gebhart/patrepeval huggingface dataset:
Lossy Source Compression Using Low-Density Generator Matrix Codes: Analysis and Algorithms (2010)

We study the use of low-density generator matrix (LDGM) codes for lossy compression of the Bernoulli symmetric source. First, we establish rigorous upper bounds on the average distortion achieved by check-regular ensemble of LDGM codes under optimal minimum distance source encoding. These bounds establish that the average distortion using such bounded degree families rapidly approaches the Shannon limit as the degrees are increased. Second, we propose a family of message-passing algorithms, ranging from the standard belief propagation algorithm at one extreme to a variant of survey propagation algorithm at the other. When combined with a decimation subroutine and applied to LDGM codes with suitably irregular degree distributions, we show that such a message-passing/decimation algorithm yields distortion very close to the Shannon rate-distortion bound for the binary symmetric source.
A low antigen dose selectively promotes expansion of high-avidity autoreactive T cells with distinct phenotypic characteristics: A study of human autoreactive CD4+T cells specific for GAD65 (2010)

T cells specific for pancreatic islet proteins can be detected in type 1 diabetes patients and at-risk individuals, suggesting a failure of the central tolerance and negative selection. We addressed the question, how antigen dose shapes the diversity of CD4+ autoreactive T cells specific for glutamate decarboxylase 65 (GAD65) in a healthy HLA-DR*0404+ individual, with a persistent GAD65-specific T-cell response. CD4+T cells from this subject were stimulated with decreasing concentrations of the GAD65 555-567 (557I) peptide, and T-cell clones were derived from the tetramer-binding cell population. Functional and structural avidity, TcR-Vβ usage, and cytokine profiles were investigated at a clonal level. T-cell clones established with a low antigen dose (0.1 and 1 μg/ml) displayed higher avidity in contrast to the clones established with the highest antigen dose (10 μg/ml; Mann-Whitney U test, p = 0.003 and 0.006, respectively). The T-cell clones stimulated with the lowest peptide dose also had a higher tetramer-binding affinity than clones stimulated with the highest dose (p = 0.026). The majority (60.0%) of the high-avidity clones expressed TcR-Vβ5.1 chain whereas only one (12.5%) low-avidity clone did. All clones displayed Th0/Th2 cytokine profiles, but intermediate and high-avidity clones produced more IL-10 than low-avidity clones (p = 0.032). The results demonstrate an important role of the antigen dose in the determination of characteristics of the responding T-cell repertoire. High IL-13 and IL-10 production by GAD65-reactive T cells suggests a more anti-inflammatory profile of this healthy individual underlying protection from T1D.
Single Variable Domain-IgG Fusion (2006)

Both laboratory and early clinical studies to date have demonstrated that bispecific antibodies (BsAb) may have potentially significant application in cancer therapy. The clinical development of BsAb as therapeutics has been hampered, however, by the difficulty in preparing the materials in sufficient quantity and quality by traditional methods. In recent years, a variety of recombinant methods has been developed for efficient production of BsAb, both as antibody fragments and as full-length IgG-like molecules. Here we describe a novel recombinant approach for the production of an Fc domain-containing, IgG-like tetravalent BsAb, with two antigen-binding sites to each of its target antigens, by genetically fusing a single variable domain antibody to the N terminus of the light chain of a functional IgG antibody of different specificity. A model BsAb was constructed using a single variable domain antibody to mouse platelet-derived growth factor receptor alpha and a conventional IgG antibody to mouse vascular endothelial growth factor receptor 2. The BsAb was expressed in mammalian cells and purified to homogeneity by one-step protein A affinity chromatography. Furthermore, the BsAb retains the antigen binding specificity and the receptor neutralizing activity of both of its parent antibodies. This design and expression of Fc domain-containing, IgG-like BsAb should be applicable to the construction of similar BsAb from antibodies recognizing any pair of antigens.
TBX4 is involved in the super-enhancer-driven transcriptional programs underlying features specific to lung fibroblasts (2017)

Lung fibroblasts participate in the pathogenesis of respiratory diseases, including lung cancer and pulmonary fibrosis. Although fibroblasts are ubiquitous constituents of various organs, their cellular diversity among different organs has been poorly characterized. Here, we aimed to investigate the distinct gene signature of lung fibroblasts that represents its pulmonary origin and the underlying gene regulatory networks. Promoter-level differential expression analysis by cap analysis of gene expression (CAGE) sequencing revealed distinct gene expression patterns of fibroblasts derived from different anatomical sites and identified 88 coding genes with higher expression in lung fibroblasts relative to other fibroblasts. Multiple key transcription factors important for lung mesenchyme development, including the T-box transcription factors TBX2, TBX4, and TBX5 were enriched in this lung-specific signature and were associated with super-enhancers. TBX4 showed highly specific expression in lung fibroblasts and was required for cell proliferation and collagen gel contraction capacity. Transcriptome analysis revealed that TBX4 could broadly regulate fibroblast-related pathways and partly contribute to super-enhancer-mediated transcriptional programs. Of pathological importance, lung fibroblast-specific genes were globally downregulated in lung cancer-associated fibroblasts (CAFs). Notably, TBX2, TBX4, and TBX5 were downregulated and hypermethylated in lung CAFs, suggesting an association between epigenetic silencing of these factors and phenotypic alteration of lung fibroblasts in cancer. Our study highlights the importance of T-box transcription factors, especially TBX4, and super-enhancers in the roles of lung fibroblasts in pulmonary physiology and pathogenesis.
Incidence of acute lung injury in the United States* (2003)

Based on this analysis, which used prospective clinical trial screening data and conservative assumptions about where patients with ALI are cared for, the incidence of ALI in the United States appears to be higher than previously reported.
Design Technique for Multiplexing Asynchronous Digital Video and Audio Signals (1978)

To apply digital transmission to the distribution of television program material it is necessary to encode both sound and picture signals, protect them from the effects of transmission errors and multiplex them into a form suitable for the transmission link that is to be used. Coding, error protection and multiplexing have all received extensive study but their combined application in a system has received little discussion in the literature. This paper shows how a system was designed for a particular experimental application with a specified total bit rate. Particular emphasis is given to the multiplexing arrangements, including the necessary use of justification techniques. The equipment designed has been used in successful field trials of digital transmission by both cable and satellite.
A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing (2015)

As whole-genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Here using tumour-normal sample pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, we conduct a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines and validation methods. We show that using PCR-free methods and increasing sequencing depth to ∼ 100 × shows benefits, as long as the tumour:control coverage ratio remains balanced. We observe widely varying mutation call rates and low concordance among analysis pipelines, reflecting the artefact-prone nature of the raw data and lack of standards for dealing with the artefacts. However, we show that, using the benchmark mutation set we have created, many issues are in fact easy to remedy and have an immediate positive impact on mutation detection accuracy.
Context-dependent signaling defines roles of BMP9 and BMP10 in embryonic and postnatal development (2013)

Many important signaling pathways rely on multiple ligands. It is unclear if this is a mechanism of safeguard via redundancy or if it serves other functional purposes. In this study, we report unique insight into this question by studying the activin receptor-like kinase 1 (ALK1) pathway. Despite its functional importance in vascular development, the physiological ligand or ligands for ALK1 remain to be determined. Using conventional knockout and specific antibodies against bone morphogenetic protein 9 (BMP9) or BMP10, we showed that BMP9 and BMP10 are the physiological, functionally equivalent ligands of ALK1 in vascular development. Timing of expression dictates the in vivo requisite role of each ligand, and concurrent expression results in redundancy. We generated mice (Bmp10(9/9)) in which the coding sequence of Bmp9 replaces that of Bmp10. Surprisingly, analysis of Bmp10(9/9) mice demonstrated that BMP10 has an exclusive function in cardiac development, which cannot be substituted by BMP9. Our study reveals context-dependent significance in having multiple ligands in a signaling pathway.
Tunability and Noise Dependence in Differentiation Dynamics (2007)

The dynamic process of differentiation depends on the architecture, quantitative parameters, and noise of underlying genetic circuits. However, it remains unclear how these elements combine to control cellular behavior. We analyzed the probabilistic and transient differentiation of Bacillus subtilis cells into the state of competence. A few key parameters independently tuned the frequency of initiation and the duration of competence episodes and allowed the circuit to access different dynamic regimes, including oscillation. Altering circuit architecture showed that the duration of competence events can be made more precise. We used an experimental method to reduce global cellular noise and showed that noise levels are correlated with frequency of differentiation events. Together, the data reveal a noise-dependent circuit that is remarkably resilient and tunable in terms of its dynamic behavior.
Iron(II) induces changes in the conformation of mammalian mitochondrial DNA resulting in a reduction of its transcriptional rate (2000)

Living isolated mitochondria incubated with iron(II) show a major alteration in mitochondrial DNA (mtDNA) conformational forms as assessed by Southern blot analysis of undigested mtDNA. In the presence of iron(II), form I is transformed into form III in a dose-dependent manner. This alteration in mtDNA conformation shows a strong correlation with a decrease in the mtDNA transcription rate (r=0.965, P < 0.002), suggesting that iron(II) load results in double-strand breaks and unwinding of mtDNA, which, in turn, is unable to maintain its normal transcriptional rate.
Protective Activity of Monoclonal Antibodies to Genome-Derived Neisserial Antigen 1870, a Neisseria meningitidis Candidate Vaccine (2004)

Genome-derived neisserial Ag (GNA) 1870 is a meningococcal vaccine candidate that can be subdivided into three variants based on amino acid sequence variability. Variant group 1 accounts for approximately 60% of disease-producing group B isolates. The Ag went unrecognized until its discovery by genome mining because it is expressed in low copy number by most strains. To investigate the relationship between Ab binding to GNA1870 and complement-mediated protective functions, we prepared a panel of four murine IgG mAbs against rGNA1870 (variant 1) and evaluated their activity against nine genetically diverse encapsulated Neisseria meningitidis strains expressing subvariants of variant 1 GNA1870. Based on flow cytometry with live encapsulated bacteria, surface accessibility of the epitopes recognized by the mAbs appeared to be low in most strains. Yet mAb concentrations <1 to 5 micro g/ml were sufficient to elicit bactericidal activity with human complement and/or activate C3b deposition on the bacterial surface. Certain combinations of mAbs were highly bactericidal against strains that were resistant to bactericidal activity of the respective individual mAbs. The mAbs conferred passive protection against bacteremia in infant rats challenged by strains resistant to bacteriolysis, and the protective activity paralleled the ability of the mAb to activate C3b deposition. Thus, despite low GNA1870 surface exposure, anti-GNA1870 variant 1 Abs are bactericidal and/or elicit C3b deposition and confer protection against bacteremia caused by encapsulated N. meningitidis strains expressing GNA1870 subvariant 1 proteins. The data support GNA1870 as a promising vaccine candidate for prevention of meningococcal group B disease caused by GNA1870 variant 1 strains.
Expression of the Escherichia coli K5 capsular antigen: immunoelectron microscopic and biochemical studies with recombinant E. coli (1990)

The capsular K5 polysaccharide, a representative of group II capsular antigens of Escherichia coli, has been cloned previously, and three gene regions responsible for polymerization and surface expression have been defined (I. S. Roberts, R. Mountford, R. Hodge, K. B. Jann, and G. J. Boulnois, J. Bacteriol. 170:1305-1310, 1988). In this report, we describe the immunoelectron microscopic analysis of recombinant bacteria expressing the K5 antigen and of mutants defective in either region 1 or region 3 gene functions, as well as the biochemical analysis of the K5 capsular polysaccharide. Whereas the K5 clone expressed the K5 polysaccharide as a well-developed capsule in about 25% of its population, no capsule was observed in whole mount preparations and ultrathin sections of the expression mutants. Immunogold labeling of sections from the region 3 mutant revealed the capsular K5 polysaccharide in the cytoplasm. With the region 1 mutant, the capsular polysaccharide appeared associated with the cell membrane, and, unlike the region 3 mutant polysaccharide, the capsular polysaccharide could be detected in the periplasm after plasmolysis of the bacteria. Polysaccharides were isolated from the homogenized mutants with cetyltrimethylammonium bromide. The polysaccharide from the region 1 mutant had the same size as that isolated from the capsule of the original K5 clone, and both polysaccharides were substituted with phosphatidic acid. The polysaccharide from the region 3 mutant was smaller and was not substituted with phosphatidic acid. These results prompt us to postulate that gene region 3 products are involved in the translocation of the capsular polysaccharide across the cytoplasmic membrane and that region 1 directs the transport of the lipid-substituted capsular polysaccharide through the periplasm and across the outer membrane.
Comparison of different methods for the determination of the oil content in oilseeds (2001)

Abstract The investigation and assessment of the oil content of oilseeds are important criteria, especially for the oil milling trade. Standard methods for the determination of the oil content of oilseeds are very time consuming, with extraction periods of 4 to 8 h. Three different oilseeds—rapeseed, sunflower, and soybean—are extracted by supercritical fluid extraction (SFE), accelerated solvent extraction, microwave‐assisted extraction, solid fluid vortex extraction, and Soxtherm, and the results are compared with the result of the German Fat Science Society (DGF) standard method B‐I 5 (87). Besides, the extracts are analyzed regarding the content of tocopherols as a parameter for mild extraction conditions and the content of diglycerides and free fatty acids as parameters for the content of more polar lipids. The results of the determination of the oil content under optimal conditions are comparable with the results of the DGF standard method B‐I 5 (87). There are no significant differences between the different methods. The content of tocopherols is dependent upon the extraction method and the type of oilseed. The highest content is obtained by SFE. The content of diglycerides and free fatty acids varied according to the oilseed.
Evolutionary coupling of structural and functional sequence information in the intracellular lipid‐binding protein family (2006)

We have mined the evolutionary record for the large family of intracellular lipid-binding proteins (iLBPs) by calculating the statistical coupling of residue variations in a multiple sequence alignment using methods developed by Ranganathan and coworkers (Lockless and Ranganathan, Science 1999:286;295-299). The 213 sequences analyzed have a wide range of ligand-binding functions as well as highly divergent phylogenetic origins, assuring broad sampling of sequence space. Emerging from this analysis were two major clusters of coupled residues, which when mapped onto the structure of a representative iLBP under study in our laboratory, cellular retinoic-acid binding protein I, are largely contiguous and provide useful points of comparison to available data for the folding of this protein. One cluster comprises a predominantly hydrophobic core away from the ligand-binding site and likely represents key structural information for the iLBP fold. The other cluster includes the portal region where ligand enters its binding site, regions of the ligand-binding cavity, and the region where the 10-stranded beta-barrel characteristic of this family closes (between strands 1' and 10). Linkages between these two clusters suggest that evolutionary pressures on this family constrain structural and functional sequence information in an interdependent fashion. The necessity of the structure to wrap around a hydrophobic ligand confounds the typical sequestration of hydrophobic side chains. Additionally, ligand entry and exit require these structures to have a capacity for specific conformational change during binding and release. We conclude that an essential and structurally apparent separation of local and global sequence information is conserved throughout the iLBP family.
Manipulation of the superantigen‐induced lymphokine response. Selective induction of interleukin‐10 or interferon‐γ synthesis in small resting CD4+ T cells (1993)

The production of several lymphokines by freshly isolated CD4+ T cells has been analyzed at the single-cell level, after stimulation with staphylococcal enterotoxin B (SEB). High frequencies of cells producing interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) were induced, but very low frequencies of CD4+ T cells produced IL-4, IL-5 or IL-10 in response to SEB. Exogenously added IL-4 markedly altered the lymphokine profile induced during primary SEB stimulation. IFN-gamma production was reduced, while a high fraction of cells contained IL-10 and IL-4 after activation in the presence of IL-4. We further demonstrate that IL-4 and IL-10 or IFN-gamma production was selectively induced in resting, high-density CD4+ T cells during primary stimulation, by SEB + IL-4 or SEB. Under conditions where both IL-10 and IFN-gamma were produced, most cells contained only one of the two lymphokines.
Low cost working set size tracking (2011)

Efficient memory resource management requires knowledge of the memory demands of applications or systems at runtime. A widely proposed approach is to construct an LRU-based miss ratio curve (MRC), which provides not only the current working set size (WSS) but also the relationship between performance and target memory allocation size. Unfortunately, the cost of LRUMRC monitoring is nontrivial. Although optimized with AVL-tree based LRU structure and dynamic hot set sizing, the overhead is still as high as 16% on average. Based on a key insight that for most programs the WSSs are stable most of the time, we design an intermittent tracking scheme, which can temporarily turn off memory tracking when memory demands are predicted to be stable. With the assistance of hardware performance counters, memory tracking can be turned on again if a significant change in memory demands is expected. Experimental results show that, by using this intermittent tracking design, memory tracking can be turned off for 82% of the execution time while the accuracy loss is no more than 4%. More importantly, this design is orthogonal to existing optimizing techniques, such as AVL-tree based LRU structure and dynamic hot set sizing. By combining the three approaches, the mean overhead is lowered to only 2%. We show that when applied to memory balancing for virtual machines, our scheme brings a speedup of 1.85.
A High Frequency of Circulating B Cells Share Clonotypic Ig Heavy-Chain VDJ Rearrangements With Autologous Bone Marrow Plasma Cells in Multiple Myeloma, as Measured by Single-Cell and In Situ Reverse Transcriptase-Polymerase Chain Reaction (1998)

In multiple myeloma (MM), the VDJ rearrangement of the immunoglobulin heavy chain expressed by MM plasma cells provides a unique clonotypic marker. Although clonotypic MM cells have been found in the circulation, their number has been controversial. Our objective was to provide direct evidence, using single-cell assays, for the frequency of clonotypic cells in blood of 18 MM patients, and to confirm their identity as B cells. The clonotypic Ig heavy-chain (IgH) VDJ was determined from single plasma cells using consensus reverse transcriptase-polymerase chain reaction (RT-PCR), subcloning, and sequencing. For all patients, using patient-specific primers, clonotypic transcripts were amplified from 10 or more individual plasma cells. Using in situ RT-PCR, for all patients greater than 80% of plasma cells were found to be clonotypic. Three separate methods, RT-PCR, single-cell RT-PCR, and in situ RT-PCR, were used to analyze clonotypic cells in peripheral blood mononuclear cells (PBMC) from MM patients. Sequencing of the IgH transcripts expressed by individual cells obtained by limiting dilution of freshly isolated PBMC from a MM patient showed that all B cells expressed an identical CDR3. This intraclonal homogeneity indicates an escape from antigenic-selection, characteristic of malignant B cells. For this patient, the frequency of clonotypic PBMC, about 25%, was comparable to the number of PBMC B cells (34%). Because the PBMC included less than 1% plasma cells, virtually all clonotypic PBMC must be B cells. Using single-cell RT-PCR, clonotypic IgH transcripts were identified in individual sorted B cells from blood. To accurately quantify the number of clonotypic B cells, sorted B cells derived from 18 MM patients (36 samples) and 18 healthy donors (53 samples) were analyzed using in situ RT-PCR with patient-specific primers. Clonotypic transcripts were not detectable among normal B cells. For the 18 MM patients, a mean of 66% ± 4% (SE) of blood B cells were clonotypic (range, 9% to 95%), with mean absolute number of 0.15 ± .02 × 109/L blood. Over time in individual patients, conventional chemotherapy transiently decreased circulating clonotypic B cells. Their numbers were increased in granulocyte colony-stimulating factor (G-CSF)– mobilized blood of one patient. However, clonotypic B cells of a one patient became undetectable after allogeneic transplant, correlating with complete remission. Although contributions to MM spread and progression is likely, their malignant status and impact has yet to be clarified. Their high frequency in the blood, and their resistence to conventional chemotherapy suggests that the number of circulating clonotypic cells should be clinically monitored, and that therapeutic targeting of these B cells may benefit myeloma patients. © 1998 by The American Society of Hematology.