gebhart/patrepeval huggingface dataset:
Distinct pathways regulated by menin and by MLL1 in hematopoietic stem cells and developing B cells (2013)

Mixed Lineage Leukemia (MLL1) translocations encode fusion proteins retaining the N terminus of MLL1, which interacts with the tumor suppressor, menin. This interaction is essential for leukemogenesis and thus is a promising drug target. However, wild-type MLL1 plays a critical role in sustaining hematopoietic stem cells (HSCs); therefore, disruption of an essential MLL1 cofactor would be expected to obliterate normal hematopoiesis. Here we show that rather than working together as a complex, menin and MLL1 regulate distinct pathways during normal hematopoiesis, particularly in HSCs and B cells. We demonstrate the lack of genetic interaction between menin and MLL1 in steady-state or regenerative hematopoiesis and in B-cell differentiation despite the fact that MLL1 is critical for these processes. In B cells, menin- or MLL1-regulated genes can be classified into 3 categories: (1) a relatively small group of coregulated genes including previously described targets Hoxa9 and Meis1 but also Mecom and Eya1, and much larger groups of (2) exclusively menin-regulated and (3) exclusively MLL1-regulated genes. Our results highlight the large degree of independence of these 2 proteins and demonstrate that menin is not a requisite cofactor for MLL1 during normal hematopoiesis. Furthermore, our data support the development of menin-MLL1-disrupting drugs as safe and selective leukemia targeting agents.
Efficacy of etanercept for the treatment of juvenile idiopathic arthritis according to the onset type (2003)

Treatment of JIA with etanercept may be associated with a wide spectrum of severe side effects. Although most patients initially respond to etanercept, this initial response is not always followed by sustained improvement over longer periods of time. In addition, the higher rate of treatment failure in the group with systemic-onset JIA indicates that these patients in particular may require alternative treatments.
Self-Propelled Micromotors for Cleaning Polluted Water (2013)

We describe the use of catalytically self-propelled microjets (dubbed micromotors) for degrading organic pollutants in water via the Fenton oxidation process. The tubular micromotors are composed of rolled-up functional nanomembranes consisting of Fe/Pt bilayers. The micromotors contain double functionality within their architecture, i.e., the inner Pt for the self-propulsion and the outer Fe for the in situ generation of ferrous ions boosting the remediation of contaminated water.The degradation of organic pollutants takes place in the presence of hydrogen peroxide, which acts as a reagent for the Fenton reaction and as main fuel to propel the micromotors. Factors influencing the efficiency of the Fenton oxidation process, including thickness of the Fe layer, pH, and concentration of hydrogen peroxide, are investigated. The ability of these catalytically self-propelled micromotors to improve intermixing in liquids results in the removal of organic pollutants ca. 12 times faster than when the Fenton oxidation process is carried out without catalytically active micromotors. The enhanced reaction-diffusion provided by micromotors has been theoretically modeled. The synergy between the internal and external functionalities of the micromotors, without the need of further functionalization, results into an enhanced degradation of nonbiodegradable and dangerous organic pollutants at small-scale environments and holds considerable promise for the remediation of contaminated water.
Unzipping Kinetics of Duplex DNA Containing Oxidized Lesions in an α-Hemolysin Nanopore (2012)

The unzipping kinetics for lesion-containing DNA duplexes was studied in an α-hemolysin (α-HL) nanopore. The lesion of focus was the guanine two-electron oxidation product, 8-oxo-7,8-dihydroguanine (OG), and its further oxidation products, the hydantoins guanidinohydantoin (Gh) and spiroiminodihydantoin (Sp). The voltage-driven unzipping of individual duplex DNA molecules with symmetrical overhangs was carried out by pulling one strand of the duplex through the α-HL channel using an electrical field. Entry from the 3' or 5' end produced distinct current blockages, allowing directional effects on unzipping kinetics to be investigated. We find that the strand dissociation of complementary duplexes or duplexes containing the slightly destabilizing lesion OG follows a first-order kinetic model, while opening of duplexes that contain the highly destabilizing lesions Gh or Sp is described by two sequential first-order reactions, in which the intermediate state is proposed to correspond to the duplex unzipped to the lesion site within the channel. The rate constants for strand separation of the duplexes containing single lesions were obtained from kinetic model fits to histograms of unzipping duration. For all duplexes, the rate constants for strand separation displayed a significant dependence on the direction of entry into the nanopore. For duplexes containing Gh, truncated duplexes were used to assign the measured rate constants for the first and second unzipping steps of symmetrically designed duplexes.
CXC chemokines in angiogenesis (2000)

A variety of factors have been identified that regulate angiogenesis, including the CXC chemokine family. The CXC chemokines are a unique family of cytokines for their ability to behave in a disparate manner in the regulation of angiogenesis. CXC chemokines have four highly conserved cysteine amino acid residues, with the first two cysteine amino acid residues separated by one non-conserved amino acid residue (i.e., CXC). A second structural domain within this family determines their angiogenic potential. The NH2 terminus of the majority of the CXC chemokines contains three amino acid residues (Glu-Leu-Arg: the ELR motif), which precedes the first cysteine amino acid residue of the primary structure of these cytokines. Members that contain the ELR motif (ELR+) are potent promoters of angiogenesis. In contrast, members that are inducible by interferons and lack the ELR motif (ELR-) are potent inhibitors of angiogenesis. This difference in angiogenic activity may impact on the pathogenesis of a variety of disorders.
Impact of an interest in asthma on prescribing costs in general practice. (1992)

FHSAs and their medical advisors should not examine high prescribing costs for individual doctors or one therapeutic category but in the context of practice total costs.
Expanded autologous regulatory T-lymphocyte infusions in ALS (2018)

This study provides Class IV evidence. This is a phase I trial with no controls.
Detection of Streptococcus pneumoniae in whole blood by PCR (1995)

Streptococcus pneumoniae is a major cause of bacteremia in both children and adults. Currently, the diagnosis of pneumococcal bacteremia relies on the isolation and identification of the bacteria from blood cultures. We have developed a sensitive assay for the detection of S. pneumoniae in whole blood by the PCR. A specific primer-probe set (JM201 and JM202 primers with JM204 probe) designed from the penicillin-binding protein 2B gene was demonstrated to reproducibly detect between 10 and 100 fg of input purified S. pneumoniae DNA. This assay system was shown to be inclusive for all strains of S. pneumoniae evaluated, including 15 different serotypes and a battery of penicillin-resistant and -sensitive strains. The specificity of this PCR-based assay was demonstrated by its inability to support amplification from a series of human, bacterial, and yeast genomic DNAs. A general specimen preparation method which should be suitable for the purification of DNA from any pathogens in whole blood was developed. With this protocol it was possible to detect S. pneumoniae-specific DNA from whole blood specimens inoculated with as little as 4 CFU/ml. Copurified human blood DNA, ranging from 0 to 4.5 micrograms per PCR, did not affect the sensitivity of S. pneumoniae detection by PCR. A blinded clinical trial was used to compare the PCR-based assay with standard microbiological blood culture for the detection of S. pneumoniae bacteremia in 36 specimens obtained from pediatric patients seen in the emergency room of Children's Hospital of Pittsburgh. With culture as the "gold standard," the PCR-based assay had a sensitivity of 80% (4 of 5 culture-positive specimens were PCR positive) and a specificity of 84% (26 of 31 culture-negative specimens were PCR negative). However, three patients whose specimens were PCR positive and culture negative had histories suggestive of bacteremia, including recent positive blood cultures, treatment with antibiotics, cellulitis, and multiple emergency room visits for fever within a 24-h period. These data suggest that PCR-based assays for S. pneumoniae may prove useful to augment current methods of detection for S. pneumoniae bacteremia.
In vivo diffusion analysis with quantum dots and dextrans predicts the width of brain extracellular space (2006)

Diffusion within the extracellular space (ECS) of the brain is necessary for chemical signaling and for neurons and glia to access nutrients and therapeutics; however, the width of the ECS in living tissue remains unknown. We used integrative optical imaging to show that dextrans and water-soluble quantum dots with Stokes-Einstein diameters as large as 35 nm diffuse within the ECS of adult rat neocortex in vivo. Modeling the ECS as fluid-filled "pores" predicts a normal width of 38-64 nm, at least 2-fold greater than estimates from EM of fixed tissue. ECS width falls below 10 nm after terminal ischemia, a likely explanation for the small ECS visualized in electron micrographs. Our results will improve modeling of neurotransmitter spread after spillover and ectopic release and establish size limits for diffusion of drug delivery vectors such as viruses, liposomes, and nanoparticles in brain ECS.
Cloning of tetradecanoyl phorbol ester-induced 'primary response' sequences and their expression in density-arrested Swiss 3T3 cells and a TPA non-proliferative variant. (1987)

The tumor promoter tetradecanoyl phorbol acetate (TPA) is also a potent mitogen for murine 3T3 cells. We have previously described the isolation of variant Swiss 3T3 cell lines unable to proliferative in response to TPA. In this report we sought to identify genes that are stimulated by TPA as 'primary responses', i.e., without intervening protein synthesis. We constructed a cDNA library in lambda gt10, using RNA from quiescent 3T3 cells treated with TPA in the presence of cycloheximide (CHX). Of 50,000 recombinant phages, we identified 50 isolates that demonstrated preferential hybridization to cDNA probes generated from TPA-stimulated cells. One of the clones contains a fragment of the proto-oncogene c-fos. Twenty-nine of the remaining 49 clones fall into six cross-hybridization families. All the characterized clones detected mRNAs that are also inducible by epidermal growth factor, fibroblast growth factor or elevated serum. TPA induction of all the characterized messages is rapid and transient. All these mRNAs are superinduced by a combination of mitogens and CHX. Induction of these messages following TPA addition also occurs in subconfluent 3T3 cultures; expression of these genes is, therefore, not restricted to the G0/G1 transition. Expression of all six clones was also induced by TPA and other mitogens in 3T3-TNR9 cells, a TPA non-proliferative variant.
In-shoe casting technique for specialized sports shoes (1989)

The use of vacuum casting to create better-fitting orthoses for special athletic shoes has been discussed. By vacuum-forming a negative cast within the confines of special athletic shoes, such as bicycling cleats or fencing shoes, a better-fitting orthosis can be fabricated with little or no special adjustments or modifications necessary to create the best fit and function.
Immunoediting Sculpts Tumor Epitopes during Immunotherapy (2007)

Immunoediting of tumor-associated antigens occurs in response to immune pressure. We show that the mutation of residues within epitopes of HER-2/neu leads to the outgrowth of autochthonous tumors after immunizing HER-2/neu transgenic mice with Listeria monocytogenes therapeutic vaccines expressing fragments of HER-2/neu. Three of these vaccines target the extracellular domain (LmLLO-EC1, LmLLO-EC2, and LmLLO-EC3), and two of these vaccines target the intracellular domain (Lm-LLO-IC1 and Lm-LLO-IC2). Mutations occurred in the regions of the HER-2/neu molecule targeted by the Listeria strain expressing that region, which suggests that the rate of generation of escape mutants was a significant factor in the efficacy of each vaccine. A longer delay in the onset of tumors after immunotherapy occurred with the vaccine that targeted the kinase domain. We verified that the mutations in this domain occurred within novel CD8(+) T-cell epitopes, and that the mutation of these residues abrogated CTL responses to these epitopes. The long delay in the onset of tumors after immunotherapy targeting the kinase domain may be because this region of HER-2/neu cannot undergo extensive mutations without impairing its ability to signal cell growth.
A systematic review of St. John’s wort for major depressive disorder (2016)

PROSPERO CRD42015016406 .
High‐throughput sequencing for biology and medicine (2013)

Advances in genome sequencing have progressed at a rapid pace, with increased throughput accompanied by plunging costs. But these advances go far beyond faster and cheaper. High-throughput sequencing technologies are now routinely being applied to a wide range of important topics in biology and medicine, often allowing researchers to address important biological questions that were not possible before. In this review, we discuss these innovative new approaches-including ever finer analyses of transcriptome dynamics, genome structure and genomic variation-and provide an overview of the new insights into complex biological systems catalyzed by these technologies. We also assess the impact of genotyping, genome sequencing and personal omics profiling on medical applications, including diagnosis and disease monitoring. Finally, we review recent developments in single-cell sequencing, and conclude with a discussion of possible future advances and obstacles for sequencing in biology and health.
Neutral mitochondrial heteroplasmy and the influence of aging (2011)

The development and maintenance of mitochondrial heteroplasmy has important consequences for both health and heredity. Previous studies using pathogenic mutations have shown considerable variability between maternally related individuals and studies of several D-loop polymorphisms have suggested a relationship between heteroplasmy and somatic aging. To broadly explore the variation of human heteroplasmy and to clarify the dynamics of somatic heteroplasmy over the course of lifespan, we analyzed mitochondrial sequence variation across a range of ages. We utilized array-generated single-nucleotide polymorphism data that were well correlated with independent measures of heteroplasmy. Significant levels of heteroplasmy were identified at 0.24% of sites evaluated. By examining mother-child pairs, we found that heteroplasmy was inherited (30%) but could occur de novo in offspring or, conversely, be present in mothers but eliminated in their children (70%). Cumulatively, mitochondrial heteroplasmy across the genome increased significantly with advanced age (r = 0.224, P =8 × 10(-30)). Surprisingly, changes in heteroplasmy were not uniform with some sites demonstrating a loss of variation (increased homoplasmy) with aging. These data suggest that both mutation and selective pressure affect blood mitochondrial DNA sequence over the course of the human lifespan and reveal the unexpectedly dynamic nature of human heteroplasmy.
Sequence-targeted cleavage of nucleic acids by oligo-[.alpha.]thymidylate-phenanthroline conjugates: parallel and antiparallel double helices are formed with DNA and RNA, respectively (1988)

Oligodeoxynucleotides can be synthesized by using the alpha anomers of nucleoside units. Oligo-alpha-deoxynucleotides are resistant to nucleases and could be used to regulate gene expression in vivo. Theoretical calculations were carried out to determine the conformational energy of an oligomeric alpha-beta duplex (dA)5.(dT)5 where the adenosine strand contains natural beta-deoxyribonucleotides and the thymidine strand contains synthetic alpha-deoxyribonucleotides. These calculations predict that in the more stable B-like conformation the two strands of the double helix should run parallel to each other whereas in the more stable A-like conformation the two strands should adopt an antiparallel orientation. In order to test these predictions 1,10-phenanthroline was covalently attached to the 5'-end of an alpha-octathymidylate. In the presence of copper ions and a reducing agent (beta-mercaptopropionic acid), the (phenanthroline)2-copper complex generates OH. radicals that cleave phosphodiester bonds in the complementary sequence to which the alpha-octathymidylate is bound. By use of a 27mer oligo-beta-deoxynucleotide containing an octadeoxyadenylate sequence as a target for the phenanthroline-substituted alpha-(dT)8, cleavage was observed on the 5'-side of the (dA)8 sequence, demonstrating that the alpha-beta DNA-DNA hybrid formed a double helix with parallel orientation of the two strands. The same result was obtained when alpha-(dT)8 was bound to beta-(dA)n with n = 8 or 10. When a beta-oligoriboadenylate was used as a target, cleavage occurred exclusively on the 3'-side of the (rA)8 or (rA)10 sequence, indicating that the alpha-beta DNA-RNA hybrid formed a double helix with an antiparallel orientation of the two strands. When a phenanthroline-substituted beta-octathymidylate was used instead of the alpha-octathymidylate, an antiparallel double helix was formed independently of whether the target beta sequence was a DNA or an RNA.
Processor element architecture for nonshared memory parallel computers (1988)

The architecture of the processor elements in a parallel computer can have a significant impact on overall performance. However, because the hardware used for architectural features can alternatively be used to add more processor elements, and hence increase parallelism, adding architectural features is not necessarily the best choice. In this dissertation, a combination of analytical techniques, program analysis, and simulations is used to explore this trade-off between processor element architecture and added parallelism in a non-shared memory parallel computer.
The impact of an architectural feature cannot, in general, be assessed by comparing program execution times. This is because execution time can be changed independently of architecture by changing either the number of processor elements or the total data memory. We argue that a fair comparison based on execution time can only be performed when total hardware and total memory remain constant. These constraints are used to explore the relationship between processor element architecture and overall performance. The key insight gained from this analysis is that features with the greatest potential for improving performance are those that affect all or most of the operations. Consequently, a substantial hardware investment for a specific class of operations, such as floating point, does not give the best performance.
The above observations are substantiated by the analysis of several specific architectural features. This study utilizes dynamic frequency and cost distributions of seven parallel programs representative of numerical computations and physical simulations. Performance estimates for these programs are combined with area estimates for the features to obtain the following results: (1) With a given amount of hardware, a 32-bit data path outperforms a serial path by a factor of five. (2) The MIMD architecture studied requires 3.4 times more hardware than an equivalent SIMD architecture. (3) Though code size increases, a reduced instruction set gives better performance. (4) Small instruction caches show promise; a data cache does not. (5) Partial support for floating point operations is more beneficial than a full floating point unit. (6) DMA for communication channels does not improve performance. (7) A few additional registers can significantly reduce the overhead of providing virtual machine facilities.
A general method to isolate genes tagged by a high copy number transposable element (1995)

The Petunia hybrida line W138 contains more than 200 copies of the transposable element dTph1. In W138 progeny these elements give rise to new unstable mutations at high frequency. With the aim of isolating these mutated genes a method was developed to isolate dTph1 flanking sequences unique for mutant plants. This method is based on differential screening of cloned inverse polymerase chain reaction (IPCR) products originating from the mutated plant. It directly yields a probe for the mutated gene which can be used to screen pre-existing cDNA and genomic libraries. This method may be generally applicable to isolate genes tagged by other high copy number transposable elements, like Mutator (Mu) or Dissociation (Ds) in Zea mays.
Synthese und Umsetzungen von 4-Acyl/Carbamoyl-N-aryl-3-chloropyrrol-2,5-dionen: Kristallstruktur eines auf Wasserstoffbrückenbindungen basierenden supramolekularen Bandes [1] / Synthesis and Reactions of 4-Acyl/Carbamoyl-N-aryl-3-chloro-pyrrol-2,5-diones: Crystal Structure of a Supramolecular Ribbon Based on Hydrogen Bonds [ 1] (1996)

Reaction of malondiamides 1 with oxalyl chloride (2) leads to the formation of 2,3-dioxo-2,3- dihydrofuran hydrochlorides 3 and 2,3-dioxo-2,3-dihydro-furanes 4, respectively. The structure of 3a was established by X-ray diffraction. The β-oxo-dibenzylamides 5 react with 2 regiospecifically to give the 2,3-dioxo-2,3-dihydrofuranes 6. Addition of water in 1,4-position to 6a yields hydroxy-enol 7, which forms bimolecular aggregates via intermolecular hydrogen bonds as shown by X-ray analysis. Intramolecular C,N-bisacylation of β-oxoamides 8 and malondiamides 11 with 2 leads to the pyrrol-2,5-diones 9 and 12. Reaction of the enols 9 and 12 with thionyl chloride leads to 3-chloro-pyrrol-2,5-diones 13. 3-Amino-pyrrol-2,5-diones 15 are obtained from 13 and amines 14, while 1, ω-diamines 16 yield the bispyrrol systems 17. X-ray diffraction analysis of 17g reveals a supramolecular ribbon based on intermolecular hydrogen bonds between two different conformeres of 17g and in addition establishes unequivocally the imid-structures of 9 and 12. Intermolecular cyclisation of 13 with amino-tetrazol 18 gives the azido-pyrrolo-pyrimidine-diones 20, which reacts with triphenylphosphane to give phosphinimines 22. The structure of 22a was established by X-ray diffraction.
CD43 monoclonal antibodies recognize the large sialoglycoprotein of human leukocytes (1987)

In this study data are presented indicating that the molecule identified by the recently described CD43 cluster of monoclonal antibodies (mAb; Oxford, 1986) is the human analogue to the one originally described in rat as leukocyte sialoglycoprotein (LSGP). This conclusion is based on several criteria. Both molecular mass (105 kDa) and cellular distribution are similar to the antigens previously described in the rat with the mAb W3/13 and subsequently in humans with L10 mAb. Sialidase treatment of the molecule immunoprecipitated by 84-3C1 mAb (CD43) resulted in a decreased electrophoretic mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. L10 mAb inhibited the binding of 84-3C1 mAb to the cell membrane suggesting that both mAb recognized the same molecule. Moreover, the presence in the CD3-4-8- thymic populations of the sialidase-sensitive epitope recognized by mAb 84-3C1 suggests that there is no simple correlation between the thymic maturation and the degree of sialylation.