gebhart/patrepeval huggingface dataset:
The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6 (2002)

To examine whether the transcription factor Sox9 has an essential role during the sequential steps of chondrocyte differentiation, we have used the Cre/loxP recombination system to generate mouse embryos in which either Sox9 is missing from undifferentiated mesenchymal cells of limb buds or the Sox9 gene is inactivated after chondrogenic mesenchymal condensations. Inactivation of Sox9 in limb buds before mesenchymal condensations resulted in a complete absence of both cartilage and bone, but markers for the different axes of limb development showed a normal pattern of expression. Apoptotic domains within the developing limbs were expanded, suggesting that Sox9 suppresses apoptosis. Expression of Sox5 and Sox6, two other Sox genes involved in chondrogenesis, was no longer detected. Moreover, expression of Runx2, a transcription factor needed for osteoblast differentiation, was also abolished. Embryos, in which Sox9 was deleted after mesenchymal condensations, exhibited a severe generalized chondrodysplasia, similar to that in Sox5; Sox6 double-null mutant mice. Most cells were arrested as condensed mesenchymal cells and did not undergo overt differentiation into chondrocytes. Furthermore, chondrocyte proliferation was severely inhibited and joint formation was defective. Although Indian hedgehog, Patched1, parathyroid hormone-related peptide (Pthrp), and Pth/Pthrp receptor were expressed, their expression was down-regulated. Our experiments further suggested that Sox9 is also needed to prevent conversion of proliferating chondrocytes into hypertrophic chondrocytes. We conclude that Sox9 is required during sequential steps of the chondrocyte differentiation pathway.
Single-Molecule Analysis of Human Telomere Sequence Interactions with G-quadruplex Ligand (2016)

Ligands that selectively promote the formation of G-quadruplexes in human telomeres have great potential for cancer treatment by inhibiting the telomere extension by telomerase. Thus, understanding the interactions of the G-quadruplex ligands with the telomere sequence at the single-molecule level is of significant importance. Here, human telomere sequence interactions with a small molecule ligand pyridostatin (PDS) were analyzed via α-hemolysin protein nanopore, and a nanopore thermodynamic analytical method was proposed. The prolonged unraveling time of the telomeric DNA G-quadruplex after PDS binding demonstrated the potent stabilization effect of ligand on G-quadruplex structure. The signature two-level electronic blocks generated by K(+)-PDS-G-quadruplex complexes suggested a two-state unraveling process, including the dissociation of the interquartet cation and the unraveling of the cation-free ligand-bound G-quadruplex. The translocation studies and the analysis of free-energy changes demonstrated a ligand-binding mode in which PDS molecule and K(+) were simultaneously bound to one G-quadruplex structure with the coordinated effect on G-quadruplex stabilization. The single-molecular nanopore platform permits the efficient and accurate determination of ligand affinity constants without the requirement for labeling, amplification, or ligand/receptor titration, which provides a general analytical tool for effectively monitoring and quantifying the G-quadruplex/ligand interactions, possessing important implications for the design and screen of anticancer drugs.
Molecular mechanisms of renal allograft fibrosis (2001)

Recent advances in understanding of the underlying molecular mechanisms involved suggest autocrine secretion of cytokines and growth factors, especially transforming growth factor beta, are associated with a change in fibroblast phenotype leading to the deposition of extracellular matrix. Repeated insults trigger upregulation of the tissue inhibitors of matrix metalloproteinases, favouring accumulation of extracellular matrix. To date, no drug has proved effective in inhibiting or reducing allograft fibrosis. The deleterious consequences of chronic immunosuppression on the development of such fibrosis are now recognized; newer immunosuppressive drugs, including rapamycin and mycophenolate mofetil, reduce profibrotic gene expression in both experimental and clinical settings, and offer potential strategies for prolonging allograft survival.
Methods for studying corrosion in reinforced concrete (1994)

This Paper reviews available techniques for monitoring steel corrosion in reinforced concrete. Electrochemical techniques are by far the most suitable for this purpose, and meet most of the requirements. me responses of direct and alternating current corrosion monitoring methods for steel–concrete systems are compared under two extreme conditions, i.e. steel being corroded in the active state and in the passive state. Most practical situations will belong to one of these or be intermediate to them. Results of polarization resistance measurements (taken by applying a potential step, a current step and small-amplitude cyclovoltammetry), a coulostatic method and electrochemical impedance spectroscopy are reported. It is shown that metal polarization resistance in particular, and electrochemical methods in general, can provide fast and reliable information on the corrosion rate of steel in concrete, suflciently accurate to distinguish between acceptable and unacceptable conditions in most scientific and technical applications.
Parkinson's Disease Society Brain Bank, London: overview and research. (1993)

The UK Parkinson's Disease Society Brain Bank receives tissue from patients with Parkinson's disease and a variety of different movement disorders. Half of the brain is used for full neuropathological examination prior to allocation for specific research projects. Clinical misdiagnosis occurs in a significant proportion of cases and clinico-pathological correlation provides valuable information for disease recognition. With the expanding number of other specialist brain banks there is a need for agreement on diagnostic criteria. Furthermore, awareness of different methods of tissue handling is essential.
Antibody-targeted photolysis: in vitro studies with Sn(IV) chlorin e6 covalently bound to monoclonal antibodies using a modified dextran carrier. (1990)

A monoclonal antibody-dextran-Sn(IV) chlorin e6 immunoconjugate was prepared by a technique involving the site-specific covalent modification of the monoclonal antibody oligosaccharide moiety. Dextran carriers were synthesized with a single chain-terminal hydrazide group, which was used as the coupling point between the carrier and the monoclonal antibody carbohydrate. Selective in vitro photolysis of SK-MEL-2 human malignant melanoma cells was accomplished using several conjugates prepared from anti-melanoma 2.1 (chromophore:antibody molar ratios, 6.8 and 11.2). Phototoxicity, as measured by clonogenic assay, was dependent on the delivered dose of 634-nm light and was observed only for conjugates that bound SK-MEL-2 cells. As judged by competitive inhibition radioimmunoassay, conjugates prepared in this fashion showed excellent retention of antigen binding activity relative to the unmodified antibody.
Management of refractory overactive bladder (2012)

Overactive bladder has significant impact on a patient’s quality of life. Conservative and pharmacologic management are effective in most patients. Whereas treatment options were limited many years ago for patients who failed first-line therapy, there are now multiple minimally invasive options for them. Detrusor injection of botulinum toxin, which is not yet officially approved for the treatment of idiopathic overactive bladder, significantly improves patient’s symptoms and quality of life, and is well tolerated. Two types of neuromodulation are also available: posterior tibial nerve stimulation and sacral nerve stimulation. Promising new medications are in the pipeline. For those who do not respond to the minimally invasive options, augmentation cystoplasty or urinary diversion remain options.
Identification of a breast cancer-specific gene, BCSG1, by direct differential cDNA sequencing. (1997)

A high-throughput direct-differential cDNA sequencing approach was employed to identify genes differentially expressed in normal breast as compared with breast cancer. Approximately 6000 expressed sequence tags (ESTs) from cDNA libraries of normal breast and breast carcinoma were selected randomly and subjected to EST-sequencing analysis. The relative expression levels of more than 2000 unique EST groups were quantitatively compared in normal versus cancerous breast. Of many putative differentially expressed genes, a breast cancer-specific gene, BCSGC1, which was expressed in high abundance in a breast cancer cDNA library but scarcely in a normal breast cDNA library, was identified as a putative breast cancer marker. In situ hybridization analysis demonstrated stage-specific BCSG1 expression as follows: BCSG1 was undetectable in normal or benign breast lesions, showed partial expression in ductal carcinoma in situ, but was expressed at an extremely high level in advanced infiltrating breast cancer. The predicted amino acid sequence of BCSG1 gene has a significant sequence homology to the non-amyloid beta protein fragment of the Alzheimer's disease amyloid protein. BCSG1 overexpression may indicate breast cancer malignant progression from benign breast or in situ carcinoma to the highly infiltrating carcinoma.
Substrate Recognition Mechanism of VAMP/Synaptobrevin-cleaving Clostridial Neurotoxins (2008)

Botulinum neurotoxins (BoNTs) and tetanus neurotoxin (TeNT) inhibit neurotransmitter release by proteolyzing a single peptide bond in one of the three soluble N-ethylmaleimide-sensitive factor attachment protein receptors SNAP-25, syntaxin, and vesicle-associated membrane protein (VAMP)/synaptobrevin. TeNT and BoNT/B, D, F, and G of the seven known BoNTs cleave the synaptic vesicle protein VAMP/synaptobrevin. Except for BoNT/B and TeNT, they cleave unique peptide bonds, and prior work suggested that different substrate segments are required for the interaction of each toxin. Although the mode of SNAP-25 cleavage by BoNT/A and E has recently been studied in detail, the mechanism of VAMP/synaptobrevin proteolysis is fragmentary. Here, we report the determination of all substrate residues that are involved in the interaction with BoNT/B, D, and F and TeNT by means of systematic mutagenesis of VAMP/synaptobrevin. For each of the toxins, three or more residues clustered at an N-terminal site remote from the respective scissile bond are identified that affect solely substrate binding. These exosites exhibit different sizes and distances to the scissile peptide bonds for each neurotoxin. Substrate segments C-terminal of the cleavage site (P4-P4') do not play a role in the catalytic process. Mutation of residues in the proximity of the scissile bond exclusively affects the turnover number; however, the importance of individual positions at the cleavage sites varied for each toxin. The data show that, similar to the SNAP-25 proteolyzing BoNT/A and E, VAMP/synaptobrevin-specific clostridial neurotoxins also initiate substrate interaction, employing an exosite located N-terminal of the scissile peptide bond.
On Measurement of Food Powder Reconstitution Properties (2007)

Dissolution of powdered ingredients is of particular importance to manufacturers and consumers as a benchmark of consumption quality. Standard methods gauging the reconstitution properties of milk powders in the dairy industry are available, although they are relatively crude with poor reproducibility. Since most procedures were developed based on “traditional” dairy powders, they may fail to recognize the important characteristics of specialty products. A critical review is presented that identifies the properties of interests and methods for analysis. It is argued that more reliable techniques tailored for different food products can be developed to predict their behaviors for specific end usage.
开创先河的建筑师扎哈·哈迪德去世,享年65岁 (2016)

出生于伊拉克的英国建筑师扎哈·哈迪德女爵士以其高耸的建筑,在世界各大城市天际线和人们的想象中留下标志,并在重塑现代建筑的过程中留下印记.哈迪德于周四（3月31日）在美国迈阿密去世,享年65岁.
Identification of HDAC10, a novel class II human histone deacetylase containing a leucine-rich domain (2002)

Histone acetylation is important for regulating chromatin structure and gene expression. Three classes of mammalian histone deacetylases have been identified. Among class II, there are five known members, namely HDAC4, HDAC5, HDAC6, HDAC7 and HDAC9. Here we describe the identification and characterization of a novel class II member termed HDAC10. It is a 669 residue polypeptide with a bipartite modular structure consisting of an N-terminal Hda1p-related putative deacetylase domain and a C-terminal leucine-rich domain. HDAC10 is widely expressed in adult human tissues and cultured mammalian cells. It is enriched in the cytoplasm and this enrichment is not sensitive to leptomycin B, a specific inhibitor known to block the nuclear export of other class II members. The leucine-rich domain of HDAC10 is responsible for its cytoplasmic enrichment. Recombinant HDAC10 protein possesses histone deacetylase activity, which is sensitive to trichostatin A, a specific inhibitor for known class I and class II histone deacetylases. When tethered to a promoter, HDAC10 is able to repress transcription. Furthermore, HDAC10 interacts with HDAC3 but not with HDAC4 or HDAC6. These results indicate that HDAC10 is a novel class II histone deacetylase possessing a unique leucine-rich domain.
A gel electrophoresis method for quantifying the binding of proteins to specific DNA regions: application to components of the Escherichia coli lactose operon regulatory system (1981)

The use of gel electrophoresis for quantitative studies of DNA-protein interactions is described. This rapid and simple technique involves separation of free DNA from DNA-protein complexes based on differences in their electrophoretic mobilities in polyacrylamide gels. Under favorable conditions both unbound DNA and DNA associated with protein can be quantified. This gel method is applied to the study of the E. coli lactose operon regulatory system. At ionic strengths in the physiological range, the catabolite activator protein (CAP) is shown to form a long-lived complex with the wild type lac promotor, but not with a CAP-insensitive mutant. Formation of a stable "open" or "melted-in" complex of RNA polymerase with the wild type promoter requires the participation of CAP and cyclic AMP. Further, it is demonstrated that even when pre-formed in the presence of CAP-cAMP, the polymerase-promoter open complex becomes unstable if CAP is then selectively removed.
Regulation of mevalonate 5-pyrophosphate decarboxylase in isolated cells from chick intestinal epithelium (1989)

The present studies were undertaken to determine whether mevalonate 5-pyrophosphate decarboxylase (EC 4.1.1.33) is subject to physiological regulation in the intestinal mucosa. Activity was determined in epithelial cells isolated in a villus-to-crypt gradient from chicks fed on different diets in order to vary the sterol flux across the intestinal epithelium. When animals were fed on cholesterol, decarboxylase activity was decreased in all the cell fractions studied, although percentages of inhibition were maximum in crypts of jejunum and ileum. In contrast, decreased sterol flux as a consequence of cholestyramine feeding stimulated decarboxylase activity, especially in villi of the duodenum, where values increased 3-fold with respect to controls. On the other hand, the total cellular sterol content was significantly increased by the cholesterol diet. In duodenum and jejunum, 20-30% of the total cholesterol was in the esterified form under these conditions. However, dietary cholestyramine did not significantly affect amounts of total cellular cholesterol in any of the cell fractions. These results demonstrate that mevalonate 5-pyrophosphate decarboxylase activity changes considerably under different dietary situations and that the existence of secondary sites in the physiological regulation of sterol synthesis in the intestinal mucosa should be considered.
Engineered CRISPR-Cas9 nuclease with expanded targeting space (2018)

The RNA-guided endonuclease Cas9 cleaves its target DNA and is a powerful genome-editing tool. However, the widely used <i>Streptococcus pyogenes</i> Cas9 enzyme (SpCas9) requires an NGG protospacer adjacent motif (PAM) for target recognition, thereby restricting the targetable genomic loci. Here, we report a rationally engineered SpCas9 variant (SpCas9-NG) that can recognize relaxed NG PAMs. The crystal structure revealed that the loss of the base-specific interaction with the third nucleobase is compensated by newly introduced non-base-specific interactions, thereby enabling the NG PAM recognition. We showed that SpCas9-NG induces indels at endogenous target sites bearing NG PAMs in human cells. Furthermore, we found that the fusion of SpCas9-NG and the activation-induced cytidine deaminase (AID) mediates the C-to-T conversion at target sites with NG PAMs in human cells.
Glutamatergic theories of schizophrenia. (2010)

Schizophrenia is a serious mental disorder that affects up to 1% of the population worldwide. Traditional models of schizophrenia have emphasized dopaminergic dysfunction. Over the last 20 years, however, limitations of the dopamine model have become increasingly apparent, necessitating development of alternative models. Glutamatergic models are based upon the observation that the psychotomimetic agents such as phencyclidine (PCP) and ketamine induce psychotic symptoms and neurocognitive disturbances similar to those of schizophrenia by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors. Because glutamate/NMDA receptors are located throughout the brain, glutamatergic models predict widespread cortical dysfunction with particular involvement of NMDA receptors throughout the brain. Further, NMDA receptors are located on brain circuits that regulate dopamine release, suggesting that dopaminergic deficits in schizophrenia may also be secondary to underlying glutamatergic dysfunction. Agents that stimulate NMDA receptor-mediated neurotransmission, including glycine-site agonists and glycine transport inhibitors, have shown encouraging results in preclinical studies and are currently undergoing clinical development. Encouraging results have been observed as well with agents such as metabotropic 2/3 agonists that decrease resting glutamate levels, reversing potential disruption in firing patterns within prefrontal cortex and possibly other brain regions. Overall, these findings suggest that glutamatergic theories may lead to new conceptualizations and treatment approaches that would not be possible based upon dopaminergic models alone.
Enzalutamide for the Treatment of Androgen Receptor–Expressing Triple-Negative Breast Cancer (2018)

Purpose Studies suggest that a subset of patients with triple-negative breast cancer (TNBC) have tumors that express the androgen receptor (AR) and may benefit from an AR inhibitor. This phase II study evaluated the antitumor activity and safety of enzalutamide in patients with locally advanced or metastatic AR-positive TNBC. Patients and Methods Tumors were tested for AR with an immunohistochemistry assay optimized for breast cancer; nuclear AR staining > 0% was considered positive. Patients received enzalutamide 160 mg once per day until disease progression. The primary end point was clinical benefit rate (CBR) at 16 weeks. Secondary end points included CBR at 24 weeks, progression-free survival, and safety. End points were analyzed in all enrolled patients (the intent-to-treat [ITT] population) and in patients with one or more postbaseline assessment whose tumor expressed ≥ 10% nuclear AR (the evaluable subgroup). Results Of 118 patients enrolled, 78 were evaluable. CBR at 16 weeks was 25% (95% CI, 17% to 33%) in the ITT population and 33% (95% CI, 23% to 45%) in the evaluable subgroup. Median progression-free survival was 2.9 months (95% CI, 1.9 to 3.7 months) in the ITT population and 3.3 months (95% CI, 1.9 to 4.1 months) in the evaluable subgroup. Median overall survival was 12.7 months (95% CI, 8.5 months to not yet reached) in the ITT population and 17.6 months (95% CI, 11.6 months to not yet reached) in the evaluable subgroup. Fatigue was the only treatment-related grade 3 or higher adverse event with an incidence of > 2%. Conclusion Enzalutamide demonstrated clinical activity and was well tolerated in patients with advanced AR-positive TNBC. Adverse events related to enzalutamide were consistent with its known safety profile. This study supports additional development of enzalutamide in advanced TNBC.
Biosynthesis of circular proteins in plants (2007)

Plant cyclotides are a large family of naturally occurring circular proteins that are produced from linear precursors containing one, two or three cyclotide domains. The mechanism of excision of the cyclotide domains and ligation of the free N- and C-termini to produce the circular peptides has not been elucidated. Here, we investigate production of the prototypic cyclotide kalata B1 from the precursor Oak1 from the African plant Oldenlandia affinis. Immunoprecipitation experiments and MALDI-TOF mass spectrometry analysis showed that O. affinis only produces mature kalata B1, whereas transgenic Arabidopsis thaliana, Nicotiana tabacum and Nicotiana benthamiana produced both linear and circular forms. Circular peptides were not produced when a highly conserved asparagine residue at the C-terminal processing site of the cyclotide domain was replaced with an alanine or an aspartate residue, or when the conserved C-terminal tripeptide motif was truncated. We propose that there are two processing pathways in planta: one to produce the mature cyclotide and the other to produce linear variants that ultimately cannot be cyclized.
Developing vaccines against minor capsid antigen L2 to prevent papillomavirus infection (2009)

A subset of human papillomavirus (HPV) genotypes is responsible for approximately 5% of all cancer deaths globally, and uterine cervical carcinoma accounts for the majority of these cases. The impact of HPV is greatest for women who do not have access to effective secondary preventive measures, and consequently over 80% of cervical cancer deaths worldwide occur in developing nations. The understanding that persistent infection by this 'oncogenic' subset of HPV genotypes is necessary for the development of cervical carcinoma has driven the development of preventive vaccines. Two preventive vaccines comprising recombinant HPV L1 virus-like particles (VLPs) have been licensed. However, the current cost of these vaccines precludes sustained global delivery, and they target only two of the approximately 15 known oncogenic HPV types, although approximately 70% of cervical cancer cases are attributed to these two types and there is evidence for some degree of cross-protection against other closely related types. A possible approach to broader immunity at lower cost is to consider vaccination against L2. L2 vaccines can be produced inexpensively and they also have the promise of conferring much broader cross-type protective immunity than that observed with L1 VLP immunization. However, L2 vaccine development lags behind L1 VLP vaccines and several technical hurdles remain.