gebhart/patrepeval huggingface dataset:
Big Data and Big Numbers (2014)

We recently encountered a difficulty when handling Big Data that is pertinent to the issues raised by Dr Sessler in his recent editorial 1. It has been brought to our attention that the number of patients (65 535) included in our recent observational audit of operative repair of hip fracture 2 is close to a very specific number, well known in computer circles as the largest 16-bit binary integer, or 216 (65 536). This is a frequently occurring limit found in data processing systems, colloquially referred to as the ‘64k’ limit, which restricts, for example, the row count of older versions of Microsoft Excel spreadsheets (before v.2007) 3, thereby affecting data storage and transfer involving older databases. Indeed, it became apparent that in our audit, which was to have run from 1 January 2012 to 31 December 2012, the data that were transferred from the Health and Social Care Information Centre (HSCIC) on behalf of the National Hip Fracture Database (NHFD) started from the point at which anaesthesia data were routinely collected (1 April 2011) and continued to the processing limit of the Excel row count, rather than to a defined time endpoint, 65 535 records (+ 1 title row =65 536) having been collected by 13 April 2012. The error was compounded by the fact that previous figures from the NHFD for annual admissions for hip fracture in the UK suggested an expected number of ~65 000 patients in the dataset, so we were not alerted by any disparity between the number of patients observed and that expected. This issue of the Journal includes a Correction 4 that re-defines the time period for the data included (thus leaving all the figures/calculations and conclusions still valid). Meanwhile, we would advise database researchers handling datasets in excess of 65 535 rows of patient records to use later versions of Microsoft Excel, and to confirm their denominator data through secondary, independent analysis.
Exogenous Gene Expression in Tumors: Noninvasive Quantification with Functional and Anatomic Imaging in a Mouse Model (2005)

A combination of noninvasive functional and anatomic imaging can be used in vivo to quantify gene transfer in tumors.
The ins and outs of leptin receptor activation (2003)

The adipocyte-derived hormone leptin signals the status of body energy stores by activating its receptor in hypothalamic nuclei. In contrast to the initial expectations, leptin treatment of human obesity was largely unsuccessful. One explanation for this is the marked leptin resistance, which likely operates in part at the receptor level. The leptin receptor is a member of the class I cytokine receptor family, which uses the Janus kinase/signal transducer and activator of transcription pathway as a major signaling route. In this review, we focus on the molecular mechanisms underlying leptin receptor activation. Different modes of leptin-induced clustering of the ectodomains and the subsequent signaling events will be discussed.
Vaccine-Induced Immune Responses in Rodents and Nonhuman Primates by Use of a Humanized Human Immunodeficiency Virus Type 1 pol Gene (2002)

A synthetic gene consisting of the reverse transcriptase (RT) and integrase (IN) domains of human immunodeficiency virus type 1 (HIV-1) pol was constructed using codons most frequently used in humans. The humanized pol gave dramatically improved levels of Rev-independent, in vitro protein production in mammalian cells and elicited much stronger cellular immunity in rodents than did virus-derived gene. Specifically, BALB/c mice were immunized with plasmids and/or recombinant vaccinia virus constructs expressing the synthetic gene. High frequencies of Pol-specific T lymphocytes were detected in these animals by the gamma interferon enzyme-linked immunospot assay against pools of short overlapping peptides. Characterization of the stimulatory peptides from these pools indicates that the optimized gene constructs are able to effectively activate both CD4+ and CD8+ T cells. Immunization of rhesus macaques with DNA vaccines expressing the humanized pol coupled to a human tissue plasminogen activator leader sequence led to pronounced in vitro cytotoxic T-lymphocyte killing activities and enhanced levels of circulating Pol-specific T cells, comparable to those observed in HIV-1-infected human subjects. Thus, optimizing the immunogenic properties of HIV-1 Pol at the level of the gene sequence validates it as an antigen and provides an important step toward the construction of a potent pol-based HIV-1 vaccine component.
Detection of hotspot mutations and polymorphisms using an enhanced PCR-RFLP approach (2003)

Ethidium gel-based PCR-RFLP is widely used, and is perhaps the simplest method for detection of known mutations in cancer-related genes and for genotyping a wide range of other human diseases. However, its application is limited by the fact that it can only detect mutant alleles that are present in more than 5-10% of wild-type alleles. Here we present a method that allows a 1-2 order enhancement in the sensitivity of the widely used PCR-RFLP without substantially increasing the effort and cost associated with it. This method is a modification to our previously reported amplification via primer ligation at the mutation (APRIL-ATM) method, which utilizes ligation of a primer at a restriction site formed by a mutation, followed by a ligation-mediated PCR amplification which amplifies only the mutation-containing DNA molecules. By combining this method with the artificial introduction of restriction sites during PCR, we demonstrate that assays can be designed and validated for detecting hot-spot mutations in codons 273, 158, and 248 of the TP53 gene (p53) and potentially for most mutations of interest. This approach is validated by using samples where the mutation was artificially introduced at these p53 positions. The increased sensitivity offered by the method further allows us to rapidly screen for low frequency polymorphisms in pooled DNA samples. The frequency of an MSH2 missense polymorphism (965G>A) was quantified in pooled genomic DNA samples from 205 and 221 U.S. and Polish colorectal cancer patients, respectively, and an equal number of ethnicity-matched controls. The data revealed a 3-5% prevalence of this polymorphism in the patient and the control populations. Individual sequencing of all 852 patient samples demonstrated an excellent agreement among the two independent approaches. The present enhanced PCR-RFLP reduces the effort involved in high throughput polymorphism studies and promises to find applications in genotyping and association studies involving low frequency polymorphisms and mutations.
A study of cross-validation and bootstrap for accuracy estimation and model selection (1995)

We review accuracy estimation methods and compare the two most common methods: crossvalidation and bootstrap. Recent experimental results on artificial data and theoretical results in restricted settings have shown that for selecting a good classifier from a set of classifiers (model selection), ten-fold cross-validation may be better than the more expensiveleaveone -out cross-validation. We report on a largescale experiment---over half a million runs of C4.5 and a Naive-Bayes algorithm---to estimate the effects of different parameters on these algorithms on real-world datasets. For crossvalidation, wevary the number of folds and whether the folds are stratified or not# for bootstrap, wevary the number of bootstrap samples. Our results indicate that for real-word datasets similar to ours, the best method to use for model selection is ten-fold stratified cross validation, even if computation power allows using more folds.
Topological analysis of network attack vulnerability (2006)

This talk will discuss issues and methods for survivability of systems under malicious attacks. To protect from such attacks, it is necessary to take steps to prevent attacks from succeeding. At the same time, it is important to recognize that not all attacks can be averted at the outset; attacks that are successful to some degree must be recognized as unavoidable and comprehensive support for identifying and responding to attacks is required.
Comment on "A new method for the nonlinear transformation of means and covariances in filters and estimators" [with authors' reply] (2002)

The above paper (Julier et al. IEEE Trans. Automat. Contr, vol. 45, pp. 477-82, 2000) generalizes the Kalman filter to nonlinear systems by transforming approximations of the probability distributions through the nonlinear process and measurement functions. This comment derives exactly the same estimator by linearizing the process and measurement functions by a statistical linear regression through some regression points (in contrast with the extended Kalman filter which uses an analytic linearization in one point). This insight allows one: 1) to understand/predict the performance of the estimator for specific applications, and 2) to make adaptations to the estimator (i.e., the choice of the regression points and their weights) in those cases where the original formulation does not assure good results. In reply the authors state that the commenters conclusion is unnecessarily narrow interpretation of results.
Functions of emulsifiers in food systems (1977)

Abstract and Summary The function of food grade emulsifiers in various food products (emulsions, starch based food, yeast raised bakery products, etc.) are reviewed. The stability of emulsions against coalescence of dispersed droplets is among other factors dependent on monoor multimolecular interfacial films with viscoelastic properties formed by adsorbed emulsifier molecules. Agglomeration of fat globules in whippable emulsion is needed to obtain desired foam stability and texture and can be controlled by lipophilic emulsifiers. Complex formation with starch components (amylose) is influenced both by the chemical structure of an emulsifier and by its physical behaviour in water. Interaction with proteins takes place primarily with anionic emulsifiers or very hydrophilic, nonionic types, which thereby improves the rheological properties of wheat gluten. Emulsifiers are also used as crystal modifying agents in fats where polymorphic changes during storage creates texture problems.
Aberrant activation of integrin α4β7 suppresses lymphocyte migration to the gut (2007)

Integrin adhesion molecules mediate lymphocyte migration and homing to normal and inflamed tissues. While the ligand-binding activity of integrins is known to be modulated by conformational changes, little is known about how the appropriate balance of integrin adhesiveness is maintained in order to optimize the migratory capacity of lymphocytes in vivo. In this study we examined the regulation of the gut homing receptor alpha4beta7 integrin by manipulating at the germline level an integrin regulatory domain known as adjacent to metal ion-dependent adhesion site (ADMIDAS). ADMIDAS normally serves to raise the activation threshold of alpha4beta7, thereby stabilizing it in the default nonadhesive state. Lymphocytes from knockin beta7 (D146A) mice, which harbor a disrupted ADMIDAS, not only expressed an alpha4beta7 integrin that persistently adhered to mucosal addressin cell adhesion molecule-1 (MAdCAM-1), but also exhibited perturbed cell migration along MAdCAM-1 substrates resulting from improper de-adhesion of the lymphocyte trailing edge. In vivo, aberrantly activated alpha4beta7 enhanced adhesion to Peyer's patch venules, but suppressed lymphocyte homing to the gut, diminishing the capacity of T cells to induce colitis. Our results underscore the importance of a proper balance in the adhesion and de-adhesion of the alpha4beta7 integrin, both for lymphocyte trafficking to the gut and for colitis progression.
Cell cycle arrest caused by CLN gene deficiency in Saccharomyces cerevisiae resembles START-I arrest and is independent of the mating-pheromone signalling pathway. (1990)

Null mutations in three genes encoding cyclin-like proteins (CLN1, CLN2, and CLN3) in Saccharomyces cerevisiae cause cell cycle arrest in G1 (cln arrest). In cln1 cln2 cln3 strains bearing plasmids containing the CLN3 (also called WHI1 or DAF1) coding sequence under the transcriptional control of a galactose-regulated promoter, shift from galactose to glucose medium (shutting off synthesis of CLN3 mRNA) allowed completion of cell cycles in progress but caused arrest in the ensuing unbudded G1 phase. Cell growth was not inhibited in arrested cells. Cell division occurred in glucose medium even if cells were arrested in S phase during the initial 2 h of glucose treatment, suggesting that CLN function may not be required in the cell cycle after S phase. However, when the coding sequence of the hyperactive C-terminal truncation allele CLN3-2 (formerly DAF1-1) was placed under GAL control, cells went through multiple cycles before arresting after a shift from galactose to glucose. These results suggest that the C terminus of the wild-type protein confers functional instability. cln-arrested cells are mating competent. However, cln arrest is distinct from constitutive activation of the mating-factor signalling pathway because cln-arrested cells were dependent on the addition of pheromone both for mating and for induction of an alpha-factor-induced transcript, FUS1, and because MATa/MAT alpha (pheromone-nonresponsive) strains were capable of cln arrest in G1 (although a residual capacity for cell division before arrest was observed in MATa/MAT alpha strains). These results are consistent with a specific CLN requirement for START transit.
Advances in Non‐metallocene Olefin Polymerization Catalysis (2003)

Abstract For Abstract see ChemInform Abstract in Full Text.
Identification of a Salmonella typhimurium invasion locus by selection for hyperinvasive mutants. (1992)

Salmonella typhimurium penetrate intestinal epithelial cells during infection. In vitro studies reveal that the availability of oxygen during bacterial growth decreases their capacity to adhere to and enter cultured epithelial cells. To identify S. typhimurium genes involved in epithelial cell entry, mutants were selected that entered HEp-2 cells when grown under repressing, aerobic culture conditions. Two types of transposons were used to generate bacterial mutations--transposons that disrupt genes (Tn10 and Tn5) and one transposon (Tn5B50) that, in addition to disrupting genes, can cause constitutive expression of genes from the neo promoter at one end of the transposon. Three classes of mutations were found that increased the ability of aerobically grown S. typhimurium to enter HEp-2 cells. One class of mutations disrupts the che operons and results in a nonchemotactic phenotype. The second class of mutations revealed that defects in rho, which encodes an essential transcription termination factor, result in hyperinvasiveness. The third class of mutations was obtained only from mutagenesis with Tn5B50, suggesting that their increased invasiveness is due to constitutive expression of a gene(s) from the exogenous neo promoter. Analysis of this third class of mutations identified a S. typhimurium locus hil (hyperinvasion locus), which is essential for bacterial entry into epithelial cells. The results suggest that hil encodes an invasion factor or an activator of invasion factor expression. hil maps between srl and mutS near minute 59.5 of the S. typhimurium chromosome, a region adjacent to other loci that have been identified as required for S. typhimurium invasiveness and virulence.
Shaker‐type Kv1 channel blockers increase the peristaltic activity of guinea‐pig ileum by stimulating acetylcholine and tachykinins release by the enteric nervous system (2003)

A constant intraluminal pressure system was used to evaluate the effects of Kv1 channel blockers on the peristaltic activity of guinea‐pig ileum. The nortriterpene correolide, a non‐selective inhibitor of all Kv1 sub‐types, causes progressive and sustained reduction of the pressure threshold for eliciting peristaltic contractions. Margatoxin (MgTX), alpha‐dendrotoxin (α‐DTX) and dendrotoxin‐K (DTX‐K), highly selective peptidyl inhibitors of certain Kv1 sub‐types, cause immediate reduction of the pressure threshold. This effect subsides with time, irrespective of the peptides' concentration in the bath. In preparations pretreated with saturating concentrations of MgTX, correolide further stimulates the peristaltic activity. Iberiotoxin (IbTX), a selective inhibitor of the high‐conductance Ca 2+ ‐activated K + (BK) channels, and charybdotoxin (ChTX), which inhibits Kv1.2 and Kv1.3 as well as BK channels, fail to stimulate the peristaltic activity. Blockade of muscarinic receptors by atropine reduces, and occasionally suppresses the peristaltic activity of guinea‐pig ileum. In atropine‐treated preparations, correolide and MgTX retain their abilities to reduce the pressure threshold and are able to restore the peristaltic reflex in the preparations where this reflex was suppressed by atropine. The stimulatory effect of correolide and MgTX in atropine‐treated preparations is abolished by subsequent addition of selective antagonists of both NK1 and NK2 receptors. In conclusion, blockade of Kv1, particularly Kv1.1 channels, increases the peristaltic activity of guinea‐pig ileum by enhancing the release of neurotransmitters at the enteric nervous system. In contrast, stimulation of the myogenic motility by blockade of BK channels does not affect the threshold for the peristaltic reflex. British Journal of Pharmacology (2003) 138 , 57–62. doi: 10.1038/sj.bjp.0705023
A Concise Asymmetric Route to Nuphar Alkaloids. A Formal Synthesis of (−)-Deoxynupharidine (2003)

[reaction: see text] A stereocontrolled route to Nuphar alkaloids is described that employs a formal [3 + 3] cycloaddition strategy to assemble the piperidine nucleus. The addition of Pd-TMM complexes to aziridine 10 was found to be sluggish; however, the addition of a functionalized allyl Grignard reagent followed by a Mitsunobu condensation reaction provided 11 in high yield. The employment of this route in the formal synthesis of (-)-deoxynupharidine 1 is described.
Beta‐glucan enhanced killing of renal cell carcinoma micrometastases by monoclonal antibody G250 directed complement activation (2004)

Metastases from renal cell carcinomas (RCC) are resistant to radiation and chemotherapy but are relatively immunogenic. We have investigated the possibility to eliminate human RCC micrometastases using MAb G250. G250 penetrates human micrometastases completely in a spheroid model and induces complement deposition rapidly on the outmost cell layers. However, complement dependent cytotoxicity (CDC) was barely detected using either (51)chromium release assays or confocal microscopy, due to relatively low expression of the G250 antigen and the effect of membrane bound complement regulatory proteins. Addition of blocking anti-CD59 MAbs enhanced formation of C5b-9 and consequently complement mediated lysis (13%). Complement assisted cellular cytotoxicity (CACC) was not detectable, although the iC3b ligand and CR3 receptor were present on respectively target and effector cells. Addition of soluble beta-glucan induced the killing of MAb and iC3b opsonized spheroids by effector cells (6-21%). Despite a lower affinity for G250 antigen, a bispecific anti-G250*anti-CD55 MAb enhanced cell killing in spheroids comparable to the parental G250 MAb. Our results suggest that complement-activating G250 in combination with anti-mCRP MAbs is able to kill human RCC cells in micrometastasis in vitro. For CACC the presence of CR3-priming beta-glucan seems to be obligatory. In vivo, bi-MAb may be more effective as therapeutic agent due to its increased C5a generating properties.
Hypermethylated DNA as a biomarker for colorectal cancer: a systematic review (2016)

Hypermethylation of the promoters of specific genes measured in blood or stool samples could be used as a CRC biomarker and provide prognostic information. The majority of studies, however, include only a few patients with poorly defined control groups. Further studies are therefore needed before hypermethylated DNA can be widely applied as a clinical biomarker for CRC detection and prognosis.
Single-Domain Antibody–Based and Linker-Free Bispecific Antibodies Targeting FcγRIII Induce Potent Antitumor Activity without Recruiting Regulatory T Cells (2013)

Antibody-dependent cell-mediated cytotoxicity, one of the most prominent modes of action of antitumor antibodies, suffers from important limitations due to the need for optimal interactions with Fcγ receptors. In this work, we report the design of a new bispecific antibody format, compact and linker-free, based on the use of llama single-domain antibodies that are capable of circumventing most of these limitations. This bispecific antibody format was created by fusing single-domain antibodies directed against the carcinoembryonic antigen and the activating FcγRIIIa receptor to human Cκ and CH1 immunoglobulin G1 domains, acting as a natural dimerization motif. In vitro and in vivo characterization of these Fab-like bispecific molecules revealed favorable features for further development as a therapeutic molecule. They are easy to produce in Escherichia coli, very stable, and elicit potent lysis of tumor cells by human natural killer cells at picomolar concentrations. Unlike conventional antibodies, they do not engage inhibitory FcγRIIb receptor, do not compete with serum immunoglobulins G for receptor binding, and their cytotoxic activity is independent of Fc glycosylation and FcγRIIIa polymorphism. As opposed to anti-CD3 bispecific antitumor antibodies, they do not engage regulatory T cells as these latter cells do not express FcγRIII. Studies in nonobese diabetic/severe combined immunodeficient gamma mice xenografted with carcinoembryonic antigen-positive tumor cells showed that Fab-like bispecific molecules in the presence of human peripheral blood mononuclear cells significantly slow down tumor growth. This new compact, linker-free bispecific antibody format offers a promising approach for optimizing antibody-based therapies.
Genetic Parameters for Clinical Mastitis, Somatic Cell Counts, and Milk Production Estimated by Multiple-Trait Restricted Maximum Likelihood (1988)

Heritabilities and genetic correlations for mastitis, SCC, and milk production in first lactation were calculated using data from the Swedish disease recording system. Genetic parameters were estimated from sire components of variance and covariance obtained from a multiple-trait restricted maximum likelihood procedure. Data were stratified into three subsets according to breed and AI stud. The numbers of cows were 46,431, 25,373, and 25,201, respectively. Heritabilities of mastitis and SCC averaged .014 and .080, but breed differences were seen. Genetic correlations between mastitis and SCC were moderately high, averaging .6. Milk production showed a slightly unfavorable genetic correlation with mastitis and SCC.