gebhart/patrepeval huggingface dataset:
Poly(ADP-ribose) glycohydrolase is a component of the FMRP-associated messenger ribonucleoparticles (2005)

PARG [poly(ADP-ribose) glycohydrolase] is the only known enzyme that catalyses the hydrolysis of poly(ADP-ribose), a branched polymer that is synthesized by the poly(ADP-ribose) polymerase family of enzymes. Poly(ADP-ribosyl)ation is a transient post-translational modification that alters the functions of the acceptor proteins. It has mostly been studied in the context of DNA-damage signalling or DNA transaction events, such as replication and transcription reactions. Growing evidence now suggests that poly(ADP-ribosyl)ation could have a much broader impact on cellular functions. To elucidate the roles that could be played by PARG, we performed a proteomic identification of PARG-interacting proteins by mass spectrometric analysis of PARG pulled-down proteins. In the present paper, we report that PARG is resident in FMRP (Fragile-X mental retardation protein)-associated messenger ribonucleoparticles complexes. The localization of PARG in these complexes, which are components of the translation machinery, was confirmed by sedimentation and microscopy analysis. A functional link between poly(ADP-ribosyl)ation modulation and FMRP-associated ribonucleoparticle complexes are discussed in a context of translational regulation.
Association of a Leukemic Stem Cell Gene Expression Signature With Clinical Outcomes in Acute Myeloid Leukemia (2010)

High expression of an LSC gene signature is independently associated with adverse outcomes in patients with AML.
Comparison of helix stability in wild-type and mutant LamB signal sequences. (1990)

Previous studies of isolated peptides corresponding to the wild-type signal sequence of the LamB protein of Escherichia coli and to several export-impaired mutants demonstrated that a high tendency to adopt an alpha-helical conformation in low dielectric environments was a property of functional sequences. We have now used nuclear magnetic resonance to establish further characteristics of the helical conformation of these signal peptides in a solvent mixture (50% trifluoroethanol, by volume, in water) which mimics the conformational distribution of these peptides in lipid vesicles. The interactions of signal sequences in vivo may depend on the location of the helix in the sequence, on the length of the helical segment, and on the stability of the helix. We find that the hydrophobic core has the most persistent helix conformation and that the stability of this helix correlates with in vivo function of different mutants of the LamB signal sequence. In the family of signal peptides studied here, the length of the helix required for function appears to be less rigidly restricted since a signal peptide from a functional pseudorevertant with 4 residues deleted from the hydrophobic core takes up helix as stably as wild type but incorporates fewer residues in the helix.
Human anti- -amyloid antibodies block -amyloid fibril formation and prevent -amyloid-induced neurotoxicity (2003)

The accumulation of beta-amyloid (A beta) in neuritic plaques is thought to be causative for the progression of Alzheimer's disease (AD). Recently, both active immunization and passive administration of A beta antibodies dramatically attenuated amyloid plaque deposition, neuritic dystrophy, astrogliosis and behaviour deficits in transgenic animals. In addition, we and others have found that titres of naturally occurring anti-A beta antibodies in the CSF of AD patients are significantly lower than those in age-matched controls. Treatment with intravenous immunoglobulins (a preparation that contained anti-A beta antibodies) significantly lowered CSF levels of A beta in non-demented patients. In this study, anti-A beta antibodies were isolated from immunoglobulin preparations and these anti-A beta antibodies strongly block fibril formation or disrupt formation of fibrilar structures. Furthermore, these antibodies almost completely prevented neurotoxicity of A beta. In contrast, immunoglobulins depleted of anti-A beta antibodies had little effect on A beta fibril formation or protection of neuronal cells. This study supports the findings that human anti-A beta antibodies may interfere with the pathogenesis of AD by more than one mechanism, and administration of polyclonal human anti-A beta antibodies isolated from plasma is a potential therapeutic agent to prevent or slow down disease progression.
Anti-Cytokine Therapy (2005)

Agents able to neutralize the effects of IL-1 or TNF have impressive effects in preclinical models of endotoxemia or sepsis. However, the ability of such therapies to reduce mortality or morbidity in critically ill septic patients appears to be, at best, very limited. Although it is simply possible that neither TNF-α nor IL-1 play an important role in clinical sepsis, it is more likely that the disappointing results of clinical trials reflects the heterogeneity of patient populations recruited into such studies. Both IL-1 and TNF-α are likely to be elevated early in proinflammatory cascades initiated by infection. These cytokines may be less important in perpetuating inflammatory processes once organ system dysfunction develops. In no study were patients identified and enrolled based on documented elevations in tissue or circulating levels of IL-1 or TNF-α. Therefore, it is difficult to know if the patients enrolled actually had excessive production of the cytokines being blocked. However, in the NORASEPTII study [30], a retrospective analysis of patients with detectable circulating TNF-α levels only showed a relative decrease in mortality of 9% in patients treated with anti-TNF-α antibodies. These results would suggest that even if septic patients with elevated TNF-α could be identified, the impact of anti-TNF-α therapies would be relatively modest.
Isoprenylation is required for the processing of the lamin A precursor. (1990)

The nuclear lamina proteins, prelamin A, lamin B, and a 70-kD lamina-associated protein, are posttranslationally modified by a metabolite derived from mevalonate. This modification can be inhibited by treatment with (3-R,S)-3-fluoromevalonate, demonstrating that it is isoprenoid in nature. We have examined the association between isoprenoid metabolism and processing of the lamin A precursor in human and hamster cells. Inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by mevinolin (lovastatin) specifically depletes endogenous isoprenoid pools and inhibits the conversion of prelamin A to lamin A. Prelamin A processing is also blocked by mevalonate starvation of Mev-1, a CHO cell line auxotrophic for mevalonate. Moreover, inhibition of prelamin A processing by mevinolin treatment is rapidly reversed by the addition of exogenous mevalonate. Processing of prelamin A is, therefore, dependent on isoprenoid metabolism. Analysis of the conversion of prelamin A to lamin A by two independent methods, immunoprecipitation and two-dimensional nonequilibrium pH gel electrophoresis, demonstrates that a precursor-product relationship exists between prelamin A and lamin A. Analysis of R,S-[5-3H(N)]mevalonate-labeled cells shows that the rate of turnover of the isoprenoid group from prelamin A is comparable to the rate of conversion of prelamin A to lamin A. These results suggest that during the proteolytic maturation of prelamin A, the isoprenylated moiety is lost. A significant difference between prelamin A processing, and that of p21ras and the B-type lamins that undergo isoprenylation-dependent proteolytic maturation, is that the mature form of lamin A is no longer isoprenylated.
An antagonistic interaction between PlexinB2 and Rnd3 controls RhoA activity and cortical neuron migration (2014)

A transcriptional programme initiated by the proneural factors Neurog2 and Ascl1 controls successive steps of neurogenesis in the embryonic cerebral cortex. Previous work has shown that proneural factors also confer a migratory behaviour to cortical neurons by inducing the expression of the small GTP-binding proteins such as Rnd2 and Rnd3. However, the directionality of radial migration suggests that migrating neurons also respond to extracellular signal-regulated pathways. Here we show that the Plexin B2 receptor interacts physically and functionally with Rnd3 and stimulates RhoA activity in migrating cortical neurons. Plexin B2 competes with p190RhoGAP for binding to Rnd3, thus blocking the Rnd3-mediated inhibition of RhoA and also recruits RhoGEFs to directly stimulate RhoA activity. Thus, an interaction between the cell-extrinsic Plexin signalling pathway and the cell-intrinsic Ascl1-Rnd3 pathway determines the level of RhoA activity appropriate for cortical neuron migration.
Low Nucleotide Diversity at the pal1 Locus in the Widely Distributed Pinus sylvestris (2002)

Nucleotide polymorphism in Scots pine (Pinus sylvestris) was studied in the gene encoding phenylalanine ammonia-lyase (Pal, EC 4.3.1.5). Scots pine, like many other pine species, has a large current population size. The observed levels of inbreeding depression suggest that Scots pine may have a high mutation rate to deleterious alleles. Many Scots pine markers such as isozymes, RFLPs, and microsatellites are highly variable. These observations suggest that the levels of nucleotide variation should be higher than those in other plant species. A 2,045-bp fragment of the pal1 locus was sequenced from five megagametophytes each from a different individual from each of four populations, from northern and southern Finland, central Russia, and northern Spain. There were 12 segregating sites in the locus. The synonymous site overall nucleotide diversity was only 0.0049. In order to compare pal1 with other pine genes, sequence was obtained from two alleles of 11 other loci (total length 4,606 bp). For these, the synonymous nucleotide diversity was 0.0056. These estimates are lower than those from other plants. This is most likely because of a low mutation rate, as estimated from between-pine species synonymous site divergence. In other respects, Scots pine has the characteristics of a species with a large effective population. There was no linkage disequilibrium even between closely linked sites. This resulted in high haplotype diversity (14 different haplotypes among 20 sequences). This could also give rise to high per locus diversity at the protein level. Divergence between populations in the main range was low, whereas an isolated Spanish population had slightly lower diversity and higher divergence than the remaining populations.
NaV1.1 channels and epilepsy (2010)

Voltage-gated sodium channels initiate action potentials in brain neurons, and sodium channel blockers are used in therapy of epilepsy. Mutations in sodium channels are responsible for genetic epilepsy syndromes with a wide range of severity, and the NaV1.1 channel encoded by the SCN1A gene is the most frequent target of mutations. Complete loss-of-function mutations in NaV1.1 cause severe myoclonic epilepsy of infancy (SMEI or Dravet's Syndrome), which includes severe, intractable epilepsy and comorbidities of ataxia and cognitive impairment. Mice with loss-of-function mutations in NaV1.1 channels have severely impaired sodium currents and action potential firing in hippocampal GABAergic inhibitory neurons without detectable effect on the excitatory pyramidal neurons, which would cause hyperexcitability and contribute to seizures in SMEI. Similarly, the sodium currents and action potential firing are also impaired in the GABAergic Purkinje neurons of the cerebellum, which is likely to contribute to ataxia. The imbalance between excitatory and inhibitory transmission in these mice can be partially corrected by compensatory loss-of-function mutations of NaV1.6 channels, and thermally induced seizures in these mice can be prevented by drug combinations that enhance GABAergic neurotransmission. Generalized epilepsy with febrile seizures plus (GEFS+) is caused by missense mutations in NaV1.1 channels, which have variable biophysical effects on sodium channels expressed in non-neuronal cells, but may primarily cause loss of function when expressed in mice. Familial febrile seizures is caused by mild loss-of-function mutations in NaV1.1 channels; mutations in these channels are implicated in febrile seizures associated with vaccination; and impaired alternative splicing of the mRNA encoding these channels may also predispose some children to febrile seizures. We propose a unified loss-of-function hypothesis for the spectrum of epilepsy syndromes caused by genetic changes in NaV1.1 channels, in which mild impairment predisposes to febrile seizures, intermediate impairment leads to GEFS+ epilepsy, and severe or complete loss of function leads to the intractable seizures and comorbidities of SMEI.
Novel Notch Detection Algorithm for Detection of Dicrotic Notch in PPG Signals (2014)

Photoplethysmography (PPG) is a non-invasive optical technique that measures relative blood volume changes in the blood vessels and is widely used for research and physiological studies. Dicrotic notch represent the closure of the aortic semi-lunar valve and subsequent receding blood flow when ventricles relax. Their location is used to calculate systolic time intervals and monitor cardiac function. They play a significant role in early evaluation of various diseases such as sclerosis, occlusion, arterial spasm etc. This paper proposes a novel Notch Detection Algorithm (NDA) for detection of dicrotic notches from PPG signal that are measured by non-invasive photoplethysmography sensors. The proposed algorithm is implemented with the help of self developed Graphical User Interface (GUI) in MATLAB.
Demand‐Driven Geometry Transmission for Distributed Virtual Environments (1996)

Abstract We present a strategy for rendering in distributed virtual environments. A geometry database is maintained by a server, while users invoke individual clients to interact with the environment. Instead of downloading a complete copy of the geometry data, the data is distributed on demand, thus gaining signifcant savings in network bandwidth. Our strategy combines several techniques, including levels of detail, progressive refinement and graceful degradation to deliver the data “just in time” over the network to the rendering process. The method allows operate on a tight resource budget, which important if attempting to use low cost systems for virtual reality applications.
Palmitoylation State Impacts Induction of Innate and Acquired Immunity by the Salmonella enterica Serovar Typhimurium msbB Mutant (2011)

Lipopolysaccharide (LPS), composed of lipid A, core, and O-antigen, is a major virulence factor of Salmonella enterica serovar Typhimurium, with lipid A being a major stimulator to induce the proinflammatory response via the Toll-like receptor 4 (TLR4)-MD2-CD14 pathway. While Salmonella msbB mutants lacking the myristate chain in lipid A were investigated widely as an anticancer vaccine, inclusion of the msbB mutation in a Salmonella vaccine to deliver heterologous antigens has not yet been investigated. We introduced the msbB mutation alone or in combination with mutations in other lipid A acyl chain modification genes encoding PagL, PagP, and LpxR into wild-type S. enterica serovar Typhimurium. The msbB mutation reduced virulence, while the pagL, pagP, and lpxR mutations did not affect virulence in the msbB mutant background when administered orally to BALB/c mice. Also, all mutants exhibited sensitivity to polymyxin B but did not display sensitivity to deoxycholate. LPS derived from msbB mutants induced less inflammatory responses in human Mono Mac 6 and murine macrophage RAW264.7 cells in vitro. However, an msbB mutant did not decrease the induction of inflammatory responses in mice compared to the levels induced by the wild-type strain, whereas an msbB pagP mutant induced less inflammatory responses in vivo. The mutations were moved to an attenuated Salmonella vaccine strain to evaluate their effects on immunogenicity. Lipid A modification caused by the msbB mutation alone and in combination with pagL, pagP, and lpxR mutations led to higher IgA production in the vaginal tract but still retained the same IgG titer level in serum to PspA, a test antigen from Streptococcus pneumoniae, and to outer membrane proteins (OMPs) from Salmonella.
A new PrfA‐regulated gene of Listeria monocytogenes encoding a small, secreted protein which belongs to the family of internalins (1996)

A mutant of Listeria monocytogenes EGD was constructed that carries an extended deletion removing the entire PrfA-regulated gene cluster from plcA to plcB and a second deletion inactivating the inlA gene. Upon supplementation of this mutant with multiple gene copies of prfA, a protein of 30 kDa was detected in the supernatant of the mutant strain. The gene encoding this protein was obtained by direct and inverse polymerase chain reaction using oligonucleotide primers that were deduced from partial amino acid sequences of the purified 30 kDa protein. The amino acid sequence of the gene product revealed a protein of 297 amino acids that carried eight repeat units with high homology to those of the two known internalin proteins A and B. This secretory protein, termed internalin C, is much smaller than InlA or InlB and its complete sequence is related to the two known internalins. The gene InlC is transcribed into a monocistronic mRNA from a single promoter which shows a typical consensus sequence for PrfA-binding at the position -40. In contrast to the transcription of the InlAB operon, which is downregulated after shift of an L. monocytogenes EGD culture from brain-heart infusion into minimum essential medium (MEM), transcription of inlC is induced in MEM like most of the other known PrfA-regulated virulence genes. In addition, InlC is strongly transcribed in the cytoplasm of phagocytic J774 cells whereas inlA is poorly transcribed under these conditions, suggesting that internalin C may play a role in a late stage of L. monocytogenes infection rather than in the uptake of L. monocytogenes by non-professional phagocytic cells. An InlC deletion mutant shows reduced virulence when tested in an intravenous mouse model, but intracellular replication of the mutant in Caco-2 and J774 cells appears to be comparable with that of the wild-type strain.
The role of the PD‐1 pathway in autoimmunity and peripheral tolerance (2011)

Programmed death-1 (PD-1) is a surface receptor critical for the regulation of T cell function during immunity and tolerance. PD-1 interactions with its ligands PD-L1 and PD-L2 inhibit T cell effector functions in an antigen-specific manner. This paper examines the role of PD-1 in limiting autoreactivity and establishing self-tolerance and discusses the hypothesis that PD-1 ligand (PD-L) expression both spatially and temporally dictates the fate of self-reactive T cells during the breakdown of peripheral tolerance and development of autoimmunity. We focus our discussion on the role of PD-1/PD-L interactions during peripheral tolerance, the differential role for PD-L1 and PD-L2 in response to environmental or self-antigens, and the impact of PD-1 signaling on dynamic T cell motility and the T cell receptor (TCR) stop signal. Finally, we discuss the potential to selectively target the PD-1 pathway therapeutically to alter T cell function during autoimmunity.
Ulinastatin Ameliorates Acute Ischemic Renal Injury in Rats (1996)

Effects of ulinastatin (a Kunitz-type proteinase inhibitor) administration was examined in a model of acute ischemic renal injury induced by bilateral renal artery occlusion in rats. Compared with rats administered vehicle, rats administered ulinastatin (150,000 U/kg body weight) intravenously 30 min preischemia had significantly lower serum creatinine and blood urea nitrogen, and much less injury evident by examination of kidney histologies over the course of 48 h postreperfusion. We conclude that ulinastatin exerts a protective effect against ischemic renal injury.
Significance of Electromagnetic Potentials in the Quantum Theory (1959)

In this paper, we discuss some interesting properties of the electromagnetic potentials in the quantum domain. We shall show that, contrary to the conclusions of classical mechanics, there exist effects of potentials on charged particles, even in the region where all the fields (and therefore the forces on the particles) vanish. We shall then discuss possible experiments to test these conclusions; and, finally, we shall suggest further possible developments in the interpretation of the potentials.
A Flow Analysis Procedure for the Translation of High-Level Languages to a Data Flow Language (1980)

A data flow analysis procedure is described which may be used in the translation of high-level languages to parallel target languages. The technique analyzes the data dependencies which exist between statements in a high-level program and constructs an intermediate form amenable to optimizing transformations and code generation.
New Developments in Therapeutic Chelating Agents as Antidotes for Metal Poisoning (1991)

An examination of the studies on therapeutic chelating agents that have been carried out during the last decade reveals that extensive efforts have been made to develop compounds superior to those previously available for the treatment of acute and chronic intoxication by many metals. These metals include primarily iron, plutonium, cadmium, lead, and arsenic, but also many other elements for which acute and chronic intoxication is less common. These studies have revealed the importance of several additional factors of importance in the design of such compounds and have led to many new compounds of considerable clinical promise. An additional development has been the introduction of previously developed chelating agents for use with certain metals on a broader scale.
Isocitrate Dehydrogenase Mutations in Glioma: From Basic Discovery to Therapeutics Development (2019)

Isocitrate dehydrogenase (IDH) is a key rate-limiting enzyme in the Krebs cycle that plays an important role in energy metabolism. In recent years, it has been found that IDH mutations are closely related to the occurrence and development of glioma, and it is a notable potential therapeutic target. First, IDH mutations can produce high levels of 2-hydroxyglutaric acid (2-HG), thereby inhibiting glioma stem cell differentiation. At the same time, IDH mutations can upregulate vascular endothelial growth factor (VEGF) to promote the formation of the tumor microenvironment. In addition, IDH mutations can also induce high levels of hypoxia-inducible factor-1α (HIF-1α) to promote glioma invasion. Ultimately, these changes will lead to the development of glioma. Currently, a large number of IDH inhibitors and vaccines have entered clinical trials, representing progress in the treatment of glioma patients.
On the preparation of 1-aryl-2-heteroaryl- and 2-aryl-1-heteroaryl-pyrroles as useful building blocks for biologically interesting heterocycles (2002)

A series of 1-aryl-2-pyridinyl/pyrimidinyl-pyrroles and 2-aryl-1-pyridinyl/pyrimidinyl-pyrroles were prepared by using 4+1 ring synthesis. The yields were strongly dependant on the reactivity of the starting amines. Synthetic procedures involving a 3+2 ring formation were discussed. Few 1-heteroaryl derivatives showed weak activity when tested as COX-1 and COX-2 inhibitors.