gebhart/patrepeval huggingface dataset:
Identification of a New Class of Inhibitors of the Voltage-Gated Potassium Channel, Kv1.3, with Immunosuppressant Properties (2002)

The voltage-gated potassium channel, K(v)1.3, is a novel target for development of immunosuppressants. Using a functional (86)Rb(+) efflux assay, a new class of high-affinity K(v)1.3 inhibitors has been identified. The initial active in this series, 4-phenyl-4-[3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl]cyclohexanone (PAC), which is representative of a disubstituted cyclohexyl (DSC) template, displays a K(i) of ca. 300 nM and a Hill coefficient near 2 in the flux assay and in voltage clamp recordings of K(v)1.3 channels in human T-lymphocytes. PAC displays excellent specificity as it only blocks members of the K(v)1 family of potassium channels but does not affect many other types of ion channels, receptors, or enzyme systems. Block of K(v)1.3 by DSC analogues occurs with a well-defined structure-activity relationship. Substitution at the C-1 ketone of PAC generates trans (down) and cis (up) isomer pairs. Whereas many DSC derivatives do not display selectivity in their interaction with different K(v)1.x channels, trans DSC derivatives distinguish between K(v)1.x channels based on their rates of C-type inactivation. DSC analogues reversibly inhibit the Ca(2+)-dependent pathway of T cell activation in in vitro assays. Together, these data suggest that DSC derivatives represent a new class of immunosuppressant agents and that specific interactions of trans DSC analogues with channel conformations related to C-type inactivation may permit development of selective K(v)1.3 channel inhibitors useful for the safe treatment of autoimmune diseases.
Leucine supplementation improves leptin sensitivity in high-fat diet fed rats (2015)

Leucine supplementation improves leptin sensitivity in rats on HFD likely by promoting leptin signaling.
Poster Presentations (2010)

Understanding the behavior of the cellular systems involves a complex series of biological relationships that make biological sense. Most of the biological pathways databases focus only on the metabolic pathways.
The Role of Reperfusion-Induced Injury in the Pathogenesis of the Crush Syndrome (1991)

RHABDOMYOLYSIS is a common syndrome in which injury to skeletal muscle results in the leakage of the contents of myocytes into the plasma. It can be induced by numerous factors, including a crush injury to a limb, overuse of skeletal muscle, heat, alcoholism, viral infections, metabolic disorders, myopathies, drugs, toxins, and hypokalemia. Massive rhabdomyolysis can produce life-threatening myoglobinuric renal failure, hyperkalemia, disseminated intravascular coagulation, acute cardiomyopathy, and various other complications.1 2 3 Traumatic rhabdomyolysis, or the crush syndrome, is the consequence of prolonged continuous pressure on the limbs. It reflects the disintegration of muscle tissue and the influx of myoglobin, potassium, and . . .
Expression of knotted1 marks shoot meristem formation during maize embryogenesis (1995)

Abstract The formation of shoot and root meristems that ultimately give rise to all tissues of the plant body occurs for the first time during embryogenesis. Meristem formation has traditionally been defined in terms of the appearance of histological features of meristems; this approach has led to varying interpretations of the timing of meristem formation relative to other events in embryogenesis. Markers that would provide more objective criteria for the analysis of meristem formation have not been widely available. The maize homeobox gene, knotted1 ( kn1 ), is expressed in shoot meristems throughout postembryonic stages of shoot development. In order to determine whether this gene is expressed in the shoot meristem from its earliest inception, we examined the expression of kn1 in embryos at a series of stages by in situ hybridization to kn1 mRNA and immunolocalization of KN1 protein. Our results show that the onset of kn1 expression is temporally and spatially coincident with the earliest histologically recognizable signs of shoot meristem formation in the embryo, and thus provides a valuable marker for this process. © 1995 Wiley‐Liss, Inc.
Aplastic Anemia in a Patient Receiving Felbamate for Complex Partial Seizures (1995)

A 53-year-old woman began taking felbamate for uncontrolled complex partial seizures. Four months later, she developed fatigue and ecchymotic skin lesions. Laboratory studies revealed very severe aplastic anemia. There have been an additional nine reported cases of aplastic anemia in the setting of felbamate treatment. The association between felbamate and aplastic anemia has resulted in a joint recommendation by the US Food and Drug Administration and the manufacturer of felbamate, Carter-Wallace, Inc., for the immediate withdrawal of patients from treatment with felbamate.
Computing local invariants of quantum-bit systems (1998)

We investigate means to describe the nonlocal properties of quantum systems and to test if two quantum systems are locally equivalent. For this we consider quantum systems that consist of several subsystems, especially multiple quantum bits, i.e., systems consisting of subsystems of dimension 2. We compute invariant polynomials, i.e., polynomial functions of the entries of the density operator that are invariant under local unitary operations. As an example, we consider a system of two quantum bits. We compute the Molien series for the corresponding representation, which gives information about the number of linearly independent invariants. Furthermore, we present a set of polynomials that generate all invariants (at least) up to degree 23. Finally, the use of invariants to check whether two density operators are locally equivalent is demonstrated.
Biochemical and immunological properties of the C-terminal domain of the alpha-toxin of Clostridium perfringens (1993)

The C-terminal domain of the alpha-toxin (cpa247–370) of Clostridium perfringens has been expressed in Escherichia coli and purified. Antiserum raised against cpa247–370 reacted in an identical manner to anti-alpha-toxin serum when used to map epitopes in the C-terminal domain, suggesting that cpa247–370 was immunologically and structurally identical to this region in the alpha-toxin. The isolated cpa247–370 was devoid of sphingomyelinase activity or haemolytic activity and was not cytotoxic for mouse lymphocytes. Haemolytic activity was detected when cpa247–370 was tested with the N-terminal domain of the alpha-toxin (cpa1–249), confirming that cpa247–370 confers haemolytic properties on the phospholipase C activity of the alpha-toxin. Haemolytic activity was not detected if cpa247–370 was tested with the Bacillus cereus phosphatidylcholine phospholipase C, nor if cpa1–249 and cpa247–370 were incubated sequentially with erythrocytes.
.omega.-[(.omega.-Arylalkyl)aryl]alkanoic acids: a new class of specific LTA4 hydrolase inhibitors (1992)

The synthesis and structure-activity profile of a new class of potent and specific LTA4 hydrolase inhibitors are described. Many compounds of this series of omega-[5-(omega-arylalkyl)-2-thienyl]- and omega-[4-(omega-arylalkyl)phenyl]alkanoic acids were found to be potent in vitro inhibitors of the LTB4 production by porcine leukocytes with IC50 ranging from 1 to 10 microM. The side-chain lengths were critical for an optimal activity. Substitutions on the terminal aromatic ring, in the benzene series, by lipophilic and electron-donating substituents substantially enhanced the LTA4 hydrolase inhibition potency. On the other hand, in the thiophene series, the effect of of such substitutions on the LTA4 hydrolase inhibition was rather small. Functionalization within the carboxylic acid side chain by a carbonyl or by a hydroxyl group led to less potent compounds. A metabolically stable LTA4 hydrolase inhibitor, RP64966, was obtained by insertion of an oxygen atom in the beta-position on the carboxylic acid side chain. After oral administration of RP64966 to rats, a plasma extract was found to display potent inhibition of the LTB4 biosynthesis (40% inhibition at 5 mg/kg, po).
Biochemical Evidence for a Novel Low Molecular Weight 2-5A-Dependent RNase L in Chronic Fatigue Syndrome (1997)

Previous studies from this laboratory have demonstrated a statistically significant dysregulation in several key components of the 2',5'-oligoadenylate (2-5A) synthetase/RNase L and PKR antiviral pathways in chronic fatigue syndrome (CFS) (Suhadolnik et al. Clin Infect Dis 18, S96-104, 1994; Suhadolnik et al. In Vivo 8, 599-604, 1994). Two methodologies have been developed to further examine the upregulated RNase L activity in CFS. First, photoaffinity labeling of extracts of peripheral blood mononuclear cells (PBMC) with the azido 2-5A photoaffinity probe, [32P]pApAp(8-azidoA), followed by immunoprecipitation with a polyclonal antibody against recombinant, human 80-kDa RNase L and analysis under denaturing conditions. A subset of individuals with CFS was identified with only one 2-5A binding protein at 37 kDa, whereas in extracts of PBMC from a second subset of CFS PBMC and from healthy controls, photolabeled/immunoreactive 2-5A binding proteins were detected at 80, 42, and 37 kDa. Second, analytic gel permeation HPLC was completed under native conditions. Extracts of healthy control PBMC revealed 2-5A binding and 2-5A-dependent RNase L enzyme activity at 80 and 42 kDa as determined by hydrolysis of poly(U)-3'-[32P]pCp. A subset of CFS PBMC contained 2-5A binding proteins with 2-5A-dependent RNase L enzyme activity at 80, 42, and 30 kDa. However, a second subset of CFS PBMC contained 2-5A binding and 2-5A-dependent RNase L enzyme activity only at 30 kDa. Evidence is provided indicating that the RNase L enzyme dysfunction in CFS is more complex than previously reported.
Synthesis of a Negatively Charged Dibenzofuran-Based β-Turn Mimetic and Its Incorporation into the WW Miniprotein-Enhanced Solubility without a Loss of Thermodynamic Stability (2002)

A versatile synthesis has been developed to functionalize the 4-(2-aminoethyl)-6-dibenzofuran propionic acid residue (1a) at the 2 and 8 positions with a variety of different substructures. The unfunctionalized version of this peptidomimetic (1a) is known to facilitate beta-hairpin formation in a variety of small peptides and proteins in aqueous solution when incorporated in place of the i + 1 and i + 2 residues of a beta-turn. In this study, we append propionate substituents on 1a at the 2 and 8 positions to successfully overcome solubility problems encountered with the incorporation of 1a in place of the i + 1 and i + 2 residues of the beta-turn in loop 1 of the WW domain. The thermodynamic stability of several WW domain analogues incorporating residues 1a and 1b was compared to that of the wild-type sequence revealing comparable DeltaG(H(2)O) unfolding values at 4 degrees C ranging from 3 to 3.6 kcal/mol. WW domains incorporating residue 1b exhibit improved solubility (exceeding 100 microM) and resistance to aggregation without compromising thermodynamic stability.
Different KGF Expression in Squamous Cell Carcinomas of the Head and Neck and in Normal Mucosa (1998)

Fibroblast growth factors (FGFs) are major factors mediating epithelial-mesenchymal interactions in the epidermis and mucosa. In this study the expression of the FGFs keratinocyte growth factor (KGF), acidic FGF (aFGF) and basic FGF (bFGF) was examined in tumour tissue specimens from 14 patients with advanced-stage squamous cell carcinoma of the head and neck (SCCHN) and 3 SCC cell lines by reverse-transcribed polymerase chain reaction (RT-PCR) and immunohistochemistry. None of the SCC cell lines was positive for KGF mRNA, whereas all cell lines were highly positive for aFGF and bFGF. In SCCHN tissue samples the level of KGF mRNA expression was significantly lower than in normal mucosa. Tumour stroma and the submucosal areas of normal mucosa stained intensely with anti-KGF antibody in immunohistochemical slides, whereas tumour cell nests were negative. Exposure of SCC cells to KGF thus differs from normal mucosa both quantitatively and regarding spatial distribution. This fact and the overexpression of aFGF and bFGF by tumour cells potentially promote tumour growth, invasion and metastasis. Since these growth factors and their receptors are well characterized, these observations could lead to new therapeutic strategies in SCCHN, for instance by blocking their receptors or antisense targeting.
Intestinal gluconeogenesis: key signal of central control of energy and glucose homeostasis (2009)

These new findings on the role of intestinal gluconeogenesis in the central control of energy and glucose homeostasis should be of interest for nutritionists and diabetologists. They pave the way to envision new strategies of prevention or treatment of obesity and type 2 diabetes in humans.
IL-18 Serum Level in Adult Onset Still’s Disease: A Marker of Disease Activity (2012)

Introduction. Immunological factors seem to play a pivotal role in Adult Onset Still's Disease (AOSD). Among all, IL-18 cytokine is overexpressed and drives the inflammatory process. Objective. We aimed to investigate the levels of IL-18 in sera of Italian patients with AOSD and to assess its possible role as a marker of disease activity. Methods. IL-18 serum levels were determined by ELISA in 26 Italian patients with AOSD. Disease activity was assessed using Pouchot's criteria. As controls, 21 patients with Rheumatoid Arthritis (RA), 21 patients with Sjogren's Syndrome (SS), 20 patients with Systemic Lupus Erythematosus (SLE), and 21 healthy subjects (normal human sera, NHS) were evaluated. Results. IL-18 serum levels were significantly higher in patients with active AOSD than in non-active (P = 0.001) and control groups (RA P = 0.0070, SS P = 0.0029, SLE P = 0.0032, NHS P = 0.0004). A significant correlation between IL-18 serum levels and disease activity (P < 0.0001), and laboratory parameters as ferritin (P = 0.0127) and C-reactive protein (P = 0.0032) was demonstrated. Conclusions. Higher levels of IL-18 are detected in active AODS patients and correlate with disease activity and inflammatory laboratory features. ROC-AUC analysis of the serum concentration of IL-18 suggests that it can be considered a diagnostic marker of AOSD. This paper supports the targeting of this cytokine as a possible therapeutic option in AOSD.
SUR L'UTILISATION D'UN COMPOSÉ DE FER DEXTRANE HYDROGÉNÉ PAR INJECTION CHEZ LA TRUIE EN GESTATION ET EN LACTATION (1968)

Trente truies primipares ont été utilisées pour examiner les possibilités de passage trans-utérin ou trans-mammaire d'un composé de fer injectable.A cet effet, un lot de la truies recevant au 55 e jour et au mo e jour de gestation une injection intramusculaire de 4 g de fer dextrane hydrogéné, était comparé à deux autres lots de la truies ne disposant que d'un régime alimentaire pauvre en fer, supplémenté ou non par 30 o p.p.m. de SO,F E .Pendant la lactation, la moitié des animaux de chaque lot recevait au ro e jour une nouvelle injection de 4 g de fer.On a obtenu les résultats sui- vants.i. Des injections de fer pendant la gestation accroissent fortement les réserves hépatiques en fer de la Truie.La diminution du taux d'hémoglobine provoquée par la gestation est limitée chez les animaux supplémentés.En revanche, la répartition du fer et sa teneur dans les productions utérines sont inchangées.2 .La distribution de fer injectable pendant la lactation permet d'accroître d'environ 5 o p. ioo la teneur en fer du lait, mais elle paraît insuffisante pour couvrir les besoins des porcelets.3 .La taille et le poids moyen des portées à la naissance ou au sevrage ne sont pas modifiés.On observe chez les porcelets en cours d'allaitement les mêmes symptômes d'anémie quel que soit le traitement effectué sur la mère.
Recent efforts toward the development of peptide secondary structure mimetics at Molecumetics Ltd. for the discoveries of new drug candidates utilizing combinatorial chemistry with solid phase synthesis are described (2000)

We describe a technology for generating recombinant polyclonal antibody libraries (PCALs) that enables the creation and perpetuation of standardized mixtures of polyclonal whole antibodies specific for a multiantigen (or polyantigen). Therefore, this technology combines the advantages of targeting multiple antigenic determinants -- high avidity, low likelihood of antigen 'escape variants', and efficient mediation of effector functions, with the advantages of using monoclonal antibodies -- unlimited supply of standardized reagents and the availability of the genetic material for desired manipulations. The technology for generating recombinant polyclonal antibody libraries begins with the creation of phage display Fab (antibody) libraries. This is followed by selection of sublibraries with desired antigen specificities, and mass transfer of the variable region gene pairs of the selected sublibraries to a mammalian expression vector for generation of libraries of polyclonal whole antibodies. We review here our experiments for selection of phage display antibody libraries against microbes and tumor cells, as well as the recent literature on the selection of phage display antibody libraries to multiantigen targets.
Therapeutic Concentrations of Local Anaesthetics Unveil the Potential Role of Sodium Channels in Neuropathic Pain (2001)

Neuropathic pain is frequently associated with hyperexcitability of primary afferents, characterized by spontaneous impulses and repetitive firing. Electrophysiology and molecular biology reveal changes in dorsal root ganglion Na+ channels under conditions of neuropathic pain, but the manner by which these changes alter the physiology of sensory afferents remains unknown. Equally mysterious is the mechanism by which i.v. local anaesthetic-like Na+ channel blockers suppress neuropathic pain behaviour at concentrations well below those reported for channel inhibition. We have compared the anti-allodynic actions of i.v. lidocaine (L) and stereoisomers of mexiletine (R-M, S-M), in rats after spinal nerve ligation, with their ability: (1) to inhibit fast, tetrodotoxin-sensitive neuronal Na+ currents, elicited by brief (1 ms) pulses, at 10 Hz, from 'resting' potentials (-80, -60 mV) and (2) to suppress the seconds long plateau and the repetitive firing produced in axons by slowing of Na+ channel inactivation (e.g. using scorpion alpha-toxins). Both L and R-M at 5-10 microM relieved allodynia; S-M was ineffective. Na+ currents also were inhibited by M, with affinities that were increased by both repetitive 'firing' (K(R,S) = 5 microM) and depolarization of the 'resting' membrane (K(R) = 15 microM; K(S) = 30 microM). Stereopotency ratios depended on the manner in which different states of the channel were inducted. Both L and M shortened the action potential's 'plateau' in alpha-toxin treated axons, without reducing the spike, and suppressed repetitive firing with IC(50)s = 5 microM, and no stereoselectivity. These findings together demonstrate that Na+ channel blockers, at 'therapeutic' concentrations, can inhibit neuronal hyperexcitability.
Are Presenilins Intramembrane-Cleaving Proteases? Implications for the Molecular Mechanism of Alzheimer's Disease (1999)

The amyloid-beta protein (Abeta) is strongly implicated in the pathogenesis of Alzheimer's disease. The final step in the production of Abeta from the amyloid precursor protein (APP) is proteolysis by the unidentified gamma-secretases. This cleavage event is unusual in that it apparently occurs within the transmembrane region of the substrate. Studies with substrate-based inhibitors together with molecular modeling and mutagenesis of the gamma-secretase cleavage site of APP suggest that gamma-secretases are aspartyl proteases that catalyze a novel intramembranous proteolysis. This proteolysis requires the presenilins, proteins with eight transmembrane domains that are mutated in most cases of autosomal dominant familial Alzheimer's disease. Two conserved transmembrane aspartates in presenilins are essential for gamma-secretase activity, suggesting that presenilins themselves are gamma-secretases. Moreover, presenilins also mediate the apparently intramembranous cleavage of the Notch receptor, an event critical for Notch signaling and embryonic development. Thus, if presenilins are gamma-secretases, then they are also likely the proteases that cleave Notch within its transmembrane domain. Another protease, S2P, involved in the processing of the sterol regulatory element binding protein, is also a multipass integral membrane protein which cleaves within or very close to the transmembrane region of its substrate. Thus, presenilins and S2P appear to be members of a new type of polytopic protease with an intramembranous active site.
On capacity of gaussian 'cheap' relay channel (2005)

In this paper, we derive the capacity of the Gaussian degraded 'cheap' relay channel, consisting of nodes using 'cheap' radios operating in TDD mode when transmitting and sending in the same frequency band. The TDD model captures a practical limitation of most of the RF radios used in commercial wireless systems. The proof of achievability relies on a combination of superposition encoding and list decoding, while the converse is derived using the min-cut max-flow theorem for networks with 'cheap' nodes (previously derived by the authors). Even with 'cheap' radios, our capacity analysis shows that cooperative coding is beneficial and has a capacity advantage over direct transmission.
The DHC1b (DHC2) Isoform of Cytoplasmic Dynein Is Required for Flagellar Assembly (1999)

Dyneins are microtubule-based molecular motors involved in many different types of cell movement. Most dynein heavy chains (DHCs) clearly group into cytoplasmic or axonemal isoforms. However, DHC1b has been enigmatic. To learn more about this isoform, we isolated Chlamydomonas cDNA clones encoding a portion of DHC1b, and used these clones to identify a Chlamydomonas cell line with a deletion mutation in DHC1b. The mutant grows normally and appears to have a normal Golgi apparatus, but has very short flagella. The deletion also results in a massive redistribution of raft subunits from a peri-basal body pool (Cole, D.G., D.R. Diener, A.L. Himelblau, P.L. Beech, J.C. Fuster, and J.L. Rosenbaum. 1998. J. Cell Biol. 141:993–1008) to the flagella. Rafts are particles that normally move up and down the flagella in a process known as intraflagellar transport (IFT) (Kozminski, K.G., K.A. Johnson, P. Forscher, and J.L. Rosenbaum. 1993. Proc. Natl. Acad. Sci. USA. 90:5519–5523), which is essential for assembly and maintenance of flagella. The redistribution of raft subunits apparently occurs due to a defect in the retrograde component of IFT, suggesting that DHC1b is the motor for retrograde IFT. Consistent with this, Western blots indicate that DHC1b is present in the flagellum, predominantly in the detergent- and ATP-soluble fractions. These results indicate that DHC1b is a cytoplasmic dynein essential for flagellar assembly, probably because it is the motor for retrograde IFT.
Prospective study of circulating T-lymphocyte subpopulations and disease progression in colorectal cancer (1997)

Reduction of CD4+ T-lymphocytes occurs before detectable recurrence of colorectal cancer. Results of the present study are consistent with impaired immunity, as measured by such lymphocyte subset populations, being important in tumor recurrence in colorectal cancer.