gebhart/patrepeval huggingface dataset:
Pb Induces MCP-1 in the Choroid Plexus (2022)

Lead (Pb) is an environmental element that has been implicated in the development of dementia and Alzheimer's disease (AD). Additionally, innate immune activation contributes to AD pathophysiology. However, the mechanisms involved remain poorly understood. The choroid plexus (CP) is not only the site of cerebrospinal fluid (CSF) production, but also an important location for communication between the circulation and the CSF. In this study, we investigated the involvement of the CP during Pb exposure by evaluating the expression of the monocyte chemoattractant protein-1 (MCP-1). MCP-1 is highly expressed in the CP compared to other CNS tissues. MCP-1 regulates macrophage infiltration and is upregulated in AD brains. Our study revealed that Pb exposure stimulated MCP-1 expression, along with a significantly increased macrophage infiltration into the CP. By using cultured Z310 rat CP cells, Pb exposure stimulated MCP-1 expression in a dose-related fashion and markedly activated both NF-κB and p38 MAP kinase. Interestingly, both SB 203580, a p38 inhibitor, and BAY 11-7082, an NF-κB p65 inhibitor, significantly blocked Pb-induced MCP-1 expression. However, SB203580 did not directly inhibit NF-κB p65 phosphorylation. In conclusion, Pb exposure stimulates MCP-1 expression via the p38 and NF-κB p65 pathways along with macrophage infiltration into the CP.
Radiotherapy Fraction in Limited-Stage Small Cell Lung Cancer in the Modern Era: A Systematic Review and Meta-Analysis of 8006 Reconstructed Individual Patient Data (2022)

The optimal thoracic radiotherapy (TRT) dose and fractionation for limited-stage small cell lung cancer (LS-SCLC) using modern techniques remain unclear. We conducted systematic review and meta-analyses of the efficacy and safety differences between definitive hypofractionated TRT (HypoTRT), conventional TRT (ConvTRT) and hyperfractionated TRT (HyperTRT), especially in the modern era. Eligible randomized controlled trials (RCTs), real-world cohorts, and single-arm trials published between 1990 and 2021 were identified. Two meta-analyses of overall survival (OS) were conducted: (i) a random-effects meta-analysis based on reconstructed individual-patient data (IPD) of all studies; and (ii) a Bayesian network meta-analysis based on study-level aggregated data (AD) of RCTs. The incidences of severe radiation-related toxicities were compared using the random-effects meta-regression model. Overall, 53 of the 30,031 publications met the inclusion criteria, and a total of 8006 IPD were reconstructed. After adjusting for key treatment variables and stratification by study type, there were no significant differences in the OS rates between the altered fractionation regimens (HypoTRT vs. HyperTRT, aHR [adjusted HR] = 1.05, 95% CI 0.93-1.19; ConvTRT vs. HyperTRT, aHR = 1.00, 95% CI 0·90-1.11; HypoTRT vs. ConvTRT, aHR = 1.05, 95% CI 0.91-1.20). In the modern era, the survival outcomes of all three schedules, while remaining comparable, have improved significantly. Results of the AD-based network meta-analysis were consistent with those of IPD analysis, and HypoTRT was ranked as the best regimen (SUCRA = 81%). There were no significant differences in toxicities between groups when using modern radiation techniques. In the modern era, no significant differences in OS or severe radiation-related toxicities were observed between altered schedules in LS-SCLC. HypoTRT may be associated with moderate and non-significant OS improvements, which should be further confirmed in prospective randomized phase III trials.
The IMRT information process—mastering the degrees of freedom in external beam therapy (2006)

The techniques and procedures for intensity-modulated radiation therapy (IMRT) are reviewed in the context of the information process central to treatment planning and delivery of IMRT. A presentation is given of the evolution of the information based radiotherapy workflow and dose delivery techniques, as well as the volume and planning concepts for relating the dose information to image based patient representations. The formulation of the dose shaping process as an optimization problem is described. The different steps in the calculation flow for determination of machine parameters for dose delivery are described starting from the formulation of optimization objectives over dose calculation to optimization procedures. Finally, the main elements of the quality assurance procedure necessary for implementing IMRT clinically are reviewed.
Continuously proliferating allospecific T cells. I. Specificity of cooperation with allogeneic B cells in the humoral antibody response to sheep erythrocytes. (1979)

Allospecific mouse T cells, positively selected in one-way mixed lymphocyte culture were maintained for 3 yr in tissue culture by sequential restimulation. Such proliferating T cells were tested for their ability to induce a positive allogeneic effect: activating B cells in an in vitro primary humoral response to sheep erythrocytes. It was found that such T lymphocytes could function as helper cells. Helper activity was shown to be specific in that the B cells activated had to share major histocompatibility complex (H-2) antigens with the strain used for selection of the cell line. Intra H-2 mapping showed that antigens coded in the IAk subregion played an important role in the induction of the positive allogeneic effect. Supernatant factors could substitute for the allogeneic T cells in activation of the in vitro humoral response. However, such supernates exhibited no strain specificity. Therefore, the specificity seen in the positive allogeneic effect is presumably a consequence of the alloantigenic recognition receptors intrinsic to the T cells, and not to any biologically restricting properties of the allogeneic effect factor itself.
Inhibition of autophagy limits vertical transmission of Zika virus in pregnant mice (2017)

Zika virus (ZIKV) infection during pregnancy leads to devastating fetal outcomes, including intrauterine growth restriction and microcephaly. Greater understanding of mechanisms underlying ZIKV maternal-fetal transmission is needed to develop new therapeutic interventions. Here, we define an important role for the autophagy pathway in ZIKV vertical transmission. ZIKV infection induced autophagic activity in human trophoblasts and pharmacological inhibition limited ZIKV infectivity. Furthermore, deficiency in an essential autophagy gene, <i>Atg16l1</i>, in mice limited ZIKV vertical transmission and placental and fetal damage and overall improved placental and fetal outcomes. This protection was due to a placental trophoblast cell-autonomous effect of autophagic activity, not to alterations in systemic maternal ZIKV infection. Finally, an autophagy inhibitor, hydroxychloroquine, approved for use in pregnant women, attenuated placental and fetal ZIKV infection and ameliorated adverse placental and fetal outcomes. Our study reveals new insights into the mechanism of ZIKV vertical transmission and suggests that an autophagy-based therapeutic warrants possible evaluation in humans to diminish the risks of ZIKV maternal-fetal transmission.
<title>Optically variable devices for use on bank notes</title> (1990)

The security of bank notes against counterfeiting can be improved by the incorporation of optically variable devices (OVDs), which change their appearance when the note is viewed in different directions. Three types of OVD; holograms, multiple diffraction gratings, and thin film interference filters will be compared in relation to the special requirements unique to bank notes; security, visibility and durability. The Bank of Canada has recently issued $50 bank notes bearing a five-layer thin film interference filter. The tests which led to this particular form of OVD will be described, together with methods of deposition, quality control, and application to sheets of bank notes.
Glycoprotein biosynthesis in yeast: purification and characterization of the endoplasmic reticulum Man9 processing α-mannosidase (1991)

Saccharomyces cerevisiae Man9-alpha-mannosidase, responsible for trimming Man9GlcNAc2 in the endoplasmic reticulum to Man8GlcNAc2, the substrate for oligosaccharide elongation, has been purified to homogeneity from stabilized microsomal membranes without employing autolytic digestion. The activity was solubilized by the zwitterionic detergent, 3-[(3-cholamidopropyl)dimethyl ammonio]-1-propanesulphonate (CHAPS), whose presence was necessary for maximal activity. Purification included Q-Sepharose ion-exchange chromatography, preparative isoelectric focusing and HPLC gel filtration on TSK 3000 matrix. Overall purification from post-nuclear supernatants was estimated to be 110,000-fold with a 50% recovery of activity. The purified enzyme hydrolysed Man9GlcNAc1,2 from thyroglobulin or oligosaccharide-lipid, but not invertase Man9GlcNAc, Man1 alpha 2Man1 alpha OCH3 or p-nitrophenyl-alpha-D-mannopyranoside. Conversion of thyroglobulin Man9GlcNAc to Man8GlcNAc was linear with time and enzyme concentration, with an apparent Km of 0.2 mM and a specific activity of 220 IU/mg. Glc3Man9GlcNAc2 from oligosaccharide-lipid was as good a substrate as Man9GlcNAc, but the lipid-linked Man7GlcNAc2 isomer was hydrolysed at only 10% of this rate. Hydrolysis of defined isomers of IgM and bovine thyroglobulin Man6,7,8GlcNAc indicated that, for maximal alpha 1,2-mannosidase activity, only the alpha 1,2-linked terminal mannoses on the alpha 3 branch of the Man9GlcNAc precursor were dispensable. Isomers lacking the terminal alpha 1,2-linked mannose on the alpha 6 branch were hydrolysed at only approximately 10% of the maximal rate. The enzyme exhibited a pI of 5.3 and a pH optimum at 6.5. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis in the absence of reducing agents gave a single sharp band at 66 kDa, while in the presence of beta-mercaptoethanol equimolar amounts of two peptides, one of 44 kDa and one of 23 kDa, were obtained. Sizing on Sephacryl SF300, Superose 12 and TSK 3000 provided a holoenzyme mol. wt of 60-68 kDa, indicating that the isolated active form of the Man9-alpha-mannosidase was composed of one each of the sulphydryl-bonded dissimilar peptides. The enzyme bound to concanavalin A (ConA)-Sepharose and was eluted with alpha-methylmannoside, indicating the presence of high-mannose oligosaccharides. The Man9-alpha-mannosidase required low levels of Ca2+, which could be removed by EGTA. Activity was restored by Ca2+ or Zn2+, but not by Mg2+ or Mn2+.
Simultaneous Orientation Locking and Translation of Samples with Phased Arrays (2022)

Acoustic levitation allows non-contact, non-destructive and non-contaminating handling of samples. Acoustic levitation is possible by overcoming gravity through acoustic radiation force. Simultaneous orientation locking and translation has been demonstrated before. Here, we demonstrate the use of these methods for precise manipulation of multiple samples simultaneously. The ability to control orientation while simultaneously translating samples could prove useful in many fields from chemistry to the assembly of small electronics. The acoustic pressure field was created with an acoustic levitator that features 450 transducers controlled by FPGAs. The FPGAs allow for amplitude, phase, and frequency control for each transducer individually.
Reduction of plasma angiotensin II to normal levels by antisense oligodeoxynucleotides against liver angiotensinogen cannot completely attenuate vascular remodeling in spontaneously hypertensive rats (2000)

On the basis of these findings, plasma AGT is thus considered to play a role in the development of hypertrophy of smooth muscle in the aorta of SHRs, it is thought to have only a slight effect, however, on the remodeling of the matrix tissue when the suppression of hypertension is insufficient.
Densification and Microhardness of Spark Plasma Sintered ZrB2+SiC Nano-Composites (2015)

Ultra-High-Temperature Ceramics (UHTCs) such as ZrB2 and HfB2 with incorporation of SiC nanofiller are useful as structural materials for applications in propulsion and thermal protection systems such as turbine-engine hot section components, leading edge of hypersonic vehicles, where extremely high heat fluxes generate very high temperatures and steep temperature gradients [1]. Spark plasma sintering (SPS) technique is used for densifying the UHTCs under the influence of uniaxial pressure and pulsed direct current [2]. Here, we study the densification, grain growth, and microhardness of ZrB2 nanocomposites with 15% and 20% SiC consolidated using SPS.
Sieving gases with twisty polymers (2022)

Ladder polymers in three dimensions show promise as gas-separation membranes.
Trans-4-hydroxy-L-proline production by the cyanobacterium Synechocystis sp. PCC 6803 (2020)

Cyanobacteria play an important role in photobiotechnology. Yet, one of their key central metabolic pathways, the tricarboxylic acid (TCA) cycle, has a unique architecture compared to most heterotrophs and still remains largely unexploited. The conversion of 2-oxoglutarate to succinate via succinyl-CoA is absent but is by-passed by several other reactions. Overall, fluxes under photoautotrophic growth conditions through the TCA cycle are low, which has implications for the production of chemicals. In this study, we investigate the capacity of the TCA cycle of <i>Synechocystis</i> sp PCC 6803 for the production of <i>trans</i>-4-hydroxy-L-proline (Hyp), a valuable chiral building block for the pharmaceutical and cosmetic industries. For the first time, photoautotrophic Hyp production was achieved in a cyanobacterium expressing the gene for the L-proline-4-hydroxylase (P4H) from <i>Dactylosporangium</i> sp. strain RH1. Interestingly, while elevated intracellular Hyp concentrations could be detected in the recombinant <i>Synechocystis</i> strains under all tested conditions, detectable Hyp secretion into the medium was only observed when the pH of the medium exceeded 9.5 and mostly in the late phases of the cultivation. We compared the rates obtained for autotrophic Hyp production with published sugar-based production rates in <i>E. coli</i>. The land-use efficiency (space-time yield) of the phototrophic process is already in the same order of magnitude as the heterotrophic process considering sugar farming as well. But, the remarkable plasticity of the cyanobacterial TCA cycle promises the potential for a 23-55 fold increase in space-time yield when using <i>Synechocystis</i>. Altogether, these findings contribute to a better understanding of bioproduction from the TCA cycle in photoautotrophs and broaden the spectrum of chemicals produced in metabolically engineered cyanobacteria.
Allosteric Regulation of Glycogen Phosphorylase by Order/Disorder Transition of the 250′ and 280s Loops (2023)

Allostery is a fundamental mechanism of protein activation, yet the precise dynamic changes that underlie functional regulation of allosteric enzymes, such as glycogen phosphorylase (GlyP), remain poorly understood. Despite being the first allosteric enzyme described, its structural regulation is still a challenging problem: the key regulatory loops of the GlyP active site (250' and 280s) are weakly stable and often missing density or have large b-factors in structural models. This led to the longstanding hypothesis that GlyP regulation is achieved through gating of the active site by (dis)order transitions, as first proposed by Barford and Johnson. However, testing this requires a quantitative measurement of weakly stable local structure which, to date, has been technically challenging in such a large protein. Hydrogen-deuterium-exchange mass spectrometry (HDX-MS) is a powerful tool for studying protein dynamics, and millisecond HDX-MS has the ability to measure site-localized stability differences in weakly stable structures, making it particularly valuable for investigating allosteric regulation in GlyP. Here, we used millisecond HDX-MS to measure the local structural perturbations of glycogen phosphorylase b (GlyPb), the phosphorylated active form (GlyPa), and the inhibited glucose-6 phosphate complex (GlyPb:G6P) at near-amino acid resolution. Our results support the Barford and Johnson hypothesis for GlyP regulation by providing insight into the dynamic changes of the key regulatory loops.
On shooting methods for calculation of potential resonances (1996)

Two shooting methods for calculation of potential (shape) resonances are described and their efficiency tested. It is found that although both methods are based on calculation of the Siegert (i.e. exponentially increasing non-normalizable) state, the methods are stable and very accurate values of resonance energies and widths are obtainable. It is hoped that the resonance parameters obtained here can serve as test examples for various approximate methods for calculating resonance energies and widths.
Spectroscopy of hydroxyphenyl benzazoles in solution and human serum albumin: detecting flexibility, specificity and high affinity of the warfarin drug binding site (2013)

The complex photophysics of 2-(2′-hydroxyphenyl)benzoxazole (HBO), 2-(2′-hydroxyphenyl)benzimidazole (HBI), and 2-(2′-hydroxyphenyl)benzothiazole (HBT) in different media makes them suitable as fluorescent probes to study the nature of binding sites in macromolecular systems. In this work, we investigate the spectroscopy of the three benzazole derivatives (HBXs) in different solvents and in human serum albumin (HSA) in order to understand the binding mechanism in subdomain IIA of HSA which has the ability to host a large variety of natural and pharmaceutical compounds. The three probes are found to specifically bind close to W214, the sole tryptophan residue in HSA, in a mode similar to that of the binding of the anticoagulant drug warfarin. The current results show that the structural differences between the three HBX molecules did not produce any measurable effects when binding with HSA. In particular, the change in planarity of the molecular backbone, from a perfectly planar and more rigid structure (HBO) to a twisted structure (HBI) and a flexible structure (HBT) has no effect on the mode of binding. Also, the strength of the intramolecular hydrogen bonds in HBXs (HBO > HBT > HBI) is shown not to intervene with the ability of HSA to ionize the ligands via through-space interaction with polar amino acid residues, similar to enzymatic reactions. The results emphasize the nature of HSA as a versatile and indiscriminate receptor, capable of binding a variety of ligands by adapting its binding pockets. In this regard, binding of HBXs, and other structurally similar ligands, in subdomain IIA is best described by the induced-fit model in which considerable flexibility of the binding site is necessary for molecular recognition. The results also point to the high affinity of the warfarin binding pocket (within subdomain IIA) for binding versatile molecular structures including several drugs. This affinity stems from the flexibility of the amino acids forming the binding pocket.
The Cloning of the Gene for Hereditary Hemochromatosis (2012)

Featured Article: Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 1996;13: 399–408.4

The early 1990s represented the beginning of modern-day human genomics. Methodologies for genetic linkage analysis of human disease genes had become well established, and a new class of polymorphic microsatellite genetic markers had recently been discovered. The ability to manipulate human genomic DNA as yeast and bacterial artificial chromosomes, coupled with these new tools, provided an unprecedented way to construct detailed physical and genetic maps. Combining these maps with emerging technologies to identify expressed sequences, as well as the introduction of high-throughput capillary-based DNA sequencing, made gene finding more tractable than ever. Collectively, the application of these methods to the isolation of human disease genes was known as “positional cloning,” and the early 1990s saw the emergence of several biotechnology companies founded to capitalize on the confluence of these technologies.

One of these companies was Mercator Genetics of Menlo Park, California. The company's plan was simple: establish a positional cloning platform and “rapidly” …
Perceptual Learning of Temporally Based Auditory Skills Thought to Be Deficient in Children With Specific Language Impairment (2012)

Learning problems related to speech and language processing affect approximately 1 child in 12 who is otherwise unimpaired. These children, numbering over 3.5 million in the United States (U.S. Department of Education, 1995), have extreme difficulties producing and understanding spoken language. This disorder, referred to as specific language impairment (SLI), can impede the academic performance and social interactions of affected children, and, consequently, can have a profound negative impact on their adult lives. Several years ago, my colleagues and I reported that children with SLI have markedly abnormal patterns of auditory masking. In the first half of this chapter I briefly review the background for that experiment, summarize our data, and describe how our results relate to the question of whether perceptual impairments contribute to the speech perception deficits associated with SLI.
The gut microbiota and colon cancer (2019)

Microbiome data should be incorporated into the prevention, diagnosis, and treatment of colon cancer
Reliability of MEM relays for zero leakage logic (2013)

Micro-electro-mechanical (MEM) relays are an intriguing alternative to transistors for ultra-low-power digital logic applications [1]. This paper investigates various failure modes for logic relays. Experimental results are presented to show that structural fatigue, dielectric charging, and contact stiction are not reliability-limiting issues. Contact resistance instability caused by surface oxidation and contamination is the primary challenge, and can be influenced by device design and operating conditions.
Amino acid sequence of the light chain variable region from a mouse anti-digoxin hybridoma antibody (1983)

A hybridoma cell line (26-10) derived from the A/J strain of mice secretes an immunoglobulin (IgG2a-k) which binds digoxin with an association constant of 1.2 nM. Such high-affinity antibodies have been utilized in clinical radioimmunoassays as well as in the reversal of toxicity due to excess digoxin. The amino acid sequence of the light chain variable region of this antibody was derived by automated sequencing of the following: the intact chain; a fragment beginning C terminal to the tryptophan residue 40, obtained by cleavage with iodosobenzoic acid; a fragment beginning C terminal to arginine residue 82, obtained by trypsin cleavage on the completely reduced, alkylated, and succinylated chain. Difficulties which had previously prevented the automated Edman sequencing of this chain (and, presumably, similar ones of the same subgroup) were overcome by increasing the duration of the cleavage step at proline residues 8 and 12. The sequences of the first two hypervariable and framework regions of this chain are virtually identical with those of the dinitrophenol- and menadione-binding myeloma light chain MOPC 460 (95% homology). This anti-digoxin hybridoma from the A/J strain makes use of a Vk gene which is similar to that utilized by some BALB/c 2,4-dinitrophenol-binding myelomas.