gebhart/patrepeval huggingface dataset:
A catalogue of somatic NRF2 gain-of-function mutations in cancer (2018)

Identification and characterization of somatic mutations in cancer have important prognostication and treatment implications. Genes encoding the Nuclear factor (erythroid-derived 2)-like 2 (NRF2) transcription factor and its negative regulator, Kelch-like ECH-associated protein 1 (KEAP1), are frequently mutated in cancer. These mutations drive constitutive NRF2 activation and correlate with poor prognosis. Despite its apparent significance, a comprehensive catalogue of somatic NRF2 mutations across different tumor types is still lacking. Here, we catalogue NRF2 mutations in The Cancer Genome Atlas (TCGA) database. 226 unique NRF2-mutant tumors were identified from 10,364 cases. NRF2 mutations were found in 21 out of the 33 tumor types. A total of 11 hotspots were identified. Of these, mutation to the R34 position was most frequent. Notably, R34 and D29 mutations were overrepresented in bladder, lung, and uterine cancers. Analyses of corresponding RNA sequencing data using a de novo derived gene expression classifier showed that the R34 mutations drive constitutive NRF2 activation with a selection pressure biased against the formation of R34L. Of all R34 mutants, R34L conferred the least degree of protein stabilization, suggesting a pro-tumor NRF2 half-life threshold. Our findings offer a comprehensive catalogue of NRF2 mutations in cancer that can help prognostication and NRF2 research.
Cholinephosphotransferase and Diacylglycerol Acyltransferase (Substrate Specificities at a Key Branch Point in Seed Lipid Metabolism) (1996)

Many oilseed plants accumulate triacylglycerols that contain unusual fatty acyl structures rather than the common 16- and 18-carbon fatty acids found in membrane lipids of these plants. In vitro experiments demonstrate that triacylglycerols are synthesized via diacylglycerols in microsomal preparations and that this same sub-cellular fraction is the site for the synthesis of phosphatidylcholine, which in seeds is synthesized from diacylglycerol by CDP-choline: diacylglycerol cholinephosphotransferase. In microsomes from Cuphea lanceolata, a plant that accumulates fatty acids with 10 carbons and no double bonds (10:0) in its oil, the diacylglycerol acyltransferase exhibited 4-fold higher activity with 10:0/10:0 molecular species of diacylglycerol than with molecular species containing 18-carbon fatty acids. In castor bean (Ricinus communis), which accumulates oil containing ricinoleic acid, diricinoleoyldiacylglycerol was the favored substrate for triacylglycerol synthesis. In contrast to these modest specificities of the diacylglycerol acyltransferases, the cholinephosphotransferases from these plants and from safflower (Carthamus tinctorius) and rapeseed (Brassica napus) showed little or no specificity across a range of different diacylglycerol substrates. Consideration of these results and other data suggests that the targeting of unusual fatty acids to triacylglycerol synthesis and their exclusion from membrane lipids are not achieved on the basis of the diacylglycerol substrate specificities of the enzymes involved and may instead require the spatial separation of two different diacylglycerol pools.
The role of CD154 in organ transplant rejection and acceptance (2001)

CD154 plays a critical role in determining the outcome of a transplanted organ. This simple statement is amply supported by experimental evidence demonstrating that anti-CD154 antibodies are potent inhibitors of allograft rejection in many rigorous transplant models. Unfortunately, despite intensive investigation over the past ten years, the precise mechanisms by which antibodies against CD154 exert their anti-rejection effects have remained less obvious. Though originally classified with reference to B-cell function, CD154-CD40 interactions have also been shown to be important in T cell-antigen-presenting cell interactions. Accordingly, CD154 has been classified as a T-cell co-stimulatory molecule. However, mounting data suggest that treatment with anti-CD154 antibodies does not simply block costimulatory signals, but rather that the antibodies appear to induce signalling in receptor-bearing T cells. Other data suggest that anti-CD154 effects may be mediated by endothelial cells and possibly even platelets. In fact, the current literature suggests that CD154 can either stimulate or attenuate an immune response, depending upon the model system under study. CD154 has secured a fundamental place in transplant biology and general immunology that will no doubt be the source of considerable investigation and therapeutic manipulation in the coming decade.
Human embryonic stem cell derived islet progenitors mature inside an encapsulation device without evidence of increased biomass or cell escape (2014)

There are several challenges to successful implementation of a cell therapy for insulin dependent diabetes derived from human embryonic stem cells (hESC). Among these are development of functional insulin producing cells, a clinical delivery method that eliminates the need for chronic immunosuppression, and assurance that hESC derived tumors do not form in the patient. We and others have shown that encapsulation of cells in a bilaminar device (TheraCyte) provides immunoprotection in rodents and primates. Here we monitored human insulin secretion and employed bioluminescent imaging (BLI) to evaluate the maturation, growth, and containment of encapsulated islet progenitors derived from CyT49 hESC, transplanted into mice. Human insulin was detectable by 7 weeks post-transplant and increased 17-fold over the course of 8 weeks, yet during this period the biomass of encapsulated cells remained constant. Remarkably, by 20 weeks post-transplant encapsulated cells secreted sufficient levels of human insulin to ameliorate alloxan induced diabetes. Further, bioluminescent imaging revealed for the first time that hESCs remained fully contained in encapsulation devices for up to 150 days, the longest period tested. Collectively, the data suggest that encapsulated hESC derived islet progenitors hold great promise as an effective and safe cell replacement therapy for insulin dependent diabetes.
Monoclonal antibodies specific immunotherapy of gastrointestinal tumors. (1986)

Monoclonal antibody 17-1A showing cytotoxic properties to GI tract adenocarcinoma cells in vitro and mediating tumor growth inhibition in nude mice, was used as immunotherapeutic agent in 95 patients with various metastatic gastrointestinal adenocarcinomas. Several clinical trials were performed in patients with metastatic disease unaccessible to more conventional therapy of proven efficacy. Results of the different trials are reported here. Tolerance to monoclonal antibody infusion was excellent with minor side effects, except when combinations of several monoclonal antibodies were used. Three complete responses, five partial responses inferior to 50% and 24 stable diseases were noticed. A randomized trial is presently performed in high risk cancer patients with B2 or C colorectal carcinomas with 17-1A as adjuvant immunotherapeutic agent after surgery.
The ADP-ribosylating Mosquitocidal Toxin from Bacillus sphaericus (2002)

The mosquitocidal toxin (MTX) from Bacillus sphaericus SSII-1 is a approximately 97-kDa protein sharing sequence homology within the N terminus with the catalytic domains of various bacterial ADP-ribosyltransferases. Here we studied the proteolytic activation of the ADP-ribosyltransferase activity of MTX. Chymotrypsin treatment of the 97-kDa MTX holotoxin (MTX(30-870)) results in a 70-kDa putative binding component (MTX(265-870)) and a 27-kDa enzyme component (MTX(30-264)), possessing ADP-ribosyltransferase activity. Chymotryptic cleavage of an N-terminal 32-kDa fragment of MTX (MTX(30-308)) also yields MTX(30-264), but the resulting ADP-ribosyltransferase activity is much greater than that of the processed MTX(30-870). Kinetic studies revealed a K(m) NAD value of 45 microm for the processed 32-kDa MTX fragment, and a K(m) NAD value of 1300 microm for the processed holotoxin. Moreover, the k(cat) value for the activated MTX(30-308) fragment was about 10-fold higher than that for the activated holotoxin (MTX(30-870)). Precipitation analysis showed that the 70-kDa proteolytic fragment of MTX remains noncovalently bound to the N-terminal 27-kDa fragment, thereby inhibiting ADP-ribosyltransferase and NAD glycohydrolase activities. Glu(197) of MTX(30-264) was identified as the "catalytic" glutamate that is conserved in all ADP-ribosyltransferases. Whereas mutated MTX(30-264)E197Q has neither ADP-ribosyltransferase nor NAD glycohydrolase activity, mutated MTX(30-264)E195Q possesses glycohydrolase activity but not transferase activity. Transfection of HeLa cells with a vector encoding a fusion protein of MTX(30-264) with a green fluorescent protein led to cytotoxic effects characterized by cell rounding and formation of filopodia-like protrusions. These cytotoxic effects were not observed with the catalytically inactive MTX(30-264)E197Q mutant, indicating that the MTX enzyme activity is essential for the cytotoxicity in mammalian cells.
Bivalent ligand MCC22 potently attenuates nociception in a murine model of sickle cell disease (2018)

Sickle cell disease (SCD) is a chronic inflammatory disorder accompanied by chronic pain. In addition to ongoing pain and hyperalgesia, vaso-occlusive crises-induced pain can be chronic or episodic. Because analgesics typically used to treat pain are not very effective in SCD, opioids, including morphine, are a primary treatment for managing pain in SCD but are associated with many serious side effects, including constipation, tolerance, addiction, and respiratory depression. Thus, there is a need for the development of novel treatments for pain in SCD. In this study, we used the Townes transgenic mouse model of SCD to investigate the antinociceptive efficacy of the bivalent ligand, MCC22, and compared its effectiveness with morphine. MCC22 consists of a mu-opioid receptor agonist and a chemokine receptor-5 (CCR5) antagonist that are linked through a 22-atom spacer. Our results show that intraperitoneal administration of MCC22 produced exceptionally potent dose-dependent antihyperalgesia as compared to morphine, dramatically decreased evoked responses of nociceptive dorsal horn neurons, and decreased expression of proinflammatory cytokines in the spinal cord. Moreover, tolerance did not develop to its analgesic effects after repeated administration. In view of the extraordinary potency of MCC22 without tolerance, MCC22 and similar compounds may vastly improve the management of pain associated with SCD.
Engineering an enzyme to resist boiling (1998)

In recent years, many efforts have been made to isolate enzymes from extremophilic organisms in the hope to unravel the structural basis for hyperstability and to obtain hyperstable biocatalysts. Here we show how a moderately stable enzyme (a thermolysin-like protease from Bacillus stearothermophilus, TLP-ste) can be made hyperstable by a limited number of mutations. The mutational strategy included replacing residues in TLP-ste by residues found at equivalent positions in naturally occurring, more thermostable variants, as well as rationally designed mutations. Thus, an extremely stable 8-fold mutant enzyme was obtained that was able to function at 100 degrees C and in the presence of denaturing agents. This 8-fold mutant contained a relatively large number of mutations whose stabilizing effect is generally considered to result from a reduction of the entropy of the unfolded state ("rigidifying" mutations such as Gly --> Ala, Ala --> Pro, and the introduction of a disulfide bridge). Remarkably, whereas hyperstable enzymes isolated from natural sources often have reduced activity at low temperatures, the 8-fold mutant displayed wild-type-like activity at 37 degrees C.
The Biotin Carboxylase-Biotin Carboxyl Carrier Protein Complex of Escherichia coli Acetyl-CoA Carboxylase (2003)

Escherichia coli acetyl-CoA carboxylase (ACC) is composed of four different protein molecules. These proteins form a large but very unstable complex. Hints of a sub-complex between the biotin carboxylase (BC) and biotin carboxyl carrier protein (BCCP) subunits have been reported in the literature, but the complex was not isolated and thus the protein stoichiometry could not be determined. We report isolation of the BC.BCCP complex. By use of affinity chromatography using two different affinity tags it was shown that the complex consists of a two BCCP molecules per BC molecule. The molar ratio in the complex is the same as the ratio of the subunit proteins synthesized in vivo. We conclude that the complex consists of a dimer of BC plus four BCCP molecules instead of the 2BC.2BCCP complex previously assumed. This subunit ratio allows two conflicting models of the ACC mechanism to be rectified. We also report that the N-terminal 30 or so residues of BCCP are responsible for the interaction of BCCP with BC and that the BC.BCCP complex is a substrate for biotinylation in vitro.
Determination of Cytochrome P450 Metabolic Activity Using Selective Markers (2012)

Cytochrome P450 enzymes (CYP) play a pivot role in phase I of xenobiotic biotransformation. Many of CYP enzymes are known to be polymorphic, with many allelic variants. As a consequence of huge number of possible allele combinations, a wide range of metabolic activity can be observed among patients in population. Individual CYP activity may be also affected by various xenobiotics -either induction or inhibition of distinct CYP isoenzyme may cause failure or toxicity of pharmacotherapy. Due to this, some prediction of metabolic activity is worthwhile in clinical practice. This chapter is going to briefly summarize the possibilities of in vivo and in vitro CYP metabolic activity assessments of CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 enzymes.
Silent Ischemia in People With Diabetes: A Condition That Must Be Heard (2003)

Angina pectoris has long been considered the cardinal symptom of myocardial ischemia. However, it is now known that angina pectoris may be a poor indicator for myocardial ischemia, particularly in patients with diabetes. Despite the recent advances in our understanding of the complex pathophysiology of coronary artery disease (CAD), the recognition of diabetic patients with asymptomatic and yet significant CAD remains difficult. CAD in diabetic patients poses diagnostic and therapeutic challenges for clinicians, especially when patients are asymptomatic during episodes of myocardial ischemia.

In diabetic patients, cardiovascular disease remains the leading cause of death, and myocardial infarctions tend to be more extensive and have a poorer survival rate than in age-, weight-, and sex-matched individuals without diabetes. The medical cost associated with diabetes is staggering, amounting to about $100 billion annually, with vascular complications accounting for the majority of this expenditure.

“Silent ischemia” refers to the presence of objective findings suggestive of myocardial ischemia that is not associated with angina or anginal equivalent symptoms. Such objective evidence includes exercise testing or ambulatory monitoring demonstrating electrocardiographic changes, nuclear imaging studies demonstrating myocardial perfusion defects, or regional wall motion abnormalities illustrated by echocardiography.

Episodes of silent ischemia can occur with minimal or no physical activity and have been demonstrated in some individuals with stressors as mild as engaging in mental arithmetic. Diabetes, hypertension, previous myocardial infarction, surgical revascularization, and advanced age are all putative risk factors for silent ischemia, although many affected individuals do not have any apparent contributor.

In the Framingham Study,1 which was based on 34 years of follow-up of more than 5,000 subjects, about one-fourth of the patients who experienced a heart attack had unrecognized events. Unrecognized infarctions consisted of silent myocardial infarctions and atypical myocardial infarctions. The latter are myocardial infarctions that are accompanied by some symptoms …
Contribution of defects to electronic, structural, and thermodynamic properties of amorphous silicon (1994)

The structure of pure, nonhydrogenated amorphous silicon (a-Si) was modified by means of ion implantation, furnace annealing, and pulsed laser annealing. Defects in a-Si were probed by measuring the photocarrier lifetime τ at low carrier densities (1018/cm3) with subpicosecond resolution using pump-probe reflectivity measurements. The average cross section of defect-related midgap states for free-carrier capture is found to be 6×10−16 cm2. In addition, the average bond-angle distortion Δθ in a-Si was derived from Raman spectroscopy. Annealing as-implanted a-Si for 1 h at T≤500 °C induces defect annihilation as well as network relaxation. In contrast, 32 ns pulsed laser heating of a-Si just below the melting threshold leads to relaxation of Δθ without significant defect annihilation. This annealing behavior can be understood on the basis of defect diffusion kinetics. Implanting fully relaxed a-Si with 1 MeV B+, Si+, and Xe+ up to damage levels of 0.004 displacements per atom raises the defect density without affecting Δθ. Only after the defect density has saturated at higher damage levels is Δθ returned to the as-implanted level. The electronic density of states of a-Si is determined using optical-absorption spectroscopy, yielding Nsat≊0.5 at. % for the saturation defect density in a-Si at room temperature. Electron paramagnetic resonance shows that a minor fraction (0.02 at. %) of these defects is spin active. The response of c-Si and relaxed a-Si to implantation damage is comparable, suggesting that the defect populations in both materials are similar. Comparing carrier lifetime measurements and Raman spectroscopy for the various experimental treatments demonstrates that there is no unique correlation between the defect density and Δθ in a-Si. Assuming that defects and Δθ have independent enthalpic contributions, the Gibbs free energy of various structural states of a-Si is calculated. These calculations indicate that the melting temperature of a-Si may vary from 1010 to 1490 K.
LI-cadherin: a marker of gastric metaplasia and neoplasia (2001)

BACKGROUND Intestinal metaplasia is considered a risk factor for the development of gastric adenocarcinomas of the intestinal type and is found in approximately 20% of gastric biopsies. Conventional histology only detects advanced stages of intestinal metaplasia. AIMS To study expression of the enterocyte specific adhesion molecule liver-intestinal (LI)-cadherin in intestinal metaplasia as well as in gastric cancer, and to evaluate its use as a diagnostic marker molecule. PATIENTS Gastric biopsies (n=77) from 30 consecutive patients (n=30; aged 28–90 years) as well as surgically resected tissue samples (n=24) of all types of gastric carcinomas were analysed. METHODS Single and double label immunofluorescence detection on cryosections of gastric biopsies; alkaline phosphatase antialkaline phosphatase method on paraffin embedded carcinoma tissue sections. RESULTS Of 77 biopsies (from 30 patients), 12 (from 10 patients) stained positive for LI-cadherin. LI-cadherin staining correlated with the presence of intestinal metaplasia. Conventional histological diagnosis however failed to detect subtle gastric intestinal metaplasia (three of 10 patients). In contrast, only LI-cadherin and villin were positive in these cases whereas sucrase-isomaltase also failed to detect intestinal metaplasia in four of 10 patients. Well differentiated gastric carcinomas showed intense staining for LI-cadherin while undifferentiated carcinomas showed only weak diffuse cytoplasmic staining. CONCLUSIONS To detect early metaplastic changes in the gastric mucosa, LI-cadherin has a sensitivity superior to sucrase-isomaltase and conventional histology and comparable with that of villin. Its specificity exceeds that of villin. Thus LI-cadherin represents a new, reliable, and powerful marker molecule for early detection of gastric intestinal metaplasia and well differentiated adenocarcinomas.
Impact of the Manaus urban plume on trace gas mixing ratios near the surface in the Amazon Basin: Implications for the NO‐NO2‐O3 photostationary state and peroxy radical levels (2012)

We measured the mixing ratios of NO, NO 2 , O 3 , and volatile organic carbon as well as the aerosol light‐scattering coefficient on a boat platform cruising on rivers downwind of the city of Manaus (Amazonas State, Brazil) in July 2001 (Large‐Scale Biosphere‐Atmosphere Experiment in Amazonia‐Cooperative LBA Airborne Regional Experiment‐2001). The dispersion and impact of the Manaus plume was investigated by a combined analysis of ground‐based (boat platform) and airborne trace gas and aerosol measurements as well as by meteorological measurements complemented by dispersion calculations (Hybrid Single‐Particle Lagrangian Integrated Trajectory model). For the cases with the least anthropogenic influence (including a location in a so far unexplored region ∼150 km west of Manaus on the Rio Manacapuru), the aerosol scattering coefficient, σ s , was below 11 Mm −1 , NO x mixing ratios remained below 0.6 ppb, daytime O 3 mixing ratios were mostly below 20 ppb and maximal isoprene mixing ratios were about 3 ppb in the afternoon. The photostationary state (PSS) was not established for these cases, as indicated by values of the Leighton ratio, Φ , well above unity. Due to the influence of river breeze systems and other thermally driven mesoscale circulations, a change of the synoptic wind direction from east‐northeast to south‐southeast in the afternoon often caused a substantial increase of σ s and trace gas mixing ratios (about threefold for σ s , fivefold for NO x , and twofold for O 3 ), which was associated with the arrival of the Manaus pollution plume at the boat location. The ratio Φ reached unity within its uncertainty range at NO x mixing ratios of about 3 ppb, indicating “steady‐state” conditions in cases when radiation variations, dry deposition, emissions, and reactions mostly involving peroxy radicals (XO 2 ) played a minor role. The median midday/afternoon XO 2 mixing ratios estimated using the PSS method range from 90 to 120 parts per trillion (ppt) for the remote cases ( σ s &lt; 11 Mm −1 and NO x &lt; 0.6 ppb), while for the polluted cases our estimates are 15 to 60 ppt. These values are within the range of XO 2 estimated by an atmospheric chemistry box model (Chemistry As A Box model Application‐Module Efficiently Calculating the Chemistry of the Atmosphere (CAABA/MECCA)‐3.0).
Low temperature linear magnetic field sensor based on magnetoresistance of the perovskite oxide La–Sr–Co–O (1995)

A linear magnetic field sensor for low temperature (T≤60 K) use based on magnetoresistance of the perovskite oxide material La0.7Sr0.3CoO3 is reported. The magnetoresistance is negative and is linear in field up to at least 7 T. It is temperature independent for T≤60 K and has a small anisotropy (20%) with respect to the direction of the measuring field.