gebhart/patrepeval huggingface dataset:
Human Macrophage Metalloelastase. GENOMIC ORGANIZATION, CHROMOSOMAL LOCATION, GENE LINKAGE, AND TISSUE-SPECIFIC EXPRESSION (1995)

Human macrophage metalloelastase (HME) is a recent addition to the matrix metalloproteinase (MMP) family that was initially found to be expressed in alveolar macrophages of cigarette smokers. To understand more about HME expression, analysis of the structure and location of the gene was performed. The gene for HME is composed of 10 exons and 9 introns, similar to the stromelysins and collagenases, and HME shares the highly conserved exon size and intron-exon borders with other MMPs. The 13-kilobase (kb) HME gene has been localized by fluorescence in situ hybridization to chromosome 11q22.2-22.3, the same location of the interstitial collagenase and stromelysin genes. We determined that HME and stromelysin 1 genes are physically linked within 62 kb utilizing pulse-field gel electrophoresis. The promoter region of the HME gene contains several features common to other MMP genes including a TATA box 29 bp upstream to the transcription initiation site, an AP-1 motif, and a PEA3 element. HME mRNA is not detectable in normal adult tissues but is induced in rapidly remodeling tissues such as the term placenta. In situ hybridization and immunohistochemistry of placental tissue demonstrated HME mRNA and protein expression in macrophages and stromal cells. Cell-specific expression and response to inflammatory stimuli such as endotoxin is conferred within 2.8 kb of the HME 5'-flanking sequence as demonstrated by HME promoter-CAT expression constructs. Knowledge of the genomic organization and chromosomal location of HME may allow us to further define mechanisms responsible for cell- and tissue-specific expression of HME.
Peritoneal fluid cytokines and the relationship with endometriosis and pain (1996)

It is generally accepted that the current scoring system for endometriosis has little correlation with clinical symptoms such as pain, and therefore we may deduce that either endometriosis does not cause pain, or that the current scoring system does not indicate the biological activity of the disease. Pain may occur because the presence of endometriosis produces an intraperitoneal inflammatory response, and several studies have shown that the cytokine content of peritoneal fluid differs between women with and without endometriosis. We studied the relationship between tumour necrosis factor alpha (TNF alpha), platelet-derived growth factor (PDGF), interleukin (IL)-6, IL-4 and TNF (alpha and beta) activity in peritoneal fluid and the clinical history of pain and infertility. TNF alpha concentrations were increased in peritoneal fluid of women with endometriosis and of infertile women; PDGF concentrations were increased in peritoneal fluid of parous women; IL-6 was increased in peritoneal fluid of women with adhesions; IL-4 was absent from peritoneal fluid. PDGF and IL-6 concentrations were cycle related, with the highest amounts in the menstrual and proliferative phases respectively. We failed to demonstrate any association between concentrations of cytokines in vitro and pain symptoms or severity of endometriosis.
Oral delivery of tumor‐targeting Salmonella exhibits promising therapeutic efficacy and low toxicity (2009)

Tumor-targeting bacteria have been developed as powerful anticancer agents. Salmonella typhimurium VNP20009, a representative tumor-targeting strain, has been systemically administered as a single-agent therapy at doses of 1 x 10(6) to 3 x 10(6) colony-forming unit (cfu)/mouse, or in combination with other antitumor agents at doses of 1 x 10(4) to 2 x 10(5) cfu/mouse. Recently, we reported that oral delivery of VNP20009 at the dose of 1 x 10(9) cfu/mouse induced significant anticancer effects comparable to that induced by systemic administration of this strain at 1 x 10(4) cfu/mouse. To further address the efficacy and safety of oral administration of bacteria, here we performed a systemically comparative analysis of anticancer efficacy and toxicity of VNP20009 administered: (i) orally at a dose of 1 x 10(9) cfu/mouse (VNP9-oral); (ii) intraperitoneally at a dose of 1 x 10(4) cfu/mouse (VNP4-i.p.); or (iii) intraperitoneally at a dose of 1 x 10(6) cfu/mouse in tumor-free and tumor-bearing murine models. The results showed that VNP9-oral, similar to VNP4-i.p., induced significant tumor growth inhibition whereas VNP6-i.p. induced better anticancer effect in the B16F10 melanoma model. Among three treatments, VNP9-oral induced the mildest and reversible toxicity whereas VNP6-i.p. resulted in the most serious and irreversible toxicities when compared to other two treatments. Moreover, the combination of VNP9-oral with a low dose of chemotherapeutics produced comparable antitumor effects but displayed significantly reduced toxicity when compared to VNP6-i.p. The findings demonstrated that oral administration, as a novel avenue in the application of bacteria, is highly safe and effective. Moreover, the present preclinical study should facilitate the optimization of bacterial therapies with improved anticancer efficacy and reduced adverse effects in future clinical trials.
Mutational sensitivity patterns define critical residues in the palm subdomain of the reverse transcriptase of human immunodeficiency virus type 1 (1995)

We have analyzed 154 single amino acid replacement mutants within a 40 amino acid region (residues 164-203) of the reverse transcriptase (RT) from human immunodeficiency virus type 1 (HIV-1). This region consists of two antiparallel beta-strands (strands 9 and 10) flanked by two alpha helices (E and F). The structure of this region of the 'palm' subdomain is conserved in a variety of DNA and RNA polymerases, indicating a critical role in enzyme structure and function. Functional assays were performed by screening RT activity of mutants expressed in E. coli. A functionally important region corresponding closely to beta-strands 9 and 10 and the loop joining them was revealed by its mutational sensitivity. Structural analysis of mutants was performed by using Western blots to assay correct folding, which is required for processing to produce the mature p66 and p51 RT species. This analysis indicates that beta-strand 10 is a structurally important region. Combined analysis of these two assays revealed diagnostic patterns of mutational sensitivity which identify key positions in the RT sequence at which a specific amino acid side chain is critical, either for structure or function, as well as residues which are external to the RT structure. This work illustrates the utility of large-scale mutagenesis in relating primary sequence to significant features of protein structure and function.
Modulation of nitrate-nitrite conversion in the oral cavity. (1996)

The formation of nitrite from ingested nitrate can give rise to the induction of methemoglobinemia and endogenous nitrosation resulting in the formation of carcinogenic N-nitroso compounds. We investigated the possibility of modulation of the conversion of nitrate into nitrite in the oral cavity in order to seek ways of reducing the formation of the deleterious nitrite. We investigated the effectiveness of several mouthwash solutions with antibacterial constituents on the reduction of nitrate into nitrite in the oral cavity. In 15 studied subjects, the mean percentage of salivary nitrate reduced to nitrite after ingestion of 235 mg (3.8 mmol) nitrate was found to be 16.1 +/- 6.2%. The use of an antiseptic mouthwash with active antibacterial constituent chlorhexidine resulted in an almost complete decrease of the mean percentage of reduced nitrate, to 0.9 +/- 0.8%. Mouthwash solutions with antibacterial component triclosan or antimicrobial enzymes amyloglucosidase and glucose oxidase did not affect the reduction of nitrate into nitrite. A toothpaste with active components triclosan and zinc citrate with synergistic antiplaque activity was also without effect. Use of a pH-regulating chewing gum resulted in a rise in the pH in the oral cavity from 6.8 to 7.3. At 30 min after nitrate ingestion, this rise was accompanied by a significant increase in the salivary nitrite concentration, which might be explained by the pH being close to the optimal pH for nitrate reductase of 8. In conclusion, a limited number of possibilities of modulation of the conversion of nitrate into nitrite in the oral cavity are available.
Generation of Memory B Cells and Plasma Cells in Vitro (1995)

After germinal center B cells undergo somatic mutation and antigen selection, they become either memory B cells or plasma cells, but the signal requirements that control entry into either pathway have been unclear. When purified human germinal center cells were cultured with interleukin-2, interleukin-10, and cells expressing CD40 ligand, cells with characteristics of memory B cells were generated. Removal of CD40 ligand from the system resulted in terminal differentiation of germinal center B cells into cells with the characteristics of plasma cells. These results indicate that CD40 ligand directs the differentiation of germinal center B cells toward memory B cells rather than toward plasma cells.
Simple Detachment Patterning of Organic Layers and Its Application to Organic Light‐Emitting Diodes (2005)

A new detachment patterning technique is applied to the fabrication of a green organic light‐emitting diode (OLED). The method (applicable to organic and inorganic substrates) involves simply placing a patterned PDMS mold in conformal contact with the organic layer to be patterned, annealing at a temperature below the glass transition temperature for a period of time, and then removing the mold after cooling to room temperature. The parts of the organic layer in contact with the mold become detached from the substrate upon removing the mold.
Haemostatic reference intervals in pregnancy (2010)

Haemostatic reference intervals are generally based on samples from non-pregnant women. Thus, they may not be relevant to pregnant women, a problem that may hinder accurate diagnosis and treatment of haemostatic disorders during pregnancy. In this study, we establish gestational age-specific reference intervals for coagulation tests during normal pregnancy. Eight hundred one women with expected normal pregnancies were included in the study. Of these women, 391 had no complications during pregnancy, vaginal delivery, or postpartum period. Plasma samples were obtained at gestational weeks 13-20, 21-28, 29-34, 35-42, at active labor, and on postpartum days 1 and 2. Reference intervals for each gestational period using only the uncomplicated pregnancies were calculated in all 391 women for activated partial thromboplastin time (aPTT), fibrinogen, fibrin D-dimer, antithrombin, free protein S, and protein C and in a subgroup of 186 women in addition for prothrombin time (PT), Owren and Quick PT, protein S activity, and total protein S and coagulation factors II, V, VII, VIII, IX, X, XI, and XII. The level of coagulation factors II, V, X, XI, XII and antithrombin, protein C, aPTT, PT remained largely unchanged during pregnancy, delivery, and postpartum and were within non-pregnant reference intervals. However, levels of fibrinogen, D-dimer, and coagulation factors VII, VIII, and IX increased markedly. Protein S activity decreased substantially, while free protein S decreased slightly and total protein S was stable. Gestational age-specific reference values are essential for the accurate interpretation of a subset of haemostatic tests during pregnancy, delivery, and puerperium.
Isoprene Formation in Bacillus subtilis : A Barometer of Central Carbon Assimilation in a Bioreactor? (2002)

Isoprene (2-methyl-1,3-butadiene) is a volatile hydrocarbon of uncertain function in Bacillus subtilis, and we hypothesized that it is an overflow metabolite produced during excess carbon utilization. Here we tested this idea for phase 2 of isoprene release, a phase that occurs during extracellular acetoin accumulation and its reassimilation. Phase 2 isoprene formation could be disrupted in three different ways, all related to acetoin metabolism. Disruption of a gene essential for acetoin biosynthesis (acetolactic acid synthase, alsS) blocked acetoin formation and led to cessation of phase 2 isoprene formation as well as a variety of pleiotropic effects related to loss of pH control. Growth of the alsS mutant with external pH control reversed most of these effects. Disruption of acetoin catabolism (acetoin dehydrogenase, acoA), also eliminated phase 2 isoprene formation and caused cells to transition directly from phase 1 to phase 3; the latter is attributed to amino acid catabolism. A third alteration of acetoin metabolism was detected in the widely used strain 168 (trpC2) but not in strain MS175, a trpC mutant constructed in the Marburg strain genetic background. Strain 168 exhibited slow acetoin assimilation compared to that of MS175 or the parental strain, with little or no isoprene formation during this growth phase. These findings support the idea that isoprene release occurs primarily when the rate of carbon catabolism exceeds anabolism and that this volatile hydrocarbon is a product of overflow metabolism when precursors are not required for higher isoprenoid biosynthesis. It is suggested that isoprene release might serve as a useful barometer of the rise and fall of central carbon fluxes during the growth of Bacillus strains in industrial bioreactors.
Identification of Specific Protein-RNA Target Sites Using Libraries of Natural Sequences (2003)

RNA-binding proteins are involved in a variety of regulatory and developmental processes such as RNA processing, transport, and translation and are integral components of ribosomes, spliceosomes, nucleoli, and other ribonucle-oprotein particles. Proteins have been shown to interact directly with mRNA at all stages from the nascent transcript through capping, polyadenylation and splicing, nuclear export, translation initiation, and translocation of ribosomes along the message as well as during degradation of the mRNA (for reviews see refs. 1–5). It is becoming increasingly clear that many RNA-binding proteins regulate gene expression through their interactions with mRNAs at various stages of development. The classic example is that of the iron-response element mRNA-binding protein, aconitase, which was shown by Klausner and co-workers to regulate translation of ferritin mRNA by binding to a stem-loop structure in its 5′ untranslated region (UTR) (reviewed in ref. 6). Additional examples include the regulated stability of transferrin, histone, and various cytokine and proto-oncogene mRNAs that are controlled by the binding of specific proteins to consensus sequences in their 3′ untranslated regions (3′ UTR) (7–9). In addition, studies of tobacco mosaic virus (10), the Drosophila developmental gene hunchback (11), 15-lipogenase (12), and various cytokine mRNAs (13) have implicated RNA-binding proteins in modulation of translational efficiency by interaction with sequences within the 3′ UTR.
The Conformation of Polymers at Interfaces (1997)

Coating of various surfaces and colloidal particles with flexible polymers greatly reduces adsorption and increases biological compatibility of surfaces and stability of colloidal particles. In addition, the immunogenicity and antigenicity of such particles decreases drastically. These findings are extremely important in the preparation of non-fouling and biocompatible surfaces. In the case of colloidal solutions, PEGylated proteins and liposomes are commercially available as novel medical formulations due to improved biological stability. The behavior of flexible polymers attached to the surface can be explained theoretically by the scaling theory. In this article this theoretical model as well as some experiments using osmotic stress technique and surface force apparatus are reviewed. Experiments show that this simplified theory fits experimental data as well as more complex treatments, indicating that general properties of such systems can be modeled by a rather simple theoretical approach.
Expedient Synthesis of Potent Cannabinoid Receptor Agonist (−)-CP55,940 (2005)

[reaction: see text] A stereocontrolled synthesis of (-)-CP55,940, a potent cannabinoid receptor agonist, has been attained using a novel aldolization/retro-aldolization interconversion strategy, in which a temporarily generated chiral aldol motif plays essential roles.
Tricyclic analogues of epidithiodioxopiperazine alkaloids with promising in vitro and in vivo antitumor activity (2015)

Epipolythiodioxopiperazine (ETP) alkaloids are structurally elaborate alkaloids that show potent antitumor activity. However, their high toxicity and demonstrated interactions with various biological receptors compromises their therapeutic potential. In an effort to mitigate these disadvantages, a short stereocontrolled construction of tricyclic analogues of epidithiodioxopiperazine alkaloids was developed. Evaluation of a small library of such structures against two invasive cancer cell lines defined initial structure-activity relationships (SAR), which identified 1,4-dioxohexahydro-6<i>H</i>-3,8a-epidithiopyrrolo[1,2-<i>a</i>]pyrazine <b>3c</b> and related structures as particularly promising antitumor agents. ETP alkaloid analogue <b>3c</b> exhibits low nanomolar activity against both solid and blood tumors <i>in vitro</i>. In addition, <b>3c</b> significantly suppresses tumor growth in mouse xenograft models of melanoma and lung cancer, without obvious signs of toxicity, following either intraperitoneal (IP) or oral administration. The short synthesis of molecules in this series will enable future mechanistic and translational studies of these structurally novel and highly promising clinical antitumor candidates.
Phase-Controlled Apertures Using Heterodyne Optical Phase-Locked Loops (2008)

In this letter, we demonstrate the use of an electronic feedback scheme using a voltage controlled oscillator (VCO) to control the optical phase of individual semiconductor lasers (SCLs) phase locked to a common reference laser using heterodyne optical phase-locked loops (OPLLs). The outputs of two external cavity SCLs phase-locked to a common reference laser are coherently combined, and the variation in the relative optical path lengths of the combining beams is corrected by dynamically changing the phase of the offset radio-frequency signal fed into one of the OPLLs by means of a VCO. A stable power combination efficiency of 94% is achieved. This inherently different method of phase control, i.e., electronic rather than the use of electrooptic crystals, is deemed essential for new applications involving coherent optoelectronics.
Immunosenescence: emerging challenges for an ageing population (2007)

It is now becoming apparent that the immune system undergoes age-associated alterations, which accumulate to produce a progressive deterioration in the ability to respond to infections and to develop immunity after vaccination, both of which are associated with a higher mortality rate in the elderly. Immunosenescence, defined as the changes in the immune system associated with age, has been gathering interest in the scientific and health-care sectors alike. The rise in its recognition is both pertinent and timely given the increasing average age and the corresponding failure to increase healthy life expectancy. This review attempts to highlight the age-dependent defects in the innate and adaptive immune systems. While discussing the mechanisms that contribute to immunosenescence, with emphasis on the extrinsic factors, particular attention will be focused on thymic involution. Finally, we illuminate potential therapies that could be employed to help us live a longer, fuller and healthier life.
A Different Model for the Right To Privacy: The Political Question Doctrine as a Substitute for Substantive Due Process (2006)

A Different Model for the Right to Privacy: The Political Question Doctrine as a Substitute for Substantive Due Process addresses the political question doctrine as it might pertain to the constitutional right of privacy. The political question doctrine is essentially a doctrine of justiciability. Under this doctrine, courts refrain from hearing certain cases that could better be resolved in the political branches. Although the doctrine is normally not applied to individual rights, the article argues that privacy constitutes a special kind of right or individual interest that could be treated more appropriately under a political question kind of approach rather than under a substantive due process approach. The article examines each prong of the test governing applicability of the political question doctrine and concludes that privacy is a type of matter that the courts should avoid and leave to the political branches.
Anti-HIV Double Variable Domain Immunoglobulins Binding Both gp41 and gp120 for Targeted Delivery of Immunoconjugates (2012)

DVD-Igs can be designed that bind to both gp120 and gp41 on the HIV envelope. DVD-Igs are effective in delivering cytotoxic immunoconjugates. The optimal design of these DVD-Igs, in which both domains are fully functional, has not yet been achieved.
Maximizing Rigidity: The Incremental Recovery of 3-D Structure from Rigid and Nonrigid Motion (1984)

The human visual system can extract 3-D shape information of unfamiliar moving objects from their projected transformations. Computational studies of this capacity have established that 3-D shape can be extracted correctly from a brief presentation, provided the moving objects are rigid. The human visual system requires a longer temporal extension, but it can cope with considerable deviations from rigidity. It is shown how the 3-D structure of rigid as well as nonrigid objects can be recovered by maintaining an internal model of the viewed object and modifying it at each instant by the minimal nonrigid change that is sufficient to account for the observed transformation. The results of applying this incremental rigidity scheme to rigid and nonrigid objects in motion are described and compared with human perception.
Adenoviral-mediated expression of a kinase-dead mutant of Akt induces apoptosis selectively in tumor cells and suppresses tumor growth in mice. (2003)

Akt/protein kinase B is a serine/threonine kinase that plays a critical role in cell survival signaling, and its activation has been linked to tumorigenesis in several human cancers. Up-regulation of Akt, as well as its upstream regulator phosphatidylinositol 3-kinase, has been found in many tumors, and the negative regulator of this pathway, mutated in multiple advanced cancers suppressor (MMAC; also known as phosphatase and tensin homologue deleted on chromosome 10), is a tumor suppressor gene. We have investigated the effects of inhibiting Akt signaling in tumor cells by expression of an Akt kinase-dead mutant in which the two regulatory phosphorylation sites have been mutated to alanines. This mutant, which functions in a dominant negative manner (Akt-DN), was introduced into tumor cells using a replication-defective adenovirus expression system. As controls we used adenoviruses expressing p53, MMAC, beta-galactosidase, and empty virus. We show that in vitro proliferation of human and mouse tumor cells expressing high levels of activated/phosphorylated Akt was inhibited by both Akt-DN and p53, in comparison with control viruses expressing beta-galactosidase. Similarly, Akt-DN mutant expression led to selective induction of apoptosis in tumor cells expressing activated Akt. On the other hand, Akt-DN expression had minimal effect in normal and tumor cells expressing low levels of activated Akt. Expression of MMAC induced selective apoptosis in tumor cell lines in which MMAC is inactivated but not in tumor cells expressing wild-type levels of MMAC. In addition, the growth of tumor cells in a mouse model was also significantly inhibited by intratumoral injection of Akt-DN virus. These studies validate the usefulness of targeting Akt for new drug discovery efforts and suggest that inhibition of Akt may have a selective antitumor effect.