gebhart/patrepeval huggingface dataset:
Improved algorithms for synchronizing computer network clocks (1995)

The Network Time Protocol (NTP) is widely deployed in the Internet to synchronize computer clocks to each other and to international standards via telephone modem, radio and satellite. The protocols and algorithms have evolved over more than a decade to produce the present NTP Version 3 specification and implementations. Most of the estimated deployment of 100000 NTP servers and clients enjoy synchronization to within a few tens of milliseconds in the Internet of today. This paper describes specific improvements developed for NTP Version 3 which have resulted in increased accuracy, stability and reliability in both local-area and wide-area networks. These include engineered refinements of several algorithms used to measure time differences between a local clock and a number of peer clocks in the network, as well as to select the best subset from among an ensemble of peer clocks and combine their differences to produce a local dock accuracy better than any in the ensemble. This paper also describes engineered refinements of the algorithms used to adjust the time and frequency of the local clock, which functions as a disciplined oscillator. The refinements provide automatic adjustment of algorithm parameters in response to prevailing network conditions, in order to minimize network traffic between clients and busy servers while maintaining the best accuracy. Finally, this paper describes certain enhancements to the Unix operating system kernel software in order to realize submillisecond accuracies with fast workstations and networks.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Small Molecule ErbB Inhibitors Decrease Proliferative Signaling and Promote Apoptosis in Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia (2013)

The presence of the Philadelphia chromosome in patients with acute lymphoblastic leukemia (Ph(+)ALL) is a negative prognostic indicator. Tyrosine kinase inhibitors (TKI) that target BCR/ABL, such as imatinib, have improved treatment of Ph(+)ALL and are generally incorporated into induction regimens. This approach has improved clinical responses, but molecular remissions are seen in less than 50% of patients leaving few treatment options in the event of relapse. Thus, identification of additional targets for therapeutic intervention has potential to improve outcomes for Ph+ALL. The human epidermal growth factor receptor 2 (ErbB2) is expressed in ~30% of B-ALLs, and numerous small molecule inhibitors are available to prevent its activation. We analyzed a cohort of 129 ALL patient samples using reverse phase protein array (RPPA) with ErbB2 and phospho-ErbB2 antibodies and found that activity of ErbB2 was elevated in 56% of Ph(+)ALL as compared to just 4.8% of Ph(-)ALL. In two human Ph+ALL cell lines, inhibition of ErbB kinase activity with canertinib resulted in a dose-dependent decrease in the phosphorylation of an ErbB kinase signaling target p70S6-kinase T389 (by 60% in Z119 and 39% in Z181 cells at 3 µM). Downstream, phosphorylation of S6-kinase was also diminished in both cell lines in a dose-dependent manner (by 91% in both cell lines at 3 µM). Canertinib treatment increased expression of the pro-apoptotic protein Bim by as much as 144% in Z119 cells and 49% in Z181 cells, and further produced caspase-3 activation and consequent apoptotic cell death. Both canertinib and the FDA-approved ErbB1/2-directed TKI lapatinib abrogated proliferation and increased sensitivity to BCR/ABL-directed TKIs at clinically relevant doses. Our results suggest that ErbB signaling is an additional molecular target in Ph(+)ALL and encourage the development of clinical strategies combining ErbB and BCR/ABL kinase inhibitors for this subset of ALL patients.
Benchmarking Various Green Fluorescent Protein Variants in Bacillus subtilis, Streptococcus pneumoniae, and Lactococcus lactis for Live Cell Imaging (2013)

Green fluorescent protein (GFP) offers efficient ways of visualizing promoter activity and protein localization in vivo, and many different variants are currently available to study bacterial cell biology. Which of these variants is best suited for a certain bacterial strain, goal, or experimental condition is not clear. Here, we have designed and constructed two "superfolder" GFPs with codon adaptation specifically for Bacillus subtilis and Streptococcus pneumoniae and have benchmarked them against five other previously available variants of GFP in B. subtilis, S. pneumoniae, and Lactococcus lactis, using promoter-gfp fusions. Surprisingly, the best-performing GFP under our experimental conditions in B. subtilis was the one codon optimized for S. pneumoniae and vice versa. The data and tools described in this study will be useful for cell biology studies in low-GC-rich Gram-positive bacteria.
Linear Viscoelasticity of Disordered Polystyrene−Polyisoprene Block Copolymer Based Layered-Silicate Nanocomposites (2000)

The melt-state linear viscoelastic properties for a series of intercalated nanocomposites are examined. The nanocomposites are based on a short disordered polystyrene−polyisoprene diblock copolymer and varying amounts of dimethyldioctadecylammonium modified montmorillonite. The linear dynamic oscillatory moduli and the stress relaxation moduli are in quantitative agreement and suggest that at short times the relaxation of the nanocomposites is essentially unaffected by the presence of the layered-silicate. However, at long times (or equivalently low frequency), the hybrids exhibit dramatically altered viscoelastic behavior. Hybrids with silicate loadings in excess of 6.7 wt % exhibit pseudo-solidlike behavior, similar to that observed in previous studies of exfoliated end-tethered nanocomposites. On the basis of simple phenomenological arguments, the long time behavior is attributed to the presence of anisotropic stacks of silicate sheets randomly oriented and forming a percolated network structure that is incapable of relaxing completely. These arguments are further supported by the ability of large-amplitude oscillatory shear to orient these nanocomposites and to increase their liquidlike character.
Potential patient benefit of a subcutaneous formulation of tocilizumab for the treatment of rheumatoid arthritis: a critical review (2014)

Treatment of rheumatoid arthritis (RA) was revolutionized during the last decade with the development of new biologic disease-modifying anti-rheumatic drugs (DMARDs) enabling the targeting of immune cells and cytokines other than tumor necrosis factor (TNF). Subcutaneous formulations of the newer biologic DMARDs facilitate not only patients' emancipation from the hospital, but reduce both societal and medical costs. Intravenous tocilizumab (TCZ) in RA has an efficacy and safety profile similar to anti-TNF in both the short and long-term. However, TCZ can be administered in monotherapy without loss of efficacy when patients do not tolerate methotrexate or synthetic DMARDs. TCZ is consistently found superior to methotrexate and possibly superior to adalimumab in monotherapy in randomized controlled trials. Subcutaneous administration of TCZ is as effective and safe as its intravenous administration in RA patients during the first year of treatment. Similar to intravenous TCZ, patients' weight and possibly previous use of anti-TNF influence the efficacy of subcutaneous TCZ. Additionally, combination with synthetic DMARDs seems to expose RA patients to more adverse events independently of its administration route. Pharmacokinetics of different administration routes could potentially lead to differences in efficacy, adverse events, and auto-immunogenicity. The concentration of free TCZ before new TCZ dose (C trough) is higher in the subcutaneous route, while the maximal concentration of free TCZ is higher in the intravenous route. The subcutaneous dosages of TCZ 162 mg every week, and every 2 weeks in RA patients with low body weight (<60 kg) work well. Nevertheless, dosage and intervals of subcutaneous TCZ administration could be adjusted during the course of treatment since 80% of non-Japanese RA patients with usually higher body weight achieved similar efficacy with the low TCZ dosage in combination with a synthetic DMARD. Patients want effective, easy-to-administer therapy with sustained prolonged efficacy without the need of polypharmacy and with minimal to no side effects. Subcutaneous TCZ in RA patients in monotherapy seems to live up to patients' expectations.
Two simple methods for detecting acrosome‐reacted human sperm (1986)

Abstract We describe two methods for detecting acrosome reactions of human sperm at the light microscopic level. The techniques include the use of a supravital stain to detect dead sperm in order to differentiate between “physiological” and “degenerative” acrosome reactions. Sperm are incubated with the supravital stain Hoechst 33258 (a fluorescent DNA‐binding dye with limited membrane permeability), washed, suspended in 95% ethanol for fixation and permeabilization, and dried onto slides. The sperm are then labeled either by indirect immunofluorescence using rabbit anti‐human sperm antiserum or with fluoresceinated Pisum sativum agglutinin (PSA). Both probes intensely label the acrosomal region of acrosome‐intact sperm. Electron microscopy revealed the major site of PSA binding to be the acrosomal contents. Acrosome‐reacted sperm have diminished acrosomal labeling by both probes; sperm with nuclei labeled by Hoechst stain are considered nonviable, and are excluded from the assay. Both assays are rapid, give similar results, and detect an increase in acrosome reactions following exposure to the ionophore A23187.
CD44 Mediated Nonviral Gene Delivery into Human Embryonic Stem Cells via Hyaluronic-Acid-Coated Nanoparticles (2016)

Gene delivery is an important tool to study and manipulate human pluripotent stem cells for regenerative medicine purposes. Yet current methods of transient gene delivery to stem cells are still inefficient. Through the combination of biologically based concepts and material design, we aim to develop new methods to enhance the efficiency of gene delivery to stem cells. Specifically, we use poly(γ-4-(((2-(piperidin-1-yl)ethyl)amino)methyl)benzyl-l-glutamate) (PVBLG-8), a membrane-active helical, cationic polypeptide, to condense plasmid DNA to form stable nanocomplexes, which are further coated with hyaluronic acid (HA). HA not only shields the positive charges of PVBLG-8 to reduce toxicity, but also acts as a targeting moiety for cell surface receptor CD44, which binds HA and facilitates the internalization of the nanocomplexes. Upon entering cells, HA is degraded by hyaluronidase in endosomes and PVBLG-8 is exposed, facilitating the endosomal escape of DNA/polypeptide complex. Our studies show that the coating of HA significantly increases gene transfection efficiency of DNA/PVBLG-8 nanocomplexes from about 28 to 36% with largely reduced toxicity.
Thermal modeling of hybrid microelectronics (2003)

An outline is presented of a computer thermal analysis model that inputs information for existing computer-aided design (CAD) layout files. This model assumes conductive heat flow to determine the difference in temperature from the junction-to-case for multiple heat sources and uses this information to create a CAD-compatible drawing of the isotherms. The development and input/output of the model are discussed. The model is verified by using experimental data obtained from hybrids built-up with thermal test chips.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Polysaccharide capsule-mediated resistance to opsonophagocytosis in Klebsiella pneumoniae (1994)

The polysaccharide capsule of Klebsiella pneumoniae is an important virulence factor that confers resistance to phagocytosis. The treatment of encapsulated bacteria with salicylate to inhibit capsule expression was found to enhance the phagocytosis of encapsulated bacteria by human neutrophils only in the presence of cell surface-specific antibodies. Both type-specific rabbit antisera and anticapsular human hyperimmune globulin were employed as opsonins. Salicylate significantly enhanced phagocytosis with homologous, but not heterologous, whole-cell antisera. Antisera, diluted 1:40, no longer opsonized fully encapsulated bacteria but promoted the uptake of multiple salicylate-treated bacteria in > 90% of neutrophils. Salicylate (0.25 to 1.0 mM) also enhanced opsonization with globulin against homologous bacteria. Higher salicylate levels (1 to 2.5 mM) enhanced the opsonization of heterologous serotypes with human globulin. The nature of antibody attachment to encapsulated bacteria was determined by immunofluorescence. Even after the addition of purified capsular polysaccharide to prevent phagocytosis, K-specific antibodies attached in large amounts to bacteria. K-specific antibodies reacted with antigens throughout the capsule and showed a predilection for a denser inner layer of the capsule, indicating that many of the K-specific antibodies may be masked underneath the capsule surface. K-specific antibodies can also be rendered nonfunctional by soluble, cell-free capsular antigen. In culture, large quantities of soluble capsular polysaccharide extrude from bacteria after overnight growth. The reduction in capsule expression caused by salicylate largely affected the soluble, cell-free fraction. Purified capsular polysaccharide was shown to retard the opsonophagocytosis of salicylate-treated bacteria in a concentration-dependent manner. However, extensive washing of encapsulated bacteria to remove loosely attached capsular material did not significantly enhance opsonophagocytosis. In conclusion, cell-free capsule and cell-associated capsule are antiphagocytic; both act to neutralize K-specific antibodies by binding or concealment. Salicylate-mediated inhibition of capsule expression, particularly of the cell-free fraction, improved K-specific opsonization dramatically.
Alternative splicing of the human c-myb gene. (1990)

Two cDNA clones of the human c-myb gene have been isolated from a CCRF-CEM leukemia cell cDNA library and sequenced in their entirety. These sequences, when compared with those previously reported for the human c-myb gene, reveal an alternative splicing process that generates at least four forms of the c-myb message. Three of these forms co-migrate on Northern blots and are co-expressed in several human hematopoietic cell types. Data on sequence comparisons with mouse and chicken homologues of c-myb coupled with oligonucleotide hybridization to genomic clones of the human c-myb gene indicate that this alternative splicing process utilizes three closely spaced splice donor sites and two unique exons present between viral defined exons 5 and 6. In one clone, the alternative splicing would generate a predicted myb protein with a three amino acid deletion in the region involved in transcription activation. In the other clone, incorporation of a new exon leads to introduction of a translation stop codon leading to loss of the entire carboxy terminus of the protein. This includes loss of a portion of the region involved in transcription activation as well as a separate highly conserved domain. The effect of these changes on protein function is currently unknown.
An Update on Non-clathrin-coated Endocytosis (1997)

Recent evidence has proved that in addition to the well-documented clathrin-mediated endocytic route (vesicles of 100-150 nm), at least three distinct non-clathrin-coated endocytic pathways function at the surface of mammalian cells. Endocytosis via these pathways is initiated by caveolae (50-80 nm), macropinosomes (500-2000 nm) and micropinosomes (95-100 nm). The current state of knowledge about these non-clathrin coated endocytic routes is presented and evidence that endocytic routes other than via clathrin-coated vesicles are utilised by viruses is discussed. The recent advances in these areas have provided us with tools to investigate the entry of those viruses which appear to enter cells via endocytosis into non-clathrin-coated vesicles. Data indicate that these four endocytic pathways differ in the absence, presence and/or type of coat on the vesicles, the size of the vesicles, their sensitivity to a variety of inhibitors, and in the ligands endocytosed. A historical perspective of the discovery of these non-clathrin-coated endocytic pathways is provided and recent information is summarised and discussed. The entry of viruses via non-clathrin-coated pits is destined to be an exciting new area of viral-cell entry, as has been indicated recently by the finding that entry of simian virus type 40 into cells occurs via caveolae. Copyright 1997 by John Wiley & Sons, Ltd.
Update On Oral Lichen Planus: Etiopathogenesis and Management (1998)

Lichen planus (LP) is a relatively common disorder of the stratified squamous epithelia, which is, in many ways, an enigma. This paper is the consensus outcome of a workshop held in Switzerland in 1995, involving a selection of clinicians and scientists with an interest in the condition and its management. The oral (OLP) eruptions usually have a distinct clinical morphology and characteristic distribution, but OLP may also present a confusing array of patterns and forms, and other disorders may clinically simulate OLP. Lesions may affect other mucosae and/or skin. Lichen planus is probably of multifactorial origin, sometimes induced by drugs or dental materials, often idiopathic, and with an immunopathogenesis involving T-cells in particular. The etiopathogenesis appears to be complex, with interactions between and among genetic, environmental, and lifestyle factors, but much has now been clarified about the mechanisms involved, and interesting new associations, such as with liver disease, have emerged. The management of lichen planus is still not totally satisfactory, and there is as yet no definitive treatment, but there have been advances in the control of the condition. There is no curative treatment available; immunomodulation, however, can control the condition. Based on the observed increased risk of malignant development, OLP patients should be offered regular follow-up examination from two to four times annually and asked to report any changes in their lesions and/or symptoms. Follow-up may be particularly important in patients with atrophic/ulcerative/erosive affections of the tongue, the gingiva, or the buccal mucosa. Much more research is required into the genetic and environmental aspects of lichen planus, into the premalignant potential, and into the possible associations with chronic liver, and other disorders. More clinical studies are required into the possible efficacy of immunomodulatory drugs such as pentoxifylline and thalidomide.
Entropy: a new definition and its applications (1991)

Shannon's definition of entropy is critically examined and a new definition of classical entropy based on the exponential behavior of information gain is proposed along with its justification. The concept is extended to defining the global, local, and conditional entropy of a gray-level image. Based on these definitions four algorithms for object extraction are developed. One of these algorithms uses a Poisson distribution-based model of an ideal image. A concept of positional entropy giving any information regarding the location of an object in a scene is introduced.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Efficient Male and Female Germline Transmission of a Human Chromosomal Vector in Mice (2001)

A small accessory chromosome that was mitotically stable in human fibroblasts was transferred into the hprt(-) hamster cell line CH and developed as a human chromosomal vector (HCV) by the introduction of a selectable marker and the 3' end of an HPRT minigene preceded by a loxP sequence. This HCV is stably maintained in the hamster cell line. It consists mainly of alphoid sequences of human chromosome 20 and a fragment of human chromosome region 1p22, containing the tissue factor gene F3. The vector has an active centromere, and telomere sequences are lacking. By transfecting a plasmid containing the 5' end of HPRT and a Cre-encoding plasmid into the HCV(+) hamster cell line, the HPRT minigene was reconstituted by Cre-mediated recombination and expressed by the cells. The HCV was then transferred to male mouse R1-ES cells and it did segregate properly. Chimeras were generated containing the HCV as an independent chromosome in a proportion of the cells. Part of the male and female offspring of the chimeras did contain the HCV. The HCV(+) F1 animals harbored the extra chromosome in >80% of the cells. The HCV was present as an independent chromosome with an active centromere and the human F3 gene was expressed from the HCV in a human-tissue-specific manner. Both male and female F1 mice did transmit the HCV to F2 offspring as an independent chromosome with properties similar to the original vector. This modified small accessory chromosome, thus, shows the properties of a useful chromosomal vector: It segregates stably as an independent chromosome, sequences can be inserted in a controlled way and are expressed from the vector, and the HCV is transmitted through the male and female germline in mice.
Inhibiting farnesylation reverses the nuclear morphology defect in a HeLa cell model for Hutchinson-Gilford progeria syndrome (2005)

Hutchinson-Gilford progeria syndrome (HGPS) is a devastating premature aging disease resulting from a mutation in the LMNA gene, which encodes nuclear lamins A and C. Lamin A is synthesized as a precursor (prelamin A) with a C-terminal CaaX motif that undergoes farnesylation, endoproteolytic cleavage, and carboxylmethylation. Prelamin A is subsequently internally cleaved by the zinc metalloprotease Ste24 (Zmpste24) protease, which removes the 15 C-terminal amino acids, including the CaaX modifications, to yield mature lamin A. HGPS results from a dominant mutant form of prelamin A (progerin) that has an internal deletion of 50 aa near the C terminus that includes the Zmpste24 cleavage site and blocks removal of the CaaX-modified C terminus. Fibroblasts from HGPS patients have aberrant nuclei with irregular shapes, which we hypothesize result from the abnormal persistence of the farnesyl and/or carboxylmethyl CaaX modifications on progerin. If this hypothesis is correct, inhibition of CaaX modification by mutation or pharmacological treatment should alleviate the nuclear morphology defect. Consistent with our hypothesis, we find that expression in HeLa cells of GFP-progerin or an uncleavable form of prelamin A with a Zmpste24 cleavage site mutation induces the formation of abnormal nuclei similar to those in HGPS fibroblasts. Strikingly, inhibition of farnesylation pharmacologically with the farnesyl transferase inhibitor rac-R115777 or mutationally by alteration of the CaaX motif dramatically reverses the abnormal nuclear morphology. These results suggest that farnesyl transferase inhibitors represent a possible therapeutic option for individuals with HGPS and/or other laminopathies due to Zmpste24 processing defects.
Probabilistic load-dependent cascading failure with limited component interactions (2004)

We generalize an analytically solvable probabilistic model of cascading failure in which failing components interact with other components by increasing their load and hence their chance of failure. In the generalized model, instead of a failing component increasing the load of all components, it increases the load of a random sample of the components. The size of the sample describes the extent of component interactions within the system. The generalized model is approximated by a saturating branching process and this leads to a criticality condition for cascading failure propagation that depends on the size of the sample. The criticality condition shows how the extent of component interactions controls the proximity to catastrophic cascading failure. Implications for the complexity of power transmission system design to avoid cascading blackouts are briefly discussed.