gebhart/patrepeval huggingface dataset:
Osteoblasts and Osteoclasts (2000)

The skeleton is a highly specialized and dynamic organ that undergoes continuous regeneration. Its functions are to maintain the shape of the body, protect vital organs, serve as a scaffold for the muscles, allowing their contractions to be translated into bodily movements, resist mechanical load during locomotion and weight bearing, and provide a reservoir of calcium, magnesium, bicarbonate, and phosphate. The skeleton consists of highly specialized cells, mineralized and unmineralized connective tissue matrix, and spaces that include the bone marrow cavity, vascular canals, canaliculi, and lacunae. During development and growth, the skeleton is sculpted in order to achieve its shape and size by the removal of bone from one site and deposition at a different one; this process is called modeling. Once the skeleton has reached maturity, regeneration continues in the form of a periodic replacement of old bone with new at the same location (1). This process is called remodeling. Removal of bone is the task of osteoclasts. The cells responsible for new bone formation are osteoblasts.
Nuclear Targeting inPlants (1992)

Thenucleus isthesite ofhighly active two-way macromolecular traffic between thenucleoplasm andthecytoplasm. Nuclear import andexport mustbehighly specific processes because thecontent ofthenucleus isdistinguished compared tothecytoplasm. Thisisrather amazing, considering thatthenuclear envelope dissolves during mitosis of animal andplant cells, necessitating reassembly ofall nuclear components andreentry ofnuclear proteins into thenucleus. Inaddition, manybasic cellular processes, suchasgene transcription andcell division, clearly require proper nuclear localization ofregulatory andhousekeeping proteins. Furthermore, experimental evidence indicates theexistence of receptors andothercellular factors thatmediate nuclear transport. Nuclear transport, although extensively studied in animal andlower eukaryotic systems (3, 20), hasonly recently beenaddressed inhigher plants (1,2,5,7,8,15,24-26). Thisattention toprotein andnucleic acidtransport intothe nucleus inplants wasstimulated notonlybya needto understand basic cell biology, butalso bythedesire tomodulate orregulate theexpression ofgenesviagenetic engineering. Thenucleus (Fig. 1)issurrounded bythenuclear envelope, whichincludes theinner andouter nuclear membranes and, between them, theperinuclear space. Theouter nuclear membrane iscontiguous withtherough ER,anditsouter surface isgenerally studded withribosomes. Underlying theinner nuclear membrane isthenuclear lamina, whichiscomposed ofanetwork offilamentous proteins. Unlike other organelles, thenuclear envelope contains NPC2, themajor sites ofbidirectional protein andnucleic acid traffic. Though understood onastructural level, knowledge ofthebiochemistry behind theNPCislimited. Onlyafewproteins associated withthe NPCinanimal systems havebeenidentified (3); however, their actual involvement innuclear import hasnotbeen demonstrated. Structurally, theNPC traverses thedouble membrane, bringing thelipid bilayers oftheinner andouter membranes together around themargins ofeachpore. TheNPCconsists ofeight large protein granules arranged inacircle witha large central granule ortransporter that isthought tocontrol active nucleocytoplasmic
Presenilin 1 Regulates the Processing of β-Amyloid Precursor Protein C-Terminal Fragments and the Generation of Amyloid β-Protein in Endoplasmic Reticulum and Golgi (1998)

Progressive cerebral deposition of the amyloid beta-protein (Abeta) is believed to play a pivotal role in the pathogenesis of Alzheimer's disease (AD). The highly amyloidogenic 42-residue form of Abeta (Abeta42) is the first species to be deposited in both sporadic and familial AD. Mutations in two familial AD-linked genes, presenilins 1 (PS1) and 2 (PS2), selectively increase the production of Abeta42 in cultured cells and the brains of transgenic mice, and gene deletion of PS1 shows that it is required for normal gamma-secretase cleavage of the beta-amyloid precursor protein (APP) to generate Abeta. To establish the subcellular localization of the PS1 regulation of APP processing to Abeta, fibroblasts from PS1 wild-type (wt) or knockout (KO) embryos as well as Chinese hamster ovary (CHO) cells stably transfected with wt or mutant PS1 were subjected to subcellular fractionation on discontinuous Iodixanol gradients. APP C-terminal fragments (CTF) were markedly increased in both endoplasmic reticulum- (ER-) and Golgi-rich fractions of fibroblasts from KO mice; moreover, similar increases were documented directly in KO brain tissue. No change in the subcellular distribution of full-length APP was detectable in fibroblasts lacking PS1. In CHO cells, a small portion of APP, principally the N-glycosylated isoform, formed complexes with PS1 in both ER- and Golgi-rich fractions, as detected by coimmunoprecipitation. When the same fractions were analyzed by enzyme-linked immunosorbent assays for Abetatotal and Abeta42, Abeta42 was the major Abeta species in the ER fraction (Abeta42:Abetatotal ratio 0.5-1.0), whereas absolute levels of both Abeta42 and Abeta40 were higher in the Golgi fraction and the Abeta42:Abetatoal ratio was 0.05-0.16 there. Mutant PS1 significantly increased Abeta42 levels in the Golgi fraction. Our results indicate PS1 and APP can interact in the ER and Golgi, where PS1 is required for proper gamma-secretase processing of APP CTFs, and that PS1 mutations augment Abeta42 levels principally in Golgi-like vesicles.
Double‐blind, triple‐crossover trial of low doses of oral physostigmine in inherited ataxias (1981)

The signs of ataxia in patients with inherited ataxias have been reported to improve after single injections or single oral doses of physostigmine. To study this effect, 21 patients with various inherited ataxias underwent a randomized, double-blind, triple-crossover trial of physostigmine and inert placebo taken orally in low doses for four sequential 3-month periods. Overall, the drug was more effective than the placebo (<i>p</i> &lt;0.051. Thirteen patients had consistent, statistically significant responses to physostigmine; 8 did not (x<sup>2</sup>=46.9, <i>p</i> &lt;0.0001). Only three patients improved on placebo. Responses did not correlate with age, sex, or severity of ataxia. Some aspects of ataxia improved in some patients, other aspects in other patients. Preliminary accounts of this work were previously reported.1-2
Induced PD-L1 Expression Mediates Acquired Resistance to Agonistic Anti-CD40 Treatment (2015)

CD40 stimulation on antigen-presenting cells (APC) allows direct activation of CD8(+) cytotoxic T cells, independent of CD4⁺ T-cell help. Agonistic anti-CD40 antibodies have been demonstrated to induce beneficial antitumor T-cell responses in mouse models of cancer and early clinical trials. We report here that anti-CD40 treatment induces programmed death ligand-1 (PD-L1) upregulation on tumor-infiltrating monocytes and macrophages, which was strictly dependent on T cells and IFNγ. PD-L1 expression could be counteracted by coadministration of antibodies blocking the PD-1 (programmed death-1)/PD-L1 axis as shown for T cells from tumor models and human donors. The combined treatment was highly synergistic and induced complete tumor rejection in about 50% of mice bearing MC-38 colon and EMT-6 breast tumors. Mechanistically, this was reflected by a strong increase of IFNγ and granzyme-B production in intratumoral CD8⁺ T cells. Concomitant CTLA-4 blockade further improved rejection of established tumors in mice. This study uncovers a novel mechanism of acquired resistance upon agonistic CD40 stimulation and proposes that the concomitant blockade of the PD-1/PD-L1 axis is a viable therapeutic strategy to optimize clinical outcomes.
Sn-Doped V2O5 Film with Enhanced Lithium-Ion Storage Performance (2013)

Homogeneous Sn-doped V2O5 sol was prepared by the sol–gel method with H2O2, V2O5, and SnCl4·5H2O as precursors, and the films were fabricated by drop-casting, drying at ambient, and then annealing at 450 °C in air for 2 h. X-ray photoelectron spectroscopy (XPS) reveals that the Sn-doped V2O5 film contains 10% V4+ likely compensates with the accommodation of Sn4+ ions. Electrochemical and lithium-ion intercalation properties of both the pure and Sn-doped V2O5 films are systematically studied by means of cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and chronopotentiometry (CP) tests. The Sn-doped V2O5 film shows much enhanced lithium-ion storage capacity, faster kinetics, and improved cyclic stability in comparison with pure V2O5 film. For example, after 50 cycles, the specific capacity of the Sn-doped V2O5 film retains 334 mAh g–1 with a current density of 500 mA g–1, much higher than 157 mAh g–1 of the pure V2O5 film. Sn-doping is found to reduce the electrochemical reaction resistance, increase the electrochemical reaction reversibility, and enhance the lithium-ion diffusivity. The possible explanation for such significant enhancement in lithium-ion intercalation capacity and cyclic stability of the Sn-doped V2O5 film is discussed.
Superoxide dismutase-rich bacteria. Paradoxical increase in oxidant toxicity. (1987)

Superoxide dismutase is considered important in protection of aerobes against oxidant damage, and increased tolerance to oxidant stress is associated with induction of this enzyme. However, the importance of superoxide dismutase in this tolerance is not clear because conditions which promote the synthesis of superoxide dismutase likewise affect other antioxidant enzymes and substances. To clarify the role of superoxide dismutase per se in organismal defense against oxidant-generating drugs, we employed Escherichia coli transformed with multiple copies of the gene for bacterial iron superoxide dismutase. These bacteria have greater than ten times the superoxide dismutase activity of wild-type E. coli but, importantly, are normal in other oxidant defense parameters including catalase, peroxidases, glutathione, and glutathione reductase. High superoxide dismutase and control bacteria were exposed to the O2- -generating drug paraquat and to elevated pO2. We find; high superoxide dismutase E. coli are more readily killed by paraquat under aerobic, but not anaerobic, conditions. During exposure to paraquat, high superoxide dismutase E. coli accumulate more H2O2. Coincidentally, the reduced glutathione content of high superoxide dismutase E. coli declines more than in control E. coli. E. coli with high superoxide dismutase activity are also more readily killed by hyperoxia. Interestingly, the susceptibility of the parental and high superoxide dismutase E. coli to killing by exogenous H2O2 is not significantly different. Thus, under these experimental conditions, greatly enhanced superoxide dismutase activity accelerates H2O2 formation. The increased H2O2 probably accounts for the exaggerated sensitivity of high superoxide dismutase bacteria to oxidant-generating drugs. These results support the concept that the product of superoxide dismutase, H2O2, is at least as hazardous as the substrate, O2-. We conclude that effective organismal defense against reactive oxygen species may require balanced increments in antioxidant enzymes and cannot necessarily be improved by increases in the activity of single enzymes.
Ca-induced Ca release in malignant hyperthermia-susceptible pig skeletal muscle (1989)

To provide information regarding the cause of the muscle rigidity in malignant hyperthermia-susceptible (MHS) pigs, the Ca-induced Ca-release mechanism of the sarcoplasmic reticulum (SR), the Ca uptake by the SR, and the Ca-activated tension production of the contractile system were examined in skinned skeletal muscle fibers from MHS and normal pigs. In muscles of MHS pigs, the rate of Ca-induced Ca release was significantly higher than in normal muscle. The potentiation effect on Ca-induced Ca release by halothane and caffeine did not differ appreciably between MHS and normal fibers. The rate of Ca uptake by the SR and the Ca sensitivity of the contractile system of MHS fibers were not different from those of normal fibers, and halothane in an anesthetic concentration exerted no effect on them. Dantrolene inhibited the Ca-induced Ca release at 38 degrees C. These results suggest that the principal cause of malignant hyperthermia (MH) in MHS pigs is due to the enhancement of the Ca-induced Ca-release mechanism of the SR of the skeletal muscle.
Carborane‐Derived Local Anesthetics are Isomer Dependent (2014)

Clinically there is a need for local anesthetics with a greater specificity of action on target cells and longer duration. We have synthesized a series of local anesthetic derivatives we call boronicaines in which the aromatic phenyl ring of lidocaine was replaced with ortho-, meta-, C,C'-dimethyl meta- and para-carborane clusters. The boronicaine derivatives were tested for their analgesic activity and compared with lidocaine using standard procedures in mice following a plantar injection. The compounds differed in their analgesic activity in the following order: ortho-carborane = C,C'-dimethyl meta-carborane > para-carborane > lidocaine > meta-carborane derivative. Both ortho-boronicaine and C,C'-dimethyl meta-boronicaine had longer durations of analgesia than lidocaine. Differences in analgesic efficacies are rationalized by variations in chemical structure and protein binding characteristics.
Binding of a 4-Methyl-4-Aza-Steroid to 5α-Reductase of Rat Liver and Prostate Microsomes (1983)

A tritium labeled 5 alpha-reductase inhibitor, [1,2-3H] 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one ([3H]4-MA), binds reversibly to a high affinity site (Kd, 6.5 nM) in liver microsomes from male rats. The binding requires a nicotinamide nucleotide coenzyme; NADH is at least 100 times less potent than NADPH, and NADP+, NAD+, flavin adenine dinucleotide, coenzyme A, and ADP are inactive. The relative potencies of 13 steroids as inhibitors of the binding of [3H]4-MA to liver microsomes correlate with their relative potencies as inhibitors of the conversion of [14C]testosterone to [14C]5 alpha-dihydrotestosterone by liver microsomes. Comparison of liver microsomes from mature female rats and microsomes from mature male rat liver, ventral prostate, spleen, kidney, and skeletal muscle shows that their NADPH-dependent [3H]4-MA binding capacities correlate with their levels of 5 alpha-reductase activity. These results suggest that [3H]4-MA binds specifically to 5 alpha-reductase in a NADPH-dependent manner. 5 alpha-Reductase was solubilized from liver microsomes with a detergent, Lubrol-WX, and the solubilized enzyme also binds [3H]4-MA. The relative potencies of 13 steroids as inhibitors of rat ventral prostate and liver 5 alpha-reductase are the same, strongly suggesting that the 5 alpha-reductases in the two tissues are the same.
Contribution of Residue 192 in Factor Xa to Enzyme Specificity and Function (1995)

Mutation of residue 192 (chymotrypsin numbering) from Glu to Gln in thrombin and activated protein C has been shown to dramatically alter substrate and inhibitor specificity, in large part by allowing these enzymes to accept substrates with acidic residues in the P3 and/or P3' positions. In factor Xa, residue 192 is already a Gln. We now compare the properties of a Q192E mutant of Gla-domainless factor X (GDFX). Kinetic analysis of prothrombin activation indicates similar affinity of factor Va for GDFXa and GDFXa Q192E (Kd(app) = 3.6 and 3.7 microM, respectively). Prothrombin activation rates are similar for both enzymes with factor Va, but are approximately 10-fold slower for the Q192E mutant without factor Va. This defect is in the activation of prethrombin 2 and is corrected by factor Va only in the presence of fragment 2. Without factor Va, fragment 2 has no influence on bovine prethrombin 2 activation by GDFXa, but fragment 2 enhances prethrombin 2 activation by the Q192E mutant at least 10-fold. These results indicate that the fragment 2 domain of prothrombin probably alters the conformation of the prethrombin 2 domain, selectively improving its presentation to GDFXa Q192E. With respect to inhibition, tissue factor pathway inhibitor and bovine pancreatic trypsin inhibitor are > or = 30 times poorer inhibitors of GDFXa Q192E than of GDFXa, but these enzymes are inhibited at comparable rates by antithrombin. These results indicate that Gln-192 in factor Xa is a key determinant of substrate/inhibitor specificity.
A glycoengineered anti‐CD19 antibody with potent antibody‐dependent cellular cytotoxicity activity in vitro and lymphoma growth inhibition in vivo (2011)

Human cluster of differentiation (CD) antigen 19 is a B cell-specific surface antigen and an attractive target for therapeutic monoclonal antibody (mAb) approaches to treat malignancies of B cell origin. MEDI-551 is an affinity-optimized and afucosylated CD19 mAb with enhanced antibody-dependent cellular cytotoxicity (ADCC). The results from in vitro ADCC assays with Natural Killer cells as effector cells, demonstrate that MEDI-551 is effective at lower mAb doses than rituximab with multiple cell lines as well as primary chronic lymphocytic leukaemia and acute lymphoblastic leukaemia samples. Targeting CD19 with MEDI-551 was also effective in several severe combined immunodeficiency lymphoma models. Furthermore, the combination of MEDI-551 with rituximab resulted in prolonged suppression of tumour growth, demonstrating that therapeutic mAbs with overlapping effector function can be combined for greater tumour growth inhibition. Together, the data demonstrate that MEDI-551 has potent antitumour activity in preclinical models of B cell malignancies. The results also suggest that the combination of the ADCC-enhanced CD19 mAb with an anti-CD20 mAb could be a novel approach for the treatment of B cell lymphomas.
Half-site spacing and orientation determines whether thyroid hormone and retinoic acid receptors and related factors bind to DNA response elements as monomers, homodimers, or heterodimers. (1992)

The receptors for thyroid hormone (T3R) and retinoic acid (RAR) are members of a nuclear receptor subfamily that are capable of recognizing similar DNA sequences. Native response elements for T3R and RAR consist of two or more putative half-site binding motifs organized as imperfect direct or inverted repeats separated by different sized nucleotide gaps. To clarify how T3R, RAR, and related factors recognize DNA response elements, we analyzed the interaction of purified receptors with a series of inverted and direct repeats of an idealized AGGTCA half-site separated by different sized nucleotide gaps. Our results indicate that RAR and T3R can bind to half-sites as monomers and, depending on the orientation and distance between half-sites, also bind as homodimers or T3R-RAR heterodimers. T3R also binds to certain DNA elements as a heterodimer with one or more nuclear factors from eucaryotic cells. Thus, the orientation and spacing of half-sites play a central role in determining which configuration of receptors and nuclear factors will interact with a specific DNA element. This along with the ability of these factors to participate in reversible protein-protein interactions serve to broaden and diversify the responses mediated by T3R, RAR, and related members of this nuclear receptor subfamily.
Quantal relationship between prostatic dihydrotestosterone and prostatic cell content: Critical threshold concept (1987)

The shape of the prostatic dihydrotestosterone (DHT) dose vs prostatic cell number response curve can be used to determine if the androgen-induced increase in prostatic cell number occurs as a continuous graded process increasing with all levels of prostatic DHT, or whether the process is quantal, beginning to occur only when a critical threshold of prostatic DHT is reached. To make this determination, castrated-adrenalectomized rats, castrated rats given no treatment, and castrated rats given testosterone-filled silastic implants of varying lengths were used to construct such a prostatic DHT dose/prostatic cell number response curve ranging from undetectable to pharmacologically high levels of prostatic DHT. The shape of this dose-response curve was found not to be continuously hyperbolic, but instead, to be discontinuously sigmoidal. This demonstrates that, in the rat, androgen-induced increase in prostatic cell number occurs as a quantal process which can only begin when the concentration of prostatic DHT is above a critical threshold value (ie, 0.4 ng/10(8) cells for the rat ventral prostate). Thus, in order to completely prevent this androgenic stimulation of prostatic cell number, the prostatic DHT level has to be lowered to below this critical threshold but does not have to be completely eliminated.
Microglial cell cytotoxicity of oligodendrocytes is mediated through nitric oxide. (1993)

Rat ameboid microglia are able to lyse rat oligodendrocytes in vitro. The lysis is inhibited by transforming growth factor-beta, antagonists of nitric oxide (NO) production, as well as antibodies to TNF-alpha, intercellular adhesion molecule-1 (ICAM-1), and leukocyte functional Ag-1. Ameboid microglial cells spontaneously produce detectable levels of the NO metabolite nitrite (NO2-). Stimuli such as PMA, LPS, and/or IFN-gamma induce micromolar concentrations of NO2- within 24 h. TNF-alpha increases IFN gamma but not LPS-induced NO2- production. Incubation with target oligodendrocytes also increases NO2- production in a contact-dependent manner. NO2- production is inhibited by NO synthase antagonists, transforming growth factor-beta, and anti TNF-alpha. Neither antileukocyte functional Ag-1 nor anti-ICAM-1 inhibit NO2- production by microglia in the presence or absence of oligodendrocytes. Indeed, anti-ICAM-1 treatment increases NO2- production. There is a correlation between ameboid microglial cell killing of oligodendrocytes and NO2- production suggesting NO may be a mechanism of death of the oligodendrocyte and possibly play a role in lesion formation in multiple sclerosis.
Cloning of a brain protein identified by autoantibodies from a patient with paraneoplastic cerebellar degeneration. (1987)

Autoantibodies directed against neuronal proteins have been identified in some patients with paraneoplastic cerebellar degeneration. To identify the molecular targets for these autoantibodies, we constructed a lambda gt11 cDNA expression library from human cerebellum and screened the library with IgG from a patient with paraneoplastic cerebellar degeneration. A single clone, pCDR2, produced a fusion protein that reacted strongly with the patient's IgG. The isolated pCDR2 clone was used to identify six overlapping cDNA clones. Sequencing of the pCDR clones revealed a distinctive pattern consisting of a unit of 18 nucleotides (6 amino acids) repeated in tandem along the entire cDNA sequence. This sequence is unlike any previously described eukaryotic gene. Southern blot analysis was consistent with single-copy representation of the CDR (cerebellar degeneration-related) gene in the human and mouse genome. RNA blotting studies with normal tissues showed expression of the CDR gene to be largely restricted to brain. Expression of the CDR message was also noted in cell lines derived from cancers of neuroectodermal, kidney, and lung origin.