gebhart/patrepeval huggingface dataset:
Self-Immolative Nitrogen Mustard Prodrugs for Suicide Gene Therapy (1998)

Four new potential self-immolative prodrugs derived from phenol and aniline nitrogen mustards, four model compounds derived from their corresponding fluoroethyl analogues and two new self-immolative linkers were designed and synthesized for use in the suicide gene therapy termed GDEPT (gene-directed enzyme prodrug therapy). The self-immolative prodrugs were designed to be activated by the enzyme carboxypeptidase G2 (CPG2) releasing an active drug by a 1, 6-elimination mechanism via an unstable intermediate. Thus, N-[(4-¿[4-(bis¿2-chloroethyl¿amino)phenoxycarbonyloxy]methyl¿pheny l)c arbamoyl]-L-glutamic acid (23), N-[(4-¿[4-(bis¿2-chloroethyl¿amino)phenoxycarbonyloxy]methyl¿pheno xy) carbonyl]-L-glutamic acid (30), N-[(4-¿[N-(4-¿bis[2-chloroethyl]amino¿phenyl)carbamoyloxy]methyl¿+ ++phen oxy)carbonyl]-L-glutamic acid (37), and N-[(4-¿[N-(4-¿bis[2-chloroethyl]amino¿phenyl)carbamoyloxy]methyl¿+ ++phen yl)carbamoyl]-L-glutamic acid (40) were synthesized. They are bifunctional alkylating agents in which the activating effects of the phenolic hydroxyl or amino functions are masked through an oxycarbonyl or a carbamoyl bond to a benzylic spacer which is itself linked to a glutamic acid by an oxycarbonyl or a carbamoyl bond. The corresponding fluoroethyl compounds 25, 32, 42, and 44 were also synthesized. The rationale was to obtain model compounds with greatly reduced alkylating abilities that would be much less reactive with nucleophiles compared to the corresponding chloroethyl derivatives. This enabled studies of these model compounds as substrates for CPG2, without incurring the rapid and complicated decomposition pathways of the chloroethyl derivatives. The prodrugs were designed to be activated to their corresponding phenol and aniline nitrogen mustard drugs by CPG2 for use in GDEPT. The synthesis of the analogous novel parent drugs (21b, 51) is also described. A colorectal cell line was engineered to express CPG2 tethered to the outer cell surface. The phenylenediamine compounds were found to behave as prodrugs, yielding IC50 prodrug/IC50 drug ratios between 20- and 33-fold (for 37 and 40) and differentials of 12-14-fold between CPG2-expressing and control LacZ-expressing clones. The drugs released are up to 70-fold more potent than 4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoic acid that results from the prodrug 4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoyl-L-glutamic acid (CMDA) which has been used previously for GDEPT. These data demonstrate the viability of this strategy and indicate that self-immolative prodrugs can be synthesized to release potent mustard drugs selectively by cells expressing CPG2 tethered to the cell surface in GDEPT.
Mouse models of ovarian failure (1998)

Ovarian failure leading to infertility can be caused by improper prenatal development of the fetal gonad or disruption of the complex postnatal process of folliculogenesis due to alterations in intragonadal or extragonadal regulation. It is critical to have physiological models that mimic events occurring during human development to understand, treat, and prevent ovarian failure in women. Many workers have chosen the mouse as the mammalian model with which to study ovarian function. This review summarizes several key events in female gonadogenesis and folliculogenesis in mice with specific emphasis on spontaneous or induced mutations yielding mouse models that have female infertility owing to ovarian failure.
Modelling and a genetic algorithm solution for the slab stack shuffling problem when implementing steel rolling schedules (2002)

Iron and steel production is a multistage process. A slab yard serves as a storage buffer between the continuous casting stage and the steel rolling mill. Slabs from continuous casting are stacked in the yard to await rolling. When implementing the rolling production schedule, slabs need to be picked up from the slab yard one by one according to the scheduled rolling sequence, heated in the heating furnace and then rolled. There are usually a number of suitable candidate slabs in the yard satisfying the requirement for each rolling item. In general, these candidate slabs are not at the most convenient positions in the stacks. To pick up a required slab, the slabs above it need to be shuffled. To save slab-handling cost and prevent the handling cranes from becoming a bottleneck, slabs for a rolling schedule must be selected from among the candidate slabs so that the total number of slabs shuffled is minimized. The paper studies the slab stack-shuffling problem using the hot strip rolling mill in Shanghai Baoshan Iron and Steel Complex as an application background. We first formulate the problem using an integer-programming model and then develop a modified genetic algorithm to solve it. Genetic codes and genetic operators are specially designed to ensure the feasibility of solutions and to speed up the solution process. The algorithm is implemented and compared with the existing algorithm that the mill has been using. Experiments on randomly generated problems show that the proposed new method reduces the number of slab shuffles by 11.19% on average.
Distribution of the Threshold Voltage Window in Nanocrystal Memories with Si Dots Formed by Chemical Vapor Deposition: Effect of Partial Self-Ordering (2004)

Non volatile memories based on Si nanocrystals (Si-ncs) offer an important alternative to conventional floating gate devices, for the numerous potential advantages associated with the discrete-trap structures [1]. Isolated Si-ncs can be obtained by chemical vapor deposition (CVD) through a fully compatible CMOS process. So far, the main limitation for scaling the CVD Si-nc memories at sub-90 nm node is related to the expected fluctuation, from bit to bit, in the device threshold voltage (VTH), due to the spread in the sur- face fraction (Rdot) covered with Si dots [2]. The reason is the assumption that the dot position and the relative distance are fully random. It will be shown that the nucleation proc- ess is not purely random and the dot formation evolves with partial self-ordering. The relative dispersion of Rdot is nu- merically evaluated as a function of gate size, for random and partially self-ordered nucleation processes. The result is compared to data on VTH distribution and extrapolated to small gate areas.
Biological effects of extracorporeal shock waves (2003)

Extracorporeal shock waves are used in medicine to destroy kidney stones and gallstones. In the body, they can affect tissues. These effects have been examined in many organs and generally consist of hemorrhages, destruction of venous walls, and venous thrombi. Tissue effects and stone destruction were considered to be due to a direct shock-wave effect or to cavitation; some experiments are presented which point to the involvement of cavitation as a mechanism of both tissue damage and stone destruction. A model of shock-wave action that could explain the observed effects is proposed.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Erythropoietin Therapy in Pre-Dialysis Patients with Chronic Renal Failure: Lack of Need for Parenteral Iron (2003)

&lt;i&gt;Background:&lt;/i&gt; During erythropoietin therapy, scant information exists regarding the optimal target percent saturation of transferrin (TSAT), ferritin and the mode and amount of iron supplementation in pre-dialysis patients with anemia due to chronic kidney disease (CKD). &lt;i&gt;Hypothesis:&lt;/i&gt; Pre-dialysis CKD patients may have different needs for iron supplementation than end-stage renal disease subjects during erythropoietin therapy. &lt;i&gt;Methods:&lt;/i&gt; Retrospective analysis of pre-dialysis CKD subjects (n = 31) treated with erythropoietin at our institution. &lt;i&gt;Results:&lt;/i&gt; In this population our results showed that target hematocrit (33–36%) was achievable with erythropoietin (mean subcutaneous dose 86 ± 17 [SD] units/kg/week) without parenteral iron therapy. The hematocrit increased from a mean baseline value of 28.4 ± 2.7 to 33.6 ± 3.4% at time 1 (4–9 weeks, p &lt; 0.0001), and to 37.7 ± 4.5% at time 2 (10–20 weeks, p &lt; 0.0001). The hemoglobin concentration increased from 9 ± 0.9 g/dl at baseline to 10.7 ± 1.1 g/dl at time 1 (p &lt; 0.0001) and to 12 ± 1.5 g/dl at time 2 (p &lt; 0.0001). Subgroup analyses of patients prescribed &lt;200 mg oral elemental iron per day (n = 10), those with TSAT &lt;20% and/or ferritin &lt;100 ng/ml (n = 19), and those prescribed erythropoietin &lt;80 units/kg/week (n = 12), all showed a significant increase in hematocrit and hemoglobin. &lt;i&gt;Conclusions:&lt;/i&gt; Our data show that pre-dialysis CKD subjects respond adequately to erythropoietin at or lower than recommended erythropoietin doses without parenteral iron. This response extends even to subgroups with TSAT and/or ferritin levels deemed to indicate iron deficiency in CKD subjects, and may be due to lack of existence of functional iron deficiency in this group of patients.
Sulfur‐Functionalized Mesoporous Carbon (2007)

Abstract A simple synthesis route to mesoporous carbons that contain heteroaromatic functionality is described. The sulfur‐functionalized mesoporous carbon (S‐FMC) materials that have been prepared show excellent thermal stability, as well as excellent hydrothermal stability, and stability over a wide range of pH values. These materials also show excellent mercury sorption performance over a broad range of pH, much broader than is possible with thiol‐based functionality or most silica‐based sorbents. The superior performance of these mesoporous heterocarbons as heavy‐metal sorbent material is demonstrated. These materials are shown to be stable at elevated temperatures and extreme pHs, making them ideally suited as a new class of absorbent material.
La privatisation en Afrique (2000)

In a way, the story of privatization in Africa reflects some of the problems which have beset many other development processes: lack of political commitment, poor design, insufficient resources, weak management, and corruption. Privatization in Africa is the outcome of a study undertaken during 1995 and 1996. Up to that time, privatization throughout the continent had been slow, with few visible results and a general feeling among observers and donors that African governments' commitment to the process was generally half-hearted. The purpose of the study was to answer three questions about privatization: (i) what has been happening? (ii) What has resulted? And (iii) what could be done to improve the process in terms of outcome. The data and analyses presented to answer these questions fill a significant gap in the published literature on privatization in Africa. The case-study countries were Benin, Burkina Faso, Ghana, Kenya, Madagascar, Nigeria, Togo, Uganda, and Zambia. The study shows that more privatization has been happening across Africa than was generally thought to be the case; but it also raises many issues about how the process has been planned and implemented. The controversy starts with why African governments have privatized. The study maintains that the evidence suggests that most governments have privatized reluctantly and not for the reasons set out in policy statements.
The microfluidics of the eccrine sweat gland, including biomarker partitioning, transport, and biosensing implications (2015)

Non-invasive and accurate access of biomarkers remains a holy grail of the biomedical community. Human eccrine sweat is a surprisingly biomarker-rich fluid which is gaining increasing attention. This is especially true in applications of continuous bio-monitoring where other biofluids prove more challenging, if not impossible. However, much confusion on the topic exists as the microfluidics of the eccrine sweat gland has never been comprehensively presented and models of biomarker partitioning into sweat are either underdeveloped and/or highly scattered across literature. Reported here are microfluidic models for eccrine sweat generation and flow which are coupled with review of blood-to-sweat biomarker partition pathways, therefore providing insights such as how biomarker concentration changes with sweat flow rate. Additionally, it is shown that both flow rate and biomarker diffusion determine the effective sampling rate of biomarkers at the skin surface (chronological resolution). The discussion covers a broad class of biomarkers including ions (Na(+), Cl(-), K(+), NH4 (+)), small molecules (ethanol, cortisol, urea, and lactate), and even peptides or small proteins (neuropeptides and cytokines). The models are not meant to be exhaustive for all biomarkers, yet collectively serve as a foundational guide for further development of sweat-based diagnostics and for those beginning exploration of new biomarker opportunities in sweat.
Deregulation of Aiolos expression in chronic lymphocytic leukemia is associated with epigenetic modifications (2010)

Chronic lymphocytic leukemia (CLL) is characterized by a clonal accumulation of mature neoplastic B cells that are resistant to apoptosis. Aiolos, a member of the Ikaros family of zinc-finger transcription factors, plays an important role in the control of mature B lymphocyte differentiation and maturation. In this study, we showed that Aiolos expression is up-regulated in B-CLL cells. This overexpression does not implicate isoform imbalance or disturb Aiolos subcellular localization. The chromatin status at the Aiolos promoter in CLL is defined by the demethylation of DNA and an enrichment of euchromatin associated histone markers, such as the dimethylation of the lysine 4 on histone H3. These epigenetic modifications should allow its upstream effectors, such as nuclear factor-κB, constitutively activated in CLL, to gain access to promoter, resulting up-regulation of Aiolos. To determine the consequences of Aiolos deregulation in CLL, we analyzed the effects of Aiolos overexpression or down-regulation on apoptosis. Aiolos is involved in cell survival by regulating the expression of some Bcl-2 family members. Our results strongly suggest that Aiolos deregulation by epigenetic modifications may be a hallmark of CLL.
The hydrodynamics of swimming microorganisms (2009)

Cell motility in viscous fluids is ubiquitous and affects many biological processes, including reproduction, infection, and the marine life ecosystem. Here we review the biophysical and mechanical principles of locomotion at the small scales relevant to cell swimming (tens of microns and below). The focus is on the fundamental flow physics phenomena occurring in this inertia-less realm, and the emphasis is on the simple physical picture. We review the basic properties of flows at low Reynolds number, paying special attention to aspects most relevant for swimming, such as resistance matrices for solid bodies, flow singularities, and kinematic requirements for net translation. Then we review classical theoretical work on cell motility: early calculations of the speed of a swimmer with prescribed stroke, and the application of resistive-force theory and slender-body theory to flagellar locomotion. After reviewing the physical means by which flagella are actuated, we outline areas of active research, including hydrodynamic interactions, biological locomotion in complex fluids, the design of small-scale artificial swimmers, and the optimization of locomotion strategies.
Zinc supplementation of young men alters metallothionein, zinc transporter, and cytokine gene expression in leukocyte populations (2006)

An effective measure to assess zinc status of humans has remained elusive, in contrast to iron, where a number of indicators of metabolism/function are available. Using monocytes, T lymphocytes, and granulocytes isolated by magnetic sorting and dried blood spots (DBS) derived from 50 mul of peripheral blood, we evaluated the response of metallothionein (MT), zinc transporter, and cytokine genes to a modest (15 mg of Zn per day) dietary zinc supplement in human subjects. Transcript abundance was measured by quantitative real-time RT-PCR (QRT-PCR). Zinc supplementation increased MT mRNA abundance by up to 2-fold in RNA from leukocyte subsets, and 4-fold in RNA from DBS. Transcript levels for the zinc transporter genes ZnT1 and Zip3 were increased and decreased, respectively, by zinc supplementation. Expression of the ZnT and Zip genes among leukocyte subsets differ by up to 270-fold. Monocytes and granulocytes from supplemented subjects were activated by LPS, whereas T lymphocytes were activated by mimicking antigen presentation. With zinc consumption, TNF-alpha and IL-1beta expression was greater in activated monocytes and granulocytes, and IFN-gamma mRNA levels were higher in activated T lymphocytes. These studies show that QRT-PCR is a tool to reliably measure transcript abundance for nutritionally responsive genes in human subjects, and that a small sample of whole dried blood, when appropriately collected, can be used as the source of total RNA for QRT-PCR analysis. The results obtained also show that zinc supplementation of human subjects programs specific leukocytic subsets to show enhanced cytokine expression upon activation by stimulators of immunity.
Human immunodeficiency virus Tat induces functional unresponsiveness in T cells (1995)

Soluble proteins of the human immunodeficiency virus (HIV) might play a significant role in the pathogenesis of HIV infection. The addition of synthetic Tat peptides, but not that of the recombinant Nef or Vif protein, inhibited proliferative responses of CD4+ tetanus antigen-specific, exogenous interleukin-2 (IL-2)-independent T-cell clones in a dose-dependent manner. In addition, Tat peptides inhibited the anti-CD3 monoclonal antibody-induced proliferative responses of both purified CD4+ and CD8+ T cells. Tat did not affect proliferative responses induced by phorbol myristate acetate plus ionomycin. The Tat peptides at the concentrations used (0.1 to 3 micrograms/ml) did not affect the viability of the cells as determined by trypan blue exclusion. Treatment of Tat peptides with polyclonal Tat antibodies abrogated the inhibitory effect of Tat. Soluble Tat proteins secreted by HeLa cells transfected with the tat gene also inhibited antigen-induced proliferation of the T-cell clones. Tat inhibited the anti-CD3 monoclonal antibody-induced IL-2 mRNA expression and IL-2 secretion but did not affect IL-2 receptor alpha-chain mRNA or protein expression on peripheral blood T cells. Finally, treatment of T-cell clones with the Tat peptide did not affect the antigen-induced increase in intracellular calcium, hydrolysis of phosphatidyl inositol to inositol trisphosphate, or translocation of protein kinase C from the cytosol to the membrane. These studies demonstrate that the mechanism of the Tat-mediated inhibition of T-cell functions involves a phospholipase C gamma 1-independent pathway.
Phytochemical Studies on Alstonia scholaris (2010)

Reinvestigation of the flowers of Alstonia scholaris of Pakistan origin have resulted in the isolation of three new triterpenoids, two of the ursane type, 3β -acetate-24-nor-urs-4,12-diene ester triterpene (1) and 3β -hydroxy-24-nor-urs-4,12,28-triene triterpene (2), and one of the oleanane type, 3,28-β - diacetoxy-5-olea-triterpene (3), together with two known triterpenes,α-amyrin acetate (4) and ursolic acid (5). This is the first report of the isolation of 4 and 5 from the flower part of this species. The structures of 1 - 5 were elucidated with the aid of extensive NMR-spectroscopic studies.
Current status and future prospect of the Nb-based fabrication process for single flux quantum circuits (2006)

The Superconductivity Research Laboratory has successfully fabricated large quantities of single flux quantum (SFQ) large scale integrated circuits, including several thousands of Josephson junctions (JJs). Using a Jc = 2.5 kA cm−2 process in which the number of Nb layers was four and the minimum JJ size was 2 µm square. We developed a new advanced fabrication process that produced a Jc = 10 kA cm−2, nine Nb layers and a minimum JJ size of 1 µm square. The increase in the number of Nb layers was achieved by using a planarization technique. The target of our next generation process is a Jc = 40 kA cm−2 with a 0.5 µm square for the minimum junction size. This specification will be achieved by using advanced semiconductor technologies. This process will enable SFQ circuits to be produced with one million JJs on a chip and achieve a clock frequency greater than 100 GHz.
Changes in the dynamics of luteinizing hormone-releasing hormone- stimulated secretion of luteinizing hormone during sexual maturation of female rats (1986)

Our aim was to identify age-related changes in the dynamics of luteinizing hormone (LH) release that may contribute to the decline in pituitary sensitivity to luteinizing hormone-releasing hormone (LHRH) during sexual maturation of female rats. We studied LHRH-stimulated LH secretion curves of superfused pituitaries from rats ranging in age from 10 days to the first estrous cycle. Pituitary fragments were exposed for 10 min to medium alone or to medium plus LHRH; incubation continued in medium alone for 130 min and effluent was collected for LH analysis. Secretion curves were compared on the basis of total secretion (area under the curve), maximal change in LH secretion rate, and rates of rise and decay of the curves. The data show that total LH secretion in response to LHRH is greatest in 15-, 20-day-old and first-proestrus animals. Also, the maximal change in LH secretion rate was greater, and the increase in LH secretion rate faster in younger animals than in 30-day-old animals. Analysis of secretory granules in LH-containing gonadotropes of 15- and 30-day-old animals revealed changes in he granule population with age. We conclude that younger animals respond faster with a greater LH secretion response to LHRH than do 30-day-old or first-estrus animals, and that these age-related changes in the dynamics of LH secretion may be due in part to maturation of the LH secretory granules.
An evaluation of the Java security model (2002)

Java is a new programming language that has been developed by Sun Microsystems. They claim that Java has a number of advantages over traditional programming languages. One of these advantages is the ability to execute untrusted programs in a secure environment. After a brief introduction to the Java language this paper investigates the problems that would arise when running untrusted programs without providing a secure environment and several possible solutions to this problem. It then takes a close look at the solution provided by the Java security model in theory as well as in current implementations and evaluates their efficiency and flexibility for present and future ranges of application.
Safety and Efficacy of Gene Transfer for Leber's Congenital Amaurosis (2008)

Leber's congenital amaurosis (LCA) is a group of inherited blinding diseases with onset during childhood. One form of the disease, LCA2, is caused by mutations in the retinal pigment epithelium-specific 65-kDa protein gene (RPE65). We investigated the safety of subretinal delivery of a recombinant adeno-associated virus (AAV) carrying RPE65 complementary DNA (cDNA) (ClinicalTrials.gov number, NCT00516477 [ClinicalTrials.gov]). Three patients with LCA2 had an acceptable local and systemic adverse-event profile after delivery of AAV2.hRPE65v2. Each patient had a modest improvement in measures of retinal function on subjective tests of visual acuity. In one patient, an asymptomatic macular hole developed, and although the occurrence was considered to be an adverse event, the patient had some return of retinal function. Although the follow-up was very short and normal vision was not achieved, this study provides the basis for further gene therapy studies in patients with LCA.