Miracle-dz/UniFAR-FTUs huggingface dataset:
Crystal structure of cytochrome P450 14α-sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors

Cytochrome P450 14α-sterol demethylases (CYP51) are essential enzymes in sterol biosynthesis in eukaryotes. CYP51 removes the 14α-methyl group from sterol precursors such as lanosterol, obtusifoliol, dihydrolanosterol, and 24(28)-methylene-24,25-dihydrolanosterol. Inhibitors of CYP51 include triazole antifungal agents fluconazole and itraconazole, drugs used in treatment of topical and systemic mycoses. The 2.1- and 2.2-Å crystal structures reported here for 4-phenylimidazole- and fluconazole-bound CYP51 from Mycobacterium tuberculosis (MTCYP51) are the first structures of an authentic P450 drug target. MTCYP51 exhibits the P450 fold with the exception of two striking differences—a bent I helix and an open conformation of BC loop—that define an active site-access channel running along the heme plane perpendicular to the direction observed for the substrate entry in P450BM3. Although a channel analogous to that in P450BM3 is evident also in MTCYP51, it is not open at the surface. The presence of two different channels, with one being open to the surface, suggests the possibility of conformationally regulated substrate-in/product-out openings in CYP51. Mapping mutations identified in Candida albicans azole-resistant isolates indicates that azole resistance in fungi develops in protein regions involved in orchestrating passage of CYP51 through different conformational stages along the catalytic cycle rather than in residues directly contacting fluconazole. These new structures provide a basis for rational design of new, more efficacious antifungal agents as well as insight into the molecular mechanism of P450 catalysis.
Effect of food or proton pump inhibitor treatment on the bioavailability of dacomitinib in healthy volunteers

This phase 1, open‐label crossover study evaluated the relative bioavailability of dacomitinib in healthy volunteers under fed and fasted conditions and following coadministration with rabeprazole, a potent acid‐reducing proton pump inhibitor (PPI). Twenty‐four male subjects received a single dacomitinib 45‐mg dose under 3 different conditions separated by washout periods of ≥16 days: coadministered with rabeprazole 40 mg under fasting conditions; alone under fasting conditions; and alone after a high‐fat, high‐calorie meal. Increased peak exposure of 23.7% (90% confidence interval [CI], 5.3%–45.2%) was detected with dacomitinib taken after food versus fasting. The adjusted geometric mean ratio (fed/fasted) for area under the plasma concentration−time curve from time zero to infinity (AUCinf) was 114.2% (90%CI, 104.7%–124.5%) and not considered clinically meaningful. In the fasted state, a decrease in dacomitinib AUCinf was observed following rabeprazole versus dacomitinib alone (PPI+fasted/fasted alone): 71.1% (90%CI, 61.7%–81.8%). Dacomitinib was generally well tolerated. Dacomitinib may be taken with or without food. Use of long‐acting acid‐reducing agents, such as PPIs with dacomitinib should be avoided if possible. Shorter‐acting agents such as antacids and H2‐receptor antagonists may have lesser impact on dacomitinib exposure and may be preferable to PPIs if acid reduction is clinically required.
Abnormal platelet hydrogen peroxide metabolism in aspirin hypersensitivity

The generation and degradation of hydrogen peroxide (H2O2) by platelets was investigated in aspirin hypersensitive and tolerant allergic subjects, and compared to that in general medical patients and healthy controls. H2O2 generation following triggering with anti‐IgE. specific allergen, and with aspirin (ASA) and indomethacin was examined using a chemiluminescence assay. Platelet levels of the main intracellular enzyme responsible for H2O2 metabolism–glutathione peroxidase–were measured by a quantitative functional assay. H2O2 secretion could be triggered by anti‐IgE in platelets from 15/29 ASA‐tolerant atopies, and by relevant allergen in platelets passively sensitized with allergen‐specific IgE. A similar response was observed following triggering with ASA, and with indomethacin, in platelets from 8/25 ASA‐sensitive subjects. Mean platelet glutathione peroxidase activity was significantly lower in subjects with ASA‐induced asthma, but not in subjects with non‐asthmatic reactions to ASA, compared to all other groups. Within the ASA‐sensitive group there was no correlation between low peroxidase activity and ASA‐triggered chemiluminescence. Our findings emphasize the heterogeneity of ASA‐intolerance syndromes and point to abnormal oxygen/peroxide metabolism as a common pathway underlying ASA‐induced asthma.
Characterization of proanthocyanidins in grape seeds using electrospray mass spectrometry.

Two proanthocyanidin (PA) fractions, one (Sdp3) with the mean degree of polymerization (mDP) of 3 and the other (Sdp9) with mDP of 9, were obtained from a Vitis vinifera cv. Shiraz grape seed extract. The PA fractions were directly analyzed by electrospray ionization mass spectrometry (ES-MS) and negative ion mass spectra were recorded. The mass spectrum of Sdp3 exhibited only singly charged ions corresponding to the molecular mass of PA with a degree of polymerization (DP) up to 9 (nonamers). In contrast, Sdp9 yielded rather complex mass spectra featuring ions with single [M - H](-), double [M - 2H](2-) and triple [M - 3H](3-) charge representing the molecular masses of PAs up to a DP of 28. In addition, the degree of galloylation per procyanidin (DG) was observed to be up to 5 (pentagallates) in Sdp3 and 8 (octagallates) in the Sdp9. This is the first evidence obtained by mass spectrometry for the distribution of grape seed PAs with such a high degree of polymerization and a broad diversity of galloylation. ES-MS data together with the complementary information provided by acid hydrolysis provides a detailed picture of the composition of grape seed PAs.
Cleavage of INDOLE-3-ACETIC ACID INDUCIBLE28 mRNA by MicroRNA847 Upregulates Auxin Signaling to Modulate Cell Proliferation and Lateral Organ Growth in Arabidopsis

A microRNA-auxin/indole acetic acid repressor module regulates the extent of cell competence, thereby affecting the duration of cell proliferation and the development of lateral organs. MicroRNAs function in a range of developmental processes. Here, we demonstrate that miR847 targets the mRNA of the auxin/indole acetic acid (Aux/IAA) repressor-encoding gene IAA28 for cleavage. The rapidly increased accumulation of miR847 in Arabidopsis thaliana coincided with reduced IAA28 mRNA levels upon auxin treatment. This induction of miR847 by auxin was abolished in auxin receptor tir1-1 and auxin-resistant axr1-3 mutants. Further analysis demonstrates that miR847 functions as a positive regulator of auxin-mediated lateral organ development by cleaving IAA28 mRNA. Importantly, the ectopic expression of miR847 increases the expression of cell cycle genes as well as the neoplastic activity of leaf cells, prolonging later-stage rosette leaf growth and producing leaves with serrated margins. Moreover, both miR847 and IAA28 mRNAs are specifically expressed in marginal meristems of rosette leaves and lateral root initiation sites. Our data indicate that auxin-dependent induction of miR847 positively regulates meristematic competence by clearing IAA28 mRNA to upregulate auxin signaling, thereby determining the duration of cell proliferation and lateral organ growth in Arabidopsis. IAA28 mRNA encodes an Aux/IAA repressor protein, which is degraded through the proteasome in response to auxin. Altered signal sensitization to IAA28 mRNA levels, together with targeted IAA28 degradation, ensures a robust signal derepression.
Maximum-likelihood fitting of data dominated by Poisson statistical uncertainties

The fitting of data by {chi}{sup 2}-minimization is valid only when the uncertainties in the data are normally distributed. When analyzing spectroscopic or particle counting data at very low signal level (e.g., a Thomson scattering diagnostic), the uncertainties are distributed with a Poisson distribution. The authors have developed a maximum-likelihood method for fitting data that correctly treats the Poisson statistical character of the uncertainties. This method maximizes the total probability that the observed data are drawn from the assumed fit function using the Poisson probability function to determine the probability for each data point. The algorithm also returns uncertainty estimates for the fit parameters. They compare this method with a {chi}{sup 2}-minimization routine applied to both simulated and real data. Differences in the returned fits are greater at low signal level (less than {approximately}20 counts per measurement). the maximum-likelihood method is found to be more accurate and robust, returning a narrower distribution of values for the fit parameters with fewer outliers.
Who Leaves and Who Stays in Special Education: A 2-Year Follow-up Study

A 2-year follow-up study assessed the stability of special education students' mobility, status, and classification labels. A total of 1,184 students were selected in fall 1982 from the elementary special education programs of three cities. Two years later, 92% remained in their school district. Of these, 71% stayed in special education with the same classification, 12% remained with a different classification, and 17% were no longer receiving special education services. The child's original primary classification was the strongest predictor of reclassification and termination. Family background contributed most to mobility. Implications for practice and research are discussed.
Ciprofloxacin decreases survival in HT‐29 cells via the induction of TGF‐β1 secretion and enhances the anti‐proliferative effect of 5‐fluorouracil

Background and purpose: Fluoroquinolones are potent anti‐microbial agents with multiple effects on host cells and tissues. Previous studies have highlighted their pro‐apoptotic effect on human cancer cells and an immunoregulatory role in animal models of inflammatory bowel disease. We examined the effect of ciprofloxacin on proliferation, cell cycle and apoptosis of HT‐29 cells, a human colonic epithelial cell line sensitive to transforming growth factor (TGF)‐β1‐mediated growth inhibition and its role in TGF‐β1 production. We also examined the effect of ciprofloxacin on proliferation of HT‐29 cells in combination with 5‐fluorouracil (5‐FU), a well‐established pro‐apoptotic agent.
The Selection and Causal Effects of Work Incentives on Labor Productivity: Evidence from a Two-Stage Randomized Controlled Trial in Malawi

Incentives are essential to promote labor productivity. We implemented a two-stage field experiment to measure effects of career and wage incentives on productivity through self-selection and causal effect channels. First, workers were hired with either career or wage incentives. After employment, a random half of workers with career incentives received wage incentives and a random half of workers with wage incentives received career incentives. We find that career incentives attract higher-performing workers than wage incentives but do not increase productivity for existing workers. Instead, wage incentives increase productivity for existing workers. Observable characteristics are limited in explaining the selection effect.
Effective Word Representation for Named Entity Recognition

Recently, various machine learning models have been built using word-level embeddings and have achieved substantial improvement in NER prediction accuracy. Most NER models only take words as input and ignore character-level information. In this paper, we propose an effective word representation that efficiently includes both the word-level and character-level information by averaging its character n-gram embeddings. Our best performing model uses a bidirectional LSTM with word and character n-gram embeddings, which obtains close to state-of-theart performance in NER prediction of the English language.
Development of a Screening Tool for Identifying Elderly People at Risk of Abuse by Their Caregivers

Objective: This study developed and assessed an instrument to identify older people at high risk of abuse based on Reis and Nahmiash's Indicators of Abuse (IOA) screen. Method: A total of 108 people 65 and older, hospitalized in internal medicine departments at two major hospitals in Israel, were screened together with their principal caregivers. The interview was based on the expanded IOA (E-IOA) and a list of evident signs of abuse. Results: Reliability and validity of the E-IOA were tested and confirmed. Indicators proved to be a significant predictor of evident signs of abuse. The E-IOA correctly discerned 92.7% of those at high risk for abuse and 97.9% of those who did not suffer abuse. The main indicators for risk were behavioral problems, emotional problems, and family problems of the caregiver and the elderly person. Fourteen (13%) experienced abuse. Discussion: The proposed assessment tool can be an instrumental guide to identify elderly people who suffer abuse (unidentified) or who are at high risk.
Urocortin II mediates pro-inflammatory effects in human colonocytes via corticotropin-releasing hormone receptor 2α

Background/Aims: Urocortin II (UcnII) is a neuropeptide that binds with high affinity to the corticotropin-releasing hormone receptor 2 (CRHR2) in peripheral tissues. UcnII is synthesised in the intestine, but its role in human intestinal inflammation is largely unknown. Methods: Responses of human colonic epithelial cells expressing CRHR2 to stimulation by UcnII were measured using ELISA, western blot analysis, real-time reverse transcription-PCR (RT-PCR) and interleukin (IL)8 promoter activity. Expression levels of CRHR2 and UcnII in human colitis were determined by immunofluorescence and real-time RT-PCR in mucosal biopsies from patients with Crohn’s and ulcerative colitis, and in human intestinal xenografts after exposure to Clostridium difficile toxin A. Results: It is reported here that expression of CRHR2 mRNA and protein in human colonic epithelial cells (HT-29) are increased by exposure to C difficile toxin A or tumour necrosis factor (TNF)α. Stimulation of non-transformed NCM460 colonocytes overexpressing CRHR2α receptor with UcnII resulted in a time- and concentration-dependent increase in IL8 production. UcnII stimulation also led to activation of nuclear factor-κB (NF-κB) and mitogen-acivated protein (MAP) kinase in these cells, as evidenced by degradation of IκBα and phosphorylation of the p65 subunit of NF-κB and extracellularly regulated kinase (ERK) 1/2. Furthermore, expression of UcnII and CRHR2 mRNA was increased in mucosal samples of patients with inflammatory bowel disease, and after exposure of human intestinal xenografts to C difficile toxin A. Conclusions: These results suggest that UcnII has pro-inflammatory effects in human intestinal cells via the CRHR2α receptor and may play an important role in the pathophysiology of colitis in humans.
Purification, characterization, and primary structure of Escherichia coli protease VII with specificity for paired basic residues: identity of protease VII and OmpT

Escherichia coli cells were found to contain a novel outer membrane-associated protease, designated protease VII (K. Sugimura and N. Higashi, J. Bacteriol. 170:3650-3654, 1988). This enzyme was purified to homogeneity and exhibited an apparent molecular weight of 36,000 on sodium dodecyl sulfate gels and 180,000 on a TSK G-3000SW column in the presence of Triton X-100. It was capable of cleaving several peptides at the center of paired basic residues but not at single basic residues, implying that it is distinct from trypsinlike proteases. Protease VII was most active at pH 6.0 and was sensitive to a serine protease inhibitor, diisopropylfluorophosphate, and to the bivalent cations Zn2+, Cu2+, and Fe2+. The nucleotide sequence of a protease VII gene-carrying DNA fragment, which had been cloned by complementation analysis (K. Sugimura, Biochem. Biophys. Res. Commun. 153:753-759, 1988) was determined. It carried two putative promoter regions and a putative Shine-Dalgarno sequence in addition to the complete structural gene, which encoded pre-protease VII of 317 amino acid residues, with the N-terminal 20 residues being a signal peptide. By comparing their amino acid sequences, protease VII and OmpT, which specifically cleaves ferric enterobactin receptor protein, were found to be identical.
Invited Article: Quantum memristors in quantum photonics

We propose a method to build quantum memristors in quantum photonic platforms. We first design an effective beam splitter, which is tunable in real time, by means of a Mach-Zehnder-type array with two equal 50:50 beam splitters and a tunable retarder, which allows us to control its reflectivity. Then, we show that this tunable beam splitter, when equipped with weak measurements and classical feedback, behaves as a quantum memristor. Indeed, in order to prove its quantumness, we show how to codify quantum information in the coherent beams. Moreover, we estimate the memory capability of the quantum memristor. Finally, we show the feasibility of the proposed setup in integrated quantum photonics.We propose a method to build quantum memristors in quantum photonic platforms. We first design an effective beam splitter, which is tunable in real time, by means of a Mach-Zehnder-type array with two equal 50:50 beam splitters and a tunable retarder, which allows us to control its reflectivity. Then, we show that this tunable beam splitter, when equipped with weak measurements and classical feedback, behaves as a quantum memristor. Indeed, in order to prove its quantumness, we show how to codify quantum information in the coherent beams. Moreover, we estimate the memory capability of the quantum memristor. Finally, we show the feasibility of the proposed setup in integrated quantum photonics.
A Study of significance of mucin histochemistry in histopathological diagnosis of cervical carcinoma

Introduction: Squamous cell carcinoma accounts for around 80% of cases followed by adenocarcinoma which is 15% of cases of cervical cancer. Adenosquamous and neuroendocrine carcinomas are other variety comprising of 5% of cases. Mucicarmine stain demonstrates the presence of cytoplasmic mucin in a minority of cases having morphologic features of squamous cell carcinoma in routinely stained sections. Methodology: Sections from cervical biopsies of 305 patients were studied. Out of these, 109 showed chronic cervicitis, 2 were endocervical polyps, 80 were cervical dysplasia, 3 were adenocarcinoma out of which 2 were clear cell type and 111 epidermoid squamous cell carcinoma. Out of these, 114 cases of carcinoma cervix were selected for present study. Observations: Out of 114 cases, 111 (97.3%) showed features of Squamous cell carcinoma and 3 (2.6%)) of adenocarcinoma on routine H & E staining. Out of 111 squamous cell carcinoma , thirty nine (35.1%) showed PAS positivity and 7(2.7%) were positive for mucicarmine. Six (5.4%) cases of squamous cell carcinoma were positive for both PAS & mucicarmine. All the 3 cases of adenocarcinoma were positive for both PAS and mucicarmine. The cases were reclassified after mucin histochemistry & result showed squamous cell carcinomas to be 92.11%, adenocarcinoma 2.63% and adenosquamous carcinoma 5.26%. Conclusion: Mucin staining should be done in all cases of carcinoma cervix to detect poorly differentiated mixed (adenosquamous) carcinomas, which may escape detection on Haematoxylin and Eosin staining alone for proper management and assessment of prognosis.
A feedforward control synthesis approach for LPV systems

It is well-known that tracking and regulation control objectives can be achieved independently. This paper focuses on the synthesis of the feedforward part of a two-degree-of-freedom LPV/LFT controller. Here, the feedforward filter synthesis, which includes a constraint on the control signal, is cast as an L2 full-information minimization problem. The effectiveness of the proposed approach is demonstrated on the design of an LPV/LFT missile autopilot.
Symptom clusters in elderly patients with lung cancer.

PURPOSE/OBJECTIVES To identify the number, type, and combination (cluster) of symptoms experienced by patients with lung cancer. DESIGN A secondary analysis of data collected as part of a larger study. SETTING 24 sites that included community hospitals, medical clinics, oncology clinics, and radiation-oncology clinics. SAMPLE 220 patients newly diagnosed with lung cancer, ranging in age from 65-89 years (mean = 72 years, SD = 5.02), 38% with early-stage and 62% with late-stage lung cancer. METHODS Subject self-report. FINDINGS Factor analysis found that the symptoms of fatigue, nausea, weakness, appetite loss, weight loss, altered taste, and vomiting form a cluster. Initial staging of cancer, the number of comorbid conditions, and being treated with chemotherapy emerged as significant predictors of the symptoms reported. Few differences were noted between men and women. Correlation was found among the numbers of symptoms reported, symptom severity, and limitations attributed to symptoms. CONCLUSIONS Patients with lung cancer report multiple distressing symptoms related to symptom severity and limitations. IMPLICATIONS FOR NURSING Assessment of multiple symptoms is recommended in patients with lung cancer.
Nesiritide: Trials and Tribulations

Standard therapy for acute decompensated heart failure, a major health problem, consists of intravenous diuretics, vasodilators, and positive inotropic agents. Nesiritide, a recombinant form of human B-type natriuretic peptide, is the only drug specifically approved for this indication. Recent meta-analyses have reported an increased risk of worsening renal function and 30-day mortality with nesiritide administration. These data understandably require physicians to carefully reevaluate their current use of nesiritide in patients with acute decompensated heart failure. In performing this reevaluation, it is important to consider our understanding of the underlying disease state, the limitations and results of these meta-analyses, and new data that provide additional insight into the possible risks and benefits associated with nesiritide therapy. Until additional therapeutic trials are conducted, therapeutic choices must be based on symptomatic and hemodynamic improvement and limited, imperfect available data, which may continue to support the use of nesiritide for its established indication.
Effect‐site targeted patient‐controlled sedation with propofol: comparison with anaesthetist administration for colonoscopy

Patient‐controlled sedation (PCS) allows patients to match their sedation requirement to perceived discomfort. The significant delay in onset of sedation may be overcome with effect‐site steered target controlled infusion, but previously only trials in volunteers have been carried out. We therefore conducted a randomised, double‐blind controlled trial comparing effect‐site steered propofol PCS with anaesthetist‐administered propofol sedation in 40 patients presenting for colonoscopy. The initial effect‐site target in the PCS group was 0.8 μg. ml−1, increment was 0.1 μg. ml−1 and lockout was 3 min. Patient and endoscopist satisfaction and operating conditions were similar between the two groups. PCS patients were sedated more slowly (13 [7.1] vs. 3 [1.1] min; p < 0.0001) and less deeply (minimum BIS value: 71 [16] vs. 58 [15]; p = 0.13) than anaesthetist‐administered propofol sedation patients. More of the latter patients were hypotensive, but all patients had similar recollection of events during the procedure and similar quality of recovery.