gebhart/patrepeval huggingface dataset:
Discovery and Characterization of 2,5-Substituted Benzoic Acid Dual Inhibitors of the Anti-apoptotic Mcl-1 and Bfl-1 Proteins (2020)

Anti-apoptotic Bcl-2 family proteins are overexpressed in a wide spectrum of cancers and have become well validated therapeutic targets. Cancer cells display survival dependence on individual or subsets of anti-apoptotic proteins that could be effectively targeted by multimodal inhibitors. We designed a 2,5-substituted benzoic acid scaffold that displayed equipotent binding to Mcl-1 and Bfl-1. Structure-based design was guided by several solved cocrystal structures with Mcl-1, leading to the development of compound <b>24</b>, which binds both Mcl-1 and Bfl-1 with <i>K</i><sub>i</sub> values of 100 nM and shows appreciable selectivity over Bcl-2/Bcl-xL. The selective binding profile of <b>24</b> was translated to on-target cellular activity in model lymphoma cell lines. These studies lay a foundation for developing more advanced dual Mcl-1/Bfl-1 inhibitors that have potential to provide greater single agent efficacy and broader coverage to combat resistance in several types of cancer than selective Mcl-1 inhibitors alone.
In Vitro Cultivation of the Syphilis Spirochete <i>Treponema pallidum</i> (2021)

For over a century, investigation of Treponema pallidum subsp. pallidum, the spiral-shaped bacterium that causes syphilis, was hindered by an inability to culture the organism in vitro. A recent breakthrough has enabled continuous in vitro growth of this organism in co-culture with mammalian tissue culture cells. This article contains the protocols needed to culture T. pallidum in the standard laboratory environment. In addition, protocols for growing and maintaining the required tissue culture cells, for generating isogenic strains by limiting dilution, and for quantitating T. pallidum by darkfield microscopy are included. © 2021 Wiley Periodicals LLC. Basic Protocol 1: In vitro cultivation of Treponema pallidum Basic Protocol 2: Generation of isogenic strains Support Protocol 1: Alternate harvest procedure Support Protocol 2: Culture of Sf1Ep cells Support Protocol 3: Assessment of T. pallidum number and viability.
Efficient management of idleness in storage systems (2009)

Various activities that intend to enhance performance, reliability, and availability of storage systems are scheduled with low priority and served during idle times. Under such conditions, idleness becomes a valuable “resource” that needs to be efficiently managed. A common approach in system design is to be nonwork conserving by “idle waiting”, that is, delay the scheduling of background jobs to avoid slowing down upcoming foreground tasks. In this article, we complement “idle waiting” with the “estimation” of background work to be served in every idle interval to effectively manage the trade-off between the performance of foreground and background tasks. As a result, the storage system is better utilized without compromising foreground performance. Our analysis shows that if idle times have low variability, then idle waiting is not necessary. Only if idle times are highly variable does idle waiting become necessary to minimize the impact of background activity on foreground performance. We further show that if there is burstiness in idle intervals, then it is possible to predict accurately the length of incoming idle intervals and use this information to serve more background jobs without affecting foreground performance.
GRapid: A compilation and runtime framework for rapid prototyping of graph applications on many-core processors (2014)

Many applications use graphs to represent and analyze data, but the effective deployment of graph algorithms on many-core processors is still a challenge. Many-core devices offer higher peak performance than multi-core devices; however, many-core programming is still a specialized skill. While compilation and runtime frameworks for parallelizing graph applications on multi-core CPUs exist, there is still a need for comparable frameworks for many-core devices. We propose GRapid: a compilation and runtime framework that generates efficient parallel implementations of generic graph applications for multi-core CPUs, NVIDIA GPUs and Intel Xeon Phi. Applications are expressed using a platform-agnostic programming API. Our source-to-source compiler performs platform-specific code transformations and optimizations, handles data transfers between the host and the coprocessor, and generates several functionally-equivalent code variants for the target platform. Our runtime library provides an efficient dynamic memory management scheme for applications where the graph topology is modified during processing. We used the proposed framework to rapidly generate efficient implementations of four graph applications on different target processors. Such rapid prototyping and re-targeting capability has obvious programmability advantages, but it can also be used to quickly identify target processors that better match the application's computational needs.
Effects of Tetra‐Alkyl Bis‐Phosphates on Butyrylcholinesterase (2012)

The progression of Alzheimer's Disease (AD) correlates positively with increasing levels of butyrylcholinesterase activity. As such, the inhibitors of this enzyme provide promise as potential therapeutics. Bisphosphates were evaluated for their inhibitory effects on the enzyme. The compounds were synthesized by the reaction of the corresponding dialkyl chlorophosphate with the appropriate diol in pyridine and dicholoromethane under inert conditions. The crude products were purified by flash chromatography to give the desired bisphosphates high purity. IC50's for the tetraethyl and tetrabutyl hexyl derivatives were determined to be 2.52 μM and 0.95 μM, respectively. The significance of the hexyl diphosphates’ inhibitory properties is highlighted when compared to the single phosphate derivative, diethyl hexyl phosphate, which showed little inhibitory activity. Moreover, analysis of the enzyme inhibition suggests that there are two binding sites, each with separate affinities. Modification of the carbon‐chain linker to produce shorter and longer bisphosphates produced an apparent increase in enzyme activity. The molecules used were tetraethyl‐3‐oxypentyl‐bisphosphate and 1,8‐bis(diethylphosphoryl)octane.
Finding recent frequent itemsets adaptively over online data streams (2003)

A data stream is a massive unbounded sequence of data elements continuously generated at a rapid rate. Consequently, the knowledge embedded in a data stream is more likely to be changed as time goes by. Identifying the recent change of a data stream, specially for an online data stream, can provide valuable information for the analysis of the data stream. In addition, monitoring the continuous variation of a data stream enables to find the gradual change of embedded knowledge. However, most of mining algorithms over a data stream do not differentiate the information of recently generated transactions from the obsolete information of old transactions which may be no longer useful or possibly invalid at present. This paper proposes a data mining method for finding recent frequent itemsets adaptively over an online data stream. The effect of old transactions on the mining result of the data steam is diminished by decaying the old occurrences of each itemset as time goes by. Furthermore, several optimization techniques are devised to minimize processing time as well as main memory usage. Finally, the proposed method is analyzed by a series of experiments.
Monoclonal Antibodies to a VWF-A2 Decapeptide with the C-Terminal Residue Tyr1605, Generated by ADAMTS13 Cleavage, Develop a Highly Sensitive ELISA for Its Activity and Characterize Upshaw-Schulman Syndrome. (2005)

Abstract We prepared murine monoclonal antibodies (mAbs) against a decapeptide of the VWF-A2 domain that has a C-terminal Tyr1605, generated by ADAMTS13 cleavage. These mAbs reacted neither with purified VWF nor the pentadecapeptide 1596-DREQAPNLVYMVTGN-1610, unless the Y1605-M1606 bond was cleaved. Using one of these mAbs, we developed a novel and highly sensitive ELISA for ADAMTS13 activity. In this assay, a recombinant VWF polypeptide (D1596–R1668) tagged with GST and His at the ends (GST-VWF73-His), is used as a substrate; upon cleavage by ADAMTS13, two fragments, GST-VWF10 and VWF63-His, are generated. Thus, the amount of GST-VWF10 can be directly measured using our mAb labeled with peroxidase. The specificity of this assay was confirmed by inhibition with EDTA, IgGs purified from thrombotic thrombocytopenic purpura (TTP) patients, and an anti-ADAMTS13 mAb. The detection limit of this assay was 0.5% of the normal. Of 20 patients with congenital TTP (Upshaw-Schulman syndrome, USS) whose ADAMTS13 gene mutations were identified, 14 had a severe deficiency (<0.5%), and 6 had a moderate deficiency (0.55~1.3%) of ADAMTS13 activity. No correlation was found between these two groups in terms of the onset of clinical manifestations. Further, a unique asymptomatic carrier of USS with two mutations (R268P/P475S) in the gene showed 4.2 % of normal plasma ADAMTS13 activity in this novel ELISA, indicating that plasma levels of ADAMTS13 activity between 1.3 and 4.2 % represent a gray zone which may lead to clinical manifestations of TTP. Table 1 shows a clinical and laboratory data of USS patients included in this study. Table 1. Clinical and laboratory data of 20 USS patients
Chemistry of the mycalamides, antiviral and antitumour compounds from a marine sponge. Part 3. Acyl, alkyl and silyl derivatives (1992)

Acyl, alkyl and silyl derivatives of the hydroxy and N-amido functionalities of the antitumour and antiviral marine sponge metabolites mycalamides A and B have been prepared, their relative reactivities established and in vitro P388 leukemia bioassays performed.
A pipelined architecture for the multidimensional DFT (2001)

This paper presents an efficient pipelined architecture for the N/sup m/-point m-dimensional discrete Fourier transform (DFT). By using a two-level index mapping scheme that is different from the conventional decimation-in-time (DIT) or decimation-infrequency (DIF) algorithms, the conventional pipelined architecture for the one-dimensional (1-D) fast Fourier transform (FFT) can be efficiently used for the computation of higher dimensional DFTs. Compared with systolic architectures, the proposed scheme is area-efficient since the computational elements (CEs) use the minimum number of multipliers, and the number of CEs increases only linearly with respect to the dimension m. It can be easily extended to the N/sup m/-point m-dimensional DFT with large m and/or N, and it is more flexible since the throughput can be easily varied to accommodate various area/throughput requirements.
Nonlinear theory of a folded waveguide gyrotron traveling-wave tube amplifier (1995)

We have developed a three-dimensional nonlinear theory for broadband gyrotron traveling-wave amplification in an H-plane-bend folded waveguide. The H-plane-bend configuration is formed by folding a rectangular waveguide so that the orientation of the magnetic field changes along the bend in contrast to the conventional E-plane bend, where the orientation of the electric field changes. Calculations show the feasibility of amplifier operation with large instantaneous bandwidth and moderate efficiency both in the slow wave region and the reduced dispersion fast wave region. Numerical results for a cold beam show an efficiency of 26% with 11% bandwidth in the slow wave region and an efficiency of 47% with 10% bandwidth in the fast wave region. For an electron beam with 2% velocity spread and 2% guiding center spread, the slow wave efficiency drops to 6% but the bandwidth increases to 16% whereas the efficiency and bandwidth of the fast waves decrease by a small amount to 42% and 9.5%, respectively. The efficiency is more sensitive to the axial beam velocity spread in the slow wave region due to larger Doppler shift. (c) 1995 The American Physical Society
Exploration with Multiple State Groupings (2005)

Exploration algorithms are relevant to the industrial practice of generating test cases from an abstract state machine whose runs define the predicted behavior of the software system under test. In this paper we describe a new exploration algorithm that allows multiple state grouping functions to simultaneously guide the search for states that are interesting or relevant for testing. In some cases, our algorithm allows exploration to be optimized from exponential to linear complexity. The paper includes an extended example that illustrates the use of the algorithm with the Spec Explorer tool developed as Microsoft Research.
Helical Pores Self-Assembled from Homochiral Dendritic Dipeptides Based on <scp>l</scp>-Tyr and Nonpolar α-Amino Acids (2007)

The synthesis of dendritic dipeptides (4-3,4-3,5)12G2-CH2-Boc-L-Tyr-X-OMe where X = Gly, L-Val, L-Leu, L-Ile, L-Phe, and L-Pro is reported. Their self-assembly in bulk and in solution and the structural and retrostructural analysis of their periodic assemblies were compared to those of the previously reported and currently reinvestigated dendritic dipeptides with X = L-Ala. All dendritic dipeptides containing as X nonpolar alpha-amino acids self-assemble into helical porous columns. The substituent of X programs the structure of the helical pore and the resulting periodic array, in spite of the fact that its molar mass represents only between 0.05 and 4.77% from the molar mass of the dendritic dipeptide. In addition to the various 2-D columnar lattices, the dendritic dipeptides based on L-Ala, L-Leu, and L-Phe self-organize into 3-D hexagonal columnar crystals while those based on L-Val and L-Ile into an unknown columnar crystal. The principles via which the aliphatic and aromatic substituents of X program the structure of the helical pores indicate synthetic pathways to helical pores with bioinspired functions based on artificial nonpolar alpha-amino acids.
Efficient invisible speculative execution through selective delay and value prediction (2019)

Speculative execution, the base on which modern high-performance general-purpose CPUs are built on, has recently been shown to enable a slew of security attacks. All these attacks are centered around a common set of behaviors: During speculative execution, the architectural state of the system is kept unmodified, until the speculation can be verified. In the event that a misspeculation occurs, then anything that can affect the architectural state is reverted (squashed) and re-executed correctly. However, the same is not true for the microarchitectural state. Normally invisible to the user, changes to the microarchitectural state can be observed through various side-channels, with timing differences caused by the memory hierarchy being one of the most common and easy to exploit. The speculative side-channels can then be exploited to perform attacks that can bypass software and hardware checks in order to leak information. These attacks, out of which the most infamous are perhaps Spectre and Meltdown, have led to a frantic search for solutions.
High-Affinity VEGF Antagonists by Oligomerization of a Minimal Sequence VEGF-Binding Domain (2012)

Vascular endothelial growth factor (VEGF) neutralizing antagonists including antibodies or receptor extracellular domain Fc fusions have been applied clinically to control angiogenesis in cancer, wet age-related macular degeneration, and edema. We report here the generation of high-affinity VEGF-binding domains by chemical linkage of the second domain of the VEGF receptor Flt-1 (D2) in several configurations. Recombinant D2 was expressed with a 13 a.a. C-terminal tag, including a C-terminal cysteine to enable its dimerization by disulfide bond formation or by attachment to divalent PEGs and oligomerization by coupling to multivalent PEGs. Disulfide-linked dimers produced by Cu(2+) oxidation of the free-thiol form of the protein demonstrated picomolar affinity for VEGF in solution, comparable to that of a D2-Fc fusion (sFLT01) and ~50-fold higher than monomeric D2, suggesting the 26 a.a. tag length between the two D2 domains permits simultaneous interaction of both faces of the VEGF homodimer. Extending the separation between the D2 domains by short PEG spacers from 0.35 kD to 5 kD produced a modest ~2-fold increase in affinity over the disulfide, thus defining the optimal distance between the two D2 domains for maximum affinity. By surface plasmon resonance (SPR), a larger (~5-fold) increase in affinity was observed by conjugation of the D2 monomer to the termini of 4-arm PEG, and yielding a product with a larger hydrodynamic radius than sFLT01. The higher affinity displayed by these D2 PEG tetramers than either D2 dimer or sFLT01 was largely a consequence of a slower rate of dissociation, suggesting the simultaneous binding by these tetramers to neighboring surface-bound VEGF. Finally, disulfide-linked D2 dimers showed a greater resistance to autocatalytic fragmentation than sFLT01 under elevated temperature stress, indicating such minimum-sequence constructs may be better suited for sustained-release formulations. Therefore, these constructs represent novel Fc-independent VEGF antagonists with ultrahigh affinity, high stability, and a range of hydrodynamic radii for application to multiple therapeutic targets.
Total Synthesis and Biological Evaluation of C16 Analogs of (−)-Dictyostatin (2007)

The structure-activity relationship of the crucial C16 region of (-)-dictyostatin was established through total synthesis of analogs followed by detailed biological characterization. A versatile synthetic strategy was used to prepare milligram quantities of 16-normethyldictyostatin, 16-epi-dictyostatin, and the C16-normethyl-C15Z isomer. Along the way, a number of other E/Z isomers and epimers were prepared, and a novel lactone ring contraction to make iso-dictyostatins with 20-membered macrolactones (instead of 22-membered macrolactones) was discovered. The synthesis of 16-normethyl-15,16-dehydrodictyostatin is the first of any dictyostatin by a maximally convergent route in which three main fragments are assembled, coupled in back-to-back steps, and then processed through refunctionalization and macrolactonization. Cell-based and biochemical evaluations showed 16-normethyl-15,16-dehydrodictyostatin and 16-normethyldictyostatin to be the most potent of the new agents, only 2- and 5-fold less active than (-)-dictyostatin itself. This data and that from previously generated dictyostatin analogs are combined to produce a picture of the structure-activity relationships in this series of anticancer agents.
Structural determinants of α‐defensin mediated anti‐inflammatory activities (2012)

α‐Defensins are cysteine‐rich, cationic host defense peptides that have bactericidal activities and immunomodulatory effects. The peptides are characterized by a canonical tridisulfide array and a 9:1 preference for Arg relative to Lys. Here, we report that mouse enteric α‐defensin cryptdin‐4 (Crp‐4) and rhesus myeloid α‐defensin‐4 (RMAD‐4 ) exert anti‐inflammatory effects and define the structural features essential for this activity. Crp‐4 and RMAD‐4 inhibit the release of TNF‐α by human leukocytes exposed to E. coli and by THP‐1 cells stimulated with LPS. Disulfide‐null variants of both peptides do not inhibit TNF‐α release, evidence that the anti‐TNF‐α effect requires the β‐sheet fold imposed by the three disulfide bonds. Anti‐TNF‐α activity is dependent on peptide primary structure, because the macaque RMAD‐3 α‐defensin lacks similar activity. Peptide mutagenesis shows that inhibition of TNF‐α release is dependent on electropositive charge contributed by Arg rather than Lys . In vitro , both peptides inhibit the TNF‐α converting enzyme (TACE), the major TNFprecursorconvertase. In vivo , Crp‐4 promotes survival in a mouse model of polymicrobial sepsis, evidence that the molecule induces systemic anti‐inflammatory effects. Thus, Crp‐4 and RMAD‐4 attenuate proinflammatory responses with potential translational applications. Grants DK044632, AI059346, R37AI022931, RO1DE15517.
TRPC6 Enhances Angiotensin II-induced Albuminuria (2011)

Mutations in the canonical transient receptor potential cation channel 6 (TRPC6) are responsible for familial forms of adult onset focal segmental glomerulosclerosis (FSGS). The mechanisms by which TRPC6 mutations cause kidney disease are not well understood. We used TRPC6-deficient mice to examine the function of TRPC6 in the kidney. We found that adult TRPC6-deficient mice had BP and albumin excretion rates similar to wild-type animals. Glomerular histomorphology revealed no abnormalities on both light and electron microscopy. To determine whether the absence of TRPC6 would alter susceptibility to hypertension and renal injury, we infused mice with angiotensin II continuously for 28 days. Although both groups developed similar levels of hypertension, TRPC6-deficient mice had significantly less albuminuria, especially during the early phase of the infusion; this suggested that TRPC6 adversely influences the glomerular filter. We used whole-cell patch-clamp recording to measure cell-membrane currents in primary cultures of podocytes from both wild-type and TRPC6-deficient mice. In podocytes from wild-type mice, angiotensin II and a direct activator of TRPC6 both augmented cell-membrane currents; TRPC6 deficiency abrogated these increases in current magnitude. Our findings suggest that TRPC6 promotes albuminuria, perhaps by promoting angiotensin II-dependent increases in Ca(2+), suggesting that TRPC6 blockade may be therapeutically beneficial in proteinuric kidney disease.
QESTRAL (Part 3): System and Metrics for Spatial Quality Prediction (2008)

The QESTRAL project aims to develop an artificial listener for comparing the perceived quality of a spatial audio reproduction against a reference reproduction. This paper presents implementation details for simulating the acoustics of the listening environment and the listener’s auditory processing. Acoustical modeling is used to calculate binaural signals and simulated microphone signals at the listening position, from which a number of metrics corresponding to different perceived spatial aspects of the reproduced sound field are calculated. These metrics are designed to describe attributes associated with location, width and envelopment attributes of a spatial sound scene. Each provides a measure of the perceived spatial quality of the impaired reproduction compared to the reference reproduction. As validation, individual metrics from listening test signals are shown to match closely subjective results obtained, and can be used to predict spatial quality for arbitrary signals.