Hagen  (Hagen et al. , 2012) , who showed that siRNA sequencing allowed the detection of tomato spotted wilt virus (TSWV) in tomato plants as early as 4 days post-inoculation, a time at which no symptoms are observed and virus detection by molecular hybridization is at best very difficult. Comparative efforts, assessing the efficiency of NGS-based approaches on spiked samples close to the limits of detection of current serological (ELISA) or molecular [(RT)-PCR] approaches are therefore clearly needed, in particular with plant matrices, for the diagnostician to have a clear idea of the sensitivity of these novel technologies.
, 2011)  or detect fungi from the studied plant. We can also reasonably anticipate that the pace of discovery of novel viral agents, either mycovirus or plant virus, will slow down in the future. Indeed, the virome of crop species will probe better characterized through the increasing number of NGS experiments carried out. As the viral sequence databases become more and more complete, the discovery of new viral agents during a certification process will become less frequent but the detection of poorly characterized viruses could remain frequent. This strengthens the importance to also develop efforts aimed at the understanding the biological significance of all these newly characterized virus species, in order to be able to make the most relevant diagnostic decisions in the future. However, it should be stressed that although the discovery of such novel or poorly characterized agents may today complicate the decision-making process, it will clearly lead, in the long run, to an improved situation of better informed decisions and to the safer movement and trade of plant propagation material.
They allow us to identify the impact of the crisis triggered by the phylloxera epidemic on violent and property crimes, as well as on minor offences. This exercise is unique from a historical perspective since comparable datasets were collected only starting in the 20th century in other countries (e. g. the Uniform crime report in the USA starts being compiled in the 1930s) or for a shorter period of time in some German states like Bavaria and Prussia (see  Mehlum et al. , 2006 and Traxler and Burhop, 2010). Our results show that the phylloxera crisis caused a strong increase in property crimes and a significant decrease in violent crimes. This paper contributes to the literature on the effects of negative economic shocks on crime in a historical perspective by covering more than eighty French départements over 1826-1936.
As such, it contributed to the birth of criminology. Although the Compte was published yearly until 1982, we only collected data for the period from 1826 to 1936. As underlined by  Perrot and Robert (1989)  the quality of the data indeed declined after the 1930s, in particular due to the decrease in the funding awarded to the judiciary system to collect statistical information. The Compte provides detailed information on the number of people charged and acquitted of violent crimes, property crimes and minor offences in each département every year (see Figure  3  for crimes -a similar table is available for minor offences). Violent crimes include homicides, sexual assaults, injuries, violence against children, abortion, plotting, rebellion and false witnesses. Property crimes encompass thefts, robberies, counterfeiting, corruption, destruction, fires and pillaging.
Given the poor quality of population data during war years, we drop years  1870-71 and 1914-1918   We also compute conviction rates for each type of crime and offence by dividing the number of people convicted by the number of people accused in each département every year. The corresponding rates vary from 64% for violent crimes to 72% for property crimes and 91% for minor offences -see Appendix Table  A1. Finally, the Compte also provides information on police forces. More precisely, we know the yearly number of urban and rural policemen, superintendents, forest wardens and guardsmen in each court-of-appeal jurisdiction between 1843 and 1932. 17 We compute an indicator of the presence of police forces defined as the ratio of the total number of police forces divided by the population in each court-of-appeal jurisdiction.
Phylloxera, wine production and wine intensity We collected data on the presence of phylloxera starting from information provided in  Galet, (1957). The book reports both the year when phylloxera was first spotted in at least one municipality of each département and the year when the département was fully contaminated (i. e. all municipalities of the département were affected). 18 Phylloxera had been spotted in 3. 3% of the 87 French départements in 1865 whereas this figure amounted to 50. 5% in 1880 and 71. 3% in 1890 -see also Figure  1. The first département to be totally affected by phylloxera was Vaucluse in 1875. This was the case of 17% of all départements in 1880. Data on wine production are also drawn from  Galet (1957). In our dataset, the number of hectolitres of wine produced is available for all départements between 1850 and 1905.
Socio-economic characteristics and urbanisation When estimating the average impact of phylloxera on crime rates, we include sociodemographic controls in some specifications. Using the data from the Statistique Générale de la France available for 1851-1911, we compute the ratio of males in the département population. We also control for the age structure of the male population, i. e. the ratio of males aged 15-19, 20-29, 30-39 and 40 years old and above. Since these data come from the Census which is available every 5 years only, we regress a 5-year moving average of crime rates on a 5-year moving average of our phylloxera indicator and the socio-demographic variables. 19 We use a similar specification when controlling for urbanisation. The data come from the INED-Urbanisation database and are also available for Census years only.
Conclusions This paper studies the effects of a large negative income shock on crime using a unique dataset based on 19 th century French administrative crime records at the département level. Our case study focuses on the effects of the phylloxera crisis, which caused a major shock to the French economy at a time when it was still largely dependent on agriculture. We provide evidence on the effects of the spread of the phylloxera epidemic both on wine production and on criminal activity. Our results show that the phylloxera crisis generated a strong increase in property crime rates, plausibly driven by the impact of phylloxera on the economic conditions of those living in the affected départements. These results are robust to various alternative explanations including possible changes in the criminal justice system or in the local presence of police forces following the phylloxera crisis.
Once the study began, however, endpoint data could not be obtained for the first eight enrolled subjects because of a laboratory equipment failure in Tunisia. Hence, a protocol amendment was approved to recruit and randomize eight additional subjects, establishing a total population of 48. Therefore, a total of 48 Tunisian adults with parasitologically positive CL ulcers were randomized 1:1 to receive WR 279,396 with either a polyurethane or gauze-and-tape Values are numbers of study subjects. Of the 74 subjects screened, 26 failed screening, most commonly due to having only one lesion that was already substantially healed (17 subjects). Forty-eight subjects were randomized, 24 in each study group. In the polyurethane group, one subject was discontinued due to an unsatisfactory result (enlargement of the index lesion at day 20).
Primer design and transcript abundance analysis by qPCR Total RNA integrity was checked by electrophoresis. For each candidate gene a blast was performed against the transcriptome of PB 260, to define highly conserved regions. The qPCR primers were designed outside these regions using the Primer 3 module of Geneious Pro software version 5. 3. 6 (Biomatters Ltd. , New Zealand). Each primer pair was blasted against the transcriptome library. qPCR and the fusion curve of the PCR amplicon were done using a mix of cDNAs. In addition, the specificity of each primer pair was checked by sequencing the PCR amplicon. The sequences of the primers used are listed in Additional file 1. cDNAs were synthesized from 2 μg of total RNA to a final reaction volume of 20 μl using a Revert AidTM M-MuLV Reverse Transcriptase (RT) kit according to the manufacturer s instructions (MBI, Fermentas, Canada).
Full-length cDNA synthesis was checked for each sample by PCR amplification of the actin. Quantitative gene expression analysis was carried out by qPCR using a Light Cycler 480 (Roche, Switzerland) as described by Putranto and coll. [52]. Real-time PCR was carried out for eleven housekeeping genes in order to select the most stable gene as the internal control for all the compared tissues (HbelF1Aa, HbUBC4, HbUBC2b, HbYLS8, HbRH2b, HbRH8, HbUBC2a, HbalphaTub, Hb40S, HbUbi, HbActin). HbRH2b was selected as the best reference gene due to its stability in the different tested tissues  [39]  (Additional files 2 and 3). The transcript abundance of each gene was relatively quantified by normalization relative to the transcript abundance of the HbRH2b reference gene. All the normalized ratios corresponding to transcript accumulation were calculated automatically by Light Cycler software version 1.
Statistical analyses qPCR reactions were carried out with 3 biological replicates. The statistical analyses were ANOVAs carried out on raw data after logarithmic transformation. An ad-hoc Tukey HSD (Honestly Significantly Different) test was carried out for the analysis of transcripts in the different organs and different clones. Values with the same letter were not significantly different. For the analysis of transcripts in response to abiotic stress and to hormone treatments, a comparison of means test (Student or Wilcoxon test, depending on the data) was carried out between the control and the treatment at each point of the kinetics. If, at one point, at least one significant difference was found an  s was indicated, otherwise  ns was indicated.