gebhart/patrepeval huggingface dataset:
Targeting BCL2 With BH3 Mimetics: Basic Science and Clinical Application of Venetoclax in Chronic Lymphocytic Leukemia and Related B Cell Malignancies (2016)

The intracellular protein B-cell-lymphoma-2 (BCL2) has been considered an attractive target for cancer therapy since the discovery of its function as a major promoter of cell survival (an anti-apoptotic) in the late 1980s. However, the challenges of targeting a protein-protein interaction delayed the discovery of fit-for-purpose molecules until the mid-2000s. Since then, a series of high affinity small organic molecules that inhibits the interaction of BCL2 with the apoptotic machinery, the so-called BH3-mimetics, have been developed. Venetoclax (formerly ABT-199) is the first to achieve US Food and Drug Administration approval, with an indication for treatment of patients with previously treated chronic lymphocytic leukemia (CLL) bearing deletion of the long arm of chromosome 17. Here, we review key aspects of the science underpinning the clinical application of BCL2 inhibitors and explore both our current knowledge and unresolved questions about its clinical utility, both in CLL and in other B-cell malignancies that highly express BCL2.
Minimal intervention in dentistry : some variations in cavity design (2012)

In about 1900 GV Black evolved a classification for caries lesions and specified the design for the cavity that should be prepared to eliminate the lesion and hopefully avoid a recurrence. He was not aware of the modern concept of caries as a bacterial disease. He regarded the union between restoration and natural tooth structure as being a weak area very subject to plaque accumulation and therefore subject to recurrence of the disease. On these grounds he suggested that the margin should always be placed out on the smooth tooth surfaces where it could be easily kept clean. That is, he decided that extension for prevention was an essential parameter in cavity design. The profession has followed his instructions with only minor variations until this time.
Apoe ε4 exacerbates age‐dependent decline of cortical microstructural changes in cognitively normal midlife individuals: the PREVENT‐Dementia and ALFA studies (2023)

Abstract Background The APOE e4 allele is the primary genetic risk factor for the sporadic type of Alzheimer’s disease (AD). However, the mechanisms by which APOE e4 is associated with neurodegeneration are still poorly understood. Here, we applied the NODDI to characterise the effects of APOE e4 and its interactions with age and education on cortical microstructure in cognitively normal individuals. Method Data from 1954 participants were included from the PREVENT‐Dementia and ALFA (ALzheimer and FAmilies) studies (mean age = 57, 1197 non‐carriers, 757 APOE e4 carriers). T1 MRIs were processed with FreeSurfer v7.2. The Microstructure Diffusion Toolbox was used to derive Orientation Dispersion Index (ODI) maps from diffusion MRI. Primary analyses were focused on the (a) main effects of APOE e4, and the (b) interactions of APOE e4 with age and education on lobar and vertex‐wise ODI and implemented using Permutation Analysis of Linear Models. Result APOE e4 carriers and non‐carriers did not differ in terms of lobar ODI. However, there were APOE e4 × age interactions in the temporo‐parietal and frontal lobes (TFCE p FWE < 0.05), indicating steeper age‐dependent ODI changes in APOE e4 (Figure 1). Lobar analyses revealed decreased temporal ODI in APOE e4 carriers after age = 60 (Figure 2). There was a three‐way interaction of APOE e4 x age x education; steeper age‐related ODI declines among APOE e4 carriers with lower years of education (Figure 3, TFCE p FWE < 0.05). There were no significant main effects or interactions of APOE e4 on cortical thickness. Conclusion We found novel evidence that APOE e4 worsened age‐related ODI decreases in brain regions typically associated with atrophy patterns of AD. This finding also suggests that APOE e4 may hasten the onset age of dementia by accelerating age‐dependent reductions in cortical ODI, although additional studies are needed to verify this hypothesis. These findings were independent of cortical thickness. While conclusions are limited due to the cross‐sectional design, our findings imply that APOE e4 related changes in ODI may precede macroscopically visible changes in cortical atrophy and may be a more sensitive marker of incipient AD.
Diastereoselective Synthesis of Alkylated 1,4-Cyclohexadiene Esters Using Epimeric Pyrroloimidazolones (2020)

A pair of ortho-benzoate esters containing epimeric pyrroloimidazolones undergo sequential Birch reduction and diastereoselective alkylation to provide products ranging from 88:12 to >95:5 diastereomeric ratio (dr) for the syn-epimer, and 50:50 to 95:5 dr for the anti-epimer. The stereochemistry of the products is confirmed by a combination of X-ray crystallography on a key anti-epimer-derived product, in combination with specific rotation measurements of enantiomers that are prepared from the syn or anti starting materials. A diastereomerically pure allyl-substituted substrate is shown to undergo Cope rearrangement, which transposes the quaternary chiral center to a remote position without racemization. This work is complementary to asymmetric reductive alkylation reported previously by Schultz using anisole substrates with chiral benzamide auxiliaries in that the pyrroloimidazolones act as surrogates for the methoxy group.
Multiple Open-Channel Electroosmotic Pumping System for Microfluidic Sample Handling (2002)

The development of a novel, fully integrated, miniaturized pumping system for generation of pressure-driven flow in microfluidic platforms is described. The micropump, based on electroosmotic pumping principles, has a multiple open-channel configuration consisting of hundreds of parallel, small-diameter microchannels. Specifically, pumps with microchannels of 1-6 microm in depth, 4-50 mm in length, and an overall area of a few square millimeters, were constructed. Flow rates of 10-400 nL/min were generated in electric-field-free regions in a stable, reproducible and controllable manner. In addition, eluent gradients were created by simultaneously using two pumps. Pressures up to 80 psi were produced with the present pump configurations. The pump can be easily interfaced with other operational elements of a micrototal analysis system (micro-TAS) device with multiplexing capabilities. A new microfluidic valving system was also briefly evaluated in conjunction with these pumps. The micropump was utilized to deliver peptide samples for electrospray ionization-mass spectrometric (ESI-MS) detection.
Differential Effects of the Rejection of Bone Marrow Allografts by the Depletion of Activating Versus Inhibiting Ly-49 Natural Killer Cell Subsets (1998)

Natural killer cells mediate the specific rejection of bone marrow cell (BMC) allografts in lethally irradiated mice. The Ly-49 family of molecules present on subsets of murine NK cells appears capable of binding class I MHC molecules, resulting in transmission of an inhibitory signal to the NK cell. These Ly-49 family members have been shown to have an immunoreceptor tyrosine-based inhibitory motif that is responsible for the inhibitory signal. However, a new Ly-49 family member was found that lacks this motif, Ly-49D, and evidence suggests that this may be an activating receptor. We therefore compared the role of the activating Ly-49 member with NK cells bearing inhibitory Ly-49 receptors in BMC rejection. Depletion of Ly-49D+ NK cells in H-2b mice abrogated their ability to reject H-2d BMC allografts. Similarly, Ly-49C+ NK cells also were shown to mediate the specific rejection of H-2d BMC. When both subsets were depleted, an additive enhancement of BMC engraftment was observed, indicating that both subsets play a role in the rejection of allogeneic H-2-homozygous H-2d BMC. However, rejection of H-2(b x d) or D8 (H-2b, Dd transgene) BMC allografts was unaffected by Ly-49C+ NK cell depletion in H-2b mice. In marked contrast, depletion of Ly-49D+ NK cells in H-2b mice totally abrogated the rejection of H-2(b x d) heterozygous BMC in support of in vitro data suggesting that Ly-49D+ NK cells receive activating signals. Therefore, NK subsets demonstrate a differential ability to reject H-2 homozygous and heterozygous BMC.
Multifactorial resistance to 5,10-dideazatetrahydrofolic acid in cell lines derived from human lymphoblastic leukemia CCRF-CEM. (1995)

5,10-dideaza-5,6,7,8-terrahydrofolic acid (DDATHF) is a potent antiproliferative agent in cell culture systems and in vivo in a number of murine and human xenograft tumors. In contrast to classical antifolates, which are dihydrofolate reductase inhibitors, DDATHF primarily inhibits GAR transformylase, the first folate-dependent enzyme along the pathway of de novo purine biosynthesis. The (6R) diastereomer of DDATHF (Lometrexol), currently undergoing clinical investigation, was used to develop CCRF-CEM human leukemia sublines resistant to increasing concentrations of the drug. Three cell lines were selected for ability to grow in medium containing 0.1 microM, 1.0 microM, and 10 microM of (6R)DDATHF, respectively. Impaired polyglutamylation was identified as a common mechanism of resistance in all three cell lines. A progressive decrease in the level of polyglutamylation was associated with diminished folylpolyglutamate synthetase activity and paralleled increasing levels of resistance to the drug. However, the expression of folylpolyglutamate synthetase RNA was not altered in the resistant cell lines compared to the parent cells. The most resistant cell subline also displayed an increased activity of gamma-glutamyl hydrolase. The sublines were scrutinized for other possible mechanisms of resistance. No alterations in drug transport or in purine economy were found. Modest increases were found in the activity of methylene tetrahydrofolate dehydrogenase but no alterations of other folate-dependent enzymes were observed. Increases in accumulation and conversion of folic acid to reduced forms, particularly 10-formyltetrahydrofolate, was also seen. The resistant cell lines were sensitive to dihydrofolate reductase inhibitors, methotrexate and trimetrexate, for a 72-h exposure period but showed cross-resistance to methotrexate for 4 and 24 h exposures. Cross-resistance was also shown toward other deazafolate analogues for both short- and long-term exposures.
Assessing Borrower Ownership Using Reform Readiness Analysis (1999)

The succesful selection and design of Bank lending operations involving policy reforms depends on the World Bank's capacity to assess borrower ownership. The Bank must know whether there is sufficient ownership to justify lending and, if not, how to work with the government to build broader ownership as a prerequisite for lending. This Note surveys the tools that the Bank has typically used to assess borrower ownership, recommends a promising new assessment instrument called reform readiness analysis, and describes how to use this new instrument. The Note also discusses how the Bank might contribute to building ownership.
Imperialist competitive algorithm: An algorithm for optimization inspired by imperialistic competition (2007)

This paper proposes an algorithm for optimization inspired by the imperialistic competition. Like other evolutionary ones, the proposed algorithm starts with an initial population. Population individuals called country are in two types: colonies and imperialists that all together form some empires. Imperialistic competition among these empires forms the basis of the proposed evolutionary algorithm. During this competition, weak empires collapse and powerful ones take possession of their colonies. Imperialistic competition hopefully converges to a state in which there exist only one empire and its colonies are in the same position and have the same cost as the imperialist. Applying the proposed algorithm to some of benchmark cost functions, shows its ability in dealing with different types of optimization problems.
Total-Ionizing-Dose Effects on Piezoelectric Micromachined Ultrasonic Transducers (2016)

Total-ionizing-dose (TID) effects on piezoelectric micromachined ultrasonic transducers (pMUTs) are investigated using 10-keV X-rays under different bias conditions. The corresponding changes in resonant frequency and quality factor are evaluated using impedance analysis methods. Radiation-generated electrons or holes are trapped in the pre-existing defects of piezoelectric materials. Therefore, the sensitivity of pMUTs to X-ray irradiation depends strongly on the device bias during irradiation. The trapped charges change stress and strain in the materials due to the inverse piezoelectric effect, resulting in resonant frequency shifts and quality factor variation.
Single-bit re-encryption with applications to distributed proof systems (2007)

We examine the implementation of the distributed proof system designed by Minami and Kotz [17]. We find that, although a high-level analysis shows that it preserves confidentiality, the implementation of the cryptographic primitives contains a covert channel that can leak information. Moreover, this channel is present with any traditional choice of public key encryption functions.
Resonant DC&#8211;DC Converter With Class-E Oscillator (2006)

This paper presents a new free-running-oscillation resonant DC-DC converter with the Class-E oscillator and the Class-E rectifier, along with its design procedure and design curves for any conditions. The proposed converter is a free-running-oscillation system and has no gate-drive circuit to drive the MOSFET. Therefore, the structure of the proposed converter is simpler than that of class E <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> dc-dc converter. The proposed converter is suitable for a constant voltage and constant power operation under the fixed designed condition. The proposed converter has the ability to achieve a high power-conversion efficiency and low noises under high-frequency operation because of Class-E switching at both the oscillator and the rectifier. We investigate operations of the proposed converter by circuit experiments and show the validity of the design curves. This paper denotes two experimental results. One achieves 79.3% power-conversion efficiency under 1.54-W output power at an operating frequency 2.00 MHz. The other does 80.5% under 1.60-W output power at an operating frequency 1.98 MHz
Learning from Labeled and Unlabeled Data with Label Propagation (2002)

We investigate the use of unlabeled data to help labeled data in classification. We propose a simple iterative algorithm, label propagation, to propagate labels through the dataset along high density areas defined by unlabeled data. We give the analysis of the algorithm, show its solution, and its connection to several other algorithms. We also show how to learn parameters by minimum spanning tree heuristic and entropy minimization, and the algorithm&apos;s ability to do feature selection. Experiment results are promising.
In vivo radioligand binding to translocator protein correlates with severity of Alzheimer’s disease (2013)

Neuroinflammation is a pathological hallmark of Alzheimer's disease, but its role in cognitive impairment and its course of development during the disease are largely unknown. To address these unknowns, we used positron emission tomography with (11)C-PBR28 to measure translocator protein 18 kDa (TSPO), a putative biomarker for inflammation. Patients with Alzheimer's disease, patients with mild cognitive impairment and older control subjects were also scanned with (11)C-Pittsburgh Compound B to measure amyloid burden. Twenty-nine amyloid-positive patients (19 Alzheimer's, 10 mild cognitive impairment) and 13 amyloid-negative control subjects were studied. The primary goal of this study was to determine whether TSPO binding is elevated in patients with Alzheimer's disease, and the secondary goal was to determine whether TSPO binding correlates with neuropsychological measures, grey matter volume, (11)C-Pittsburgh Compound B binding, or age of onset. Patients with Alzheimer's disease, but not those with mild cognitive impairment, had greater (11)C-PBR28 binding in cortical brain regions than controls. The largest differences were seen in the parietal and temporal cortices, with no difference in subcortical regions or cerebellum. (11)C-PBR28 binding inversely correlated with performance on Folstein Mini-Mental State Examination, Clinical Dementia Rating Scale Sum of Boxes, Logical Memory Immediate (Wechsler Memory Scale Third Edition), Trail Making part B and Block Design (Wechsler Adult Intelligence Scale Third Edition) tasks, with the largest correlations observed in the inferior parietal lobule. (11)C-PBR28 binding also inversely correlated with grey matter volume. Early-onset (<65 years) patients had greater (11)C-PBR28 binding than late-onset patients, and in parietal cortex and striatum (11)C-PBR28 binding correlated with lower age of onset. Partial volume corrected and uncorrected results were generally in agreement; however, the correlation between (11)C-PBR28 and (11)C-Pittsburgh Compound B binding was seen only after partial volume correction. The results suggest that neuroinflammation, indicated by increased (11)C-PBR28 binding to TSPO, occurs after conversion of mild cognitive impairment to Alzheimer's disease and worsens with disease progression. Greater inflammation may contribute to the precipitous disease course typically seen in early-onset patients. (11)C-PBR28 may be useful in longitudinal studies to mark the conversion from mild cognitive impairment or to assess response to experimental treatments of Alzheimer's disease.
[Immunological control in the system of epidemiological surveillance over infections with different mechanisms of causative agent transmission]. (1994)

The results of immunological control of infections with different mechanisms of the transmission of their causative agents (diphtheria, measles, viral hepatitis, salmonellosis) for many years are summarized. About 25,000 serum samples taken from humans and more than 10,000 probes from agricultural animals have been studied in the passive hemagglutination test and more than 3,600 serum samples have been studied in the enzyme immunoassay for the presence viral hepatitis markers. Planned immunological control has ensured greater possibilities of the epidemiological diagnosis and prognostication of complications in the epidemic and epizootic situations. Urgent immunological control has made it possible to establish the proportion of non-manifest forms of diseases, to differentiate the foci of infection by transmission routes, to determine the degree of protection from infection and to substantiate the tactics of individual immunization.
Study on Skin‐Irritating and Biological Properties of Monoalkyl Phosphate Anionic Surfactants (1979)

Abstract Monoalkyl phosphate type of low irritating anionic surfactants were investigated with respect to their effect on various biological systems including proteins, enzymes, and lysosomes. Our results indicated that a remarkably weak membrane rupture effect at a concentration less than critical micellar concentration is important for low irritating feature. Mechanism by which irritation is caused by surfact‐ants is discussed.
Neurotoxic Mechanisms Caused by the Alzheimer's Disease-linked Swedish Amyloid Precursor Protein Mutation (2003)

Autosomal dominant forms of familial Alzheimer's disease (FAD) are caused by mutations of the amyloid precursor protein (APP) gene and by mutations of the genes encoding for presenilin 1 or presenilin 2. Simultaneously, evidence is provided that increased oxidative stress might play a crucial role in the rapid progression of the Swedish FAD. Here we investigated the effect of the Swedish double mutation (K670M/N671L) in the beta-amyloid precursor protein on oxidative stress-induced cell death mechanisms in PC12 cells. Western blot analysis and cleavage studies of caspase substrates revealed an elevated activity of the executor caspase 3 after treatment with hydrogen peroxide in cells containing the Swedish APP mutation. This elevated activity is the result of the enhanced activation of both intrinsic and extrinsic apoptosis pathways, including activation of caspase 2 and caspase 8. Furthermore, we observed an enhanced activation of JNK pathway and an attenuation of apoptosis by SP600125, a JNK inhibitor, through protection of mitochondrial dysfunction and reduction of caspase 9 activity. Our findings provide evidence that the massive neurodegeneration in early age of FAD patients could be a result of an increased vulnerability of neurons through activation of different apoptotic pathways as a consequence of elevated levels of oxidative stress.
Robot Builder's Bonanza (2000)

Presents instructions for more than one hundred robotic projects, describing useful tools, materials, and techniques, along with practical advice on power supply, robot locomotion, arm systems, circuit boards, microcontrollers, and remote control systems
Lightweight extendable and retractable pole (2023)

A lightweight extendable and retractable telescopic pole is disclosed comprising a plurality of non-metallic telescoping cylinders with sliding and sealing surfaces between the cylinders, a first plug member on the upper end of the smallest cylinder, and a second plug member on the lower end of the largest cylinder, whereby fluid pressure admitted to the largest cylinder will cause the telescoping cylinders to slide relative to one another causing the pole to extend. An elastomeric member connects the first plug member with one of the intermediate cylinders to urge the cylinders back into a collapsed position when the fluid pressure in the cylinders is vented. Annular elastomer members are provided which seal one cylinder to another when the pole is fully extended and further serve to provide a cushion to prevent damage to the cylinders when the pole is urged back into its retractable position by the elastomeric members and the venting of the pressure. A value mechanism associated with the pole is provided to admit a fluid under pressure to the interior of the telescoping cylinders of the pole while pressurizing a pressure relief port having an opening larger than the inlet port in a closed position whereby removal of the pressure on the relief port will cause the relief port to open to quickly lower the pressure in the interior of the telescoping cylinders to thereby assist in the rapid retraction of the extended pole.
Poly(ε-caprolactone)-Grafted Fe<sub>3</sub>O<sub>4</sub> Nanoparticles: Preparation and Superparamagnetic Nanocomposites with Epoxy Thermosets (2014)

Poly(ε-caprolactone)-grafted magnetic iron oxide nanoparticles (Fe3O4 NPs) were prepared via a surface-initiated ring opening polymerization approach. First, the surface of the unmodified Fe3O4 NPs were treated with 3-aminopropyltriethoxysilane to afford the 3-aminopropyl-functionalzed Fe3O4 NPs. Second, the surface-initiated ring-opening polymerization of ε-caprolactone was carried out with the surface-functionalized Fe3O4 NPs as the initiator to afford the poly(ε-caprolactone)(PCL)-grafted Fe3O4 NPs. The PCL-grafted Fe3O4 NPs have been characterized by means of Fourier transform infrared spectroscopy, X-ray diffraction, thermogravimetric analysis, and transmission electron microscopy. It was found that the PCL-grafted Fe3O4 NPs can be well dispersed into epoxy thermosets. The nanocomposites were successfully obtained with the content of the PCL-grafted Fe3O4 NPs up to 40 wt %. The fine dispersion of Fe3O4 nanoparticles in epoxy was demonstrated by transmission electron microscopy and dynamic mechanical thermal analysis. The results of magnetic analysis with vibrating sample measuring technology indicated that the nanocomposites involving epoxy resins and Fe3O4 nanoparticles possessed superparamagnetic properties.