gebhart/patrepeval huggingface dataset:
Biological Membranes as Bilayer Couples. A Molecular Mechanism of Drug-Erythrocyte Interactions (1974)

We propose that membranes whose proteins and polar lipids are distributed asymmetrically in the two halves of the membrane bilayer can act as bilayer couples, i.e., the two halves can respond differently to a perturbation. This hypothesis is applied to the interactions of amphipathic drugs with human erythrocytes. It is proposed that anionic drugs intercalate mainly into the lipid in the exterior half of the bilayer, expand that layer relative to the cytoplasmic half, and thereby induce the cell to crenate, while permeable cationic drugs do the opposite and cause the cell to form cup-shapes. This differential distribution of the drugs is attributed to interactions with the phosphatidylserine that is concentrated in the cytoplasmic half of the membrane. Impermeable amphipathic drugs intercalate only into the exterior half of the bilayer, and therefore are crenators of the intact cell. Several predictions of this hypothesis have been confirmed experimentally with erythrocytes and erythrocyte ghosts. The bilayer couple hypothesis may contribute to the explanation of many membrane-mediated phenomena in cell biology.
N-Terminal Protein Modification Using Simple Aminoacyl Transferase Substrates (2011)

Methods for synthetically manipulating protein structure enable greater flexibility in the study of protein function. Previous characterization of the Escherichia coli aminoacyl tRNA transferase (AaT) has shown that it can modify the N-terminus of a protein with an amino acid from a tRNA or a synthetic oligonucleotide donor. Here, we demonstrate that AaT can efficiently use a minimal adenosine substrate, which can be synthesized in one to two steps from readily available starting materials. We have characterized the enzymatic activity of AaT with aminoacyl adenosyl donors and found that reaction products do not inhibit AaT. The use of adenosyl donors removes the substrate limitations imposed by the use of synthetases for tRNA charging and avoids the complex synthesis of an oligonucleotide donor. Thus, our AaT donors increase the potential substrate scope and reaction scale for N-terminal protein modification under conditions that maintain folding.
Vortex via process: analysis and mask fabrication for contact CDs <80 nm (2003)

In an optical vortex, the wavefront spirals like a corkscrew, rather than forming planes or spheres. Since any nonzero optical amplitude must have a well-defined phase, the axis of a vortex is always dark. Printed in negative resist at 248nm and NA=0.63, 250nm pitch vortex arrays would produce contact holes with 80nm<CD<160nm(0.2<<i>k</i><sub>1</sub><0.4), depending on exposure dose. Arrays of vortices with <i>k</i><sub>pitch</sub>>0.6 can be patterned using a chromeless phase-edge mask composed of rectangles with nominal phases of 0°, 90°, 180° and 270°. Analytic and numerical calculations have been performed to characterize the aerial images projected from such vortex masks using the Kirchhoff-approximation and rigorous EMF methods. Combined with resist simulations, these analyses predict process windows with &#8776;10%<i>E</i><sub>lat</sub> and >200nm DOF for 80nm CDs on pitches greater than or equal to 250nm at &#963; greater than or equal to 0.15. Smaller CDs and pitches are possible with shorter wavelength and larger NA while larger pitches give rise to larger CDs. At pitch >0.8&#956;m, the vortices begin to print independently for &#963; greater than or equal to 0.3. Such “independent” vortices have a quasi-isofocal dose that gives rise to 100nm contacts with <i>E</i><sub>lat</sub>>9% and DOF>500nm at &#963;=0.3. The extra darkness of the nominal 270° phase step can be accommodated by fine-tuning the etch depth. A reticle fabrication process that achieves the required alignment and vertical wall profiles has been exercised and test masks analyzed. In an actual chip design, unwanted vortices and phase step images would be erased from the resist pattern by exposing the wafer with a second, more conventional trim mask. Vortex via placement is consistent with the coarse-gridded grating design paradigms which would - if widely exercised - lower the cost of the required reticles. Compared to other ways of producing deep sub-wavelength contacts, the vortex via process requires fewer masks and reduces the overlay and process control challenges. A high resolution negative-working resist process is essential, however.
Human pluripotent stem cell-derived neural constructs for predicting neural toxicity (2015)

Human pluripotent stem cell-based in vitro models that reflect human physiology have the potential to reduce the number of drug failures in clinical trials and offer a cost-effective approach for assessing chemical safety. Here, human embryonic stem (ES) cell-derived neural progenitor cells, endothelial cells, mesenchymal stem cells, and microglia/macrophage precursors were combined on chemically defined polyethylene glycol hydrogels and cultured in serum-free medium to model cellular interactions within the developing brain. The precursors self-assembled into 3D neural constructs with diverse neuronal and glial populations, interconnected vascular networks, and ramified microglia. Replicate constructs were reproducible by RNA sequencing (RNA-Seq) and expressed neurogenesis, vasculature development, and microglia genes. Linear support vector machines were used to construct a predictive model from RNA-Seq data for 240 neural constructs treated with 34 toxic and 26 nontoxic chemicals. The predictive model was evaluated using two standard hold-out testing methods: a nearly unbiased leave-one-out cross-validation for the 60 training compounds and an unbiased blinded trial using a single hold-out set of 10 additional chemicals. The linear support vector produced an estimate for future data of 0.91 in the cross-validation experiment and correctly classified 9 of 10 chemicals in the blinded trial.
Mutations affecting eye morphology in the developing zebrafish (Danio rerio) (1997)

The zebrafish (Danio rerio) has received considerable attention as a mainstream model for the molecular and genetic study of vertebrate development. In our laboratory, we have conducted a third-generation screen of chemically mutagenized zebrafish for recessive mutations affecting the visual system. This report describes the visible phenotypes and number of morphological mutants so far observed and presents a more detailed histological analysis of six of these mutations. Through analysis of mutant larvae, it was determined that several of the subtle morphological mutations resulted in degeneration of specific cellular layers of the retina. Other mutations resulted in some degeneration distributed diffusely across the entire retina or concentrated at the retinal margin. A single mutation affecting invagination of the optic cup and lens vesicle formation resulted in a failure to develop an anterior chamber. These results demonstrate the utility of a small-scale, highly focused screen for uncovering novel loci involved in retinal and eye development. Dev. Genet. 20:288–295, 1997. © 1997 Wiley-Liss, Inc.
Concrete Petrography - a Forensic Approach (2001)

This paper discusses the role of microscopy in the forensic analysis of deteriorated concrete structures. It can be used not only to identify the original mineralogy and textural relationships of the aggregates and cementitious components, but also provide valuable insight into any secondary deleterious phases, cracking patterns, water/cement ratios, aggregate/cement paste ratios, and size and distribution of void space. This powerful, cost-effective technique can be used not only as a tool in quality assurance, but in troubleshooting various concrete problems, and in the prediction of long-term performance.
A natural mutation in the Tyk2 pseudokinase domain underlies altered susceptibility of B10.Q/J mice to infection and autoimmunity (2003)

The B10.Q/J strain of mice was serendipitously discovered to be highly susceptible to infection by the intracellular protozoan parasite, Toxoplasma gondii but markedly resistant to induction of autoimmune arthritis. We have previously shown that the B10.Q/J phenotype is controlled by a single recessive locus and is associated with lymphocyte hyporesponsiveness to IL-12. Using genetic approaches, we have now localized the B10.Q/J locus to chromosome 9 and established its identity as Tyk2, a Janus kinase essential for IL-12 and IFN-alpha/beta cytokine signaling. The B10.Q/J Tyk2 gene contained a single missense mutation resulting in a nonconservative amino acid substitution (E775K) in an invariant motif of the pseudokinase (Janus kinase homology 2) domain. This mutation appeared to result in the absence of the B10.Q/J-encoded Tyk2 protein, despite presence of Tyk2-specific transcripts. Phenotypically, B10.Q/J cells were indistinguishable from Tyk2-deficient cells, showing impaired signaling and biologic responses to IL-12, IL-23, and type I IFNs. The analogous E782K mutant of human Tyk2 failed to restore IFN-alpha responsiveness in Tyk2 null 11,1 cells. Our results indicate a crucial role for Tyk2 in T helper 1-mediated protective and pathogenic immune responses. An additional implication of our findings is that naturally occurring mutations in the Tyk2 gene may underlie altered susceptibilities to infectious or autoimmune diseases in human and animal populations.
Dose-Dependent Effect of Anti-CTLA-4 on Survival in Sepsis (2011)

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is one of the critical inhibitory regulators of early stages of T-cell activation and proliferation, which opposes the actions of CD28-mediated costimulation. Anti-CTLA-4 therapy has been effective clinically in enhancing immunity and improving survival in patients with metastatic cancer. Sepsis is a lethal condition that shares many of the same mechanisms of immune suppression with cancer. Given the similarities in immune defects in cancer and sepsis, we examined the ability of anti-CTLA-4 antibody to block apoptosis, reverse the immunosuppression of sepsis, and improve survival in the cecal ligation and puncture model. Mice underwent sham or cecal ligation and puncture, and spleens harvested at various time points after surgery. Expression of CTLA-4 on CD4, CD8, and regulatory T cells was quantitated. Anti-CTLA-4 was administrated 6 and 24 h after surgery. Spleens were harvested at 48 h after surgery, and apoptosis and cytokine production determined. Seven-day survival studies were also conducted. Expression of CTLA-4 on CD4, CD8, and regulatory T cells increased during sepsis. Anti-CTLA-4 therapy decreased sepsis-induced apoptosis but had little effect on proinflammatory or anti-inflammatory cytokines. There was a dose-dependent effect of anti-CTLA-4 on survival. At high dose, anti-CTLA-4 worsened survival, but at lower doses, survival was significantly improved. Survival in sepsis depends on the proper balance between the proinflammatory and anti-inflammatory/immunologic systems. Anti-CTLA-4-based immunotherapy offers promise in the treatment of sepsis, but care must be used in the timing and dose of administration of the drug to prevent adverse effects.
Modifying muscular dystrophy through transforming growth factor‐β (2013)

Muscular dystrophy arises from ongoing muscle degeneration and insufficient regeneration. This imbalance leads to loss of muscle, with replacement by scar or fibrotic tissue, resulting in muscle weakness and, eventually, loss of muscle function. Human muscular dystrophy is characterized by a wide range of disease severity, even when the same genetic mutation is present. This variability implies that other factors, both genetic and environmental, modify the disease outcome. There has been an ongoing effort to define the genetic and molecular bases that influence muscular dystrophy onset and progression. Modifier genes for muscle disease have been identified through both candidate gene approaches and genome-wide surveys. Multiple lines of experimental evidence have now converged on the transforming growth factor-β (TGF-β) pathway as a modifier for muscular dystrophy. TGF-β signaling is upregulated in dystrophic muscle as a result of a destabilized plasma membrane and/or an altered extracellular matrix. Given the important biological role of the TGF-β pathway, and its role beyond muscle homeostasis, we review modifier genes that alter the TGF-β pathway and approaches to modulate TGF-β activity to ameliorate muscle disease.
Patterns of Morbidity and Mortality in Typhoid Fever Dependent on Age and Gender: Review of 552 Hopitalized Patients with Diarrhea (1990)

Features of typhoid fever were correlated with age and gender through a review of the charts of 552 hospitalized culture-positive patients with diarrhea in Bangladesh. Seizures occurred more frequently in children from birth through 10 years of age (5%-11%) and pneumonia more frequently in children from birth through 5 years of age (8%-15%) than in older age groups (P less than .05), whereas intestinal perforation occurred more frequently in patients greater than or equal to 11 years of age (5%-25%) than in younger age groups (P less than .005). Compared with older age groups, children from birth through 10 years of age were more anemic, those from birth through 5 years of age had a higher mean white blood cell count, and those from birth through 1 year of age had a lower mean blood carbon dioxide content (all P less than .05). Female patients were more severely anemic than male patients (P less than .05). The case-fatality rate was 4.3% overall, with the highest rates for children from birth through 1 year of age (11%) and adults greater than or equal to 31 years of age (10%). Female patients had a higher case-fatality rate (6%) than male patients (3%), although the difference was not significant (P greater than .05). Death was independently associated with seizures, intestinal perforation, pneumonia, and delirium or coma. These results indicated that the patients with typhoid fever who were at highest risk of complications and death were children from birth through 1 year of age and adults greater than or equal to 31 years of age.
Design of Self-Immolative Linkers for Tumour-Activated Prodrug Therapy (2008)

The main drawback of most cancer chemotherapy is its relatively low ability to target tumour cells versus normal cells. As a consequence, chemotherapy is usually connected with severe side effects due to the toxicity of traditional cytostatic agents towards normal tissues. A few years ago, the site-specific activation of non-toxic prodrugs in tumours has been proposed in order to enhance the selectivity for the killing of cancer cells. Within this framework, most of the prodrugs that have been designed were three part compounds comprising trigger, linker and effector units. The main function of the linker is to release the effector unit after selective trigger activation via a spontaneous chemical breakdown. However, its structure also affects significantly many prodrug properties such as stability, pharmacokinetic, organ distribution, bioavailability or trigger activation. This review, focussed on the linker unit, is an update of our previous article published in 2002. It deals with recent advances in the design of prodrug linkers including new delivery systems such as elongated linkers or self-immolative dendrimers.
Solid-Phase Supported Polymer Synthesis of Sequence-Defined, Multifunctional Poly(amidoamines) (2006)

A novel synthesis route toward multifunctional, sequence-defined polyamides is described. A fully automated, solid-phase supported polymer synthesis was developed and utilized to obtain linear poly(amidoamine) segments (PAAs) that exhibit the absence of molecular weight and chemical distribution. This was achieved by an alternating assembly of diacids and diamines, using a forced step-growth mechanism, and driving each coupling step to completion. Within the monodisperse PAA segment, functionalities can be precisely positioned along the polymer chain allowing local control of the chain properties. The versatility of the approach was demonstrated by the conjugation of the monodisperse PAA segment toward an oligopeptide, leading to a single component block copolymer as verified by mass spectrometry. Moreover, two different poly(ethylene oxide)-PAA conjugates were synthesized utilizing the direct, solid-phase supported route. By varying the PAA repeat unit, the cationic nature of the PAA segment was adjusted, demonstrating the potential of the approach. The products were characterized by means of 1H NMR and matrix-assisted laser desorption mass spectrometry (MALDI-TOF-MS) methods, which confirmed the chemical structures conclusively.
Hydrazine Detection by Polyaniline Using Fluorinated Alcohol Additives (2005)

A new sensor for hydrazine detection is reported using conventional polyaniline thin films processed from hexafluoroisopropanol. This and other fluorinated alcohols are shown to react with hydrazine to produce a strong acid. The hydrofluoric acid (HF) protonates the emeraldine base form of polyaniline leading to large increases in conductivitygreater than 4 orders of magnitude. In contrast, conventional polyaniline films processed from other organic solvents and polyaniline nanofiber films processed from water become more insulating upon exposure to hydrazine. In these cases, hydrazine acts as a strong reducing agent, converting the emeraldine form of polyaniline to its leucoemeraldine oxidation state. The concept of using additives to enhance the sensing ability of polyaniline films could prove useful for other analytes as well as for other conducting polymers.
Photothermal deflectometry enhanced by total internal reflection enables non-invasive glucose monitoring in human epidermis (2014)

We present TIR-PTD spectroscopy, an IR-pump/VIS-probe method for the measurement of IR absorption spectra by means of photothermal deflectometry (PTD) enhanced by total internal reflection (TIR). It overcomes the limitations of IR spectroscopy for the study of opaque samples and allows molecular fingerprinting of IR-active liquids or solids. Another important advantage of the presented approach over traditional IR spectroscopy methods is the ability to obtain IR information by means of VIS detection, which is generally much cheaper and easier to handle than IR detection. By application of mid-IR TIR-PTD spectroscopy on human skin in vivo, we are demonstrating the correlation between epidermal- and blood-glucose levels on a type 1 diabetic patient.
Responses to Terror: The New "War". (2002)

The events of 11 September 2001 profoundly challenged the existing principles of international law, both as to the right of a state to use military force and as to the principles of international humanitarian law. This article assesses whether international law can provide a legal framework by which to judge state responses to acts of terrorism, the organisation and preparation of which occur in another state but where the acts are committed by non-state actors. It explores the difficulties of applying international humanitarian law in selecting military objectives when directing attacks against ‘terrorists’ and in classifying captured fighters. Finally, it considers the impact of the detention of individuals suspected of ‘terrorist’ activities on international human rights standards.
A Multicast Control Scheme for Parallel Software-only Video Effects Processing (1999)

We have developed a parallel software-only processing system for creating real-time video effects such as titling and compositing (e.g., picture-in-picture) using compressed Internet video sources. The system organizes processors into a hierarchy of levels. Processes at each level of the hierarchy can exploit different types of parallelism and coordinate the actions of lower levels. To control the effect, control messages must be distributed to processors in the hierarchy while preserving the independence of each level. This requires a control mechanism that supports efficient delivery of messages to groups of processors, tunable reliability semantics, and recoverable state information. We describe a mechanism that meets these requirements that uses IP-Multicast, the Scalable Reliable Multicast protocol, and the Scalable Naming and Announcement Protocol. We also describe an optimization that provides a flexible framework for linking the control of different aspects of one or more related video effects.
Spin-Polarized Resonant Tunneling in Magnetic Tunnel Junctions (2002)

Insertion of a thin nonmagnetic copper Cu(001) layer between the tunnel barrier and the ferromagnetic electrode of a magnetic tunnel junction is shown to result in the oscillation of the tunnel magnetoresistance as a function of the Cu layer thickness. The effect is interpreted in terms of the formation of spin-polarized resonant tunneling. The amplitude of the oscillation is so large that even the sign of the tunnel magnetoresistance alternates. The oscillation period depends on the applied bias voltage, reflecting the energy band structure of Cu. The results are encouraging for the development of spin-dependent resonant tunneling devices.
A novel histone deacetylase inhibitor identified by high-throughput transcriptional screening of a compound library. (2000)

Libraries of compounds are increasingly becoming commercially available for the use of individual academic laboratories. A high-throughput system based on a stably integrated transcriptional reporter was used to screen a library of random compounds to identify agents that conferred robust augmentation of a signal transduction pathway. A novel histone deacetylase (HDAC) inhibitor, termed scriptaid, conferred the greatest effect, a 12- to 18-fold augmentation. This facilitation of transcriptional events was generally applicable to exogenous gene constructs, including viral and cellular promoters, different cell lines and reporter genes, and stably integrated and transiently introduced sequences. Scriptaid did not interfere with a further induction provided by stimulation of the cognate signal transduction pathway (transforming growth factor beta/Smad4), which implied the functional independence of ligand-stimulated transcriptional activation and histone acetylation states in this system. Additional insights into this and other signal transduction systems are likely to be afforded through the application of compound screening technologies.
Regeneration of the native bacteriorhodopsin structure from two chymotryptic fragments. (1983)

Chymotrypsin cleaves bacteriorhodopsin to two fragments: C-1, amino acids 72-248, and C-2, amino acids 1-71. Denaturation and renaturation of these fragments have been studied. Following denaturation in sodium dodecyl sulfate, both C-1 and C-2 regain secondary structure in phospholipid/cholate/sodium dodecyl sulfate mixed micelles. When combined, they form a complex with a secondary structure resembling that of bacterio-opsin. However, on further incubation in phospholipid/cholate/sodium dodecyl sulfate, separate fragments as well as the C-1 and C-2 complex denature again. Retinal binds tightly to the C-1 and C-2 complex (Kb greater than 10(7) M-1) and stabilizes the folded conformation. The formation of the complex of C-1, C-2, and retinal is maximal at pH 6.0. The ternary complex contains two species: one which absorbs similarly to the light-adapted purple membrane and a second with a lambda max between 450 and 500 nm. The formation of the latter species is favored at higher temperatures and is reversible. Vesicles formed from the ternary complex of C-1, C-2, and retinal translocate protons at a level close to that of intact bacteriorhodopsin.