gebhart/patrepeval huggingface dataset:
Diet, microbiota, and dysbiosis: a ‘recipe’ for colorectal cancer (2016)

The food we consume feeds not only us, but also a vast and diverse community of microbiota within our gastrointestinal tract. In a process of symbiotic co-evolution, the gut microbiota became essential for the maintenance of the health and integrity of our colon. The advent of next-generation DNA sequencing technology and metabolic profiling have, in the recent years, revealed the remarkable complexity of microbial diversity and function, and that the microbiota produce a wide variety of bioactive products that are not only active at the mucosal surface, but also absorbed and circulated throughout the body, influencing distant organ health and function. As a result, several microbiota compositional patterns and their associations with both health and disease states have been identified. Importantly, a disturbed microbiota-host relationship, termed dysbiosis, is now recognized to be the root cause for a growing list of diseases, including colorectal cancer (CRC). There is mounting in vitro and in vivo evidence to suggest that diet selects for the microbiota composition and several health promoting and deleterious effects of diet are, in fact, mediated by the microbiota. Recent findings of the feasibility of dietary fiber to boost the colonic microbial synthesis of anti-proliferative and counter carcinogenic metabolites, particularly butyrate, underscores the prerequisite of dietary modification as a key measure to curb the pandemic of CRC in westernized countries. Better understanding of the diet-microbiota interplay and large-scale studies to evaluate the efficacy of dietary modification and gut microbiota modulation in reversing dysbiosis and restoring health could offer novel preventative and/or therapeutic strategies against westernized diseases, which are now considered the chief threat to public health.
Frequentist Estimation of Coalescence Times From Nucleotide Sequence Data Using a Tree-Based Partition (2002)

This article proposes a method of estimating the time to the most recent common ancestor (TMRCA) of a sample of DNA sequences. The method is based on the molecular clock hypothesis, but avoids assumptions about population structure. Simulations show that in a wide range of situations, the point estimate has small bias and the confidence interval has at least the nominal coverage probability. We discuss conditions that can lead to biased estimates. Performance of this estimator is compared with existing methods based on the coalescence theory. The method is applied to sequences of Y chromosomes and mtDNAs to estimate the coalescent times of human male and female populations.
Lipid Transport Mediated by Arabidopsis TGD Proteins is Unidirectional from the Endoplasmic Reticulum to the Plastid (2010)

The transfer of lipids between the endoplasmic reticulum (ER) and the plastid in Arabidopsis involves the TRIGALACTOSYLDIACYLGLYCEROL (TGD) proteins. Lipid exchange is thought to be bidirectional based on the presence of specific lipid molecular species in Arabidopsis mutants impaired in the desaturation of fatty acids of membrane lipids in the ER and plastid. However, it was unclear whether TGD proteins were required for lipid trafficking in both directions. This question was addressed through the analysis of double mutants of tgd1-1 or tgd4-3 in genetic mutant backgrounds leading to a defect in lipid fatty acid desaturation either in the ER (fad2) or the plastid (fad6). The fad6 tgd1-1 and fad6 tgd4-3 double mutants showed drastic reductions in the relative levels of polyunsaturated fatty acids and of galactolipids. The growth of these plants and the development of photosynthetic membrane systems were severely compromised, suggesting a disruption in the import of polyunsaturated fatty acid-containing lipid species from the ER. Furthermore, a forward-genetic screen in the tgd1-2 dgd1 mutant background led to the isolation of a new fad6-2 allele with a marked reduction in the amount of digalactosyldiacylglycerol. In contrast, the introduction of fad2, affecting fatty acid desaturation of lipids in the ER, into the two tgd mutant backgrounds did not further decrease the level of fatty acid desaturation in lipids of extraplastidic membranes. These results suggest that the role of TGD proteins is limited to plastid lipid import, but does not extend to lipid export from the plastid to extraplastidic membranes.
Acute Effects of Intraperitoneal Versus Subcutaneous Insulin Delivery on Glucose Homeostasis in Patients With NIDDM (1996)

OBJECTIVE The objective of this study is to compare the effect of intraperitoneal versus subcutaneous insulin injection on hepatic glucose production (HGP) and systemic glucose utilization (Rd) in patients with NIDDM. RESEARCH DESIGN AND METHODS Eight male volunteers with NIDDM, each of whom had a programmable-rate, implantable insulin pump, were given an injection of insulin (0.15 units/kg body wt) by intraperitoneal or subcutaneous injection on separate days in randomized order. Plasma glucose was kept constant for 5 h using the glucose clamp technique, and HGP and Rd were measured using isotope dilution. RESULTS Intraperitoneal insulin injection resulted in higher and earlier peak systemic insulin concentrations (1,469 ± 245 vs. 454 ± 48 pmol/l, P &amp;lt; 0.01). Glucose Rd doubled within 1 h after intraperitoneal injection and was greater than that attained with subcutaneous injection (3.91 ± 0.27 vs. 2.60 ± 0.19 mg · kg−1 · min−1, P &amp;lt; 0.01). Intraperitoneal and subcutaneous injections suppressed HGP and plasma free fatty acid to a similar extent during the first 3 h, effects that persisted through 5 h after subcutaneous insulin injection but waned 3–4 h after intraperitoneal injection. CONCLUSIONS In patients with NIDDM, intraperitoneal insulin injection achieves more rapid and greater peak values for stimulation of glucose Rd than subcutaneous insulin injection. With regard to HGP and lipolysis, intraperitoneal and subcutaneous injections achieve similar initial suppression but this is maintained for a more limited duration with intraperitoneal as compared with subcutaneous injection. These differences in insulin action seem directly related to the rapidity of insulin absorption with intraperitoneal injection.
Comparative study of five instruments measuring stratum corneum hydration (Corneometer CM 820 and CM 825, Skicon 200, Nova DPM 9003, DermaLab). Part II. In vivo (1999)

Background/aims: The hydration state of stratum corneum can be measured with different instruments. In the present study, five instruments were compared under different experimental in vivo conditions: Corneometer CM 820 and CM 825 (both capacitance based), Skicon 200 (conductance), Nova DPM (impedance based capacitance) and DermaLab (capacitance). Methods: Seven anatomical sites were tested, a sorption‐de‐sorption test (SDT) and a moisture accumulation test (MAT) were performed. Different hydration states were created on the volar forearms by occluded application of an oil‐in‐water (o/w) emulsion, glycerol and urea containing oil‐in‐water (o/w) emulsion, an untreated control site and a site after lipid extraction with acetone. Measurements were performed 15 min after removal of occlusion. Results: The coefficient of variation for CM 820 ranged between 9.3% and 23.7%; for CM 825 between 14.9% and 36.8%; for Skicon 200 between 53.0% and 167.3%; for Nova DPM between 36.4% and 95.8%; for DermaLab between 23.6% and 45.6%. All devices showed a highly significant correlation (P&lt;0.0001) with a high Spearman coefficient r ranging between 0.7928 and 0.9358. Conclusions: CM 820 and CM 825 seem to differentiate more precisely than Nova DPM, Skicon 200 and DermaLab in dry conditions according to previous findings, i.e., that conductance measurements might be more sensitive for hydrated skin and capacitance measurements might be more sensitive for dry skin conditions. The CM 825, the Skicon 200 and the Nova DPM are suitable for dynamic measurements of hydration parameters of the stratum corneum.
Treatment with buspirone in a patient with autism (1997)

This study evaluates the safety and efficacy of buspirone hydrochloride for the treatment of a patient with autism and hyperactivity disorder and determines the effect of buspirone on the number of performance tasks completed by the patient at school. A 3-week, double-blind, placebo-controlled crossover study was performed in a private physician, office-based practice. A child with autism, which was diagnosed by Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised, criteria, was studied. The child received placebo for 3 weeks and buspirone for 3 weeks; there was a 1-week interval between the 2 treatments. The outcome was measured by using Conners abbreviated parent and teacher questionnaires and by determining the number of daily performance tasks completed by the child at school. Statistical analysis was performed by linear models and standard F tests. Buspirone was found to be safe and efficacious, without side effects, for decreasing hyperactivity and increasing completed performance tasks. The beneficial effects of buspirone in helping this patient with autism in his natural daily settings suggest that buspirone may be an alternative to neuroleptic agents in the medical therapy of autism; further study in other patients is needed.
High-Performance Transparent Conductors from Networks of Gold Nanowires (2011)

We report the deposition and characterization of thin networks of gold nanowires on plastic substrates. The average nanowire diameter was 47 nm, while the networks had mean thicknesses in the range of 35–750 nm. The conductivity of networks with mean thicknesses below 100 nm was controlled by percolation, as characterized by the percolation exponent, n = 0.8, and the percolative figure of merit, Π = 28. However, networks with thicknesses above 100 nm had thickness-independent direct current conductivity of σDC,B = 5.4 × 105 S/m. The conductivity was limited by junction resistances, which we estimate at ∼3 kΩ. Networks of all thicknesses were described by an optical conductivity of σOp = 1.0 × 104 S/m. These electrical and optical properties result in networks with sheet resistance and transmittance very close to industry requirements, that is, 49 Ω/□ @ 83%. These values are superior to almost all reported carbon nanotube networks and are competitive with silver nanowire networks. We measured the work function of these networks to be 4.6 eV, suggesting them to be suitable for hole injection or collection in electronic devices.
Combined Therapy with Mutant-Selective EGFR Inhibitor and Met Kinase Inhibitor for Overcoming Erlotinib Resistance in EGFR -Mutant Lung Cancer (2012)

Although the EGF receptor tyrosine kinase inhibitors (EGFR-TKI) erlotinib and gefitinib have shown dramatic effects against EGFR mutant lung cancer, patients become resistant by various mechanisms, including gatekeeper EGFR-T790M mutation, Met amplification, and HGF overexpression, thereafter relapsing. Thus, it is urgent to develop novel agents to overcome EGFR-TKI resistance. We have tested the effects of the mutant-selective EGFR-TKI WZ4002 and the mutant-selective Met-TKI E7050 on 3 EGFR mutant lung cancer cell lines resistant to erlotinib by different mechanisms: PC-9/HGF cells with an exon 19 deletion, H1975 with an L858R mutation, and HCC827ER with an exon 19 deletion, with acquired resistance to erlotinib because of HGF gene transfection, gatekeeper T790M mutation, and Met amplification, respectively. WZ4002 inhibited the growth of H1975 cells with a gatekeeper T790M mutation, but did not inhibit the growth of HCC827ER and PC-9/HGF cells. HGF triggered the resistance of H1975 cells to WZ4002, whereas E7050 sensitized HCC827ER, PC-9/HGF, and HGF-treated H1975 cells to WZ4002, inhibiting EGFR and Met phosphorylation and their downstream molecules. Combined treatment potently inhibited the growth of tumors induced in severe-combined immunodeficient mice by H1975, HCC827ER, and PC-9/HGF cells, without any marked adverse events. These therapeutic effects were associated with the inhibition of EGFR and Met phosphorylation in vivo. The combination of a mutant-selective EGFR-TKI and a Met-TKI was effective in suppressing the growth of erlotinib-resistant tumors caused by gatekeeper T790M mutation, Met amplification, and HGF overexpression. Further evaluations in clinical trials are warranted.
Human High Temperature Requirement Serine Protease A1 (HTRA1) Degrades Tau Protein Aggregates (2012)

Protective proteases are key elements of protein quality control pathways that are up-regulated, for example, under various protein folding stresses. These proteases are employed to prevent the accumulation and aggregation of misfolded proteins that can impose severe damage to cells. The high temperature requirement A (HtrA) family of serine proteases has evolved to perform important aspects of ATP-independent protein quality control. So far, however, no HtrA protease is known that degrades protein aggregates. We show here that human HTRA1 degrades aggregated and fibrillar tau, a protein that is critically involved in various neurological disorders. Neuronal cells and patient brains accumulate less tau, neurofibrillary tangles, and neuritic plaques, respectively, when HTRA1 is expressed at elevated levels. Furthermore, HTRA1 mRNA and HTRA1 activity are up-regulated in response to elevated tau concentrations. These data suggest that HTRA1 is performing regulated proteolysis during protein quality control, the implications of which are discussed.
Discovery of a Novel Series of Pyrazolo[1,5-<i>a</i>]pyrimidine-Based Phosphodiesterase 2A Inhibitors Structurally Different from <i>N</i>-((1<i>S</i>)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-<i>b</i>]pyrazine-4(1<i>H</i>)-carboxamide (TAK-915), for the Treatment of Cognitive Disorders (2017)

It has been hypothesized that selective inhibition of phosphodiesterase (PDE) 2A could potentially be a novel approach to treat cognitive impairment in neuropsychiatric and neurodegenerative disorders through augmentation of cyclic nucleotide signaling pathways in brain regions associated with learning and memory. Following our earlier work, this article describes a drug design strategy for a new series of lead compounds structurally distinct from our clinical candidate 2 (TAK-915), and subsequent medicinal chemistry efforts to optimize potency, selectivity over other PDE families, and other preclinical properties including in vitro phototoxicity and in vivo rat plasma clearance. These efforts resulted in the discovery of N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6-methyl-5-(3-methyl-1H-1,2,4-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (20), which robustly increased 3',5'-cyclic guanosine monophosphate (cGMP) levels in the rat brain following an oral dose, and moreover, attenuated MK-801-induced episodic memory deficits in a passive avoidance task in rats. These data provide further support to the potential therapeutic utility of PDE2A inhibitors in enhancing cognitive performance.
Epidermal growth factor receptor tyrosine kinase is modulated by GM3 interaction with N-linked GlcNAc termini of the receptor (2006)

Epidermal growth factor receptor (EGFR) at membrane microdomains plays an essential role in the growth control of epidermal cells, including cancer cells derived therefrom. Ligand-dependent activation of EGFR tyrosine kinase is known to be inhibited by ganglioside GM3, but to a much lesser degree by other glycosphingolipids. However, the mechanism of the inhibitory effect of GM3 on EGFR tyrosine kinase has been ambiguous. The mechanism is now defined by binding of N-linked glycan having multiple GlcNAc termini to GM3 through carbohydrate-to-carbohydrate interaction, based on the following data: (i) EGFR (molecular mass, approximately 170 kDa) has N-linked glycan with GlcNAc termini, as probed by mAb (J1) or lectin (GS-II); (ii) GS-II-bound EGFR also bound to anti-EGFR Ab as well as to GM3-coated beads; (iii) GM3 inhibitory effect on EGFR tyrosine kinase was abrogated in vitro by coincubation with glycan having multiple GlcNAc termini and in cell culture in situ incubated with the same glycan; and (iv) cells treated with swainsonine, which increased expression of complex-type and hybrid-type glycans with GlcNAc termini, displayed higher inhibition of EGFR kinase by GM3 than swainsonine-untreated control cells. A similar effect was observed with 1-deoxymannojirimycin, which increased hybrid-type structure in addition to major accumulation of high mannose-type glycan. These findings indicate that N-linked glycan with GlcNAc termini linked to EGFR is the target to interact with GM3, causing inhibition of EGF-induced EGFR tyrosine kinase.
The scurfy mouse mutant has previously unrecognized hematological abnormalities and resembles Wiskott-Aldrich syndrome. (1990)

The X chromosome-linked scurfy (sf) mutant of the mouse is recognized by the scaliness of the skin from which the name is derived and results in death of affected males at about 3-4 weeks of age. Consideration of known man-mouse homologies of the X chromosome prompted hematological studies, which have shown that the blood is highly abnormal. The platelet and erythrocyte counts are both reduced and become progressively lower relative to normal as the disease progresses. There is gastrointestinal bleeding, and most animals appear to die of severe anemia. By contrast, the leukocyte count is consistently raised. Some animals showed signs of infection but it is not yet clear whether there is immunodeficiency. Other features include the scaly skin and apparently reduced lateral growth of the skin, conjunctivitis, and diarrhea in some animals. The mutant resembles Wiskott-Aldrich syndrome in man, which is characterized by thrombocytopenia, eczema, diarrhea, and immunodeficiency. The loci of the human and mouse genes lie in homologous segments of the X chromosome, although apparently in somewhat different positions relative to other gene loci. Scurfy differs from Wiskott-Aldrich syndrome in that scurfy males are consistently hypogonadal.
Ultraporous nanocrystalline TiO2-based films: synthesis, patterning and application as anti-reflective, self-cleaning, superhydrophilic coatings (2015)

Crack-free, anatase-based optical coatings with a refractive index down to 1.27, a porosity up to 80 vol%, and a tunable thickness up to 1.5 μm were fabricated. The extraordinary stability of the porosity upon thermally induced crystallisation and template removal was attributed to the combined effects of the presence of 10% molar silica in the inorganic phase, a flash treatment at 500 °C, and the use of templates with different dimensions ranging from a few nanometers to 50 nm. The hierarchical porous system was directly patterned by UV lithography and used as multifunctional anti-reflective, self-cleaning coatings.
Rapid Detection of the StaphylococcalmecA Gene from BACTEC Blood Culture Bottles by the Polymerase Chain Reaction (1996)

A rapid polymerase chain reaction (PCR) method for the direct detection of the staphylococcal mecA gene from BACTEC blood culture bottles (Becton Dickinson, Sparks, MD) was developed. Published primer sequences and sample preparation using Achromopeptidase for cell lysis were adapted to the use of the Idaho Technology Air Thermocycler 1605 (Idaho Technologies, Idaho Falls, ID). The method was validated with 80 strains of coagulase-positive and coagulase-negative geographically diverse methicillin-resistant and susceptible isolates of staphylococci. There was a 100% correlation between the PCR results and the results of standard susceptibility testing methods. From BACTEC 9240 blood cultures, mixed aliquots of blood and broth containing gram-positive cocci in clusters were centrifuged at low speed to sediment red blood cells. After additional centrifugation and wash steps, PCR was performed on the resuspended pellet. The turnaround time from initial Gram stain detection of positive BACTEC bottles to PCR amplicon detection by agarose gel electrophoresis is less than 3 hours. In a clinical evaluation of 181 blood culture isolates, there was a 99% correlation with standard susceptibility results for Staphylococcus aureus. Discrepant results for Staphylococcus aureus isolates were verified by a Mueller Hinton plate supplemented with 6 microg/mL of oxacillin and 2% sodium chloride. For coagulase-negative staphylococci, the PCR method detected an additional seven resistant isolates that were reported by the Vitek as susceptible. Coagulase-negative staphylococcal susceptibility results that were in disagreement with the PCR assay were confirmed by the disk-diffusion method. This procedure is accurate, rapid and fits well into laboratory work flow. Rapid detection of the mecA gene on positive blood culture vials has become a routine test in the authors' clinical microbiology laboratory.
Cerebrospinal fluid protein variations in common to Alzheimer's disease and schizophrenia. (1992)

Analysis of silver stained two-dimensional (2D) gels of cerebrospinal fluid (CSF) from 27 patients with schizophrenia (SCZ) and 10 patients with Alzheimer's disease (AD) revealed an increase in the relative amount of a polypeptide of 18,000M(r) and isoelectric point of 6.5 when compared to the appropriate controls. This protein was identified by its electrophoretic characteristics and by immune analysis of Western blots as an isoform of alpha-2 haptoglobin, provisionally identified as alpha-2FS haptoglobin. Alzheimer's disease versus control CSF samples showed a 6.8-fold increase in the percent mean density value of this haptoglobin isoform (n = 10 AD vs 11 control; P > 0.025) while a 4.4-fold increase was observed in the schizophrenic patients (n = 17 SCZ vs 10 control; P > 0.001). Two additional polypeptides (proteins '127' and '128') of 40,000 M(r) and isoelectric points 5.7 and 5.9, respectively, described previously by this laboratory, were found in the CSF of 27% of schizophrenics, 23% of the Alzheimer's disease patients, and 4% of the controls in the current study. The presence of proteins 127 and 128, as well as the increased concentrations of alpha-2 haptoglobin in the CSF of Alzheimer's disease and schizophrenic patients, may be useful as diagnostic biological markers. They may also indicate a common pathophysiology between these diseases.