gebhart/patrepeval huggingface dataset:
Mitochondria-targeted drugs stimulate mitophagy and abrogate colon cancer cell proliferation (2018)

Mutations in the KRAS proto-oncogene are present in 50% of all colorectal cancers and are increasingly associated with chemotherapeutic resistance to frontline biologic drugs. Accumulating evidence indicates key roles for overactive KRAS mutations in the metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis in cancer cells. Here, we sought to exploit the more negative membrane potential of cancer cell mitochondria as an untapped avenue for interfering with energy metabolism in KRAS variant-containing and KRAS WT colorectal cancer cells. Mitochondrial function, intracellular ATP levels, cellular uptake, energy sensor signaling, and functional effects on cancer cell proliferation were assayed. 3-Carboxyl proxyl nitroxide (Mito-CP) and Mito-Metformin, two mitochondria-targeted compounds, depleted intracellular ATP levels and persistently inhibited ATP-linked oxygen consumption in both KRAS WT and KRAS variant-containing colon cancer cells and had only limited effects on nontransformed intestinal epithelial cells. These anti-proliferative effects reflected the activation of AMP-activated protein kinase (AMPK) and the phosphorylation-mediated suppression of the mTOR target ribosomal protein S6 kinase B1 (RPS6KB1 or p70S6K). Moreover, Mito-CP and Mito-Metformin released Unc-51-like autophagy-activating kinase 1 (ULK1) from mTOR-mediated inhibition, affected mitochondrial morphology, and decreased mitochondrial membrane potential, all indicators of mitophagy. Pharmacological inhibition of the AMPK signaling cascade mitigated the anti-proliferative effects of Mito-CP and Mito-Metformin. This is the first demonstration that drugs selectively targeting mitochondria induce mitophagy in cancer cells. Targeting bioenergetic metabolism with mitochondria-targeted drugs to stimulate mitophagy provides an attractive approach for therapeutic intervention in KRAS WT and overactive mutant-expressing colon cancer.
Functional requirement of p23 and Hsp90 in telomerase complexes (1999)

Most normal human diploid cells have no detectable telomerase; however, expression of the catalytic subunit of telomerase is sufficient to induce telomerase activity and, in many cases, will bypass normal senescence. We and others have previously demonstrated in vitro assembly of active telomerase by combining the purified RNA component with the reverse transcriptase catalytic component synthesized in rabbit reticulocyte extract. Here we show that assembly of active telomerase from in vitro-synthesized components requires the contribution of proteins present in reticulocyte extracts. We have identified the molecular chaperones p23 and Hsp90 as proteins that bind to the catalytic subunit of telomerase. Blockade of this interaction inhibits assembly of active telomerase in vitro. Also, a significant fraction of active telomerase from cell extracts is associated with p23 and Hsp90. Consistent with in vitro results, inhibition of Hsp90 function in cells blocks assembly of active telomerase. To our knowledge, p23 and Hsp90 are the first telomerase-associated proteins demonstrated to contribute to telomerase activity.
Selection of Embryonic Stem Cell-Derived Enhanced Green Fluorescent Protein-Positive Dopamine Neurons Using the Tyrosine Hydroxylase Promoter Is Confounded by Reporter Gene Expression in Immature Cell Populations (2007)

Transplantation of mouse embryonic stem (mES) cells can restore function in Parkinson disease models, but can generate teratomas. Purification of dopamine neurons derived from embryonic stem cells by fluorescence-activated cell sorting (FACS) could provide a functional cell population for transplantation while eliminating the risk of teratoma formation. Here we used the tyrosine hydroxylase (TH) promoter to drive enhanced green fluorescent protein (eGFP) expression in mES cells. First, we evaluated 2.5-kilobase (kb) and 9-kb TH promoter fragments and showed that clones generated using the 9-kb fragment produced significantly more eGFP+/TH+ neurons. We selected the 9-kb TH clone with the highest eGFP/TH overlap for further differentiation, FACS, and transplantation experiments. Grafts contained large numbers of eGFP+ dopamine neurons of an appropriate phenotype. However, there were also numerous eGFP+ cells that did not express TH and did not have a neuronal morphology. In addition, we found cells in the grafts representing all three germ layers. Based on these findings, we examined the expression of stem cell markers in our eGFP+ population. We found that a majority of eGFP+ cells were stage-specific embryonic antigen-positive (SSEA-1+) and that the genetically engineered clones contained more SSEA-1+ cells after differentiation than the original D3 mES cells. By negative selection of SSEA-1, we could isolate a neuronal eGFP+ population of high purity. These results illustrate the complexity of using genetic selection to purify mES cell-derived dopamine neurons and provide a comprehensive analysis of cell selection strategies based on tyrosine hydroxylase expression. Disclosure of potential conflicts of interest is found at the end of this article.
Biogenetically inspired syntheses of alkaloid natural products (2009)

Since the synthesis of tropinone in the early 20th century, generations of chemists have looked to nature for inspiration in developing elegant syntheses of natural products. Analyzing molecules in their native context greatly enriches the chemist’s understanding of nature’s solution to the rapid generation of molecular complexity. In this tutorial review, we examine select examples from the alkaloid literature to highlight ways in which the close interplay of chemistry and biology have resulted in the development of elaborate biosynthetic hypotheses as well as strikingly beautiful syntheses. In addition, we present a case study on this topic through the lens of our total synthesis of (+)-11,11′-dideoxyverticillin A.
Low vitamin D level is an independent predictor of poor outcomes in Clostridium difficile-associated diarrhea (2013)

In this study, vitamin D level and age are independent predictors of CDAD resolution in hospitalized patients. Low vitamin D levels and age >70 years old are associated with increased likelihood of recurrence. Low vitamin D levels are not a marker of comorbidity or advanced age.
Secnidazole. A 5-nitroimidazole derivative with a long half-life. (1978)

The therapeutic activity of a single 2 g dose of secnidazole was studied in patients with urogenital trichomoniasis. In 140 patients, 97% were cured and the drug was well tolerated. In the laboratory, tests on sensitivity were made and the minimal inhibitory concentration (MIC) and the minimal trichomonacidal concentration (MTC) were determined on cultures that had recently been isolated at the clinic, and the pharmacokinetic properties of secnidazole in man were compared with those of tinidazole. The therapeutic efficacy of all the metronidazole derivatives was reviewed and a single-dose treatment is recommended. Therapeutic and prophylactic treatment is achieved by products with a long half-life. Secnidazole, with a half-life of 14.3 +/- 1.3 h (women) and 20.2 +/- 3.1 h (men), is particularly suitable for this type of treatment.
Isolation and Phytotoxicity of Apocarotenoids from Chenopodium album (2004)

Two new compounds (1, 2) and 16 apocarotenoids (3-18) were isolated from the weed Chenopodium album. The structures of new apocarotenoids were determined to be (3R,6R,7E,9E,11E)-3-hydroxy-13-apo-alpha-caroten-13-one (1) and (6S,7E,9E,11E)-3-oxo-13-apo-alpha-caroten-13-one (2) by spectroscopic, NMR, and MS analysis. Five of the known compounds (5, 6, 13, 15, and 17) were previously reported only as synthetic compounds. Effects of these compounds on germination and growth of Lactuca sativa (lettuce) were studied in the 10(-4)-10(-7) M concentration range.
Junctional Adhesion Molecule-C Promotes Metastatic Potential of HT1080 Human Fibrosarcoma (2007)

The junctional adhesion molecule (JAM) family is a key molecule in a process called transendothelial migration or diapedesis. Here, we report implications of JAM-C in cancer metastasis. We first determined the mRNA expression of JAMs in 19 kinds of cancer cell lines. JAM-C was expressed in most of tumors having potent metastatic properties. Especially in murine K-1735 melanoma cell lines, the highly metastatic sublines (M2 and X21) strongly expressed JAM-C when compared with the poorly metastatic ones (C-10 and C23). Next, we investigated the role of JAM-C in cancer metastasis by using human JAM-C (hJAM-C) gene-transfected HT1080 fibrosarcoma cells. In comparison with mock-transfected HT1080 cells, these cells showed a significant increase in the adhesion to various extracellular substrates and the invasion across a Matrigel-coated membrane. The knockdown of hJAM-C using small interfering RNA resulted in the suppression of both the adhesion and the invasion of HT1080 cells, suggesting that endogenous hJAM-C might be involved in tumor metastasis. Finally, we studied the role of hJAM-C in an in vivo experimental metastatic model. The results showed that the overexpression of hJAM-C in HT1080 cells significantly decreased the life spans of the tumorbearing mice. In contrast, the knockdown of hJAM-C in HT1080 cells suppressed the weight gain of the lungs with metastatic colonies. We conclude that the expression of JAM-C promotes metastasis by enhancing both the adhesion of cancer cells to extracellular matrices and the subsequent invasion.
Glucose 6-phosphate causes translocation of phosphorylase in hepatocytes and inactivates the enzyme synergistically with glucose (2004)

The role of glucose 6-P (glucose 6-phosphate) in regulating the activation state of glycogen synthase and its translocation is well documented. In the present study, we investigated the effects of glucose 6-P on the activation state and compartmentation of phosphorylase in hepatocytes. Glucose 6-P levels were modulated in hepatocytes by glucokinase overexpression or inhibition with 5-thioglucose and the effects of AMP were tested using AICAR (5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside), which is metabolized to an AMP analogue. Inhibition of glucokinase partially counteracted the effect of glucose both on the inactivation of phosphorylase and on the translocation of phosphorylase a from a soluble to a particulate fraction. The increase in glucose 6-P caused by glucokinase overexpression caused translocation of phosphorylase a to the pellet and had additive effects with glucose on inactivation of phosphorylase. It decreased the glucose concentration that caused half-maximal inactivation from 20 to 11 mM, indicating that it acts synergistically with glucose. AICAR activated phosphorylase and counteracted the effect of glucose 6-P on phosphorylase inactivation. However, it did not counteract translocation of phosphorylase by glucose 6-P. Glucose 6-P and AICAR had opposite effects on the activation state of glycogen synthase, but they had additive effects on translocation of the enzyme to the pellet. There was a direct correlation between the translocation of phosphorylase a and of glycogen synthase to the pellet, suggesting that these enzymes translocate in tandem. In conclusion, glucose 6-P causes both translocation of phosphorylase and inactivation, indicating a more complex role in the regulation of glycogen metabolism than can be explained from regulation of glycogen synthase alone.
Molecular Profiling Improves Diagnoses of Rejection and Infection in Transplanted Organs (2006)

The monitoring of transplanted hearts is currently based on histological evaluation of endomyocardial biopsies, a method that is fairly insensitive and that does not always accurately discriminate between rejection and infection in the heart. Accurate diagnosis of rejection and infection is absolutely crucial, however, as the respective treatments are completely different. Using microarrays, we analyzed gene expression in 76 cardiac biopsies from 40 heart recipients undergoing rejection, no rejection, or Trypanosoma cruzi infection. We found a set of genes whose expression patterns were typical of acute rejection, and another set of genes that discriminated between rejection and T cruzi infection. These sets revealed acute rejection episodes up to 2 weeks earlier, and trypanosome infection up to 2 months earlier than did histological evaluation. When applied to raw data from other institutions, the 2 sets of predictive genes were also able to accurately pinpoint acute rejection of lung and kidney transplants, as well as bacterial infections in kidneys. In addition to their usefulness as diagnostic tools, the data suggest that there are similarities in the biology of the processes involved in rejection of different grafts and also in the tissue responses to pathogens as diverse as bacteria and protozoa.
A novel technique for containerless protein crystallization (1996)

Heterogeneous nucleation, which is often detrimental to the production of suitable crystals for X-ray diffraction, can be induced by the contact of a crystallization sample with the walls of its supporting vessel. A novel method for creating a 'containerless' environment for the growth of protein crystals is described. Contact between the container walls and a crystallization drop is eliminated by suspending the drop between two oils of different density: one of higher and the other of lower density than that of water and the common precipitating agents. A number of proteins were crystallized in 2-10 microliters drops using this procedure. It was found that the number of crystals obtained in such suspended drops was reduced significantly compared with the number of crystals obtained in trials where the crystallization drop was situated at the bottom of a vial under a single layer of oil. This method has potential in controlling heterogeneous nucleation.
Frequency and features ofTP53mutation in 30 Chinese patients with sporadic basal cell carcinoma (2014)

The incidence of TP53 mutation in BCC in our Chinese subjects was lower than that reported for white populations. Many of the patients carried mutations of other genes in addition to of TP53. The majority of TP53 mutations were UV-induced specific alterations. However, the results of the two studies on TP53 and PTCH1 indicated that the incidence of UV-specific mutations is much lower in Chinese than in white populations.
High-efficiency nondoped white organic light-emitting devices (2007)

High-efficiency nondoped white organic light-emitting devices (WOLEDs) were demonstrated by using both the intrinsic and exciplex emissions from a single electroluminescent material, 4,4′,4″-trispyrenylphenylamine (TPyPA). The simple device structure of indium tin oxide/N,N′-bis(1-naphthyl)-N,N′-diphenyl-1,1′-biphenyl-4,4′-diamine/TPyPA/4,7-diphenyl-1,10-phenanthroline/LiF∕Al exhibited a luminance of 10000cd∕m2 at a low driving voltage of 4.5V, and high current and power efficiencies of 9.4cd∕A and 9.0lm∕W, respectively. Such WOLED showed excellent color stability and purity with the Commission Internationale de L’Eclairage coordinates of (0.31, 0.35), which remained unchanged over a wide range of luminance from 100to20000cd∕m2.
Composition and Microstructure of Chemically Vapor‐Deposited Boron Nitride, Aluminum Nitride, and Boron Nitride + Aluminum Nitride Composites (1991)

The composition and microstructure of dispersed‐phase ceramic composites containing BN and AIN as well as BN and AIN single‐phase ceramics prepared by chemical vapor deposition have been characterized using X‐ray diffraction, scanning electron microscopy, electron microprobe, and transmission electron microscopy techniques. Under certain processing conditions, the codeposited coating microstructure consists of small single‐crystal AIN fibers (whiskers) surrounded by a turbostratic BN matrix. Other processing conditions resulted in single‐phase films of AIN with a fibrous structure. The compositions of the codeposits range from 2 to 50 mol% BN, 50 to 80 mol% AIN with 7% to 25% oxygen impurity as determined by electron microprobe analysis.
Prostate‐specific antigen in screening of prostate cancer (1994)

Prostate-specific antigen (PSA) is a well-characterized human prostate-specific glycoprotein. PSA has been shown to be the most effective immunohistologic marker for prostate cancer, as well as the most useful serologic test in staging and monitoring prostate cancer and in early detection of recurrent disease. The greatest clinical value of PSA is an aid for early detection of prostate cancer. Recent studies have indicated that PSA-based screening of the older population for organ-confined early-stage prostate cancer is an acceptable, practical, and reliable modality. The accuracy of PSA screening is within the same range as the mammogram. The cost-effectiveness of PSA is comparable to other cancer screening tests. Although the increase in the patient's survival due to PSA-based detection of early prostate cancer remains to be documented, it is generally agreed that the PSA test along with digital rectal examination (DRE) should be included in the annual physical examination for men 50 years of age or older. High-risk men are urged to commence at age 40. Asymptomatic men who have both a negative DRE and normal PSA blood test need only to continue an annual DRE and PSA check-up. Men who have a negative DRE and elevated PSA, and all those who have a suspicious DRE regardless of PSA results, should undergo further diagnostic workup, such as transrectal ultrasonography with biopsy of visible lesions. The cure rate is high with timely treatment, when prostate cancer is detected while still confined to the prostate.
Rapid and selective cerebral hypothermia achieved using a cooling helmet (2004)

This helmet delivers initial rapid and selective brain cooling and maintains a significant temperature gradient between the core and brain temperatures throughout the hypothermic period to provide sufficient regional hypothermia yet minimize systemic complications. It results in delayed systemic hypothermia, creating a safe window for possible ultra-early delivery of regional hypothermia by EMS personnel in the field.
Expansion in vitro of transplantable human cord blood stem cells demonstrated using a quantitative assay of their lympho-myeloid repopulating activity in nonobese diabetic– scid/scid  mice (1997)

Human hematopoiesis originates in a population of stem cells with transplantable lympho-myeloid reconstituting potential, but a method for quantitating such cells has not been available. We now describe a simple assay that meets this need. It is based on the ability of sublethally irradiated immunodeficient nonobese diabetic-scid/scid (NOD/SCID) mice to be engrafted by intravenously injected human hematopoietic cells and uses limiting dilution analysis to measure the frequency of human cells that produce both CD34(-)CD19(+) (B-lymphoid) and CD34(+) (myeloid) colony-forming cell progeny in the marrow of such recipients 6 to 8 weeks post-transplant. Human cord blood (CB) contains approximately 5 of these competitive repopulating units (CRU) per ml that have a similar distribution between the CD38(-) and CD38(+) subsets of CD34(+) CB cells as long-term culture-initiating cells (LTC-IC) (4:1 vs. 2:1). Incubation of purified CD34(+)CD38(-) human CB cells in serum-free medium containing flt-3 ligand, Steel factor, interleukin 3, interleukin 6, and granulocyte colony-stimulating factor for 5-8 days resulted in a 100-fold expansion of colony-forming cells, a 4-fold expansion of LTC-IC, and a 2-fold (but significant, P < 0.02) increase in CRU. The culture-derived CRU, like the original CB CRU, generated pluripotent, erythroid, granulopoietic, megakaryopoietic, and pre-B cell progeny upon transplantation into NOD/SCID mice. These findings demonstrate an equivalent phenotypic heterogeneity amongst human CB cells detectable as CRU and LTC-IC. In addition, their similarly modest response to stimulation by a combination of cytokines that extensively amplify LTC-IC from normal adult marrow underscores the importance of ontogeny-dependent changes in human hematopoietic stem cell proliferation and self-renewal.
Moving into mass customization : information systems and management principles (2002)

Mass Customization leads the strategy of today's well succeeded companies. It indulges the customer with the so long yearned for product and/or service that exactly fits his desires and specifications. This book compiles a hand-selected variety of testimonies from Mass Customization experts worldwide with different experiences both on an academic research basis as well as on practical case studies. This diversity makes it a compulsory guide to use in any enterprise throughout the world that wants to take its business into new and more ambitious dimensions. Furthermore, its contents are structured in a way that will help everyone that wants to learn, teach or put into practice the concepts of Mass Customization
Definitions and guidelines for assessment of wounds and evaluation of healing (1994)

<h3>Background:</h3> Chronic wounds represent a worldwide problem. For laboratory and clinical research to adequately address this problem, a common language needs to exist. <h3>Observation:</h3> This language should include a system of wound classification, a lexicon of wound descriptors, and a description of the processes that are likely to affect wound healing and wound healing end points. <h3>Conclusions:</h3> The report that follows defines wound, acute wound, chronic wound, healing and forms of healing, wound assessment, wound extent, wound burden, and wound severity. The utility of these definitions is demonstrated as they relate to the healing of a skin wound, but these definitions are broadly applicable to all wounds. (Arch Dermatol. 1994;130:489-493)
OPIOIDS: A PHARMACOLOGIST'S DELIGHT! (1995)

1. Opioids, in one form or another, have been used for their pain-relieving properties from prehistoric times: they are still the first line medication for the treatment of severe nociceptive pain and are likely to remain so for the foreseeable future. 2. The therapeutic index of opioids used for pain management is low: opioid side effects are essentially extensions of therapeutic effects and no available agent has a marked advantage over the others. When used for opioid 'anaesthesia', differences in therapeutic index are more obvious due to differences in non-opioid effects. 3. Opioid receptors in brain and spinal cord periphery are the main 'therapeutic targets' and clinical dosage strategies have been derived using a variety of systemic (indirect or blood-borne) methods as well as intraspinal and intracerebroventricular (direct) methods: no method, however, is without potential side effects. Peripheral opioid effects are now being exploited with intra-articular injection. 4. Opioid pharmacokinetics and pharmacodynamics are characterized by high inter-subject variability: accordingly, patient-controlled dosage strategies are found to be more successful for pain control than deterministic recipes.
Protein Conduction and Negative Differential Resistance in Large‐Scale Nanojunction Arrays (2007)

Tunnel vision: Transport in molecular tunnel junctions (see image) based on the blue-copper protein Azurin is investigated at the single-molecule level under ambient conditions. The conduction of Azurin is governed by tunneling processes through molecular redox levels and the pathway for the charge transport inside the molecule is discussed. This novel fabrication allows for nanojunction arrays for complex circuits of nano-objects.