gebhart/patrepeval huggingface dataset:
Transmission Dynamics and Prospective Environmental Sampling of Adenovirus In a Military Recruit Setting (2005)

(See the editorial commentary by Gray, on pages 871–3.) Background. High levels of morbidity caused by adenovirus among US military recruits have returned since the loss of adenovirus vaccines in 1999. The transmission dynamics of adenovirus have never been well understood, which complicates prevention efforts. Methods. Enrollment and end-of-study samples were obtained and active surveillance for febrile respiratory illnesses (FRIs) was performed for 341 recruits and support personnel. Environmental samples were collected simultaneously. Classic and advanced diagnostic techniques were used. Results. Seventy-nine percent (213/271) of new recruits were seronegative for either adenovirus serotype 4 (Ad-4) or adenovirus serotype 7 (Ad-7). FRI caused by Ad-4 was observed in 25 % (67/271) of enrolled recruits, with 100 % of them occurring in individuals with enrollment titers!1:4. The percentage of recruits seropositive for Ad-4 increased from 34 % at enrollment to 97 % by the end of the study. Adenovirus was most commonly detected in the environment on pillows, lockers, and rifles Conclusions. Potential sources of adenovirus transmission among US military recruits included the presence of adenovirus on surfaces in living quarters and extended pharyngeal viral shedding over the course of several days. The introduction of new recruits, who were still shedding adenovirus, into new training groups was docu-
Clinical and pharmacologic aspects of blinatumomab in the treatment of B-cell acute lymphoblastic leukemia (2013)

Acute lymphoblastic leukemia (ALL) in adults remains a challenging disease to treat, and novel therapies are needed. Precursor-B ALL comprises 80% of cases, and the CD19 antigen is expressed in nearly all precursor-B ALL patients. Bispecific T-cell-engaging antibodies are novel bioengineered proteins. The bispecific T-cell-engaging antibody blinatumomab engages polyclonal T cells to CD19-expressing B cells. By binding to both CD3 and CD19, blinatumomab physically brings these T cells in close proximity to malignant B cells and potentiates T-cell-induced cytotoxic cell kill. Blinatumomab requires continuous intravenous infusion due to its short half-life, the need for continuous exposure for the drug to exert sufficient efficacy, and lessened toxicity. A phase II trial of B-cell ALL patients with persistent or relapsed minimal residual disease demonstrated an 80% rate of complete molecular remission. Cytokine-release syndrome and central nervous system events, such as seizures and encephalopathy, are reversible toxicities. Promising results in B-cell ALL with minimal residual disease have led to further evaluation of this drug in newly diagnosed and relapsed B-cell ALL.
Human insulin receptors mutated at the ATP-binding site lack protein tyrosine kinase activity and fail to mediate postreceptor effects of insulin. (1987)

Transfected Chinese hamster ovary cell lines were developed that expressed equivalent numbers of either normal human receptor or receptor that had alanine substituted for Lys-1018 in the ATP-binding domain of the beta subunit. The mutated receptor was processed into subunits and bound insulin but lacked protein tyrosine kinase activity. Five effects of insulin were assayed: deoxyglucose uptake, S6 kinase activity, endogenous protein-tyrosine phosphorylation, glycogen synthesis, and thymidine uptake. In each case, cells bearing normal human receptors were 10-100-fold more sensitive to insulin than the parental cells. Cells with the mutant receptor behaved like the parental cells with respect to S6 kinase activation, endogenous substrate phosphorylation, glycogen synthesis, and thymidine uptake, but their deoxyglucose uptake was significantly depressed and relatively insensitive to insulin. The analyses led to the following conclusions: substitution of alanine for lysine at amino acid 1018 inactivates the kinase activity of the receptor; a kinase-negative receptor can be properly processed and bind insulin; insulin-dependent deoxyglucose uptake, S6 kinase activation, endogenous substrate phosphorylation, glycogen synthesis, and thymidine incorporation into DNA are mediated by the normal but not by the kinase-deficient human receptor.
Sperm treatment with extracellular ATP increases fertilization rates in in-vitro fertilization for male factor infertility (1999)

Previous work from our laboratory has revealed that extracellular ATP is a rapid and potent activator of human sperm acrosome reaction and fertilizing ability. In the present study, we assessed the effects of in-vitro sperm incubation with ATP on fertilization and embryo development in couples undergoing in-vitro fertilization (IVF) for male factor infertility. Oocytes from 22 women undergoing ovulation induction were divided in two groups and inseminated in vitro either with selected spermatozoa from the corresponding partner suffering from male factor infertility pre-incubated with ATP (2.5 mM) for 1 h, or with spermatozoa incubated with 0.9% NaCl solution (control group). After insemination, fertilization was assessed by the presence of pronuclei and then by embryo cleavage. The fertilization rate in the group of oocytes inseminated with ATP-treated spermatozoa improved significantly with respect to the control group (65.7 versus 42.5%, P < 0.01). No significant differences were observed in embryo cleavage and embryo quality. Embryos from both treated and control groups were transferred together in 20 transfer procedures, and in two couples fertilization was not obtained. Nine pregnancies occurred: one biochemical, one miscarriage, and seven patients delivered 9 healthy babies. Two pregnancies were twin with an overall pregnancy rate of 40.9% per cycle and of 45% per transfer. In conclusion, the results of the present study demonstrate that, in humans, extracellular ATP induces a significant increase of sperm fertilizing potential, as these findings are a rationale for the use of ATP for in-vitro treatment of human spermatozoa during IVF.
Recent Advances in Semiconductor Performance and Printing Processes for Organic Transistor-Based Electronics (2004)

The past two years have been a time of dramatic growth in the field of organic and printable electronics. This review summarizes the most recent advances in the design, application, and understanding of semiconducting materials relevant to this technology. Pentacene, other organic molecular solids, solution-deposited oligomers and polymers, and higher mobility inorganic and nanostructured materials are discussed. In addition, scientific investigations of single-crystal properties and contact barriers are covered, and the most advanced organic-based circuits are pointed out.
The DNA Binding Site of the Dof Protein NtBBF1 Is Essential for Tissue-Specific and Auxin-Regulated Expression of the rolB Oncogene in Plants (1999)

The Dof proteins are a large family of plant transcription factors that share a single highly conserved zinc finger. The tobacco Dof protein NtBBF1 was identified by its ability to bind to regulatory domain B in the promoter of the rolB oncogene. In this study, we show that the ACT T TA target sequence of NtBBF1 in domain B is necessary for tissue-specific expression of rolB. beta-Glucuronidase (GUS) activity of tobacco plants containing a rolB promoter-GUS fusion with a mutated NtBBF1 target sequence within domain B is almost completely suppressed in apical meristems and is severely abated in the vascular system. The ACT T TA motif is shown here also to be one of the cis-regulatory elements involved in auxin induction of rolB. The pattern of NtBBF1 expression in plants is remarkably similar to that of rolB, except in mesophyll cells of mature leaves, in which only NtBBF1 expression could be detected. Ectopic expression of rolB in mesophyll cells was achieved by particle gun delivery if the NtBBF1 binding sequence was intact. These data provide evidence that in the plant, a Dof protein DNA binding sequence acts as a transcriptional regulatory motif, and they point to NtBBF1 as the protein involved in mediating tissue-specific and auxin-inducible expression of rolB.
Protein Lipidation in Cell Signaling (1995)

The ability of cells to communicate with and respond to their external environment is critical for their continued existence. A universal feature of this communication is that the external signal must in some way penetrate the lipid bilayer surrounding the cell. In most cases of such signal acquisition, the signaling entity itself does not directly enter the cell but rather transmits its information to specific proteins present on the surface of the cell membrane. These proteins then communicate with additional proteins associated with the intracellular face of the membrane. Membrane localization and function of many of these proteins are dependent on their covalent modification by specific lipids, and it is the processes involved that form the focus of this article.
New Insights into Paroxysmal Nocturnal Hemoglobinuria (2006)

Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon acquired hemolytic anemia that manifests with abdominal pain, esophageal spasm, fatigue, and thrombosis. The hallmark of PNH at the cellular level is a deficiency in cell surface glycosylphosphatidylinositol anchored proteins; this deficiency on erythrocytes leads to intravascular hemolysis. Free hemoglobin from hemolysis leads to circulating nitric oxide depletion and is responsible for many of the clinical manifestations of PNH, including fatigue, erectile dysfunction, esophageal spasm, and thrombosis. The recently FDA approved complement inhibitor eculizumab has been shown to decrease hemolysis, decrease erythrocyte transfusion requirements, and improve quality of life for PNH patients.
Sensitization to TLR7 Agonist in IFN-β-Preactivated Dendritic Cells (2007)

TLRs interact with a growing list of pathogen-derived products and these interactions drive the activation of innate and adaptive immune responses. Dendritic cells (DC) play a key role in these events expressing a heterogeneous repertoire of TLRs. We have previously demonstrated the production of type I IFNs in DC following bacterial infections and TLR triggering. In this study, we sought to characterize the transcriptome specifically induced in human DC by IFN-beta production stimulated upon LPS treatment. To this aim, by using cDNA microarrays, we compared the transcriptome of DC following LPS treatment in the absence or presence of neutralizing anti-type I IFN Abs. Interestingly, we found that the expression of TLR7 was induced during LPS-induced maturation of DC in a type I IFN-dependent manner. The induction of TLR7 in maturing DC was mainly a consequence of the transcriptional activity of IRF-1, whose binding site was located within TLR7 promoter. Moreover, we also demonstrated that "priming" of immature DC, that usually express TLR8 but not TLR7, with exogenous IFN-beta induced a functionally active TLR7. In fact, treatment with the TLR7-specific ligand 3M-001 up-regulated the expression of CD83, CD86, and CD38 in IFN-beta-primed DC but not in immature DC. Therefore, a robust enhancement in proinflammatory as well as regulatory cytokines was observed. These data suggest that TLR4-mediated type I IFN release activates specific transcription programs in DC amplifying the expression of pathogen sensors to correctly and combinatorially respond to a bacterial as well as viral infection.
Chemical Biology Approaches Reveal Conserved Features of a C‐Terminal Processing PDZ Protease (2012)

Several proteases like the high temperature requirement A (HtrA) protein family containing internal or C-terminal PDZ domains play key roles in protein quality control in the cell envelope of Gram-negative bacteria. While several HtrA proteases have been extensively characterized, many features of C-terminal processing proteases such as tail-specific protease (Tsp) are still unknown. To fully understand these cellular control systems, individual domains need to be targeted by specific peptides acting as activators or inhibitors. Here, we describe the identification and design of potent inhibitors and activators of Tsp. Suitable synthetic substrates of Tsp were identified and served as a basis for the generation of boronic acid-based peptide inhibitors. In addition, a proteomic screen of E. coli cell envelope proteins using a synthetic peptide library was performed to identify peptides capable of amplifying Tsp's proteolytic activity. The implications of these findings for the regulation of PDZ proteases and for future mechanistic studies are discussed.
Development of a broad spectrum polymer‐released antimicrobial coating for the prevention of resistant strain bacterial infections (2012)

More than 400,000 primary hip and knee replacement surgeries are performed each year in the United States. From these procedures, approximately 0.5-3% will become infected and when considering revision surgeries, this rate has been found to increase significantly. Antibiotic-resistant bacterial infections are a growing problem in patient care. This in vitro research investigated the antimicrobial potential of the polymer released, broad spectrum, Cationic Steroidal Antimicrobial-13 (CSA-13) for challenges against 5 × 10(8) colony forming units (CFU) of methicillin-resistant Staphylococcus aureus (MRSA). It was hypothesized that a weight-to-weight (w/w) concentration of 18% CSA-13 in silicone would exhibit potent bactericidal potential when used as a controlled release device coating. When incorporated into a polymeric device coating, the 18% (w/w) broad-spectrum polymer released CSA-13 antimicrobial eliminated 5 × 10(8) CFU of MRSA within 8 h. In the future, these results will be utilized to develop a sheep model to assess CSA-13 for the prevention of perioperative device-related infections in vivo.
Furostanol bisglycosides corresponding to dioscin and gracillin. (1974)

Two compounds, positive (red) to the Ehrlich reagent and predominant in the methanol extracts of the fresh rhizomes of Dioscorea gracillima MIQ., were isolated. Their structures were established as 26-O-β-D-glucopyranosyl 22-methoxyfurost-5-ene-3β, 26-diol 3-O-β-chacotrioside (I), mp 187-191°(decomp.), [α]D-95.6°, and its 22-hydroxy analog (I'), mp 190-196°(decomp.), [α]D-79.8°, the furostanol bisglycosides corresponding to 25D-spirost-5-en-3β-ol (diosgenin) 3-O-β-chacotrioside (dioscin) (III), the major component of the stored materials. I is regarded as an artifact formed from I', and I'and I are named proto-dioscin and methyl proto-dioscin, respectively. Smilax-saponin B, which had been assigned a structure, diosgenin hexaglycoside, was identical with I and the structure is revised. Among the Ehrlich positive compounds in the methanol extracts of the fresh rhizomes of D. septemloba THUNB., the major, mp 249-251°(decomp.), [α]D-76.9°, was isolated and characterized as the analog (II) of I, chacotriose being replaced by gracillimtriose, corresponding to gracillin (IV). One of the minor components was identified with the 22-hydroxy compound (II') of II, mp 235-238°(decomp.), [α]D-57.8°. II'and II are named proto-gracillin and methyl proto-gracillin, respectively. Kikuba-saponin, which had been assigned the structure, IV monoglucoside, was identical with II and the structure is revised.
Three-Dimensional Shape-Based Searching of Conformationally Flexible Compounds (1997)

Steric shape plays a crucial role in receptor-ligand binding. This paper describes a three-phase database searching strategy for rapidly finding compounds similar in shape to a given shape query. The query is constructed from a receptor surface model which is derived from one or more structures. The first phase of the search screens the database, using shape-based indices as screens, for compounds which are potentially similar in shape. The second phase aligns the candidate structures and evaluates shape similarity based upon a grid-volume comparison and optional volume overlap optimization. The third phase flexibly fits candidate structures to the surface model and evaluates steric strain and electrostatic complementary. Conformational flexibility is first addressed by representing compounds in the shape database as a set of diverse conformers and later by the flexible fitting process.
Epidermal Growth Factor—Interactions with Normal and Malignant Urothelium: In Vivo and in Situ Studies (1987)

Epidermal growth factor (EGF) is excreted in urine in high concentrations and thus incubates with bladder epithelial cells continuously. However, it is not known whether any urothelial cells can bind urinary EGF or respond to it. Using a monoclonal antibody (528) to the binding portion of the human EGF receptor, immunoperoxidase staining demonstrated that the basal cell layer of normal urothelium is richly endowed with cell surface EGF receptors while the superficial cell layer is not. Alternatively, superficial cells of premalignant and malignant urothelium have many surface EGF receptors. Intravesical EGF induces in vivo activity of ornithine decarboxylase and DNA synthesis in rat bladders, with nuclear thymidine incorporation being limited to the basal epithelial cell layer. These studies indicate that urothelium can respond to urinary EGF and that this response parallels the distribution of EGF receptors. These findings combined with the difference in EGF-receptor expression between malignant and normal cells indicate that urinary EGF may play a role in bladder tumor development and/or growth.
Isotype-specific Ras.GTP-levels predict the efficacy of farnesyl transferase inhibitors against human astrocytomas regardless of Ras mutational status. (2001)

Previous studies have demonstrated that astrocytomas express elevated levels of activated Ras.GTP despite the absence of activating Ras mutations. Farnesyl transferase inhibitors (FTIs) exert their antitumor effect in part through inhibition of Ras-mediated signaling. SCH66336 is a potent FTI presently undergoing clinical trials in patients with solid tumors. We evaluated the efficacy of SCH66336 against a panel of eight human astrocytoma cell lines and three human astrocytoma explant xenograft models in NOD-SCID mice. SCH66336 demonstrated variable antiproliferative effects against the cell lines, with IC(50) ranging from 0.6 microM to 32.3 microM. Two of the three human glioblastoma multiforme (GBM) xenografts demonstrated substantial growth inhibition in response to SCH66336, with up to 69% growth inhibition after 21 days of treatment. Drug efficacy could be accurately predicted using a combination of the H-, K-, and N-isotype-specific Ras.GTP levels. These data indicate that the absence of Ras mutations does not preclude chemotherapeutic efficacy by FTIs, that Ras is likely a major target of FTIs regardless of Ras mutational status, and that isotype-specific Ras.GTP levels are a promising marker of drug efficacy.
Prolongation of survival following depletion of CD4+CD25+ regulatory T cells in mice with experimental brain tumors (2006)

The results of this study indicate that CD4+CD25+ Treg cells play an important role in suppressing the immune response to CNS tumors. These Treg cells may therefore represent a potentially novel target for immunotherapy of malignant gliomas.
Stabilization of α‐chymotrypsin upon PEGylation correlates with reduced structural dynamics (2008)

Protein stability remains one of the main factors limiting the realization of the full potential of protein therapeutics. Poly(ethylene glycol) (PEG) conjugation to proteins has evolved into an important tool to overcome instability issues associated with proteins. The observed increase in thermodynamic stability of several proteins upon PEGylation has been hypothesized to arise from reduced protein structural dynamics, although experimental evidence for this hypothesis is currently missing. To test this hypothesis, the model protein alpha-chymotrypsin (alpha-CT) was covalently modified with PEGs with molecular weights (M(W)) of 700, 2,000 and 5,000 and the degree of modification was systematically varied. The procedure did not cause significant tertiary structure changes. Thermodynamic unfolding experiments revealed that PEGylation increased the thermal transition temperature (T(m)) of alpha-CT by up to 6 degrees C and the free energy of unfolding [DeltaG(U) (25 degrees C)] by up to 5 kcal/mol. The increase in stability was found to be independent of the PEG M(W) and it leveled off after an average of four PEG molecules were bound to alpha-CT. Fourier-transformed infrared (FTIR) H/D exchange experiments were conducted to characterize the conformational dynamics of the PEG-conjugates. It was found that the magnitude of thermodynamic stabilization correlates with a reduction in protein structural dynamics and was independent of the PEG M(W). Thus, the initial hypothesis proved positive. Similar to the thermodynamic stabilization of proteins by covalent modification with glycans, PEG thermodynamically stabilizes alpha-CT by reducing protein structural dynamics. These results provide guidance for the future development of stable protein formulations.
[Susceptibility genes for the development of autoimmune thyroid disease]. (2006)

Autoimmune thyroid disease (AITD) is caused by an immune response to self thyroid antigens. Twin studies and familial aggregation indicated that AITD is a complex disease with genetic factors and major histocompatibility complex is the most clearly established genetic factor. We confirmed the association of the co-receptor CTLA4 with AITD. We have identified the association of the SNP in the Fc receptor-like 3 with several autoimmune diseases, including AITD, SLE and rheumatoid arthritis, which SNP affected the level of autoantibody production. Furthermore, we have identified ZFAT as a susceptibility gene in 8q24 for AITD by whole-genome linkage analysis and further SNP-based dense mapping. The associated SNP in ZFAT affected the antisense transcript of ZFAT, which in turn affected the ZFAT expression.
The internal pH of the forespore compartment of Bacillus megaterium decreases by about 1 pH unit during sporulation (1994)

Previous work has shown that the internal pH of dormant spores of Bacillus species is more than 1 pH U below that of growing cells but rises to that of growing cells in the first minutes of spore germination. In the present work the internal pH of the whole Bacillus megaterium sporangium was measured by the distribution of the weak base methylamine and was found to decrease by approximately 0.4 during sporulation. By using fluorescence ratio image analysis with a fluorescein derivative, 2',7'-bis(2-carboxyethyl)-5 (and -6)-carboxyfluorescein (BCECF), whose fluorescence is pH sensitive, the internal pH of the mother cell was found to remain constant during sporulation at a value of 8.1, similar to that in the vegetative cell. Whereas the internal pH of the forespore was initially approximately 8.1, this value fell to approximately 7.0 approximately 90 min before synthesis of dipicolinic acid and well before accumulation of the depot of 3-phosphoglyceric acid. The pH in the forespore compartment was brought to that of the mother cell by suspending sporulating cells in a pH 8 potassium phosphate buffer plus the ionophore nigericin to clamp the internal pH of the cells to that of the external medium. We suggest that at a minimum, acidification of the forespore may regulate the activity of phosphoglycerate mutase, which is the enzyme known to be regulated to allow 3-phosphoglyceric acid accumulation during sporulation.