gebhart/patrepeval huggingface dataset:
HAPLO: A Program Using the EM Algorithm to Estimate the Frequencies of Multi-site Haplotypes (1995)

Journal Article HAPLO: A Program Using the EM Algorithm to Estimate the Frequencies of Multi-site Haplotypes Get access M. E. Hawley, M. E. Hawley Department of Genetics, Yale University School of MedicineNew Haven, CT 06510-8005 Search for other works by this author on: Oxford Academic PubMed Google Scholar K. K. Kidd K. K. Kidd Department of Genetics, Yale University School of MedicineNew Haven, CT 06510-8005 Search for other works by this author on: Oxford Academic PubMed Google Scholar Journal of Heredity, Volume 86, Issue 5, September 1995, Pages 409–411, https://doi.org/10.1093/oxfordjournals.jhered.a111613 Published: 01 September 1995 Article history Received: 25 May 1994 Accepted: 02 May 1995 Published: 01 September 1995
Guided selection of human antibody light chains against TAG-72 using a phage display chain shuffling approach. (2007)

To enhance therapeutic potential of murine monoclonal antibody, humanization by CDR grafting is usually used to reduce immunogenic mouse residues. Most humanized antibodies still have mouse residues critical for antigen binding, but the mouse residues may evoke immune responses in humans. Previously, we constructed a new humanized version (AKA) of mouse CC49 antibody specific for tumor-associated glycoprotein, TAG-72. In this study, to select a completely human antibody light chain against TAG-72, guided selection strategy using phage display was used. The heavy chain variable region (VH) of AKA was used to guide the selection of a human TAG-72-specific light chain variable region (VL) from a human VL repertoire constructed from human PBL. Most of the selected VLs were identified to be originated from the members of the human germline VK1 family, whereas the VL of AKA is more homologous to the VK4 family. Competition binding assay of the selected Fabs with mouse CC49 suggested that the epitopes of the Fabs overlap with that of CC49. In addition, they showed better antigen-binding affinity compared to parental AKA. The selected human VLs may be used to guide the selection of human VHs to get completely human anti-TAG72 antibody.
Differential activation and inhibition of the multiple forms of cyclic nucleotide phosphodiesterase. (1975)

The brain as well as other mammalian tissues contains several different forms of cyclic nucleotide phosphodiesterase separable by polyacrylamide gel electrophoresis. Each tissue and each individual type of cell has its own distinctive pattern and ratio of these multiple forms of phosphodiesterase. The different forms have several distinguishing properties and characteristics, and their activities may be differentially regulated both acutely and chronically. The enzyme forms have different stabilities, kinetic properties, substrate specificities, and sensitivities to an endogenous activator and to several inhibitors of phosphodiesterase. The phosphodiesterase inhibitors studied not only inhibit the different forms of phosphodiesterase to different degrees but apparently do so by different mechanisms. Thus whereas theophylline, cyclic GMP, and low concentrations of papaverine inhibit the phosphodiesterases by competing with the substrate (cyclic AMP), trifluoperazine apparently inhibits phosphodiesterase by interfering with the phosphodiesterase activator. This confers a great deal of specificity to this drug, since only one form of phosphodiesterase is markedly activated by the activator. Chronically, a specific form of phosphodiesterase appears to be inducible. This induction is probably controlled by the intracellular cyclic AMP concentration. The phosphodiesterase activator also appears to be regulatable, the age of the animal being one of the factors controlling its activity. Finally, since different types of cells have different relative amounts of the phosphodiesterases and since these forms of the enzyme can be differentially inhibited by drugs, it may be possible to develop drugs which will selectively increase the cyclic AMP concentration in discrete cell types. Evidence that cyclic AMP is involved in certain disease states suggests further that by selectively altering the concentration of cyclic AMP in these cells, one might be able to alter the course of the disease.
Inactivated rabies virus vectored SARS-CoV-2 vaccine prevents disease in a Syrian hamster model (2021)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emergent coronavirus that has caused a worldwide pandemic. Although human disease is often asymptomatic, some develop severe illnesses such as pneumonia, respiratory failure, and death. There is an urgent need for a vaccine to prevent its rapid spread as asymptomatic infections accounting for up to 40% of transmission events. Here we further evaluated an inactivated rabies vectored SARS-CoV-2 S1 vaccine CORAVAX in a Syrian hamster model. CORAVAX adjuvanted with MPLA-AddaVax, a TRL4 agonist, induced high levels of neutralizing antibodies and generated a strong Th1-biased immune response. Vaccinated hamsters were protected from weight loss and viral replication in the lungs and nasal turbinates three days after challenge with SARS-CoV-2. CORAVAX also prevented lung disease, as indicated by the significant reduction in lung pathology. This study highlights CORAVAX as a safe, immunogenic, and efficacious vaccine that warrants further assessment in human trials.
Evaluation and PK/PD modeling of the dose regimen chronomodulation of Trastuzumab-MC-vc-PAB-MMAF (Tmab-vc-MMAF) in tumor bearing mouse models (2007)

C167 Background. The humanized monoclonal antibody trastuzumab, linked to the cytotoxic antimitotic agent Monomethylauristatin E Phenylalanine (MMAF), produces potent and selective antitumor activity in vivo against trastuzumab resistant HER2-positive breast cancer cell lines. Dose and dose-schedule optimization for antibody drug conjugates further improves the therapeutic index of potent toxins derived from combining the powerful antiproliferative activities of chemotherapeutic small molecules like MMAF with the targeting capabilities of antibodies like trastuzumab. The objective of this analysis was to determine the impact of dose-schedule of Tmab-vc-MMAF on tumor outcome and, secondarily, develop a pharmacokinetic/ pharmacodynamic (PK/PD) model that accurately captures Tmab-vc-MMAF antitumor activity across different dosing regimes.  Methods. Tmab-vc-MMAF antitumor activity from FO5 and BT474EEI tumor bearing mouse models were used for this analysis. The tumor efficacy study designs included single and multiple dose regimens of Tmab-vc-MMAF over a broad dose range (2.0-48 mg/kg). To evaluate the impact of dose-schedule on tumor outcome, total Tmab-vc-MMAF doses were fractionated into once weekly, once every 2 weeks, and once every 3 weeks regimens and tumor outcomes were compared based on equivalent drug exposure. Computed net tumor growth rates following single dose administration were used to determine the minimum activity dose (MAD) and compare Tmab-vc-MMAF antitumor activity in FO5 and BT474EEI tumor bearing mouse models. Mixed effects modeling of individual mouse tumor mass data with a fixed pharmacokinetic forcing function from separate studies was performed using the NONMEM program.  Results. Results from dose fractionation studies indicated that Tmab-vc-MMAF antitumor activity is dosing schedule independent. AUC/TSC (area under concentration-vs.-time curve/ tumoristatic concentration) was determined to be the key driver of Tmab-vc-MMAF antitumor activity, with total drug exposure being predictive of tumor killing. Estimates of the MAD were 3.6 mg/kg and 1.5 mg/kg for BT474EEI and FO5 tumor bearing mouse models, respectively. A population tumor growth-kill PK/PD model, with transit delay compartments representing delayed cell death manifestation in mechanical tumor mass measurement, was developed that accurately described the composite experimental data set. Median TSC’s, derived from the PK/PD model parameters, were 5.46 μg/mL and 6.80 μg/mL in BT474EEI and FO5 mouse models, respectively.  Conclusion. Tmab-vc-MMAF dose regimen chronomodulation studies indicated there is schedule flexibility in dosing Tmab-vc-MMAF for antitumor activity. AUC/TSC is the PK driver of Tmab-vc-MMAF antitumor activity. The mouse population tumor growth-kill PK/PD model provides useful information to support decision making in Tmab-vc-MMAF drug development.
Transgenic expression of human leukocyte antigen‐E attenuates GalKO.hCD46 porcine lung xenograft injury (2017)

We conclude human NK cell activation contributes significantly to GalTKO.hCD46 pig endothelial injury and lung inflammation and show that expression of HLA-E is associated with physiologically meaningful protection of GalTKO.hCD46 cells and organs exposed to human blood.
Fusion with E2A converts the Pbx1 homeodomain protein into a constitutive transcriptional activator in human leukemias carrying the t(1;19) translocation. (1994)

E2A-PBX1 is a chimeric gene formed by the t(1;19)(q23;p13.3) chromosomal translocation of pediatric pre-B-cell leukemia. The E2A-Pbx1 fusion protein contains sequences encoding the transactivation domain of E2A joined to a majority of the Pbx1 protein, which contains a novel homeodomain. Earlier, we found that expression of E2A-Pbx1 causes malignant transformation of NIH 3T3 fibroblasts and induces myeloid leukemia in mice. Here we demonstrate that the homeodomains encoded by PBX1, as well as by the highly related PBX2 and PBX3 genes, bind the DNA sequence ATCAATCAA. E2A-Pbx1 strongly activates transcription in vivo through this motif, while Pbx1 does not. This finding suggests that E2A-Pbx1 transforms cells by constitutively activating transcription of genes regulated by Pbx1 or by other members of the Pbx protein family.
The dawning of the autonomic computing era (2003)

This special issue of the IBM Systems Journal explores a broad set of ideas and approaches to autonomic computing—some first steps in what we see as a journey to create more self-managing computing systems. Autonomic computing represents a collection and integration of technologies that enable the creation of an information technology computing infrastructure for IBM's agenda for the next era of computing—e-business on demand. This paper presents an overview of IBM's autonomic computing initiative. It examines the genesis of autonomic computing, the industry and marketplace drivers, the fundamental characteristics of autonomic systems, a framework for how systems will evolve to become more self-managing, and the key role for open industry standards needed to support autonomic behavior in heterogeneous system environments. Technologies explored in each of the papers presented in this issue are introduced for the reader.
Human interleukin 7: molecular cloning and growth factor activity on human and murine B-lineage cells. (1989)

A cDNA encoding biologically active human interleukin 7 was isolated by hybridization with the homologous murine clone. Nucleotide sequence analysis indicated that this cDNA was capable of encoding a protein of 177 amino acids with a signal sequence of 25 amino acids and a calculated mass of 17.4 kDa for the mature protein. Recombinant human interleukin 7 stimulated the proliferation of murine pre-B cells and was active on cells harvested from human bone marrow that are enriched for B-lineage progenitor cells. Analysis of RNA by blot hybridization demonstrated the presence of two size classes of interleukin 7 mRNA in human splenic and thymic tissue.
Statistical Modeling of the Drug Load Distribution on Trastuzumab Emtansine (Kadcyla), a Lysine-Linked Antibody Drug Conjugate (2014)

Trastuzumab emtansine (Kadcyla) is a recently approved antibody-drug conjugate produced by attachment of the anti-tubulin drug, DM1, to lysine amines via the SMCC linker. The resulting product exhibits a drug load distribution from 0 to 8 drugs per antibody that can be quantified using mass spectrometry. Different statistical models were tested against the experimental data derived from samples produced during process characterization studies to determine best fit. The Poisson distribution gives the best correlation for samples manufactured using the target process conditions (yielding the target average drug to antibody ratio (DAR) of 3.5) as well as those produced under conditions that exceed the allowed manufacturing ranges and yield products with average DAR values that are significantly different from the target (i.e., ≤3.0 or ≥4.0). The Poisson distribution establishes a link between average DAR values and drug load distributions, implying that measurement and control of the former (i.e., via a simple UV spectrophotometric method) could be used to indirectly control the latter in trastuzumab emtansine.
Reciprocal-wedge transform for space-variant sensing (1995)

The reciprocal-wedge transform (RWT) is presented as an alternative to the log-polar transform which has been a popular model for space-variant sensing in computer vision. The RWT facilitates an anisotropic variable resolution. Unlike the log-polar, its variable resolution is predominantly in one dimension. Consequently, the RWT preserves linearity of lines and translations in the original image. In this paper, a concise matrix representation of the RWT is presented. Its properties in geometrical transformations and data reduction are described. A projective model for the transform and a potential hardware RWT camera design are also illustrated. As examples of initial applications, the RWT is used for finding road directions in navigation, and for recovering depth in motion stereo. Two types of motion stereo are presented, namely the longitudinal and lateral motion stereo. In all cases, the RWT images offer much reduced and adequate data owing to the variable resolution. Preliminary experimental results from test images of road-vehicle navigation and moving objects on a miniature assembly line are demonstrated.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Development of an Isotope Dilution Assay for Precise Determination of Insulin, C-peptide, and Proinsulin Levels in Non-diabetic and Type II Diabetic Individuals with Comparison to Immunoassay (1997)

We describe the application of a stable isotope dilution assay (IDA) to determine precise insulin, C-peptide, and proinsulin levels in blood by extraction from serum and quantitation by mass spectrometry using analogues of each target protein labeled with stable isotopes. Insulin and C-peptide levels were also determined by immunoassay, which gave consistently higher results than by IDA, the relative difference being larger at low concentrations. Insulin, C-peptide, and proinsulin levels were all shown by IDA to be higher in type II diabetics than in non-diabetics, with mean values rising from 22 (+/- 2) to 92 (+/- 8), 335 (+/- 11) to 821 (+/- 24), and 6 (+/- 1) to 37 (+/- 3) pM, respectively. Interestingly, the ratio between IDA and immunoassay values for insulin levels increased from 1.3 in non-diabetics to 1.7 in type II diabetics. The ratio between proinsulin and insulin levels by IDA increased from 0.24 in non-diabetics to 0.36 in type II diabetics, whereas the ratio between C-peptide and insulin levels by IDA decreased from 17.6 to 10.7. This disproportionate change in protein levels between different types of individuals has implications for the metabolism of insulin in the diabetics studied (type II) and suggests that C-peptide levels are not always a reliable guide as to pancreatic insulin secretion. In addition, levels of the 33-residue C-peptide (partially trimmed form) were shown to be less than 10% that of the fully trimmed 31-residue C-peptide levels, and we tested IDA in a clinical context by two post-pancreatic graft studies. IDA was shown to give direct, positive identification of the target protein with unrivaled accuracy, avoiding many of the problems associated with present methodology for protein determination.
Analysis of Interdomain Interactions of the Androgen Receptor (2011)

High-affinity binding of testosterone or dihydrotestosterone to the androgen receptor (AR) triggers the androgen-dependent AR NH2- and carboxyl-terminal (N/C) interaction between the AR NH2-terminal FXXLF motif and the activation function 2 (AF2) hydrophobic binding surface in the ligand-binding domain. The functional importance of the AR N/C interaction is supported by naturally occurring loss-of-function AR AF2 mutations where AR retains high-affinity androgen binding but is defective in AR FXXLF motif binding. Ligands with agonist activity in vivo such as testosterone, dihydrotestosterone, and the synthetic anabolic steroids induce the AR N/C interaction and increase AR transcriptional activity in part by slowing the dissociation rate of bound ligand and stabilizing AR against degradation. AR ligand-binding domain competitive antagonists inhibit the agonist-dependent AR N/C interaction. Although the human AR N/C interaction is important for transcriptional activity, it has an inhibitory effect on transcriptional activity from AF2 by competing for p160 coactivator LXXLL motif binding. The primate-specific AR coregulatory protein, melanoma antigen gene protein-A11 (MAGE-A11), modulates the AR N/C interaction through a direct interaction with the AR FXXLF motif. Inhibition of AF2 transcriptional activity by the AR N/C interaction is relieved by AR FXXLF motif binding to the F-box region of MAGE-11. Described here are methods to measure the androgen-dependent AR N/C interdomain interaction and the influence of transcriptional coregulators.
Characteristics of single-longitudinal-mode selection in short-coupled-cavity (SCC) injection lasers (1984)

Effective single-longitudinal-mode selection can be achieved in short-coupled-cavity (SCC) injection lasers consisting of a cleaved short-cavity laser (length <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">L</tex> , refractive index <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">n</tex> ) with a short external resonator (spacing d). The mode-selectivity is due to the combined advantages of large gain-rolloff for the adjacent modes in the short ( cavity, and resonator-loss-modulation in the coupled cavity. This I paper discusses the theoretical considerations and experimental studies for the SCC lasers. The results show that for good single-longitudinal-mode operation, the resonator-loss modulation period factor <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">m</tex> , given by the effective optical length ratio <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">nL/d</tex> , should be between approximately three and eight, with typical short-cavity laser length <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">L</tex> in the <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">40-100-\mu</tex> m range and external resonator spacing <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">d</tex> also in the <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">40-120- \mu</tex> m range, depending on the specific <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">L</tex> .
Biocatalytic Membrane Reactors: Applications In Biotechnology And The Pharmaceutical Industry (1998)

Introduction Part 1: General Principles 1. Membranes and Membrane Processes 2. Catalytic Membrane Reactors (CMRs) Part 2: Applications of Catalytic Membrane Reactors 3. Catalytic Membrane Reactors in Integrated Processes for Production of Bioactive Compounds 4. Catalytic Membrane Reactors for Production of Pure Optical Active Compounds 5. Catalytic Membrane Reactors for Retention and Recycling of Co-enzyme 6. Catalytic Membrane Reactors for Bioconversion of Low Water Solubility Substrates 7. Membranes and Membrane Reactors in Artificial Organs.
THE RELATIONSHIP OF SERUM IL-6 LEVELS TO ACUTE GRAFT-VERSUS-HOST DISEASE AND HEPATORENAL DISEASE AFTER HUMAN BONE MARROW TRANSPLANTATION (1992)

The potential involvement of cytokines in acute graft-versus-host disease led us to analyze interleukin-6 in serial serum sets from 22 allogeneic marrow recipients who developed either grade 3 or 4 GVHD (n = 10), grade 2 GVHD (n = 6), or grade 1 or no diagnosed GVHD (n = 6). A total of 279 serial serum samples taken three times weekly before day 35 were analyzed. Maximum IL-6 levels were greater than 40 U/ml (range, 40-1536 U/ml), 11-40 U/ml, and less than or equal to 10 U/ml for six, eleven, and five patients, respectively. Serum IL-6 peaks were temporally related to onset of GVHD, onset of a syndrome of hepatorenal dysfunction (HRD), or bilateral lung infiltration. Eight of ten patients who developed grade 3 or 4 GVHD overall had IL-6 maxima of greater than 10 U/ml an average of 1.5 +/- 1.8 days before the clinical onset. Fifteen of 17 patients with peak IL-6 levels greater than 10 U/ml developed symptoms of hepatic and renal dysfunction within three days of the peak, while none of five patients with less than or equal to 10 U/ml of Il-6 developed HRD. Regression analysis demonstrated a linkage between the log magnitudes of the serum IL-6 peaks and onset of either GVHD or HRD within three days (P = 0.001). Furthermore, IL-6 peaks tended to precede GVHD onset for the 10 patients whose GVHD onset and IL-6 peak were within three days of each other (P = 0.02). These results, confirmed by both specific bioassay and by IL-6 ELISA, support the idea that acute GVHD in humans involves a cytokine cascade that includes production of IL-6 in addition to the previously reported involvement of tumor necrosis factor alpha and interferon-gamma.
Dual inhibition of renin-angiotensin-aldosterone system and endothelin-1 in treatment of chronic kidney disease (2016)

Inhibition of the renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in treatment of chronic kidney diseases (CKD). However, reversal of the course of CKD or at least long-term stabilization of renal function are often difficult to achieve, and many patients still progress to end-stage renal disease. New treatments are needed to enhance protective actions of RAAS inhibitors (RAASis), such as angiotensin-converting enzyme (ACE) inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), and improve prognosis in CKD patients. Inhibition of endothelin (ET) system in combination with established RAASis may represent such an approach. There are complex interactions between both systems and similarities in their renal physiological and pathophysiological actions that provide theoretical rationale for combined inhibition. This view is supported by some experimental studies in models of both diabetic and nondiabetic CKD showing that a combination of RAASis with ET receptor antagonists (ERAs) ameliorate proteinuria, renal structural changes, and molecular markers of glomerulosclerosis, renal fibrosis, or inflammation more effectively than RAASis or ERAs alone. Practically all clinical studies exploring the effects of RAASis and ERAs combination in nephroprotection have thus far applied add-on designs, in which an ERA is added to baseline treatment with ACEIs or ARBs. These studies, conducted mostly in patients with diabetic nephropathy, have shown that ERAs effectively reduce residual proteinuria in patients with baseline RAASis treatment. Long-term studies are currently being conducted to determine whether promising antiproteinuric effects of the dual blockade will be translated in long-term nephroprotection with acceptable safety profile.