gebhart/patrepeval huggingface dataset:
Thermodynamic consequences of changing a sulfur atom to a methylene group in the M13Nle mutation in Ribonuclease-S (1994)

Two fragments of pancreatic ribonuclease A, a truncated version of S-peptide (residues 1-15) and 

S-protein (residues 21-124), combine to give a catalytically active complex. We have substituted the wild-type 

residue at position 13, methionine (Met), with norleucine (Nle), where the only covalent change is the replacement 

of the sulfur atom with a methylene group. The thermodynamic parameters associated with the binding of this 

variant to S-protein, determined by titration calorimetry in the temperature range 10-40 °C, are reported and 

compared to values previously reported [Varadarajan, R., Connelly, P. R., Sturtevant, J. M., & Richards, F. 

M. (1992) Biochemistry 31, 1421-1426] for other position 13 analogs. The differences in the free energy and 

enthalpy of binding between the Met and Nle peptides are 0.6 and 7.9 kcal/mol at 25° C, respectively. These 

differences are slightly larger than, but comparable to, the differences in the values for the Met/Ile and Met/Leu 

pairs. The structure of the mutant complex was determined to 1.85 Angstrom resolution and refined to an R-factor 

of 17.4% The structures of mutant and wild-type complexes are practically identical although the Nle side chain has 

a significantly higher average B-factor than the corresponding Met side chain. In contrast, the B-factors of the 

atoms of the cage of residues surrounding position 13 are all somewhat lower in the Nle variant than in the Met 

wild-type. Thus, the large differences in the binding enthalpy appear to reside entirely in the difference in chemical 

properties or dynamic behavior of the -S- and -CH 2 - groups and not in differences in the geometry 

of the side chains or the internal cavity surface. In addition, a novel method of obtaining protein stability data by 

means of isothermal titration calorimetry is introduced.
Human T‐cell responses to the RD1‐encoded protein TB27.4 (Rv3878) from Mycobacterium tuberculosis (2003)

In recent years, there has been considerable focus on the discovery and characterization of proteins derived from Mycobacterium tuberculosis leading to the identification of a number of candidate antigens for use in vaccine development or for diagnostic purposes. Previous experiments have demonstrated an important immunological role for proteins encoded by the RD1 region, which is absent from all strains of bacillus Calmette-Guérin (BCG) but present in the genomes of virulent M. bovis and M. tuberculosis. Herein, we have studied human T-cell responses to the antigen encoded by the putative open reading frame (rv3878) of the RD1 region. Immunoblot analysis revealed that rv3878 was expressed and the native protein was designated TB27.4. Immunological evaluations demonstrate that TB27.4 elicits a prominent immune response in human tuberculosis patients with a dominant region in the C-terminal part of the molecule. In contrast, very limited responses were seen in M. bovis BCG-vaccinated donors. This study therefore emphasizes the diagnostic potential of proteins encoded by the RD1 region.
Melanocortin 2, 3 and 4 Receptor Gene Expressions are Downregulated in CD8+ T Cytotoxic Lymphocytes and CD19+ B Lymphocytes in Rheumatoid Arthritis Responding to TNF‐α Inhibition (2017)

Melanocortin signalling in leucocyte subsets elicits anti-inflammatory and immune tolerance inducing effects in animal experimental inflammation. In man, however, the effects of melanocortin signalling in inflammatory conditions have scarcely been examined. We explored the differential reactions of melanocortin 1-5 receptors (MC1-5R) gene expressions in pathogenetic leucocyte subsets in rheumatoid arthritis (RA) to treatment with TNF-α inhibitor adalimumab. Seven patients with active RA donated blood at start and at 3-month treatment. CD4<sup>+</sup> T helper (h) lymphocytes (ly), CD8<sup>+</sup> T cytotoxic (c) ly, CD19<sup>+</sup> B ly and CD14<sup>+</sup> monocytes were isolated, using immunomagnetic beads, total RNA extracted and reverse transcription quantitative polymerase chain reaction (RT-qPCR) performed. Fold changes in MC1-5R, Th1-, inflammatory- and regulatory cytokine gene expressions were assessed for correlation. Six patients responded to adalimumab treatment, while one patient was non-responder. In all lymphocyte subtypes, MC1-5R gene expressions decreased in responders and increased in the non-responder. In responders, decrease in MC2R, MC3R and MC4R gene expressions in CD8<sup>+</sup> Tc and CD19<sup>+</sup> B ly was significant. Fold change in MC1-5R and IFNγ gene expressions correlated significantly in CD8<sup>+</sup> Tc ly, while fold change in MC1R, MC3R and MC5R and IL-1β gene expressions correlated significantly in CD4<sup>+</sup> Th ly. Our results show regulation of MC2R, MC3R and MC4R gene expressions in CD8<sup>+</sup> Tc ly and CD19<sup>+</sup> B ly. The correlations between fold change in different MCRs and disease driving cytokine gene expressions in CD8<sup>+</sup> Tc ly and CD4<sup>+</sup> Th ly point at a central immune modulating function of the melanocortin system in RA.
Proof-of-Concept of the Time and Spectral Optical Aggregation Network (2020)

In this article, we present the proof of concept (PoC) of the time and spectral optical aggregation (TISA) approach that allows a better filling of the time and spectral resources of an optical transport network. Some innovative solutions have been implemented, such as a new and fast tunable laser that permits to color the bursts sent in the TISA network, as well as their transmission with both DP-QPSK and DP-16QAM coherent multi-band (MB) OFDM formats. BER versus OSNR measurements have been achieved showing less than 1-dB penalty in back-to-back or after transmission. The tolerance of bursts against frequency mismatch occurring between the transceiver and the optical filter that extracts a sub-band inside the MB-OFDM signal has also been evaluated, and ~1.5 GHz tolerance has been measured for bursts of ~6.7 GHz bandwidth. Furthermore, in order to mitigate the transients in the coherent receiver that faces alternatively the presence or absence of signal, a novel channel estimator based on a sliding window has been introduced. Its efficiency and performance has been experimentally validated, and its ability to suppress the error threshold of the BER versus OSNR curves has been demonstrated. By the experimental proof of concept delivered here, the ability of the TISA network to perform with a good level of performance the transparent routing and sub-wavelength aggregation/disaggregation in the time and spectral domains simultaneously has been established. Beyond the important and crucial aspect of the optimal filling of the optical resources, our PoC demonstrate the ability of the TISA approach to push the flexibility of an optical transport network at its limit while allowing a cost and power consumption limitation obtained by the removal of costly and power-hungry optical-electrical-optical regenerators.
Insulin Regulation of Sugar Transport in Isolated Pancreatic Acini from Diabetic Mice (1982)

Insulin-stimulated sugar transport was studied in isolated pancreatic acini prepared from streptozotocintreated mice. In this tissue, insulin increased the uptake of two nonmetabolized D-glucose analogues, [3H] 2-deoxy-D-glucose (2DG), and [3H]3-O-methyl-D-glucose (30MG), but had no effect on the uptake of [3H] L-glucose. A significant effect of insulin on 2DG uptake was seen at 100 pM, whereas a maximal effect required a concentration of 100 nM. The action of insulin on 2DG uptake was time-dependent; 90 min was required for a maximal hormonal effect. This increase in 2DG uptake was due to a greater than twofold increase in the maximal rate of uptake (Vmax); no significant effects were seen on Km. The mode of insulin action on sugar transport was investigated further. In pancreatic acinar cells, insulin did not alter either membrane potential or 45Ca2+ efflux, two proposed mechanisms for regulation of sugar transport in other tissues. The action of insulin was not due to either contamination with cholecystokinin (CCK) or an action via the CCK receptor. CCK is known to stimulate sugar transport in isolated pancreatic acini via the elevation of intracellular Ca2+. The effect of insulin on 2DG uptake, however, was additive to that of CCK; conversely, dibutyryl cyclic GMP, a known competitive antagonist of CCK, had no effect on insulin stimulation of 2DG uptake, insulin increased 2DG uptake in the presence of 10 μM puromycin, a concentration sufficient to inhibit greater than 90% of protein synthesis. Dihydrocytochalasin B, a compound known to alter acinar cell motility by disrupting microfilaments, progressively blocked insulin stimulation of 2DG uptake over a drug concentrationrange of 1–15 μg/ml These data suggest, therefore,that the time-dependent increase of sugar transport by insulin is unrelated to electrical potential, 45Ca2+ efflux, and new protein synthesis, but may result from a microfilament-related translocation of glucose carrier sites to the plasma membrane.
A dc method for the absolute determination of conductivities of the primary standard KCl solutions from 0-degrees-C to 50-degrees-C (1994)

A new method for the absolute determination of electrolytic conductivity based on direct current and Potentiometric measurements is described. The unique design of the cell uses a removable center section whose length and cross-sectional area are accurately known. Two pairs of matched Ag, AgCl electrodes are used in a four terminal mode of resistance measurement. Measurements of the electrolytic conductivity of primary standard potassium chloride solution using [his novel dc conductance cell are compared with the currently adopted IUPAC and OIML recommendations. In addition, measurements have heen made of the electrolytic conductivity of a solution of potassium chloride having a molality of 1 mol/kg (mole KCl per kilogram H<sub>2</sub>O). The values so obtained over the temperature range of 0 °C to 50 °C are recommended as the new primary standards for electrolytic conductivity.
Final results of a randomized phase II study of perifosine in combination with capecitabine (P-CAP) versus placebo plus capecitabine (CAP) in patients (pts) with second- or third-line metastatic colorectal cancer (mCRC). (2010)

3531 Background: Perifosine (P), a synthetic alkylphospholipid, inhibits or modifies signal transduction pathways including AKT, MAPK and JNK. We previously reported initial results of a phase II randomized study of P-CAP vs. CAP which demonstrated improved clinical activity of P-CAP over CAP in pts with mCRC. We now report the final safety, overall response rate (ORR), time to progression (TTP) and overall survival (OS) results. Methods: Pts with 2nd or 3rd line mCRC and no previous CAP in metastatic setting were randomized to P-CAP (P 50 mg PO QD + CAP 825 mg/m2 PO BID d1-14) or CAP (placebo + CAP 825 mg/m2 PO BID d 1-14). Cycles were 21 days. Results: 38 pts were randomized (20 P-CAP/18 CAP). Median age 67 (32-83); 61% male. Median prior Rx = 2 (1–5). Prior Rx of P-CAP arm vs. CAP arm: FOLFIRI (90% vs. 87%); FOLFOX (75% vs. 73%); bevacizumab (75% vs. 80%); EGFR antibody (45% vs. 60%); progressed on prior 5-FU-based Rx (70% vs. 73%). All 38 pts were evaluable for toxicity. Most frequent AEs (P-CAP vs. CAP): G3 /4: hand/foot syndrome (HFS) (30% vs. 0%), anemia (15% vs. 0%), fatigue (0% vs. 11%), bowel obstruction (0% vs. 11%); G1/2: diarrhea (65% vs. 28%), nausea (45% vs. 28%), fatigue (50% vs. 33%), HFS (25% vs. 22%). 35/38 pts were evaluable for response (3 CAP pts off study for AE). Results for P-CAP vs. CAP: ORR: 20% vs. 7%; Median TTP: 28 vs. 11 wks (p=0.012); and OS: 18 vs. 11 mos (p=0.0136). Subset analysis in pts with 5-FU refractory disease is shown in the Table. Conclusions: P-CAP is a well-tolerated regimen that has promising activity over CAP as 2nd or 3rd line therapy for pts with metastatic colorectal cancer. This improvement is consistent for the subset of pts with 5-FU refractory disease. A randomized phase III trial of P-CAP vs. CAP is planned for refractory colorectal cancer pts. Group 5-FU ref n (%) PR/SD Median TTP wks Median OS mos P-CAP 14 (70%) 1/8 18 [95% CI (12-36)] p=0.0004 15.3 [95% CI (8.4-26)] p=0.0088 CAP 11 (73%) 0/3 10 [95% CI (6.6-11)] 6.8 [95% CI (4.8-11.7)] Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Keryx Biopharmaceuticals Keryx Biopharmaceuticals Keryx Biopharmaceuticals
Abstract 5615: Antibodies targeting TIP1 enhance the efficacy of radiotherapy in lung cancer and glioblastoma (2018)

Abstract Antigens that are over-expressed in cancer in response to radiation are being used as novel targets. We showed tax interacting protein 1 (TIP-1) to be radiation-inducible that translocated to the surface of the cancer cell following irradiation. TIP-1, which consists of a single PDZ domain plays an important role in cell signaling, cancer development, and progression. TIP-1's involvement in various survival pathways makes it an attractive target for anticancer therapeutics. We used antibodies specific to this PDZ domain to determine its role in cancer cell survival. We monitored the proliferation of lung cancer (A549 and H460) and glioblastoma (D54 and U251) cells after 24, 48, 72 and 96h treatment with the anti-PDZ antibody. We observed a time-dependent proliferation arrest with anti-PDZ antibody treatment which was associated with increased apoptosis. The anti-PDZ antibody, when combined with radiation (3Gy), led to reduced proliferation and colony formation. Anti-PDZ antibody had no effect on the proliferation of normal lung (MRC-5) and endothelial (HUVEC) cells. Cells treated with anti-PDZ antibody showed decreased levels of the phosphorylated forms of AKT, mTOR, and a downstream substrate of mTOR, 4EBP1. Anti-PDZ antibody treatment also led to an overall reduction in basal levels of AKT, mTOR, and 4EBP1. Further, we evaluated the effect of the anti-PDZ antibody on tumor growth in heterotopic mouse models of lung cancer (A549) and glioma (U251). We observed significant growth delay in mice treated with anti-PDZ antibody treatment when compared to mice treated with the isotype control. The combination of the anti-PDZ antibody with radiation showed an additive effect. Immunoblot analysis of tumor tissues also showed downregulation of phosphorylated and total levels of AKT, mTOR and 4EBP1 in the tumors treated with anti-PDZ antibody. Overall, our results suggest that TIP-1 is a promising therapeutic target for treatment of lung cancer and glioblastoma. Antibodies specific to the PDZ domain of TIP-1 enhance the efficacy of radiotherapy. The anti-PDZ antibodies need to be optimized further before translating it into the clinic. Citation Format: Vaishali Kapoor, Abhay K. Singh, David Dadey, Kelly Hoye, Andrea Collins, Dinesh Thotala, Dennis Hallahan. Antibodies targeting TIP1 enhance the efficacy of radiotherapy in lung cancer and glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5615.
Highly Selective Tau-SPECT Imaging Probes for Detection of Neurofibrillary Tangles in Alzheimer’s Disease (2016)

Neurofibrillary tangles composed of aggregates of hyperphosphorylated tau proteins are one of the neuropathological hallmarks of Alzheimer's disease (AD) in addition to the deposition of β-amyloid plaques. Since the deposition of tau aggregates is closely associated with the severity of AD, the in vivo detection of tau aggregates may be useful as a biomarker for the diagnosis and progression of AD. In this study, we designed and synthesized a new series of radioiodinated benzoimidazopyridine (BIP) derivatives, and evaluated their utility as single photon emission computed tomography (SPECT) imaging agents targeting tau aggregates in AD brains. Five radioiodinated BIP derivatives were successfully prepared in high radiochemical yields and purities. In in vitro autoradiographic studies using postmortem AD brains, all BIP derivatives displayed high accumulation of radioactivity in the brain sections with abundant neurofibrillary tangles, while no marked radioactivity accumulation was observed in the brain sections with only β-amyloid aggregates, indicating that the BIP derivatives exhibited selective binding to tau aggregates. Biodistribution studies in normal mice showed high brain uptake at 2 min postinjection (3.5-4.7% ID/g) and rapid clearance at 60 min postinjection (0.04-0.23% ID/g), which is highly desirable for tau imaging agents. The results of the present study suggest that [<sup>123</sup>I]BIP derivatives may be useful SPECT agents for the in vivo imaging of tau aggregates in AD.
Purification of mammalian filamin. Similarity to high molecular weight actin-binding protein in macrophages, platelets, fibroblasts, and other tissues. (1978)

We have purified the high molecular weight actin-binding protein, filamin from guinea pig vas deferens. We find this mammalian filamin is very similar to chicken gizzard filamin in subunit molecular weight, amnio acid composition, actin-binding properties, immunological cross-reactivity, and the ability to be phosphorylated by cyclic AMP-dependent protein kinase. Anti-filamin antibodies cross-react with a high molecular weight macrophage actin-binding protein, and with a high molecular weight protein in platelets and fibroblasts. Furthermore like filamin, these proteins are also phosphorylated and cyclic AMP stimulates their phosphorylation. Anti-filamin antibodies do not cross-react with the erythrocyte membrane protein spectrin or with high molecular weight proteins in brain extracts. We conclude that filamin from avian and mammalian smooth muscle are very similar proteins and furthermore that many, but not all, non-muscle cells contain a protein closely related to filamin.
(7-Benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic Acids as S1P1 Functional Antagonists (2014)

S1P1 is a validated target for treatment of autoimmune disease, and functional antagonists with superior safety and pharmacokinetic properties are being sought as second generation therapeutics. We describe the discovery and optimization of (7-benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acids as potent, centrally available, direct acting S1P1 functional antagonists, with favorable pharmacokinetic and safety properties.
Strategic Petroleum Reserve Cemented Annulus Modeling and Testing; FY16 Progress (2016)

Sandia National Laboratories has begun developing modeling and analysis tools of flow through the cemented port ion of a cemented annulus in a Strategic Petroleum Reserve (SPR) well since August of 201 5 . The goal of this work is to develop model s and testing procedures to diagnose the health of cemented annuli at SPR sites. In Fiscal Year 2016 (FY16), we have developed several tests and associated models that we believe are sufficient for this purpose. This report outlines progress made in FY16 and future work.
Developments in liquid-crystalline dimers and oligomers (2017)

Liquid-crystalline dimers and bimesogens have attracted much attention due to their propensity to exhibit the spontaneously chiral twist-bend mesophase (NTB), most often by dimers with methylene spacers. Despite their relative ease of synthesis, the number of ether-linked twist-bend materials significantly lags behind those of methylene-linked compounds. In this work, we have prepared and studied a range of ether-linked bimesogens homologous in structure to the FFO9OCB; as with methylene-linked systems, it appears that it is molecular topology and the gross molecular shape that are the primary drivers for the formation of this phase of matter. Dimers and bimesogens are well studied within the context of the twist-bend phase; however, present understanding of this mesophase in oligomeric systems lags far behind. We report our recent efforts to prepare further examples of oligomeric twist-bend nematogens, including further examples of our ‘n+1’ methodology, which may allow the synthesis of high-purity, monodisperse materials of any given length to be prepared. We have observed that there is a tendency for these materials to exhibit highly ordered soft-crystalline mesophases as opposed to the twist-bend phase.
Reconstructions of images of partially coherent objects from samples of mutual intensity (1977)

It is known that if the mutual intensity is sampled on an array of spacings, such samples can be Fourier transformed to yield images of incoherently radiating objects. In this paper, this result is extended to the imaging of partially coherent and coherent objects. An analysis of partially coherent imaging is first developed using a rather new approach, and the role of the complex ambiguity function in such imaging is emphasized. Next, using sampling theory, it is shown that in order to reconstruct images of partially coherent objects it is necessary to sample the mutual intensity on a discrete array of translations as well as on a discrete array of spacings. The required spacing and translation increments are shown to be inversely proportional to the object size and coherence extent, respectively. These requirements are stated in the form of a sampling theorem. Based on these results, an image synthesis procedure is outlined, and the capability of such a procedure for removing misfocus and other imaging aberrations is discussed. Lastly, experimental results are presented that demonstrate the aberration removal capability of this technique, using a coherent imaging system with defocus error.
Intestinal Secretion Induced by Vasoactive Intestinal Polypeptide (1978)

A B S T R A C T The effect of vasoactive intestinal poly- peptide (VIP) on intestinal water and electrolyte trans- port and transmucosal potential difference was inves- tigated in the dog jejunum in vivo and compared to secretion induced by cholera toxin. Isolated jejunal loops were perfused with a plasma-like electrolyte so- lution. VIP (0.08 ug/kg per min) was administered di- rectly into the superior mesenteric artery by contin- uous infusion over 1 h. From a dye dilution method, it was estimated that a mean plasma VIP concentra- tion of 12,460 pglml reached the loops. VIP caused secretion of water and electrolytes; for example, chlo- ride: control, 8 ,ueq/cm per h absorption; VIP, 92 ,eq/ cm per h secretion. A marked increase in transmucosal potential difference (control, -1.0 mV; VIP, -5.9 mV, lumen negative) occurred within 1 min after starting VIP infusion. Analysis of unidirectional fluxes showed increased plasma-to-lumen flux of sodium and chloride and decreased lumen-to-plasma flux of sodium. Chlo- ride and bicarbonate were actively secreted against an electrochemical gradient. Although sodium secretion occurred down an electrochemical gradient, flux ratio analysis suggested a component of active sodium se- cretion. VIP caused a slight increase in protein out- put into the loops; light microscopy revealed capillary dilatation and closed intercellular spaces. The effect of VIP was readily reversible. Except for the delayed onset of secretion, the effect of cholera toxin was qualitatively similar to VIP; however, capillary dilatation and increased protein output were not noted with cholera toxin.
Improved Z-scan techniques for ultrasensitive measurements of nonlinear refraction and absorption (1993)

Z-scan is a method for measuring both nonlinear refraction and absorption using a single beam. Changes in transmission of the beam through a far-field, on-axis aperture are measured as the sample is scanned through the focal plane[1].