gebhart/patrepeval huggingface dataset:
Aggregation drives “misfolding” in protein amyloid fiber formation (2007)

Protein amyloid fibers are often found to have a beta-pleated sheet structure regardless of their sequence, leading some to believe that it is the molecule's misfolding that leads to aggregation. In this article, an alternative model is introduced for the amyloid community to consider, that fiber formation is a surface-energy minimization process, starting with the generation of colloidal particles and their linear assembly, and ending with structural evolution of the aggregates into mature fibers. We propose that aggregation drives conformational change and that a conformational change is not essential to initiate the aggregation process.
Identification of a frameshift mutation resulting in premature termination and loss of cell wall anchoring of the PAc antigen of Streptococcus mutans GS-5 (1997)

Most strains of Streptococcus mutans possess a 190-kDa protein antigen (PAc) on their cell surfaces, while strain GS-5 produces extracellularly a 155-kDa PAc protein. The pac gene of strain GS-5 consists of 3,477 bp and codes for a protein of 1,158 amino acids. One insertion of an adenine into the 3,469th, 3,470th, or 3,471st position from the start codon results in a frameshift mutation at codon 1157 with subsequent termination after 3 additional codons.
Gossypol and derivatives: a new class of aldose reductase inhibitors (1991)

Gossypol and 17 derivatives were tested as inhibitors of aldose reductase from human placenta. Gossypol and a number of the derivatives were potent inhibitors. The order of inhibitory activity was interpreted in relation to the Kador-Sharpless pharmacophor model for the aldose reductase inhibitor site. The structural but not the electronic aspects of the model were found to apply to this series of compounds.
Optical resonator with steep internal dispersion (1997)

We present an optical resonator with modified properties due to a nonabsorbing highly dispersive medium. The steep nonabsorbing dispersion is created with an additional pump field in an atomic beam using the effect of coherent population trapping. The linewidth of such a resonator depends on the slope of the dispersion line, which in turn depends on the atomic density and the intensity of pump and probe field. In the experiments presented here, the cavity linewidth is reduced by a factor of more than 50 relative to the linewidth of the empty resonator. We have studied the influence of the relative intensities of pump and probe field on the line profile. Due to the dispersion of the medium, the resonance frequency is nearly independent of the geometrical length of the resonator.
Homologous and heterologous desensitization of capsaicin and mustard oil responses utilize different cellular pathways in nociceptors (2007)

The transient receptor potential channel subtypes V1 (TRPV1) and A1 (TRPA1) play a critical role in the development of hyperalgesia in inflammatory pain models. Although several studies in animals and humans have demonstrated that capsaicin (CAP), a TRPV1-specific agonist, and mustard oil (MO), a TRPA1 agonist, evoke responses that undergo functional cross-desensitization in various models, the mechanisms mediating this phenomenon are largely unknown. In the present study, we evaluated the mechanisms underlying homologous and heterologous desensitization between CAP and MO responses in peripheral nociceptors using an in vitro neuropeptide release assay from acutely isolated rat hindpaw skin preparation and in vivo behavioral assessments. The pretreatment with CAP or MO significantly inhibited (50-60%) both CAP- and MO-evoked CGRP release indicating homologous and heterologous desensitization using this assay. Further studies evaluating the requirement of calcium in these phenomena revealed that homologous desensitization of CAP responses was calcium-dependent while homologous desensitization of MO responses was calcium-independent. Moreover, heterologous desensitization of both CAP and MO responses was calcium-dependent. Further studies evaluating the role of calcineurin demonstrated that heterologous desensitization of CAP responses was calcineurin-dependent while heterologous desensitization of MO responses was calcineurin-independent. Homologous and heterologous desensitization of CAP and MO was also demonstrated using in vivo behavioral nocifensive assays. Taken together, these results indicate that TRPV1 and TRPA1 could be involved in a functional interaction that is regulated via different cellular pathways. The heterologous desensitization of these receptors and corresponding inhibition of nociceptor activity might have potential application as a therapeutic target for developing novel analgesics.
Gene therapy of maliganant brain tumors: A rat glioma line bearing the herpes simplex virus type 1‐thymidine kinase gene and wild type retrovirus kills other tumor cells (1992)

Tumor cells infected with a retrovirus vector (VIK) containing the herpes simplex virus thymidine kinase (HSV-TK) gene can be selectively killed by treatment with nucleoside analogues, such as ganciclovir. To mediate delivery of the HSV-TK gene to "recipient" tumor cells, "donor" C6 rat glioma cells infected with the VIK vector (C6VIK) were superinfected with wild type Moloney murine leukemia virus (WT Mo-MLV). These modified donor cells (C6VIKWT) produced both wild type retrovirus and the VIK vector. In culture, C6VIKWT cells were 300-fold more sensitive to the toxicity of ganciclovir than were C6VIK cells, suggesting that the presence of wild type retrovirus contributed to the toxicity. Co-culture of C6VIKWT cells with the C6 subline, C6BAG, sensitized the latter to ganciclovir treatment. Nude mice inoculated subcutaneously with a mixture of C6VIKWT and C6BAG cells showed regression of subsequent tumors when treated with ganciclovir. The observations show that tumor cells modified in culture by infection with a retrovirus bearing the HSV-TK gene and wild type retrovirus are not only sensitive to ganciclovir, but can transfer this sensitivity to neighboring "naive" tumor cells in culture and in vivo.
Cholesterol interaction with recombinant human sterol carrier protein‐2 (1995)

The interaction of human recombinant sterol carrier protein-2 (SCP-2) with sterols was examined. Two independent ligand binding methods, Lipidex 1000 binding of [3H]cholesterol and a fluorescent dehydroergosterol binding assay, were used to determine the affinity of SCP-2 for sterols. Binding analysis indicated SCP-2 bound [3H]cholesterol and dehydroergosterol with a Kd of 0.3 and 1.7 microM, respectively, and suggested the presence of a single binding site. Phase fluorometry and circular dichroism were used to characterize the SCP-2 sterol binding site. Alterations in dehydroergosterol lifetime, SCP-2 tryptophan lifetime, and SCP-2 tryptophan quenching by acrylamide upon cholesterol binding demonstrated a shielding of the SCP-2 tryptophan from the aqueous solvent by bound sterol. Differential polarized phase fluorometry revealed decreased SCP-2 tryptophan rotational correlation time upon cholesterol binding. Circular dichroism of SCP-2 indicated that cholesterol elicited a small decrease in SCP-2 alpha helical content. The data suggest that SCP-2 binds sterols with affinity consistent with a lipid transfer protein that may act either as an aqueous carrier or at a membrane surface to enhance sterol desorption.
A new route to naphtho[2,3-b]furan-4,9-diones from thio-substituted 1,4-naphthoquinones (1990)

Reaction of 2-phenylthio- or 2-ethylthio-1,4-naphthoquinones (1) and (2) with lithium enolates or pyridinium ylides was found to give alkylated 1,4-naphthoquinones (3)–(6) in high yields. Alkylated 1,4-naphthoquinones (5) and (6) were then effectively cyclized to 2-substituted naphtho[2,3-b]furan-4,9-diones (8) by action of bromine in acetic acid.
Density Functional Theory Study of Photophysical Properties of Iridium(III) Complexes with Phenylisoquinoline and Phenylpyridine Ligands (2011)

Linear and quadratic response time-dependent density functional theory is applied to study the photophysical properties of iridium complexes with phenylisoquinoline and phenylpyridine ligands. The ground-state geometries, frontier molecular orbitals, absorption spectra, phosphorescence wavelengths, and radiative rate constants are computed to facilitate better understanding of the structure–property relationships of these iridium complexes used in organic light-emitting diodes (OLEDs) to enhance spin–orbit coupling and triplet state emission. The agreement obtained between calculated and available experimental data indicates a possibility to guide the design of phosphorescence-based OLEDs by predicting their relevant properties through quantum mechanical calculations.
Non-A, non-B hepatitis: research progress and current perspectives. (1983)

Recent studies have documented the existence of at least two transmissible agents of posttransfusion non-A, non-B hepatitis. The disease frequently progresses to a state of chronic liver disease and/or persistent viremia, often in the absence of elevated liver enzymes. Difficulties encountered in the development of serologic tests for NANB antigens may be related to a lack of potent antibody coupled with low concentrations of infectious agent. The ultrastructural changes we have observed in infected chimpanzee hepatocytes are primarily confined to the cytoplasm and are, in the aggregate, most similar to those induced by a variety of RNA, but not DNA, viruses. At least one of the NANB hepatitis agents interferes with concurrent HAV or HBV infection in experimentally inoculated chimpanzees.
Livestock Predation by Common Leopard in Binsar Wildlife Sanctuary, India: Human-Wildlife Conflicts and Conservation Issues (2013)

We investigate livestock predation by the common leopard (Panthera pardus) and emerging conflicts between this species, local people, and wildlife authorities at the Binsar Wildlife Sanctuary in the Himalayan region of India. We scrutinized secondary data that were collected by wildlife authorities; we also conducted informal interviews of villagers living within sanctuary, and wildlife staff to understand various human–leopard conflicts. Leopard density was approximately 0.33/km2 in the sanctuary. Leopards killed 1,763 domestic animals, about 90% of which were cattle, during a 14-year period. Within the sanctuary, leopards killed 1 person and injured 9 others. This high depredation rate may be due to many factors, including low density of wild prey species in the sanctuary. The high level of livestock depredation by leopards in and around the sanctuary has caused severe conflicts.
Video Propagation Networks (2017)

We propose a technique that propagates information forward through video data. The method is conceptually simple and can be applied to tasks that require the propagation of structured information, such as semantic labels, based on video content. We propose a Video Propagation Network that processes video frames in an adaptive manner. The model is applied online: it propagates information forward without the need to access future frames. In particular we combine two components, a temporal bilateral network for dense and video adaptive filtering, followed by a spatial network to refine features and increased flexibility. We present experiments on video object segmentation and semantic video segmentation and show increased performance comparing to the best previous task-specific methods, while having favorable runtime. Additionally we demonstrate our approach on an example regression task of color propagation in a grayscale video.
Abstract 897: Thymidine kinase 1, a novel biomarker specific to the plasma membrane of cancerous cell lines (2011)

Abstract Thymidine Kinase 1 (TK1), an important nucleotide salvage pathway enzyme, has been shown to be upregulated in most malignant cancers. Recent studies have shown that TK1 not only has diagnostic and prognostic potential, but could also be used as a molecular target for therapeutic treatments. Previous research from our lab has shown the expression of TK1 on the plasma membrane of lymphoma. This study provides further insight on the role of TK1 as a diagnostic target for several different tumor cell lines. This study analyzed the localization of TK1 in ten different cancer cell lines using flow cytometry (FCM). The lines studied were A375, a malignant melanoma, CAL27, a squamous cell carcinoma derived from tongue, MDA-MB-231, a breast adenocarcinoma, MDA-MB-435S, previously described as a ductal carcinoma, HT29, a colorectal adenocarcinoma, SW620, a colorectal adenocarcinoma, A549, a lung carcinoma, NCI-H460, a large cell lung carcinoma, DU 145, a prostrate carcinoma, and PC3, a prostate adenocarcinoma. FCM was carried out using a polyclonal antibody against human TK1 as the primary antibody and a FITC conjugated secondary antibody. A sample stained with only secondary antibody was used as a negative control for the experiment. Five replicates were analyzed for each cell line. TK1 was found to bind between 48% and 96%, depending on the cell line. Non-cancerous tonsil tissue and normal lymphocytes were used as controls, where TK1 surface binding was less than 20%. These data indicate the feasibility of TK1 as a possible molecular target for immunotherapy in many types of cancer. Further research is ongoing to determine specific immunotherapy treatment options, and to verify the expression of TK1 in other cancer cell lines. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 897. doi:10.1158/1538-7445.AM2011-897
Synchronous distance education via the Internet (2002)

Describes a vision for networked distance education and ongoing experiments intended to increase our understanding of how distance education can be conducted most successfully at the university level. Our vision includes the relationship between delivery media and modes in the future learning environment, the role of information technologies in scholarship, and the benefits of unlimited access to global information resources. A special concern is the effective use of various media in distance education. For example, the traditional role of video delivery is analyzed and seen to be, in many cases, more a matter of past necessity than effective future delivery. In support of our conclusions a series of experiments conducted at the author's university are described. These have involved teaching real, for-credit courses to remote students using the Internet. While many universities are experimenting with asynchronous delivery via e-mail, Web and related technologies, our work is unusual in that it involves synchronous delivery. The most enlightening of our experiments involved use of the Internet multicast backbone (Mbone) and its associated suite of multimedia tools. Ongoing experiments involve use of commercial off-the-shelf multimedia with low-cost workstations and a commercial Internet service.
Hepatitis C Genotype Determination by Melting Curve Analysis with a Single Set of Fluorescence Resonance Energy Transfer Probes (2002)

Melting analysis with a single pair of FRET probes can rapidly provide information about HCV genotypes and identifies type 1 samples with high specificity.
Designed Peptide Analogues of the Potassium Channel Blocker ShK Toxin (2001)

ShK toxin, a potassium channel blocker from the sea anemone Stichodactyla helianthus, is a 35-residue polypeptide cross-linked by 3 disulfide bridges. In an effort to generate truncated peptidic analogues of this potent channel blocker, we have evaluated three analogues, one in which the native sequence was truncated and then stabilized by the introduction of additional covalent links (a non-native disulfide and two lactam bridges), and two in which non-native structural scaffolds stabilized by disulfide and/or lactam bridges were modified to include key amino acid residues from the native toxin. The effect of introducing a lactam bridge in the first helix of ShK toxin (to create cyclo14/18[Lys14,Asp18]ShK) was also examined to confirm that this modification was compatible with activity. All four analogues were tested in vitro for their ability to block Kv1.3 potassium channels in Xenopus oocytes, and their solution structures were determined using 1H NMR spectroscopy. The lactam bridge in full-length ShK is well tolerated, with only a 5-fold reduction in binding to Kv1.3. The truncated and stabilized analogue was inactive, apparently due to a combination of slight deviations from the native structure and alterations to side chains required for binding. One of the peptide scaffolds was also inactive because it failed to adopt the required structure, but the other had a K(d) of 92 microM. This active peptide incorporated mimics of Lys22 and Tyr23, which are essential for activity in ShK, and an Arg residue that could mimic Arg11 or Arg24 in the native toxin. Modification of this peptide should produce a more potent, low molecular weight peptidic analogue which will be useful not only for further in vitro and in vivo studies of the effect of blocking Kv1.3, but also for mapping the interactions with the pore and vestibule of this K(+) channel that are required for potent blockade.
Specificity and versatility of SH3 and other proline-recognition domains: structural basis and implications for cellular signal transduction (2005)

Protein-protein interactions occurring via the recognition of short peptide sequences by modular interaction domains play a central role in the assembly of signalling protein complexes and larger protein networks that regulate cellular behaviour. In addition to spatial and temporal factors, the specificity of signal transduction is intimately associated with the specificity of many co-operative, pairwise binding events upon which various pathways are built. Although protein interaction domains are usually identified via the recognition code, the consensus sequence motif, to which they selectively bind, they are highly versatile and play diverse roles in the cell. For example, a given interaction domain can bind to multiple sequences that exhibit no apparent identity, and, on the other hand, domains of the same class or different classes may favour a given consensus motif. This promiscuity in ligand selection is typified by the SH3 (Src homology 3) domain and several other interaction modules that commonly recognize proline-rich sequences. Furthermore, interaction domains are highly adaptable, a property that is essential for the evolution of novel pathways and modulation of signalling dynamics. The ability of certain interaction domains to perform multiple tasks, however, poses a challenge for the cell to control signalling specificity when cross-talk between pathways is undesired. Extensive structural and biochemical analysis of many interaction domains in recent years has started to shed light on the molecular basis underlying specific compared with diverse binding events that are mediated by interaction domains and the role affinity plays in affecting domain specificity and regulating cellular signal transduction.
Phase II study of 5-azacytidine in solid tumors. (1977)

A phase II study utilizing 5-azacytidine in the treatment of patients with solid tumors was carried out by the Southwest Oncology Group (SWOG-7208). Of 214 patients entered in the study 191 were eligible and 167 were evaluable. While initially they received 225 mg/m2 iv on Days 1--5 every 3 weeks because of toxicity the dose was subsequently reduced to 175mg/m2 and later to 150 mg/m2. Five partial regressions, 2.6% of the eligible patients and 3% of the evaluable patients, lasting from 28 to 77 days were observed. Sixteen patients 8.4% of the eligible patients and 9.6% of the evaluable patients, had no significant change in their disease for 39--255 days. The major toxicities were myelosuppressive and gastrointestinal with 13 deaths attributable to drug toxicity: 11 due to sepsis and two due to cerebral hemorrhage. 5-Azacytidine induced few favorable responses; those that did occur usually were of poor quality and short duration and were associated with significant toxicity.
The attenuated phenotype of a Salmonella typhimurium flgM mutant is related to expression of FliC flagellin (1996)

The flgM gene of Salmonella typhimurium encodes a negative regulator of flagellin synthesis that acts by inhibiting the flagellum-specific sigma factor FliA (sigma 28), but only when a mutation in a flagellar basal body, hook, or switch gene is present. We previously showed that FlgM is also necessary for the virulence of S. typhimurium in the mouse model of typhoid fever and proposed that FlgM is required to modulate the activity of the FliA sigma factor, which, in turn, regulates a gene involved in virulence. In this investigation, we observed that (i) the in vitro generation times of flgM mutant and wild-type strains of S. typhimurium were indistinguishable, as were the amounts of flagellin produced by the strains; (ii) the 50% lethal doses of fliA mutant and wild-type strains of S. typhimurium were similar in orally infected mice; and (iii) inactivation of the FliA-regulated flagellin gene fliC in an flgM S. typhimurium mutant resulted in a virulent phenotype. Therefore, we now conclude that expression of the FliC flagellin subunit in an flgM strain is responsible for the attenuated phenotype of an flgM mutant and that FliA does not appear to positively regulate virulence genes in S. typhimurium. Our results suggest that the normal regulation of flagellum synthesis appears to be necessary for virulence and that there may be an advantage conferred in vivo by expression of a particular flagellar phenotype of S. typhimurium.
Poly(ADP-ribose) degradation by glycohydrolase starts with an endonucleolytic incision. (1988)

We have recently shown that poly(ADP-ribose) polymerase forms poly(ADP-ribose) by adding ADP-ribose residues to the polymerase-proximal end of an enzyme-bound nascent chain. In this light we have reexamined the mode of hydrolysis of enzyme-bound poly(ADP-ribose) by poly(ADP-ribose) glycohydrolase. When the substrate has been labeled by a pulse-chase protocol, soluble glycohydrolase releases a significant amount of labeled oligomer which can only come from the enzyme-distal (2') end of the polymer. This constitutes additional evidence for the proximal growth of chains. Oligomer is infrequently released from the proximal (1") end of enzyme-bound chains. Rather, the bulk of the poly(ADP-ribose) is digested directly to ADP-ribose monomers. We conclude that poly(ADP-ribose) glycohydrolase starts digestion with an endonucleolytic incision and then removes ADP-ribose residues processively in the 2'----1" direction. Therefore, in contrast to earlier models of polymer growth and hydrolysis, a single poly(ADP-ribose) chain may be extended at one end and simultaneously degraded at the other end. The balance between synthesis and degradation may control the quantity and distribution of polymer around the DNA break which occasions its synthesis.