gebhart/patrepeval huggingface dataset:
Enhanced Phosphoinositide 3-Kinase δ Activity Is a Frequent Event in Systemic Lupus Erythematosus That Confers Resistance to Activation-Induced T Cell Death (2011)

Systemic lupus erythematosus (SLE) is a human chronic inflammatory disease caused by the action of autoreactive T and B cells. Class I phosphoinositide-3-kinases (PI3K) are enzymes that trigger formation of 3-poly-phosphoinositides that induce cell survival. Enhanced PI3K activation is a frequent event in human cancer. Nonetheless, in a genetic model with enhanced activation of class I(A) PI3K in T cells, mice show a greater tumor index but die of a lupus-like disease. In this study, we studied the potential PI3K involvement in human SLE. The PI3K pathway was frequently activated in SLE patient PBMC and T cells (∼70% of cases), more markedly in active disease phases. We examined the mechanism for PI3K pathway activation and found enhanced activation of PI3Kδ in SLE peripheral blood T cells. The magnitude of PI3K pathway activation in patients paralleled activated/memory T cell accumulation. We examined potential tolerance mechanisms affected by increased PI3K activity; SLE patients showed reduced activation-induced cell death of activated/memory T cells. Moreover, the defective activation-induced cell death in SLE T cells was corrected after reduction of PI3Kδ activity, suggesting that PI3Kδ contributes to induction of enhanced SLE memory T cell survival. These observations point to PI3Kδ as a target of clinical interest for SLE.
Probabilistic reliable dissemination in large-scale systems (2003)

The growth of the Internet raises new challenges for the design of distributed systems and applications. In the context of group communication protocols, gossip-based schemes have attracted interest as they are scalable, easy to deploy, and resilient to network and process failures. However, traditional gossip-based protocols have two major drawbacks: 1) they rely on each peer having knowledge of the global membership; and 2) being oblivious to the network topology, they can impose a high load on network links when applied to wide-area settings. In this paper, we provide a theoretical analysis of gossip-based protocols which relates their reliability to key system parameters (the system size, failure rates, and number of gossip targets). The results provide guidelines for the design of practical protocols. In particular, they show how reliability can be maintained while alleviating drawback by: 1) providing each peer with only a small subset of the total membership information and drawback; and 2) organizing members into a hierarchical structure that reflects their proximity according to some network-related metric. We validate the analytical results by simulations and verify that the hierarchical gossip protocol considerably reduces the load on the network compared to the original, non-hierarchical protocol.
A Randomized, Placebo-Controlled Multicenter Study of the Efficacy and Safety of Terazosin in the Treatment of Benign Prostatic Hyperplasia (1992)

The clinical manifestations of benign prostatic hyperplasia (BPH) are related primarily to bladder outlet obstruction resulting from enlargement of the prostate gland. Transurethral prostatectomy is the most common treatment currently offered for BPH in the United States. The primary objective of the present randomized placebo controlled multicenter study was to determine the efficacy and safety of terazosin, a selective long-acting alpha 1-blocker, for the treatment of symptomatic BPH. A total of 285 men with symptomatic BPH was randomly assigned in equal proportions to receive placebo, or 2, 5 or 10 mg. terazosin administered once daily. Of the patients 237 completed the 4-week single-blind placebo lead-in and 12-week double-blind treatment periods. The primary outcome parameters were changes in peak and mean urinary flow rates, and changes in the Boyarsky symptom scores. All terazosin treatment groups exhibited significantly greater decreases in total Boyarsky symptom score than the placebo group. The 10 mg. terazosin group exhibited significantly greater increases in peak and mean urinary flow rates than the placebo group. The improvements in symptom scores and urinary flow rates did not reach a plateau within the dose range evaluated, suggesting that further efficacy may be achieved with doses of terazosin exceeding 10 mg. This study unequivocally demonstrates the safety and efficacy of terazosin for the treatment of BPH. Selective alpha 1-blockade is likely to gain widespread acceptance for the treatment of BPH due to its safety and efficacy.
Atrial tissue Doppler imaging for prediction of new-onset atrial fibrillation (2008)

A prolonged PA-TDI interval may predict the development of new-onset AF. This measure may be used to identify patients at risk in future strategies to prevent the development or complications of AF.
DNA-directed alkylating agents. 3. Structure-activity relationships for acridine-linked aniline mustards: consequences of varying the length of the linker chain (1990)

Four series of acridine-linked aniline mustards have been prepared and evaluated for in vitro cytotoxicity, in vivo antitumor activity, and DNA cross-linking ability. The anilines were attached to the DNA-intercalating acridine chromophores by link groups (-O-, -CH2-, -S-, and -SO2-) of widely varying electronic properties, providing four series of widely differing mustard reactivity where the alkyl chain linking the acridine and mustard moieties was varied from two to five carbons. Relationships were sought between chain length and biological properties. Within each series, increasing the chain length did not alter the reactivity of the alkylating moiety but did appear to position it differently on the DNA, since cross-linking ability (measured by agarose gel assay) altered with chain length, being maximal with the C4 analogue. The in vivo antitumor activities of the compounds depended to some extent on the reactivity of the mustard, with the least reactive SO2 compounds being inactive. However, DNA-targeting did appear to allow the use of less reactive mustards, since the S-linked acridine mustards showed significant activity whereas the parent S-mustard did not. Within each active series, the most active compound was the C4 homologue, suggesting some relationship between activity and extent of DNA alkylation.
Identification of unique mechanisms for triterpene biosynthesis in Botryococcus braunii (2011)

Botryococcene biosynthesis is thought to resemble that of squalene, a metabolite essential for sterol metabolism in all eukaryotes. Squalene arises from an initial condensation of two molecules of farnesyl diphosphate (FPP) to form presqualene diphosphate (PSPP), which then undergoes a reductive rearrangement to form squalene. In principle, botryococcene could arise from an alternative rearrangement of the presqualene intermediate. Because of these proposed similarities, we predicted that a botryococcene synthase would resemble squalene synthase and hence isolated squalene synthase-like genes from Botryococcus braunii race B. While B. braunii does harbor at least one typical squalene synthase, none of the other three squalene synthase-like (SSL) genes encodes for botryococcene biosynthesis directly. SSL-1 catalyzes the biosynthesis of PSPP and SSL-2 the biosynthesis of bisfarnesyl ether, while SSL-3 does not appear able to directly utilize FPP as a substrate. However, when combinations of the synthase-like enzymes were mixed together, in vivo and in vitro, robust botryococcene (SSL-1+SSL-3) or squalene biosynthesis (SSL1+SSL-2) was observed. These findings were unexpected because squalene synthase, an ancient and likely progenitor to the other Botryococcus triterpene synthases, catalyzes a two-step reaction within a single enzyme unit without intermediate release, yet in B. braunii, these activities appear to have separated and evolved interdependently for specialized triterpene oil production greater than 500 MYA. Coexpression of the SSL-1 and SSL-3 genes in different configurations, as independent genes, as gene fusions, or targeted to intracellular membranes, also demonstrate the potential for engineering even greater efficiencies of botryococcene biosynthesis.
Machine transliteration (1997)

It is challenging to translate names and technical terms across languages with different alphabets and sound inventories. These items are commonly transliterated, i.e., replaced with approximate phonetic equivalents. For example, computer in English comes out as ~ i/l:::'=--~--(konpyuutaa) in Japanese. Translating such items from Japanese back to English is even more challenging, and of practical interest, as transliterated items make up the bulk of text phrases not found in bilingual dictionaries. We describe and evaluate a method for performing backwards transliterations by machine. This method uses a generative model, incorporating several distinct stages in the transliteration process. 1
Noninvasive Detection of Microsatellite Instability and High Tumor Mutation Burden in Cancer Patients Treated with PD-1 Blockade (2019)

These analyses demonstrate the feasibility of noninvasive pan-cancer screening and monitoring of patients who exhibit MSI or TMB-High and have a high likelihood of responding to immune checkpoint blockade.<i>See related commentary by Wang and Ajani, p. 6887</i>.
Using the quantum capacitance in graphene to enable varactors for passive wireless sensing applications (2011)

A wireless sensor concept based upon the quantum capacitance effect in graphene is described. By utilizing thin gate dielectrics (EOT <; 2 nm), the capacitance in a metal-insulator-graphene structure varies with charge concentration through the quantum capacitance effect. The high capacitance per unit area allows orders of magnitude improvement in scalability compared to MEMS-based sensors, while the high mobility in graphene allows high quality factors, Q, to be obtained. When operated away from the Dirac point, simulations using realistic structural and transport parameters predict capacitance tuning ratios of >; 4 and Q values >; 30 at 1 GHz. When operated at the Dirac point, the capacitance shows a strong temperature sensitivity, suggesting potential applications as a wireless temperature sensor.
Rational Design of Cytophilic and Cytophobic Polyelectrolyte Multilayer Thin Films (2002)

Nanostructured polyelectrolyte multilayer thin films electrostatically assembled alternately from such polymers as poly(allylamine hydrochloride) (PAH) and poly(acrylic acid) (PAA) were investigated for their in vitro cell interactions. Not surprisingly, NR6WT cells, a highly adhesive murine fibroblast cell line, attached to many different multilayer combinations tested. However, PAH/PAA multilayers constructed at pH deposition conditions of 2.0/2.0 were completely bioinert. Analogous cell interactions were observed with PAH/poly(methacrylic acid) (PAH/PMA), PAH/sulfonated poly(styrene) (PAH/SPS), and poly(diallyldimethylammonium chloride)/SPS (PDAC/SPS) systems, thereby suggesting a general trend in the fibroblasts' response to multilayers. Specifically, highly ionically stitched films attracted cells, whereas weakly ionically cross-linked multilayers, which swell substantially in physiological conditions to present richly hydrated surfaces, resisted fibroblast attachment. Thus, by manipulating the multilayer pH or ionic strength assembly conditions or both, which in turn dictate the molecular architecture of the thin films, one may powerfully direct a single multilayer combination to be either cell adhesive or cell resistant.
httperf—a tool for measuring web server performance (1998)

This paper describes httperf, a tool for measuring web server performance. It provides a flexible facility for generating various HTTP workloads and for measuring server performance. The focus of httperf is not on implementing one particular benchmark but on providing a robust, high-performance tool that facilitates the construction of both micro- and macro-level benchmarks. The three distinguishing characteristics of httperf are its robustness, which includes the ability to generate and sustain server overload, support for the HTTP/1.1 protocol, and its extensibility to new workload generators and performance measurements. In addition to reporting on the design and implementation of httperf this paper also discusses some of the experiences and insights gained while realizing this tool.
Targeting hyperproliferative disorders with cyclin dependent kinase inhibitors (2000)

Deregulated cell proliferation is associated with a variety of diseases including dysplasias and metaplasias of different tissues, psoriasis, atherosclerosis, restenosis after angioplastic surgery, and cancer [1-3]. Until recently, treatments for hyperproliferative disorders have revolved around chemical agents that kill actively dividing cells [4]. These agents include drugs that block DNA synthesis, such as DNA alkylators, topoisomerase, polymerase and nucleotide biosynthesis inhibitors. In addition, microtubule depolymerising and stabilising compounds have had widespread use as agents that interfere with spindle function essential for chromosome segregation and the process of cell division. Over the last seven years, understanding the mechanism regulating entry and exit from the cell cycle has led to the identification of signal transduction, transcriptional and cell cycle regulatory pathways orchestrating cell proliferation. Abnormalities in these regulatory mechanisms have been implicated in a variety of hyperproliferative disorders, prompting the development of cyclindependent kinase (CDK) inhibitors as therapeutic agents [5-9]. Unlike drugs that are meant to kill actively dividing cells, CDK inhibitors can be used to re-establish order in the biochemical mechanisms governing a cell’s decision to grow and divide - a departure from the traditional chemotherapeutic approach to the treatment of hyperproliferative disorders.
Comparison of fluconazole and amphotericin B for prevention and treatment of experimental Candida endocarditis (1991)

Fluconazole and amphotericin B were compared in the prophylaxis and treatment of Candida albicans aortic endocarditis in a rabbit model. In the prophylaxis study, catheterized rabbits received, prior to intravenous (i.v.) challenge with C. albicans (2 x 10(7) blastospores), either no therapy, single-dose i.v. amphotericin B (1 mg/kg of body weight), single-dose fluconazole (50 mg/kg or 100 mg/kg i.v. or intraperitoneally [i.p.]), or fluconazole (50 mg/kg or 100 mg/kg i.v. or i.p.) with a second dose 24 h after inoculation. A single dose of amphotericin B was significantly more effective than either the one- or two-dose regimens of fluconazole at both 50 mg/kg (P less than 0.001 and P less than 0.03, respectively) and 100 mg/kg (P less than 0.01 and P less than 0.001, respectively) in the prevention of C. albicans endocarditis. In parallel treatment studies of established C. albicans endocarditis, i.v. amphotericin B (1 mg/kg) or i.p. fluconazole (50 mg/kg) was begun 24 or 60 h postinfection and continued daily for 9 or 12 days. At these dose regimens, amphotericin B was consistently more effective than fluconazole in reducing fungal vegetation densities, regardless of the timing of initiation of therapy. We also examined the efficacy of fluconazole at a daily dose of 100 mg/kg i.p. administered for 21 days in the treatment of established C. albicans endocarditis. When therapy was continued for 2 weeks or longer, fluconazole was more effective than no drug and approximately twice as effective as 12 days of amphotericin B in reducing intravegetation fungal densities. Our results suggest that amphotericin B is superior to fluconazole in both the prophylaxis and treatment of C. albicans endocarditis in the rabbit model. These findings may relate to the predominantly fungistatic activity of fluconazole against C. albicans in vitro.
lag-2 may encode a signaling ligand for the GLP-1 and LIN-12 receptors of C. elegans (1994)

The C. elegans lag-2 gene is required for several cell-cell interactions that rely on the receptors GLP-1 and LIN-12. In this paper, we report that lag-2 encodes a putative membrane protein with sequence similarity to Drosophila Delta, a proposed ligand for the Notch receptor. Furthermore, we show that the lag-2 promoter drives expression of a reporter protein in the signaling distal tip cell (DTC) of the DTC/germline interaction. By in situ hybridization, we have found that endogenous lag-2 mRNA is present in the DTC but not the germ line. One fusion protein, called LAG-2::beta-gal(intra), rescues a lag-2 null mutant and can be detected in both DTC and germ line. Taking these results together, we propose that lag-2 may encode a signaling ligand for GLP-1/LIN-12 and that the entire LAG-2 protein may be taken up into the receiving cell during induction by GLP-1 and lateral signaling by LIN-12.
Generation propagation, and targeting of human CD4+ helper/killer T cells induced by anti-CD3 monoclonal antibody plus recombinant IL-2. An efficient strategy for adoptive tumor immunotherapy (1992)

We developed a culture system for the rapid generation of CD4+ T cells that have both helper and killer functions. CD4+ T cells isolated from human PBL did not proliferate or develop significant cytotoxicity when treated with rIL-2 because of the lack of p75 IL-2R expression. However, culture of isolated CD4+ T cells with immobilized anti-CD3 mAb plus rIL-2 resulted in a marked proliferation (500-fold increase in 14 days) of CD4+ T cells. The proliferating CD4+ T cells produced IL-2 (92 U/ml) and showed strong cytotoxicity against OKT3 hybridoma cells and Daudi, K562, and U937 tumor cells in an anti-CD3 mAb-dependent manner. The CD4+ T cells contained significant amounts of cytolytic granule-related proteins such as serine esterase and perforin. Activated CD4+ helper/killer cells can be generated from both healthy donors and tumor patients and can be propagated in vitro for 14 to 35 days by biweekly restimulation with immobilized anti-CD3 mAb plus rIL-2. This culture yielded about 20,000-fold increase in cell number after a 21-day culture. Bispecific antibody containing anti-CD3 and anti-glioma Fab components enhanced the cytotoxicity of activated CD4+ helper/killer cells against IMR32 glioma cells. Moreover, the activated CD4+ helper/killer cells showed both helper and antitumor activity in vivo and prevented growth of anti-CD3 hybridoma cells in nude mice whether or not IL-2 was administered. These results indicate that anti-CD3 mAb plus IL-2-activated CD4+ helper/killer cells may provide an effective strategy for adoptive tumor immunotherapy of cancer.
Thermische Strukturisomerisierung der Additionsprodukte von HAl(iso‐C4H9)2 an 1,4‐Pentadiene (1975)

Abstract Die Additionsprodukte 1a und 2a von HAl(iso‐C 4 H 9 ) 2 an 1,4‐Pentadien unterliegen oberhalb 140°C der Isomerisierung, wobei 2‐Methylbutan nach Hydrolyse und 2‐Methyl‐l.4‐ butandiyldiacetet nach Oxidation und Acetolyse des Reaktionsgemisches entstehen. Auch die Hydroaluminierungsprodukte 1b ‐ 1d und 2b/3b von 2‐Methyl‐, 2,4‐Dimethyl‐ und 3,3‐ Dimethyl‐l,4‐pentadien sind in geringerem Umfang analogen Isomerisierungen zugänglich, wobei nach Hydrolyse 2,3‐Dimethyl‐, 2,2,3‐Trimethylbutan bzw. 2,3‐Dimethylpentan erhalten werden. Als Reaktionsmechanismus wird die intermediäre Bildung aluminiumorganischer 6‐Ring‐Heterocyclen (z. B. 4 ) und deren unter Strukturisomerisierung verlaufende Ringverengung zu 5‐Ring‐Heterocyclen (z. B. 5 ) vorgeschlagen.
Comparison of the induction of immunoglobulin M and G antibodies in mice with purified pneumococcal type 3 and meningococcal group C polysaccharides and their protein conjugates (1982)

The nature and kinetics of the serum antibody response to pneumococcal type 3 and meningococcal group C polysaccharides and their protein conjugates were studied in mice. Bovine serum albumin and diphtheria and tetanus toxoids were used as carrier proteins. The purified polysaccharides induced only immunoglobulin M (IgM) antibodies in thymus-bearing as well as congenic athymic (nude) mice. The polysaccharides covalently conjugated to proteins produced IgM and IgG antibodies in normal mice, but only IgM antibodies in nude mice. A second dose of the polysaccharide-protein conjugates resulted in a booster effect in the IgG response to the polysaccharides. Moreover, memory B-cells, generated after a primary injection with the polysaccharide-protein conjugates, could be triggered to the production of IgG antibodies after a second injection with the pure polysaccharides alone. These data indicate that the antibody response to the pure polysaccharides is thymus independent and that this response can be changed into a thymus-dependent response by covalent conjugation of the polysaccharide to a thymus-dependent protein.
In VivoProliferation of Postmitotic Cochlear Supporting Cells by Acute Ablation of the Retinoblastoma Protein in Neonatal Mice (2010)

Cochlear hair cells (HCs) are mechanosensory receptors that transduce sound into electrical signals. HC damage in nonmammalian vertebrates induces surrounding supporting cells (SCs) to divide, transdifferentiate and replace lost HCs; however, such spontaneous HC regeneration does not occur in the mammalian cochlea. Here, we acutely ablate the retinoblastoma protein (Rb), a crucial cell cycle regulator, in two subtypes of postmitotic SCs (pillar and Deiters' cells) using an inducible Cre line, Prox1-CreER(T2). Inactivation of Rb in these SCs results in cell cycle reentry of both pillar and Deiters' cells, and completion of cell division with an increase in cell number of pillar cells. Interestingly, nuclei of Rb(-/-) mitotic pillar and Deiters' cells migrate toward the HC layer and divide near the epithelial surface in a manner similar to the SCs in the regenerating avian auditory epithelium. In contrast to postmitotic Rb(-/-) HCs which abort cell division, postmitotic Rb(-/-) pillar cells can proliferate, maintain their SC fate and survive for more than a week. However, no newly formed HCs are detected and SC death followed by HC loss occurs. Our studies accomplish a crucial step toward functional HC regeneration in the mammalian cochlea in vivo, demonstrating the critical role of Rb in maintaining quiescence of postmitotic pillar and Deiters' cells and highlighting the heterogeneity between these two cell types. Therefore, the combination of transient Rb inactivation and further manipulation of transcription factors (i.e., Atoh1 activation) in SCs may represent an effective therapeutic avenue for HC regeneration in the mammalian cochlea.
Interpreting Neural Network Judgments via Minimal, Stable, and Symbolic Corrections (2018)

We present a new algorithm to generate minimal, stable, and symbolic corrections to an input that will cause a neural network with ReLU activations to change its output. We argue that such a correction is a useful way to provide feedback to a user when the network's output is different from a desired output. Our algorithm generates such a correction by solving a series of linear constraint satisfaction problems. The technique is evaluated on three neural network models: one predicting whether an applicant will pay a mortgage, one predicting whether a first-order theorem can be proved efficiently by a solver using certain heuristics, and the final one judging whether a drawing is an accurate rendition of a canonical drawing of a cat.
Chemoenzymatic Asymmetric Total Synthesis of Phosphodiesterase Inhibitors:  Preparation of a Polycyclic Pyrazolo[3,4-d]pyrimidine from an Acylnitroso Diels−Alder Cycloadduct-Derived Aminocyclopentenol (2005)

[reaction: see text] Enzymatic resolution of Boc-protected 4-aminocyclopenten-1-ol 4c gave both enantiomers 5c and 6c in high ee. Boc removal and separate condensation with chloropyrazolopyrimidine 18 provided elaborated 1,4-aminocyclopentenol derivatives 20 and 26, respectively. Separate treatment of 20 and 26 with Pd(0) under basic conditions induced cyclization to unsaturated polycycles 22 and 27, which, upon catalytic hydrogenation, were transformed to new cyclopentane-containing pyrazolopyrimidines 24 and 28, analogues of recently described novel phosphodiesterase inhibitors.