gebhart/patrepeval huggingface dataset:
Neuroprotection by the Inhibition of Apoptosis (2000)

Accumulating evidence strongly suggests that apoptosis contributes to neuronal cell death in a variety of neurodegenerative contexts. Activation of the cysteine protease caspase-3 appears to be a key event in the execution of apoptosis in the central nervous system (CNS). As a result, mice null for caspase-3 display considerable neuronal expansion usually resulting in death by the second week of life. At present, 14 caspase family members have been identified and subdivided into three subgroups on the basis of preference for specific tetrapeptide motifs using a positional scanning combinatorial substrate library. Caspase-3 is a group II member (2, 3, 7) categorized by an absolute substrate requirement for aspartic acid in the P4 position of the scissile bond. The preferred cleavage motif (DExD) for group II caspases is found in many structural, metabolic and repair proteins essential for cellular homeostasis. Consistent with the proposal that apoptosis plays a central in role human neurodegenerative disease, caspase-3 activation has recently been observed in stroke, spinal cord trauma, head injury and Alzheimer's disease. Indeed, peptide-based caspase inhibitors prevent neuronal loss in animal models of head injury and stroke suggesting that these compounds may be the forerunners of non-peptide small molecules that halt apoptosis processes implicated in these neurodegenerative disorders. A clear link between an hereditary neurodegenerative disorder and failed caspase inhibition has recently been proposed for spinal muscular atrophy (SMA). In severe SMA, the neuronal specific inhibitor of apoptosis (IAP) family member known as NAIP is often dysfunctional due to missense and truncation mutations. IAPs such as NAIP potently block the enzymatic activity of group II caspases (3 and 7) suggesting that NAIP mutations may permit unopposed developmental apoptosis to occur in sensory and motor systems resulting in lethal muscular atrophy. Conversely, adenovirally-mediated overexpression of NAIP or the X-linked IAP called XIAP reduces the loss of CA1 hippocampal neurons following transient forebrain ischemia. Taken together, these findings suggest that anti-apoptotic strategies may some day have utility in the treatment of neurodegenerative disease. The present review will summarize some of the recent evidence suggesting that apoptosis inhibitors may become a practical therapeutic approach for both acute and chronic neurodegenerative conditions.
Cultured NK1.1+ CD4+ T cells produce large amounts of IL-4 and IFN-gamma upon activation by anti-CD3 or CD1 (1997)

NK1.1+ CD4+ T cells produce more IL-4 and IFN-gamma in response to stimulation with anti-CD3 than conventional CD4+ T cells that have been primed to be, respectively, Th2 or Th1 cells. Furthermore, NK1.1+ CD4+ T cells produce IL-4 even if cultured in the absence of IL-4, whereas conventional CD4+ T cells require IL-4 to develop into IL-4 producers. The IFN-gamma-producing capacity of NK1.1+ CD4+ T cells is enhanced by IL-12. In addition, NK1.1+ CD4+ T cells produce substantial amounts of IL-3, IL-5, and IL-10 upon anti-CD3 stimulation. NK1.1+ CD4+ T cells can be stimulated to produce IL-4 by culture with L cells expressing CD1 (L-CD1), but primary IL-4 production was rather slow and weak. Restimulation of L-CD1-activated NK1.1+ CD4+ T cells with L-CD1 gave rise to a much stronger and more rapid response, yielding IL-4 production comparable with anti-CD3 activation of cells initially primed with anti-CD3. L-CD1 stimulation of L-CD1-primed cells resulted in far less IFN-gamma than that elicited by anti-CD3 from cells that had been primed with anti-CD3, but such production is substantially increased by adding IL-12 to the culture. The differing patterns of cytokine production by NK1.1+ CD4+ T cells suggest that these cells may have complex effects on the priming of conventional T cells and may not simply drive such cells to the acquisition of a Th2 phenotype.
A role for phospholipid polyunsaturation in modulating membrane protein function (1996)

Visual transduction is one of the best characterized G protein--coupled signalling systems. In addition, about 50% of the disk membrane phospholipid acyl chains are 22:6n-3, making this system ideal for determining the role of polyunsaturation in modulating membrane-signalling systems. The extent of formation of metarhodopsin II (MII), the G protein--activating photointermediate of rhodopsin, was studied in phospholipid vesicles composed of a variety of phosphatidylcholines, differing in their acyl chain composition at the sn-2 position. The amount of MII formed increased progressively with the level of acyl chain unsaturation at the sn-2 position. The effect of added cholesterol was to reduce the amount of MII formed. The acyl chain packing free volume of the rhodopsin containing lipid vesicles was characterized by a fractional volume parameter fv derived from measurements of the time-resolved fluorescence anisotropy decay of the hydrophobic membrane probe 1,6-diphenyl-1,3,5-hexatriene. The relationship among sn-2 acyl chain unsaturation, cholesterol content, and MII formation is explained on the basis of variation in fv with bilayer lipid composition and a novel model for the packing of phospholipids containing polyenoic acyl chains, such as 22:6n-3.
Localization of the membrane-associated region of vesicular stomatitis virus M protein at the N terminus, using the hydrophobic, photoreactive probe 125I-TID (1990)

The membrane-reactive, photoactivatable probe 125I-TID [3-(trifluoromethyl)-3-(m-[125I]iodophenyl)-3H-diazirine] was found to label the M protein of vesicular stomatitis virus about 40% as much as G protein in intact virions, in agreement with labeling studies with other probes. By analyzing limited tryptic digestion and specific chemical cleavage products, the label was essentially entirely localized within the first 19, and probably within the first 5 to 10, amino acid residues at the N terminus, identifying this short amphipathic segment as the likely site of interaction of M protein with the viral bilayer.
Accelerated evolution in the protein-coding regions is universal in crotalinae snake venom gland phospholipase A2 isozyme genes. (1995)

The nucleotide sequences of four genes encoding Trimeresurus gramineus (green habu snake, crotalinae) venom gland phospholipase A2 (PLA2; phosphatidylcholine 2-acylhydrolase, EC 3.1.1.4) isozymes were compared internally and externally with those of six genes encoding Trimeresurus flavoviridis (habu snake, crotalinae) venom gland PLA2 isozymes. The numbers of nucleotide substitutions per site (KN) for the noncoding regions including introns were one-third to one-eighth of the numbers of nucleotide substitutions per synonymous site (KS) for the protein-coding regions of exons, indicating that the noncoding regions are much more conserved than the protein-coding regions. The KN values for the introns were found to be nearly equivalent to those of introns of T. gramineus and T. flavoviridis TATA box-binding protein genes, which are assumed to be a general (nonvenomous) gene. Thus, it is evident that the introns of venom gland PLA2 isozyme genes have evolved at a similar rate to those of nonvenomous genes. The numbers of nucleotide substitutions per nonsynonymous site (KA) were close to or larger than the KS values for the protein-coding regions in venom gland PLA2 isozyme genes. All of the data combined reveal that Darwinian-type accelerated evolution has universally occurred only in the protein-coding regions of crotalinae snake venom PLA2 isozyme genes.
Chronobiology Implications for cancer chemotherapy (1995)

Experimental studies have documented that both the toxicity and the antitumor activity of many cancer drugs are time dependent. Early clinical trials have confirmed this observation for several drugs. The basic concepts of chronobiology and its application to pharmacology are reviewed. As an example, clinical trials of circadian fluoropyrimidine delivery are reviewed. Other clinical results are presented in table form. The mechanisms pertinent to the circadian time dependence of fluoropyrimidines are discussed.
Prediction and prevention of sudden cardiac death in heart failure (2005)

The definition of sudden cardiac death (SCD) remains controversial. Many such deaths are not witnessed, and without cardiac monitoring at the time of death the assumption of an underlying arrhythmic cause is speculative. Nevertheless, it has been estimated that SCD accounts for 300 000 to 400 000 deaths annually in the USA.1 The degeneration of monomorphic ventricular tachycardia (VT) into ventricular fibrillation (VF) accounts for the majority of sudden arrhythmic deaths.w1

Despite considerable advances in the treatment of heart failure over the past 20 years, morbidity and mortality remain high with a four year survival of less than 50% in population based studies (fig 1). Ventricular arrhythmias (including non-sustained VT) have been documented in up to 85% of patients with severe congestive heart failure.2



 Figure 1 
 Cumulative survival of 552 incident (new) cases of heart failure identified in the London heart failure studies 1995 to 1998. Kaplan-Meier estimates with 95% point wise confidence bands (authors’ own data).



The implantable cardioverter-defibrillator (ICD) is highly effective at terminating life threatening ventricular tachyarrhythmia (fig 2). In selected high risk patients ICDs have proven to be a cost effective method of reducing mortality. At present, 1–2% of the population has heart failure and numbers continue to increase,3 but the ICD remains expensive. The challenge lies in identifying patients with heart failure who are at significant risk of arrhythmia and who would benefit from an ICD in addition to other antiarrhythmic strategies.



 Figure 2 
 Implantable cardioverter-defibrillator (ICD) data showing an episode of ventricular fibrillation terminated by a 21 J shock delivered by the device. Intracardiac electrograms are recorded from the right atrium (A) and right ventricle (V) along with a surface ECG. Sensed intracardiac intervals are shown at the bottom of the figure. Following cardioversion, ventricular fibrillation is terminated and bradycardia is seen requiring atrioventricular …
INGESTIBLE ELECTRONICALLY CONTROLLED DRUG - CAPSULE IN THE GUT (2012)

The Ingestible Electronically Controlled Drug-delivery System consists of electronically design capsule that navigates the digestive system by assessing human pH levels, which it reads through pH sensors. When the pH sensors identify a specified pH level that indicates arrival at the destination, the e-Capsule begins dispensing medication which it can do all immediately, in a sustained released, extended release or controlled release form. When it is activated, they send messages to a detector located on the patient's body that can send e-mails or text messages to doctors or Pharmacist notifying them the effect of medication that has been taken and they altered the medication accordingly if needed. Researchers are hopeful that this technology will improve medication observance, targeted drug delivery and drug of choice.
Characterization of protein release from hydrolytically degradable poly(ethylene glycol) hydrogels (2010)

We present a novel fully hydrophilic, hydrolytically degradable poly(ethylene glycol) (PEG) hydrogel suitable for soft tissue engineering and delivery of protein drugs. The gels were designed to overcome drawbacks associated with current PEG hydrogels (i.e., reaction mechanisms or degradation products that compromise protein stability): the highly selective and mild cross-linking reaction allowed for encapsulating proteins prior to gelation without altering their secondary structure as shown by circular dichroism experiments. Further, hydrogel degradation and structure, represented by mesh size, were correlated to protein release. It was determined that polymer density had the most profound effect on protein diffusivity, followed by the polymer molecular weight, and finally by the specific chemical structure of the cross-linker. By examining the diffusion of several model proteins, we confirmed that the protein diffusivity was dependent on protein size as smaller proteins (e.g., lysozyme) diffused faster than larger proteins (e.g., Ig). Furthermore, we demonstrated that the protein physical state was preserved upon encapsulation and subsequent release from the PEG hydrogels and contained negligible aggregation or protein-polymer adducts. These initial studies indicate that the developed PEG hydrogels are suitable for release of stable proteins in drug delivery and tissue engineering applications.
Chemical Detoxification of Nerve Agent VX (1998)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTChemical Detoxification of Nerve Agent VXYu-Chu YangView Author Information U.S. Army Edgewood Research, Development and Engineering Center (ERDEC), Aberdeen Proving Ground, Maryland 21010-5423 Cite this: Acc. Chem. Res. 1999, 32, 2, 109–115Publication Date (Web):November 4, 1998Publication History Received16 March 1998Published online4 November 1998Published inissue 1 February 1999https://pubs.acs.org/doi/10.1021/ar970154shttps://doi.org/10.1021/ar970154sresearch-articleACS PublicationsCopyright © Not subject to U.S. Copyright. Published 1998 American Chemical SocietyRequest reuse permissionsArticle Views3911Altmetric-Citations350LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Chemical reactions,Hydrolysis,Oxidation,Solvents,Substitution reactions Get e-Alerts
Trazodone is metabolized to m-chlorophenylpiperazine by CYP3A4 from human sources. (1998)

The metabolism of the antidepressant drug trazodone to its active metabolite, m-chlorophenylpiperazine (mCPP), was studied in vitro using human liver microsomal preparations and cDNA-expressed human cytochrome P450 (P450) enzymes. The kinetics of mCPP formation from trazodone were determined, and three in vitro experiments were performed to identify the major P450 enzyme involved. Trazodone (100 microM) was incubated with 16 different human liver microsomal preparations characterized for activities of 7 different P450 isoforms. The production of mCPP correlated significantly with activity of cytochrome P4503A4 (CYP3A4) only. Trazodone (100 microM) was then incubated with microsomes from cells expressing human CYP1A1, CYP1A2, CYP2C8, CYP2C9arg, CYP2C9cys, CYP2C19, CYP2D6, or CYP3A4. Only incubations with CYP3A4 resulted in mCPP formation. In the third experiment, the CYP3A4 inhibitor ketoconazole was found to inhibit mCPP formation concentration dependently in both human liver microsomes and in microsomes from cells expressing human CYP3A4. The present results indicate that trazodone is a substrate for CYP3A4, that CYP3A4 is a major isoform involved in the production of mCPP from trazodone, and that there is the possibility of drug-drug interactions with trazodone and other substrates, inducers and/or inhibitors of CYP3A4.
Expedient Solid-Phase Synthesis of Fluorogenic Protease Substrates Using the 7-Amino-4-carbamoylmethylcoumarin (ACC) Fluorophore (2002)

A highly efficient solid-phase synthesis method for the preparation of fluorogenic protease substrates based upon the bifunctional leaving group 7-amino-4-carbamoylmethylcoumarin (ACC) is reported. Methods for the large-scale preparation of the novel fluorogenic leaving-group ACC are provided (Scheme 1). Detailed procedures are also provided for loading a diverse set of amino acids to support-bound ACC in good yields and with minimal racemization. Finally, procedures are included for the preparative synthesis of optimized ACC substrates for HIV-1 protease and plasmin.
Inhaled Nitric Oxide Inhibits Human Platelet Aggregation, P-Selectin Expression, and Fibrinogen Binding In Vitro and In Vivo (1998)

NO-dependent inhibition of platelet aggregation may be caused by a decrease in fibrinogen binding to the platelet GP IIb/IIIa receptor.
Use of mRNA- and protein-destabilizing elements to develop a highly responsive reporter system (2005)

Reporter assays are widely used in applications that require measurement of changes in gene expression over time (e.g. drug screening). With standard reporter vectors, the measurable effect of a treatment or compound (altered reporter activity) is substantially diluted and delayed, compared with its true effect (altered transcriptional activity). This problem is caused by the relatively long half-lives of both the reporter protein and its mRNA. As a result, the activities of compounds, ligands or treatments that have a relatively minor effect, or a substantial but transient effect, often remain undetected. To circumvent this problem, we introduced modular protein- and mRNA-destabilizing elements into a range of commonly used reporters. Our data show that both elements are required for maximal responses to both increases and decreases in transcriptional activity. The double-destabilized reporter vectors showed markedly improved performance in drug screening, kinetic assays and dose-response titrations.
Stability projections for high temperature superconductors (1989)

The stability of the high-temperature superconducting oxides has been analyzed, using the methodology developed for conventional type II superconductors. The results are presented in graphical form for the temperature range from 4 to 100 K. For a 90-K superconductor the first flux jump field peaks above 7 T at 60 K, and for a 120-K superconductor it peaks above 12 T at 75 K. The maximum adiabatically stable thickness increases greatly. The linear dimension of the minimum propagating zone increases by a factor of 3 to 5, and the quench propagation velocity drops by four orders of magnitude. It is concluded that the high-temperature superconducting materials will have much higher stability than conventional type II superconductors and that their high flux jump fields will make ultrafine multifilamentary conductors unnecessary and improve the outlook for tape conductors. The energy required to create a propagating zone is increased. However, methods of coil protection will have to be modified.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
p75 neurotrophin receptor mediates apoptosis in transit-amplifying cells and its overexpression restores cell death in psoriatic keratinocytes (2010)

p75 neurotrophin receptor (p75NTR) belongs to the TNF-receptor superfamily and signals apoptosis in many cell settings. In human epidermis, p75NTR is mostly confined to the transit-amplifying (TA) sub-population of basal keratinocytes. Brain-derived neurotrophic factor (BDNF) or neurotrophin-4 (NT-4), which signals through p75NTR, induces keratinocyte apoptosis, whereas β-amyloid, a ligand for p75NTR, triggers caspase-3 activation to a greater extent in p75NTR transfected cells. Moreover, p75NTR co-immunoprecipitates with NRAGE, induces the phosphorylation of c-Jun N-terminal kinase (JNK) and reduces nuclear factor kappa B (NF-κB) DNA-binding activity. p75NTR also mediates pro-NGF-induced keratinocyte apoptosis through its co-receptor sortilin. Furthermore, BDNF or β-amyloid cause cell death in TA, but not in keratinocyte stem cells (KSCs) or in p75NTR silenced TA cells. p75NTR is absent in lesional psoriatic skin and p75NTR levels are significantly lower in psoriatic than in normal TA keratinocytes. The rate of apoptosis in psoriatic TA cells is significantly lower than in normal TA cells. BDNF or β-amyloid fail to induce apoptosis in psoriatic TA cells, and p75NTR retroviral infection restores BDNF- or β-amyloid-induced apoptosis in psoriatic keratinocytes. These results demonstrate that p75NTR has a pro-apoptotic role in keratinocytes and is involved in the maintenance of epidermal homeostasis.
World AIDS Day: Sydney West Area Health Service (2007)

The Sydney West Area Health Service (SWAHS) 2006 World AIDS Day (WAD) activities were held at Mt Druitt Holy Family Church where all those affected by HIV/AIDS are brought together and awareness of HIV/AIDS is spread throughout the Aboriginal Communities. The 1st of December every year is commemorated as World AIDS Day, a day to remember that HIV is still very much in existing in the world and will continue to be till the medical world discovers a vaccine and a cure for this deadly virus.
Sulfur and Selenium: The Role of Oxidation State in Protein Structure and Function (2003)

Sulfur and selenium occur in proteins as constituents of the amino acids cysteine, methionine, selenocysteine, and selenomethionine. Recent research underscores that these amino acids are truly exceptional. Their redox activity under physiological conditions allows an amazing variety of posttranslational protein modifications, metal free redox pathways, and unusual chalcogen redox states that increasingly attract the attention of biological chemists. Unlike any other amino acid, the "redox chameleon" cysteine can participate in several distinct redox pathways, including exchange and radical reactions, as well as atom-, electron-, and hydride-transfer reactions. It occurs in various oxidation states in the human body, each of which exhibits distinctive chemical properties (e.g. redox activity, metal binding) and biological activity. The position of selenium in the periodic table between the metals and the nonmetals makes selenoproteins ideal catalysts for many biological redox transformations. It is therefore apparent that the chalcogen amino acids cysteine, methionine, selenocysteine, and selenomethionine exhibit a unique biological chemistry that is the source of exciting research opportunities.
A Peripheral Adrenoceptor-mediated Sympathetic Mechanism Can Transform Stress-induced Analgesia into Hyperalgesia (2011)

Sympathetic postganglionic nerves can enhance pain sensation via a peripheral α-1-adrenoceptor mechanism when sympathetic outflow is disinhibited. The net effect of stress on pain sensation reflects a balance between descending spinal inhibition and sympathetic outflow that can shift toward pain facilitation when central and peripheral α-2-adrenoceptor inhibitory mechanisms are attenuated.