gebhart/patrepeval huggingface dataset:
Arabidopsis amidase 1, a member of the amidase signature family (2007)

Amidase 1 (AMI1), a specific indole-3-acetamide amidohydrolase, is an Arabidopsis thaliana amidase signature enzyme that catalyzes the synthesis of indole-3-acetic acid from indole-3-acetamide. Amidase signature family members catalyze a diverse range of enzymatic reactions and are found widespread in nature, for instance in bacteria, mammals, and plants. At the protein level, the family members share a conserved stretch of approximately 50-130 amino acids, the name-giving amidase signature. Elucidation of the crystal structures of a mammalian fatty acid amide hydrolase and the bacterial malonamidase E2 revealed an unusual Ser-cisSer-Lys catalytic triad in proteins of this family. In addition, other members, such as the amidase from Rhodococcus rhodochrous strain J1 or Sulfolobus solfataricus, seem to use an accessory Cys-cisSer-Lys center. AMI1 possesses all conserved amino-acid residues of the Ser-cisSer-Lys triad, but lacks the CX(3)C motif and therefore the Cys-cisSer-Lys catalytic site. Using a set of point-mutated variants of AMI1 and chemical modifications, we analyzed the relative importance of single amino-acid residues of AMI1 with respect to substrate conversion. These experiments revealed that a specific serine residue, Ser137, is essential for AMI1 enzymatic activity. We also report structural and functional differences of AMI1 from other amidase signature enzymes.
Solution Structure of the Mature HIV-1 Protease Monomer (2003)

We present the first solution structure of the HIV-1 protease monomer spanning the region Phe1-Ala95 (PR1-95). Except for the terminal regions (residues 1-10 and 91-95) that are disordered, the tertiary fold of the remainder of the protease is essentially identical to that of the individual subunit of the dimer. In the monomer, the side chains of buried residues stabilizing the active site interface in the dimer, such as Asp25, Asp29, and Arg87, are now exposed to solvent. The flap dynamics in the monomer are similar to that of the free protease dimer. We also show that the protease domain of an optimized precursor flanked by 56 amino acids of the N-terminal transframe region is predominantly monomeric, exhibiting a tertiary fold that is quite similar to that of PR1-95 structure. This explains the very low catalytic activity observed for the protease prior to its maturation at its N terminus as compared with the mature protease, which is an active stable dimer under identical conditions. Adding as few as 2 amino acids to the N terminus of the mature protease significantly increases its dissociation into monomers. Knowledge of the protease monomer structure and critical features of its dimerization may aid in the screening and design of compounds that target the protease prior to its maturation from the Gag-Pol precursor.
A Mild and Selective Method for the Hydrolysis of Esters with Trimethyltin Hydroxide (2005)

Mild, selective, and efficient: A new method that involves the use of trimethyltin hydroxide for the hydrolysis of specific ester groups allows chemists to steer clear of unwanted elimination reactions and epimerizations. For example, the conversion of ester 1 into carboxylic acid 2 takes place under mild conditions, with nearly complete retention of stereochemical integrity. 1,2-DCE=1,2-dichloroethane.
Therapeutic targeting of Trk supresses tumor proliferation and enhances cisplatin activity in HNSCC (2010)

Head and neck squamous cell carcinoma (HNSCC) is a biologically aggressive disease that has been modestly impacted by improvements in therapeutic strategies. Several lines of evidence support the role of TrkB for invasion and metastasis in various solid tumor models, and we have shown an important function of this receptor in HNSCC tumor biology. Therapeutic modulation of TrkB function has been supported in the literature by the development of small molecule inhibitors (SMI) with minimal success. To assess the validity of targeting TrkB in HNSCC, we tested a novel agent, AZ64 and show significant dose and time-dependent inhibition of cellular proliferation in cell lines. Genetic studies revealed the specificity of this compound for the TrkB receptor, as exposure of cells that had genetic suppression of TrkB did not demonstrate abrogated oncogenic signaling. We next assessed the impact of AZ64 as a chemotherapy-sensitizer and identified an enhancement of cisplatin-mediated anti-proliferation across all cell lines. We then demonstrated that AZ64 can overcome chemotherapy resistance in a novel model of cisplatin resistance in HNSCC. Modulation of the pro-oncogenic STAT3 and Src pathways was identified, suggesting molecular mechanisms of action for AZ64. In this study, we demonstrate the feasibility of targeting TrkB and suggest a novel approach for the treatment of some chemotherapy-resistant HNSCC.
Evaluation of current algorithms for segmentation of scar tissue from late Gadolinium enhancement cardiovascular magnetic resonance of the left atrium: an open-access grand challenge (2013)

The study concludes that currently no algorithm is deemed clearly better than others. There is scope for further algorithmic developments in LA fibrosis and scar quantification from LGE CMR images. Benchmarking of future scar segmentation algorithms is thus important. The proposed benchmarking framework is made available as open-source and new participants can evaluate their algorithms via a web-based interface.
Ligand-activated site-specific recombination in mice. (1996)

Current mouse gene targeting technology is unable to introduce somatic mutations at a chosen time and/or in a given tissue. We report here that conditional site-specific recombination can be achieved in mice using a new version of the Cre/lox system. The Cre recombinase has been fused to a mutated ligand-binding domain of the human estrogen receptor (ER) resulting in a tamoxifen-dependent Cre recombinase, Cre-ERT, which is activated by tamoxifen, but not by estradiol. Transgenic mice were generated expressing Cre-ERT under the control of a cytomegalovirus promoter. We show that excision of a chromosomally integrated gene flanked by loxP sites can be induced by administration of tamoxifen to these transgenic mice, whereas no excision could be detected in untreated animals. This conditional site-specific recombination system should allow the analysis of knockout phenotypes that cannot be addressed by conventional gene targeting.
Delivery to cancer cells of antisense L‐myc oligonucleotides incorporated in fusogenic, cationic‐lipid‐reconstituted influenza‐virus envelopes (cationic virosomes) (1998)

Antisense oligodeoxy-nucleoside phosphorothioates (OPTs) of L-myc were encapsulated into reconstituted influenza-virus-A envelopes (virosomes). The envelopes of the virosomes consisted of a single positively charged (cationic) lipid bilayer. Binding of cationic virosomes to cellular receptors that are membrane glycoproteins or glycolipids containing terminal sialic acid is mediated by the hemagglutinin glycoprotein (HA) of the influenza virus. After internalization through receptor-mediated endocytosis, cationic virosomes fuse efficiently with the membranes of the endosomal-cell compartment, and as a consequence the encapsulated OPT are delivered to the cell cytoplasma. Examination by fluorescence microscopy of the cellular uptake of cationic virosomes containing fluorescein-labeled OPT showed rapid and efficient incorporation of virosomes. Addition of cationic virosomes (75–150 μl) containing antisense L-myc OPT in the picomolar range to small-cell-lung-cancer (SCLC) cell cultures that expressed highly the L-myc oncogene led to strong inhibition of thymidine incorporation in a concentration-dependent manner. Virosome-entrapped sense L-myc OPT and random-order OPT had only minimal effects on the thymidine uptake. Cells of SCLC cell line NCI-H82 expressing a very low level of L-myc were not affected by antisense-L-myc virosomes. In Western-blot analysis, expression of L-myc protein was suppressed in the antisense-virosome-treated NCI-H209 cells but not in untreated control NCI-H209 cells. These results suggest that cationic virosomes may have great potential as an efficient delivery system for antisense oligonucleotides in cancer therapy. Int. J. Cancer 77:728–733, 1998. © 1998 Wiley-Liss, Inc.
Adenovirus expressing RIZ1 in tumor suppressor gene therapy of microsatellite-unstable colorectal cancers. (2001)

Viral vector-mediated delivery of tumor suppressor genes represents a promising strategy of cancer therapy. Several best-studied tumor suppressor genes, such as p53 and retinoblastoma (Rb), have been evaluated for gene therapy of tumors that carry mutations in these genes. However, these genes may not be applicable to microsatellite instability positive [MSI(+)] tumors because they are rarely mutated in these tumors. The Rb-interacting zinc finger gene RIZ1 is commonly mutated in MSI(+) colorectal, gastric, and endometrial cancers and has demonstrated a capacity to induce cell cycle arrest and apoptosis. Here, we found that RIZ1 expression through adenovirus vectors suppressed growth of MSI(+) HCT116 colorectal xenograft tumors that carry RIZ1 mutations. Malignant cells in the established tumors were efficiently transduced by RIZ1 adenoviruses and underwent apoptosis in response to RIZ1 expression. In comparison, a recombinant p53 adenovirus did not induce apoptosis and tumor suppression. These results suggest that RIZ1 may be useful in gene therapy of MSI(+) colorectal cancers.
Disruption of the Lcn2 gene in mice suppresses primary mammary tumor formation but does not decrease lung metastasis (2010)

Based largely on studies in xenograft models, lipocalin-2 (Lcn2) has been implicated in the progression of multiple types of human tumors, including breast cancer. Here we examine the role of Lcn2 in mammary tumorigenesis and lung metastasis using an in vivo molecular genetics approach. We crossed a well-characterized transgenic mouse model of breast cancer, the MMTV-PyMT (mouse mammary tumor virus-polyoma middle T antigen) mouse, with two independent gene-targeted Lcn2(-/-) mouse strains of the 129/Ola or C57BL/6 genetic background. The onset and progression of mammary tumor development and lung metastasis in the female progeny of these crosses were monitored over a 20-week period. Female Lcn2(-/-)MMTV-PyMT mice of the 129/Ola background (Lcn2(-/-)PyMT(129)) showed delayed onset of mammary tumors, and both Lcn2(-/-)PyMT(129) mice and Lcn2(-/-)MMTV-PyMT mice of the C57BL/6 background (Lcn2(-/-)PyMT(B6)) exhibited significant decreases in multiplicity and tumor burden (approximately 2- to 3-fold), as measured by total tumor weight and volume. At the molecular level, mammary tumors derived from Lcn2(-/-)PyMT(B6) females showed reduced matrix metalloproteinase-9 (MMP-9) activity and a lack of high molecular weight MMP activity. However, although increased MMP-9 activity has been linked to tumor progression, neither Lcn2(-/-)PyMT(B6) nor Lcn2(-/-)PyMT(129) female mice showed a reduction in lung metastases compared to Lcn2(+/+)PyMT controls. Our results demonstrate, using an in vivo animal model approach, that Lcn2 is a potent inducer of mammary tumor growth but not a significant promoter of lung metastasis.
The Effect of Stem Stiffness on Femoral Bone Resorption After Canine Porous-Coated Total Hip Arthroplasty (1990)

Bilateral noncemented total hip arthroplasty (THA) was produced in dogs to determine the effect of stem stiffness on stress-related bone resorption. Two porous-coated femoral implants of substantially different stiffnesses were designed for direct comparison. One was manufactured from cobalt-chromium (CoCr) alloy, the other from titanium alloy. The titanium stem was hollowed out to a wall thickness of 1 mm to further reduce its stiffness. The cumulative stiffness differences were about 5.4-fold axially and 3.6-fold in bending and torsion. Staged bilateral THA was performed on eight dogs. Each dog received a stiff CoCr stem on one side and a flexible titanium stem on the other. After death, the femora were removed and processed for undecalcified thin-section histology. Bone ingrowth and remodeling were quantified by computer-aided image analysis and compared between stem designs. All femoral specimens showed bone ingrowth fixation of both stiff and flexible stems along the implant length. Tetracycline labeling indicated active bone turnover in the femoral cortex and in regions of ingrowth. However, gross differences in femoral bone remodeling were observed both roentgenographically and histologically. Femora with the flexible stems consistently showed much less bone resorption than those with the stiff stems. Quantitative analysis of paired cross-sections indicated an average of 25%-35% more cortical bone area in the femora with flexible stems. Severe resorption of the cortex in the midstem region occurred in three of the femora with the stiff stems but in none with the flexible stems. Stem stiffness strongly influences bone remodeling. The flexible stem results in more uniform load transfer and less stress shielding.
Identification of RTX toxin target cell specificity domains by use of hybrid genes (1991)

The Escherichia coli hemolysin (HlyA) and Pasteurella haemolytica leukotoxin (LktA) are cytolytic toxins encoded by genes belonging to the recently described RTX gene family. These cytotoxins are, respectively, 1,023 and 953 amino acids in length and are encoded by genes within identically organized operons. They share 45% amino acid sequence identities but differ in their target cell specificities. In vitro-derived recombinant hybrid genes between hlyA and lktA were constructed by using restriction endonuclease sites created by oligonucleotide site-directed mutagenesis. The cytolytic activity of hybrid proteins was investigated using as targets sheep erythrocytes and two cultured cell lines from different species (BL3, bovine leukemia-derived B lymphocytes; and Raji, human B-cell lymphoma cells). HlyA is cytolytic to all three cell types. LktA lyses only BL3 cells. Among the hybrid proteins displaying cytolytic activity, the striking finding is that the hemolytic activity of several LktA-HlyA hybrids was independent of any cytolytic activity against either cultured cell species. The hemolytic activity was associated with the HlyA region between amino acids 564 and 739. Structures that are critical for HlyA cytolytic activity against BL3 or Raji cells were destroyed when LktA-HlyA and HlyA-LktA hybrids were made, respectively, at amino acid positions 564 and 739 of HlyA. In contrast to HlyA, which lysed the two different cultured cell lines with equal efficiency, Lkt-HlyA hybrids possessing the amino-terminal 169 residues of LktA lysed BL3 cells more efficiently than Raji cells. This suggests that a significant but not exclusive element of the LktA ruminant cell specificity resides in the amino-terminal one-fifth of the protein. A molecular model of the functional domains of HlyA and LktA is presented.
Soft contact-lens biosensor for real-time tear sugar monitoring at the eye (2012)

A soft contact-lens (SCL) biosensor for in-situ tear sugar monitoring was fabricated and tested. In contrast to the previously reported continuous glucose monitoring (CGM) devices, we focused on the relationship between blood glucose and tear glucose. The SCL biosensor was constructed by applying microelectromechanical systems (MEMS) techniques to functional polymers. The sensor has film electrodes on the surface of a rounded surface of polydimethyl siloxane (PDMS) contact-lens and glucose oxidase (GOD) was immobilized on the sensing region of the electrodes. Sufficiently adhesive and flexible electrodes were formed on the polymer device (PDMS and 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer). In the in-vitro characterization, the SCL-biosensor showed excellent relationship between the output current and glucose concentration from 0.03 to 10.0 mmol/L, which included the reported tear glucose concentrations (0.14 mM) of humans. Based on the result, in-situ tear glucose monitoring with the SCL-biosensor was carried out. The output current of the SCL-biosensor was sufficiently stable and reflected the tear glucose levels. The static glucose level in the basal tear of a rabbit was measured and estimated to 0.13 mmol/L. Since the biosensor was also possible to be sotored for more than 50 days, daily disposable application was expected with the SCL biosensor.
pH-induced difference spectrophotometric assay of acetazolamide, hydrochlorothiazide, and furosemide. (1978)

On the basis of pH-induced spectral changes for acetazolamide, hydrochlorothiazide, and furosemide, 3 different spectrophotometric methods are described. The methods were successfully applied to the assay of these drugs in different pharmaceutical formulations (tablets and ampoules). The accuracy of the analysis is increased by using the suggested methods as compared with conventional spectrophotometry.
The histology of skin treated with a picosecond alexandrite laser and a fractional lens array (2016)

These intra-epidermal cavities result from areas of laser-induced optical breakdown (LIOB). This injury is most consistent with a localized plasma formation in the epidermis initiated by the melanin absorption of the high energy picosecond light. It appears that treatments with this device and optic result in improvements in dyspigmentation and acne scars with new collagen, elastic tissue, and mucin. The production of this LIOB could directly stimulate an epidermal repair mechanism that results in these clinical findings. Lasers Surg. Med. 48:646-652, 2016. © 2016 Wiley Periodicals, Inc.
Diagnosis of Duchenne dystrophy by enhanced detection of small mutations (2001)

A highly sensitive single-strand conformation polymorphism method substantially increased detection of small dystrophin gene mutations and made it possible to diagnose approximately 90% of patients with Duchenne dystrophy by DNA analysis. These findings, combined with cost savings and safety issues, provide compelling reasons to consider DNA analysis as the initial diagnostic test for the suspected dystrophin-deficient patient.
A characterization of telecommunication services in the 1990s (1989)

A characterization is presented of voice, data, facsimile, image, audio and video telecommunication services of the next decade. User-oriented features such as performance criteria are related to transport requirements. A broad diversity of services is described, and these are then classified into groups from a transport perspective. This leads to implications for cell priority designation for asynchronous time-division multiplexing (ATDM). A service groups based on a community of interest is shown to offer a scenario for the introduction of ATDM which is attractive both to the user and the telecommunications company.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Identification of new sensitive biomarkers for the in vivo response to interferon‐β treatment in multiple sclerosis using DNA‐array evaluation (2009)

We identify IFI27, CCL2 and CXCL10 as sensitive biomarkers for the response to IFN-beta. The expression of these markers adequately reflects bioactivity of IFN-ss as documented by the decreased induction in low NAb-positive patients and the lost induction in patients with moderate/high NAb levels.
A Unique Bivalent Binding and Inhibition Mechanism by the Yatapoxvirus Interleukin 18 Binding Protein (2012)

Interleukin 18 (IL18) is a cytokine that plays an important role in inflammation as well as host defense against microbes. Mammals encode a soluble inhibitor of IL18 termed IL18 binding protein (IL18BP) that modulates IL18 activity through a negative feedback mechanism. Many poxviruses encode homologous IL18BPs, which contribute to virulence. Previous structural and functional studies on IL18 and IL18BPs revealed an essential binding hot spot involving a lysine on IL18 and two aromatic residues on IL18BPs. The aromatic residues are conserved among the very diverse mammalian and poxviruses IL18BPs with the notable exception of yatapoxvirus IL18BPs, which lack a critical phenylalanine residue. To understand the mechanism by which yatapoxvirus IL18BPs neutralize IL18, we solved the crystal structure of the Yaba-Like Disease Virus (YLDV) IL18BP and IL18 complex at 1.75 Å resolution. YLDV-IL18BP forms a disulfide bonded homo-dimer engaging IL18 in a 2∶2 stoichiometry, in contrast to the 1∶1 complex of ectromelia virus (ECTV) IL18BP and IL18. Disruption of the dimer interface resulted in a functional monomer, however with a 3-fold decrease in binding affinity. The overall architecture of the YLDV-IL18BP:IL18 complex is similar to that observed in the ECTV-IL18BP:IL18 complex, despite lacking the critical lysine-phenylalanine interaction. Through structural and mutagenesis studies, contact residues that are unique to the YLDV-IL18BP:IL18 binding interface were identified, including Q67, P116 of YLDV-IL18BP and Y1, S105 and D110 of IL18. Overall, our studies show that YLDV-IL18BP is unique among the diverse family of mammalian and poxvirus IL-18BPs in that it uses a bivalent binding mode and a unique set of interacting residues for binding IL18. However, despite this extensive divergence, YLDV-IL18BP binds to the same surface of IL18 used by other IL18BPs, suggesting that all IL18BPs use a conserved inhibitory mechanism by blocking a putative receptor-binding site on IL18.
Molecular typing of meningococci: recommendations for target choice and nomenclature (2006)

The diversity and dynamics of Neisseria meningitidis populations generate a requirement for high resolution, comprehensive, and portable typing schemes for meningococcal disease surveillance. Molecular approaches, specifically DNA amplification and sequencing, are the methods of choice for various reasons, including: their generic nature and portability, comprehensive coverage, and ready implementation to culture negative clinical specimens. The following target genes are recommended: (1) the variable regions of the antigen-encoding genes porA and fetA and, if additional resolution is required, the porB gene for rapid investigation of disease outbreaks and investigating the distribution of antigenic variants; (2) the seven multilocus sequence typing loci-these data are essential for the most effective national, and international management of meningococcal disease, as well as being invaluable in studies of meningococcal population biology and evolution. These targets have been employed extensively in reference laboratories throughout the world and validated protocols have been published. It is further recommended that a modified nomenclature be adopted of the form: serogroup: PorA type: FetA type: sequence type (clonal complex), thus: B: P1.19,15: F5-1: ST-33 (cc32).
The wisdom of crowds: regulating cell function through condensed states of living matter (2017)

Our understanding of cells has progressed rapidly in recent years, mainly because of technological advances. Modern technology now allows us to observe molecular processes in living cells with high spatial and temporal resolution. At the same time, we are beginning to compile the molecular parts list of cells. However, how all these parts work together to yield complex cellular behavior is still unclear. In addition, the established paradigm of molecular biology, which sees proteins as well-folded enzymes that undergo specific lock-and-key type interactions, is increasingly being challenged. In fact, it is now becoming clear that many proteins do not fold into three-dimensional structures and additionally show highly promiscuous binding behavior. Furthermore, proteins function in collectives and form condensed phases with different material properties, such as liquids, gels, glasses or filaments. Here, I examine emerging evidence that the formation of macromolecular condensates is a fundamental principle in cell biology. I further discuss how different condensed states of living matter regulate cellular functions and decision-making and ensure adaptive behavior and survival in times of cellular crisis.