gebhart/patrepeval huggingface dataset:
Redox-mediated activation of latent transforming growth factor-beta 1. (1996)

Transforming growth factor beta 1 (TGF beta) is a multifunctional cytokine that orchestrates response to injury via ubiquitous cell surface receptors. The biological activity of TGF beta is restrained by its secretion as a latent complex (LTGF beta) such that activation determines the extent of TGF beta activity during physiological and pathological events. TGF beta action has been implicated in a variety of reactive oxygen-mediated tissue processes, particularly inflammation, and in pathologies such as reperfusion injury, rheumatoid arthritis, and atherosclerosis. It was recently shown to be rapidly activated after in vivo radiation exposure, which also generates reactive oxygen species (ROS). In the present studies, the potential for redox-mediated LTGF beta activation was investigated using a cell-free system in which ROS were generated in solution by ionizing radiation or metal ion-catalyzed ascorbate reaction. Irradiation (100 Gray) of recombinant human LTGF beta in solution induced 26% activation compared with that elicited by standard thermal activation. Metal-catalyzed ascorbate oxidation elicited extremely efficient recombinant LTGF beta activation that matched or exceeded thermal activation. The efficiency of ascorbate activation depended on ascorbate concentrations and the presence of transition metal ions. We postulate that oxidation of specific amino acids in the latency-conferring peptide leads to a conformation change in the latent complex that allows release of TGF beta. Oxidative activation offers a novel route for the involvement of TGF beta in tissue processes in which ROS are implicated and endows LTGF beta with the ability to act as a sensor of oxidative stress and, by releasing TGF beta, to function as a signal for orchestrating the response of multiple cell types. LTGF beta redox sensitivity is presumably directed toward recovery of homeostasis; however, oxidation may also be a mechanism of LTGF beta activation that can be deleterious during disease mechanisms involving chronic ROS production.
Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy (2015)

Aging reduces skeletal muscle mass and strength, but the underlying molecular mechanisms remain elusive. Here, we used mouse models to investigate molecular mechanisms of age-related skeletal muscle weakness and atrophy as well as new potential interventions for these conditions. We identified two small molecules that significantly reduce age-related deficits in skeletal muscle strength, quality, and mass: ursolic acid (a pentacyclic triterpenoid found in apples) and tomatidine (a steroidal alkaloid derived from green tomatoes). Because small molecule inhibitors can sometimes provide mechanistic insight into disease processes, we used ursolic acid and tomatidine to investigate the pathogenesis of age-related muscle weakness and atrophy. We found that ursolic acid and tomatidine generate hundreds of small positive and negative changes in mRNA levels in aged skeletal muscle, and the mRNA expression signatures of the two compounds are remarkably similar. Interestingly, a subset of the mRNAs repressed by ursolic acid and tomatidine in aged muscle are positively regulated by activating transcription factor 4 (ATF4). Based on this finding, we investigated ATF4 as a potential mediator of age-related muscle weakness and atrophy. We found that a targeted reduction in skeletal muscle ATF4 expression reduces age-related deficits in skeletal muscle strength, quality, and mass, similar to ursolic acid and tomatidine. These results elucidate ATF4 as a critical mediator of age-related muscle weakness and atrophy. In addition, these results identify ursolic acid and tomatidine as potential agents and/or lead compounds for reducing ATF4 activity, weakness, and atrophy in aged skeletal muscle.
The Length of Homology Required for Gene Targeting in Embryonic Stem Cells (1991)

Homologous recombination has been used to introduce site-specific mutations into murine embryonic stem (ES) cells with both insertion and replacement vectors. In this study, we compared the frequency of gene targeting with various lengths of homology and found a dramatic increase in targeting with an increase in homology from 1.3 to 6.8 kb. We examined in detail the relationship between the length of homology and the gene-targeting frequency for replacement vectors and found that a critical length of homology is needed for targeting. Adding greater lengths of homology to this critical length has less of an effect on the targeting frequency. We also analyzed the lengths of homology necessary on both arms of the vector for gene replacement events and found that 472 bp of homology is used as efficiently as 1.2 kb in the formation and resolution of crossover junctions.
Retinoids irreversibly inhibit in vitro growth of Epstein-Barr virus- immortalized B lymphocytes (1996)

Natural and synthetic retinoids have proved to be effective in the treatment and prevention of various human cancers. In the present study, we investigated the effect of retinoids on Epstein-Barr virus (EBV)-infected lymphoblastoid cell lines (LCLs), since these cells closely resemble those that give rise to EBV-related lymphoproliferative disorders in the immunosuppressed host. All six compounds tested inhibited LCL proliferation with no significant direct cytotoxicity, but 9-cis-retinoic acid (RA), 13-cis-RA, and all-trans-RA (ATRA) were markedly more efficacious than Ro40-8757, Ro13-6298, and etretinate. The antiproliferative action of the three most effective compounds was confirmed in a large panel of LCLs, thus appearing as a generalized phenomenon in these cells. LCL growth was irreversibly inhibited even after 2 days of treatment at drug concentrations corresponding to therapeutically achievable plasma levels. Retinoid-treated cells showed a marked downregulation of CD71 and a decreased S-phase compartment with a parallel accumulation in Gzero/ G1 phases. These cell cycle perturbations were associated with the upregulation of p27 Kip1, a nuclear protein that controls entrance and progression through the cell cycle by inhibiting several cyclin/cyclin-dependent kinase complexes. Unlike what is observed in other systems, the antiproliferative effect exerted by retinoids on LCLs was not due to the acquisition of a terminally differentiated status. In fact, retinoid-induced modifications of cell morphology, phenotype (downregulation of CD19, HLA-DR, and s-Ig, and increased expression of CD38 and c-Ig), and IgM production were late events, highly heterogeneous, and often slightly relevant, being therefore only partially indicative of a drug-related differentiative process. Moreover, EBV-encoded EBV nuclear antigen-2 and latent membrane protein-1 proteins were inconstantly downregulated by retinoids, indicating that their growth-inhibitory effect is not mediated by a direct modulation of viral latent antigen expression. The strong antiproliferative activity exerted by retinoids in our experimental model indicates that these compounds may represent a useful tool in the medical management of EBV-related lymphoproliferative disorders of immunosuppressed patients.
Carbonic Anhydrase Inhibitors:  Synthesis of Water-Soluble, Aminoacyl/Dipeptidyl Sulfonamides Possessing Long-Lasting Intraocular Pressure-Lowering Properties via the Topical Route (1999)

Reaction of 26 aromatic/heterocyclic sulfonamides containing amino, imino, hydrazino, or hydroxyl groups with Boc-Gly, Boc-Sar, TrS-Crt, or Boc-Gly-Gly (Sar = sarcosine, N-Me-Gly; Crt = creatine, N-amidinosarcosine; TrS = tritylsulfenyl; Boc = tert-butoxycarbonyl) in the presence of carbodiimide derivatives afforded after removal of the protecting groups a series of water-soluble compounds (as salts of strong acids, such as hydrochloric, trifluoroacetic, or trifluoromethanesulfonic). The new derivatives were assayed as inhibitors of the zinc enzyme carbonic anhydrase (CA) and more precisely of three of its isozymes, CA I, II (cytosolic forms), and IV (membrane-bound form), involved in important physiological processes. Efficient inhibition was observed against all three isozymes and especially against CA II and IV (in the nanomolar range), the two isozymes known to play a critical role in aqueous humor secretion within the ciliary processes of the eye. Some of the best inhibitors synthesized were applied as 2% water solutions into the eye of normotensive or glaucomatous albino rabbits, when strong and long-lasting intraocular pressure (IOP) lowering was observed with many of them. Thus, the aminoacyl/dipeptidyl tail conferring water solubility to these sulfonamide CA inhibitors coupled with strong enzyme inhibitory properties and balanced lipid solubility seem to be the key factors for obtaining compounds with effective topical antiglaucoma activity.
High-speed, low-switching noise CMOS memory data output buffer (1994)

This paper describes a data output buffer for highspeed CMOS integrated memories with a high data output pin count. The buffer minimizes the switching noise induced on supply lines while achieving very fast output transitions by combining output presetting techniques together with adequate driving of the output pull-up and pull-down transistors. Tristate operation and zero static power consumption are also provided. The buffer was integrated in a 16-Mb EPROM device. It occupies 0.06 mm/sup 2/ and ensures a better than 15 ns output transition time with a load capacitor of 100 pF.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
A Conserved Seven Amino Acid Stretch Important for Murine Mitochondrial Glycerol-3-phosphate Acyltransferase Activity (1999)

Glycerol-3-phosphate acyltransferase (GPAT) catalyzes the initial and committed step in glycerolipid biosynthesis. We previously cloned the cDNA sequence to murine mitochondrial GPAT (Yet, S-F., Lee, S., Hahm, Y. T., and Sul, H.S. (1993) Biochemistry 32, 9486-9491). We expressed the protein in insect cells which was targeted to mitochondria, purified, and reconstituted mitochondrial GPAT activity using phospholipids (Yet, S.-F., Moon, Y., and Sul, H. S. (1995) Biochemistry 34, 7303-7310). Deletion of the seven amino acids from mitochondrial GPAT, (312)IFLEGTR(318), which is highly conserved among acyltransferases in glycerolipid biosynthesis, drastically reduced mitochondrial GPAT activity. Treatment of mitochondrial GPAT with arginine-modifying agents, phenylglyoxal and cyclohexanedione, inactivated the enzyme. Two highly conserved arginine residues, Arg-318, in the seven amino stretch, and Arg-278, were identified. Substitution of Arg-318 with either alanine, histidine, or lysine reduced the mitochondrial GPAT activity by over 90%. On the other hand, although substitution of Arg-278 with alanine and histidine decreased mitochondrial GPAT activity by 90%, replacement with lysine reduced activity by only 25%. A substitution of the nonconserved Arg-279 with either alanine, histidine, or lysine did not alter mitochondrial GPAT activity. Moreover, R278K mitochondrial GPAT still showed sensitivity to arginine-modifying agents, as in the case of wild-type mitochondrial GPAT. These results suggest that Arg-318 may be critical for mitochondrial GPAT activity, whereas Arg-278 can be replaced by a basic amino acid. Examination of the other conserved residues in the seven amino acid stretch revealed that Phe-313 and Glu-315 are also important, but conservative substitutions can partially maintain activity; substitution with alanine reduced activity by 83 and 72%, respectively, whereas substituting Phe-313 with tyrosine and Glu-315 with glutamine had even lesser effect. In addition, there was no change in fatty acyl-CoA selectivity. Kinetic analysis of the R318K and R318A mitochondrial GPAT showed an 89 and 95%, respectively, decrease in catalytic efficiency but no major change in substrate binding as indicated by the K(m) values for palmitoyl-CoA and glycerol 3-phosphate. These studies indicate importance of the conserved seven amino acid stretch for mitochondrial GPAT activity and the significance of Arg-318 for catalysis.
Aging in vertebrates, and the effect of caloric restriction: a mitochondrial free radical production–DNA damage mechanism? (2004)

Oxygen is toxic to aerobic animals because it is univalently reduced inside cells to oxygen free radicals. Studies dealing with the relationship between oxidative stress and aging in different vertebrate species and in caloric-restricted rodents are discussed in this review. Healthy tissues mainly produce reactive oxygen species (ROS) at mitochondria. These ROS can damage cellular lipids, proteins and, most importantly, DNA. Although antioxidants help to control this oxidative stress in cells in general, they do not decrease the rate of aging, because their concentrations are lower in long- than in short-lived animals and because increasing antioxidant levels does not increase vertebrate maximum longevity. However, long-lived homeothermic vertebrates consistently have lower rates of mitochondrial ROS production and lower levels of steady-state oxidative damage in their mitochondrial DNA than short-lived ones. Caloric-restricted rodents also show lower levels of these two key parameters than controls fed ad libitum. The decrease in mitochondrial ROS generation of the restricted animals has been recently localized at complex I and the mechanism involved is related to the degree of electronic reduction of the complex I ROS generator. Strikingly, the same site and mechanism have been found when comparing a long- with a short-lived animal species. It is suggested that a low rate of mitochondrial ROS generation extends lifespan both in long-lived and in caloric-restricted animals by determining the rate of oxidative attack and accumulation of somatic mutations in mitochondrial DNA.
Polyspirane, 14. — Umlagerungskaskaden, 9. Fünffache Cyclobutylmethyl‐Cyclopentyl‐Umlagerung an einem Pentaspiro[3.0.3.0.3.0.3.0.3.1]henicosanol — Eine Schlüsselsequenz zur Synthese des [6.5]Coronans (1988)

Abstract Das Pentaspirohenicosanol 6 reagiert mit Thionylchlorid in Pyridin unter fünffacher Cyclobutylmethyl‐Cyclopentyl‐Umlagerung zu einem all‐cis ‐anellierten hexacyclischen Olefin 17 , dessen Struktur und Konfiguration über eine Kristallstrukturanalyse eines hiervon abgeleiteten Epoxids 18 geklärt wurde. Die Umlagerung ist konformativ kontrolliert und für eine Synthese des [6.5]Coronans ( 5 ) geeignet. Der Alkohol 6 wurde aus dem Trion 7 über eine Folge aus selektiver Dicyclopropylidenierung, erschöpfender Epoxydierung, Oxaspiropentan‐Cyclobutanon‐Umlagerung, selektiver Reduktion und Addition von Methyllithium erhalten ( 7→8→10→11→12→6 ).
Light microscopic visualization of colloidal gold on resin-embedded tissue. (1983)

RNase labeled with colloidal gold was used as a model for the present technique evolved for the light microscopic localization of gold-labeled substances in semithin resin-embedded sections. Tissue sections placed on glass slides were treated with the gold-enzyme complex and subsequently exposed to a photographic developed containing silver lactate. During the development gold particles are encapsulated in growing shells of metallic silver and gradually made visible in the light microscope. The amplification method can be applied to paraffin-embedded and frozen sections as well. This technique may prove useful as a supplement to studies utilizing colloidal gold or silver as markers normally used at the electron microscopic level.
Low dose high frequency ultrasound therapy for stellate ganglion blockade in complex regional pain syndrome type I: a randomised placebo controlled trial. (2014)

Low dose high frequency US applied on stellate ganglion did not make a sympathetic blockade and was not of further benefit for pain, range of motion, grip strength and upper extremity disability in CRPS type I patients.
Unleashing the potential of NOD- and Toll-like agonists as vaccine adjuvants (2014)

Innate immunity confers an immediate nonspecific mechanism of microbial recognition through germ line-encoded pattern recognition receptors (PRRs). Of these, Toll-like receptors (TLRs) and nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) have shaped our current understanding of innate regulation of adaptive immunity. It is now recognized that PRRs are paramount in instructing an appropriate adaptive immune response. Their ligands have been the focus of adjuvant research with the goal of generating modern vaccine combinations tailored to specific pathogens. In this review we will highlight the recent findings in the field of adjuvant research with a particular focus on the potential of TLR and NLR ligands as adjuvants and their influence on adaptive immune responses.
Policy-directed code safety (2000)

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2000.
Ceramide Signaling Downstream of the p75 Neurotrophin Receptor Mediates the Effects of Nerve Growth Factor on Outgrowth of Cultured Hippocampal Neurons (1999)

The p75 neurotrophin receptor (p75NTR) binds all known neurotrophins and has been suggested to either function as a coreceptor for the trk receptor tyrosine kinases or be involved in independent signaling leading to cell death. We have analyzed the effects of nerve growth factor (NGF) on the growth of cultured hippocampal pyramidal neurons and examined the possibility that the effects of NGF are mediated via generation of ceramide produced by neutral sphingomyelinase (N-SMase). During the initial hour of culture, the only detectable NGF receptor is p75NTR, which by comparative Western blot is expressed at 50- to 100-fold lower levels than on PC12 cells. At this early stage of culture, NGF accelerates neurite formation and outgrowth and induces ceramide formation in a dose-dependent manner. An NGF mutant that is deficient in p75NTR binding has no effect on neuronal morphology or ceramide formation. Furthermore, two anti-p75NTR antibodies (REX and 9651), which are known to compete with NGF for binding to p75NTR, mimic the effects of NGF, whereas a monoclonal antibody (MC192) targeted against a different epitope does not. Finally, scyphostatin, a specific N-SMase inhibitor, blocks the effects of NGF. We propose that a neurotrophin–p75NTR–ceramide signaling pathway influences outgrowth of hippocampal neurons. This signaling role of p75NTR may be distinct from other signaling pathways that lead to apoptosis.
A Liver-Selective LXR Inverse Agonist That Suppresses Hepatic Steatosis (2012)

Fatty liver, which often accompanies obesity and type 2 diabetes, frequently leads to a much more debilitating hepatic disease including non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. Current pharmacological therapies lack conclusive efficacy and thus treatment options are limited. Novel therapeutics that suppress either hepatic lipogenesis and/or hepatic inflammation may be useful. Here, we describe the development of the first selective synthetic LXR inverse agonist (SR9238) and demonstrate that this compound effectively suppresses hepatic lipogenesis, inflammation, and hepatic lipid accumulation in a mouse model of non-alcoholic hepatosteatosis. SR9238 displays high potency for both LXRα and LXRβ (40-200 nM IC50) and was designed to display liver specificity so as to avoid potential side effects due to suppression of LXR in the periphery. Unexpectedly, treatment of diet-induced obese mice with SR9238 suppressed plasma cholesterol levels. These data indicate that liver-selective LXR inverse agonists may hold utility in the treatment of liver disease.
Role of Oxidants in Ischemic Brain Damage (1996)

I conclude that molecular genetic approaches in modifying antioxidant levels in the brain offer a unique tool for understanding the role of oxidants in ischemic brain damage.
Transmission of THz radiation through InSb gratings of subwavelength apertures (2005)

We demonstrate the extraordinary transmission of terahertz THz radiation through gratings of subwavelength apertures structured in indium antimonide InSb. This transmission can be attributed to the tunneling of surface plasmons polaritons which are excited in semiconductors at THz frequencies. By thermally controlling the permittivity of the grating the transmittance increases by more than one order of magnitude. This increase might be associated to the larger the skin depth in InSb at low temperatures, nwhich gives rise to a larger effective size of the apertures.
[Antigen-specific T-cell factors in the regulation of the immune response (author's transl)]. (1980)

We have examined in this brief review several facets of antigen-specific T-cell mediators found independently by different investigators. These factors have many common properties: (1) they are produced as a consequence of antigen stimulation; (2) they are obtained from T-cell populations and not from B cells or macrophages; their synthesis by T cells, however, has not been formally demonstrated; (3) they are antigen-specific and are selectively adsorbed by antigen-Sepharose columns; (4) they lack immunoglobulin constant region determinants of either L or H chain; (5) their estimated molecular weight by gel filtration is between 40,000 and 50,000 daltons; (6) they bear distinct I region controlled determinants; the helper factors are removed by anti-I-A immunoadsorbents; the suppressor factors in different distinct systems bear determinants coded foor by the I-J sub-region.
Multidimensional QKD Based on Combined Orbital and Spin Angular Momenta of Photon (2013)

It has been widely recognized that the underlying principles of quantum mechanics could be used to enable secure communications, without any additional conventional cryptographic systems, while utilizing the properties of the photons. Considerable research efforts have been invested to develop an efficient quantum key distribution (QKD) scheme over either free-space optical or fiber-optics channels. Most of these research efforts have been focused on a two-dimensional QKD, commonly realized by the use of the polarization state of photons. However, the data rates for the quantum key exchange in two-dimensional QKD are still low, while transmission distance is limited. On the other hand, it is well known that photons can carry both the spin angular momentum (SAM) and the orbital angular momentum (OAM), associated with the polarization and azimuthal phase of the complex electric field, respectively. Accordingly, we can define the combined-OAM-SAM state of a photon as |l, σ〉, where l and σ correspond to OAM and SAM indexes, respectively. Since the OAM eigenstates are orthogonal, an arbitrary number of bits per single photon can be transmitted, which could considerably increase the total secure bit rate. To improve secure data rates, we propose two types of protocols, namely, nonentangled-based (such as weak coherent state) and entanglement-assisted protocols, both employing the photon combined-OAM-SAM state, which can be used for secure key distribution over free-space optical and few-mode fiber channels. Two types of entanglement-assisted protocols are described, namely, two-basis and (D + 1)-basis protocols ( D is dimensionality of corresponding Hilbert space). We further describe how to implement the qudit gates required for implementation of these protocols. Finally, we discuss the security issues of the proposed protocols and determine both infinite and finite secret key fraction rates.