Miracle-dz/UniFAR-FTUs huggingface dataset:
Arginine 91 is not essential for flavin incorporation in hepatic cytochrome b(5) reductase.

Cytochrome b(5) reductase (cb5r) catalyzes the transfer of reducing equivalents from NADH to cytochrome b(5). Utilizing an efficient heterologous expression system that produces a histidine-tagged form of the hydrophilic, diaphorase domain of the enzyme, site-directed mutagenesis has been used to generate cb5r mutants with substitutions at position 91 in the primary sequence. Arginine 91 is an important residue in binding the FAD prosthetic group and part of a conserved "RxY(T)(S)xx(S)(N)" sequence motif that is omnipresent in the "ferredoxin:NADP(+) reductase" family of flavoproteins. Arginine 91 was replaced with K, L, A, P, D, Q, and H residues, respectively, and all the mutant proteins purified to homogeneity. Individual mutants were expressed with variable efficiency and all exhibited molecular masses of approximately 32 kDa. With the exception of R91H, all the mutants retained visible absorption spectra typical of a flavoprotein, the former being produced as an apoprotein. Visible absorption spectra of R91A, L, and P were red shifted with maxima at 458 nm, while CD spectra indicated an altered FAD environment for all the mutants except R91K. Fluorescence spectra showed a reduced degree of intrinsic flavin fluorescence quenching for the R91K, A, and P, mutants, while thermal stability studies suggested all the mutants, except R91K, were somewhat less stable than the wild-type domain. Initial-rate kinetic measurements demonstrated that the mutants exhibited decreased NADH:ferricyanide reductase activity with the R91P mutant retaining the lowest activity, corresponding to a k(cat) of 283 s(-1) and a K(NADH)(m) of 105 microM, when compared to the wild-type domain (k(cat) = 800 s(-1) K(NADH)(m) = 6 microM). These results demonstrate that R91 is not essential for FAD binding in cb5r; however, mutation of R91 perturbs the flavin environment and alters both diaphorase substrate recognition and utilization.
Nitric Oxide Plays an Important Role in the Diurnal Change of Tuberoinfundibular Dopaminergic Neuronal Activity and Prolactin Secretion in Ovariectomized, Estrogen/Progesterone-Treated Rats* * This study was supported, in part, by Grants NSC86-2314-B010-M10 and NSC87-2314-B010-016 (to J.-T.P) from t

A significant diurnal change of tuberoinfundibular dopaminergic (TIDA) neuronal activity coincident with the estrogen (E 2 )-induced afternoon PRL surge has been reported in ovariectomized, E 2 -primed (OVX 1 E 2 ) rats. Systemic injection of a nitric oxide (NO) synthase (NOS) inhibitor, N G -nitro- L -arginine ( L -NA, 50 mg/kg, ip at 1000 and 1200 h), significantly blocked the diurnal changes of TIDA neuronal activity and PRL secretion at 1500 and 1700 h in OVX 1 E 2 rats. Coadministration of L -arginine (300 mg/kg, ip) with L -NA completely prevented the effects of L -NA. Total nitrite/nitrate levels in the serum of L -NA- and L -NA 1 L -arginine-treated rats substantiated the effects of L -NA and L -arginine on NO production. Pretreatment of antisense oligodeoxynucleotide (ODN; 1 m g/3 m l; intracerebroventricularly at 48, 24, and 7 h before sacrifice) against the messenger RNA (mRNA) of constitutive NOS, i.e. neuronal NOS or endothelial NOS, was also effective in preventing the diurnal changes of TIDA neuronal activity and PRL surge at 1500 h. The same treatment of antisense ODN against the mRNA of inducible NOS, i.e. macrophage NOS, had no effect.Progesterone (P 4 ) has been reported to advance and augment the diurnal changes of TIDA neuronal activity and the afternoon PRL surge, by 1 h, in both proestrous and OVX 1 E 2 rats. We further showed that L -NA dose dependently (50 but not 5 mg/kg, ip at 1000 and 1200 h) blocked the effect of P 4 on TIDA neurons and serum PRL at 1300 h, which effect could be negated by simultaneous administration of L -arginine (300 mg/kg, ip). Pretreatment with antisense ODNs against the mRNA of neuronal NOS or endothelial NOS, but not macrophage NOS, was also effective in preventing the P 4 ’s effect on TIDA neuronal activity and PRL secretion at 1300 h. In summary, NO may play a physiological role in the E 2 - and P 4 -regulated diurnal changes of TIDA neuronal activity and PRL secretion. ( Endocrinology 140: 286–291, 1999)
Irregular Speech Rate Dissociates Auditory Cortical Entrainment, Evoked Responses, and Frontal Alpha

The entrainment of slow rhythmic auditory cortical activity to the temporal regularities in speech is considered to be a central mechanism underlying auditory perception. Previous work has shown that entrainment is reduced when the quality of the acoustic input is degraded, but has also linked rhythmic activity at similar time scales to the encoding of temporal expectations. To understand these bottom-up and top-down contributions to rhythmic entrainment, we manipulated the temporal predictive structure of speech by parametrically altering the distribution of pauses between syllables or words, thereby rendering the local speech rate irregular while preserving intelligibility and the envelope fluctuations of the acoustic signal. Recording EEG activity in human participants, we found that this manipulation did not alter neural processes reflecting the encoding of individual sound transients, such as evoked potentials. However, the manipulation significantly reduced the fidelity of auditory delta (but not theta) band entrainment to the speech envelope. It also reduced left frontal alpha power and this alpha reduction was predictive of the reduced delta entrainment across participants. Our results show that rhythmic auditory entrainment in delta and theta bands reflect functionally distinct processes. Furthermore, they reveal that delta entrainment is under top-down control and likely reflects prefrontal processes that are sensitive to acoustical regularities rather than the bottom-up encoding of acoustic features. SIGNIFICANCE STATEMENT The entrainment of rhythmic auditory cortical activity to the speech envelope is considered to be critical for hearing. Previous work has proposed divergent views in which entrainment reflects either early evoked responses related to sound encoding or high-level processes related to expectation or cognitive selection. Using a manipulation of speech rate, we dissociated auditory entrainment at different time scales. Specifically, our results suggest that delta entrainment is controlled by frontal alpha mechanisms and thus support the notion that rhythmic auditory cortical entrainment is shaped by top-down mechanisms.
Blinded histopathological characterisation of POLE exonuclease domain‐mutant endometrial cancers: sheep in wolf's clothing

POLE exonuclease domain mutations identify a subset of endometrial cancer (EC) patients with an excellent prognosis. The use of this biomarker has been suggested to refine adjuvant treatment decisions, but the necessary sequencing is not widely performed and is relatively expensive. Therefore, we aimed to identify histopathological and immunohistochemical characteristics to aid in the detection of POLE‐mutant ECs.
Inhibition of neuromuscular transmission in the intact rat by emetine

Whether the skeletal muscular weakness which often complicates treatment with emetine hydrochloride (Goodman & Gillman, 1965) arises from a direct action on the muscle (Klatskin & Friedman, 1948) or is secondary to an action on the nerve (Brown, 1935) is still uncertain. Young & Tudhope (1926), in experiments on the rat, found no evidence of inflammation in the nerve but observed degenerative changes in muscle; and recently Ng (1966) showed that the drug blocked the indirectly elicited contraction of the rat isolated diaphragm without significantly affecting the directly elicited contraction. This problem has been further investigated by studying the effect of emetine on neuromuscular transmission in the intact rat using the sciatic nerve-gastrocnemius muscle preparation. Emetine is already known to produce morphological as well as in vitro functional changes in the neuromuscular system of the rat. Twelve rats were given subcutaneous injections of emetine, 1 mg/kg (comparable to the human dose), daily for ten days. Twenty-four h after the last injection, a sciatic nerve-gastrocnemius muscle preparation was made. Similar nerve-muscle preparations were also made in 12 untreated rats. The nerve was stimulated supramaximally with square pulses of 100 to 1000 p s duration. Single twitches of the muscles were elicited at a frequency of 8/min, and, at intervals, tetani were elicited by increasing the stimulation rate to 64/s for 15 s. Nerve stimulation in treated rats produced twitches of the muscle in the usual manner. However, unlike the normal rat preparation, the twitches were often of irregular height, and after 2-5 min there was a progressive fall in twitch height with
Effect of Aerobic Fitness on the Physiological Stress Response in Women

Stress reactivity was assessed in aerobically fit (n = 14) and unfit (n = 8) females during the follicular phase of the menstrual cycle. Participants completed the Spielberger State-Trait Anxiety Inventory and provided a urine sample for catecholamine analysis before and after mental stress testing, Stroop Color-Word Test. Blood pressure, heart rate, muscle tension, and skin conductance were measured during mental stress testing. Fit and unfit participants differed significantly in baseline heart rate but not in stress reactivity or in state or trait anxiety. These data suggest that aerobic fitness does not attenuate the stress response in women prior to menopause.
Discriminative‐stimulus control by morphine in the pigeon under a fixed‐interval schedule of reinforcement

The stimulus control by morphine under a fixed-interval (FI) 180-s schedule of reinforcement was examined in five pigeons trained to discriminate 5.0 mg/kg of i.m. morphine from saline. After training, dose-response relationships were determined for morphine, d-amphetamine, pentobarbital, fentanyl, and MK-801. At low doses of morphine, responding of individual subjects was predominantly on the saline-appropriate key. At intermediate doses responding occurred on both keys throughout the interval. Following doses of 5.6 mg/kg and higher, responding on both keys was observed in the early portions of the interval with responding shifting to the morphine-appropriate key as the interval progressed. Thus, a graded dose-effect curve for morphine was obtained under the FI schedule. The fentanyl dose-effect curve was similar to that obtained with morphine, but the other test drugs were not generalized. Five other pigeons were trained to discriminate 5.0 mg/kg of morphine from saline under a fixed-ratio (FR)100 schedule of reinforcement. During testing with morphine, responses were confined to the saline-appropriate key at 0.3 and 1.0 mg/kg of morphine, but at higher doses responses were confined to the drug key. In contrast to the results obtained using the FI schedule, a quantal relationship for responding on the two keys was observed when a FR schedule was employed.
A Byzantine Grand Embassy to Russia in 1400

The Acta Patriarchatus Constantinopolitani, published by Miklosich and Müller, contain a pittakion sent by Matthew I, Patriarch of Constantinople (1397–1410), to his subordinate and representative in Moscow, Cyprian, Metropolitan of Kiev and All Russia. The document is undated, but it is clear from the contents that it was written either in the last three weeks of December 1399 or, more probably, in 1400. Its professed aim was to persuade the Russian primate to embark on a fund-raising campaign in aid of Constantinople, besieged by the forces of the Ottoman Sultan, Bayazid I.
ROLE OF PSEUDOMONAS IN NOSOCOMIAL INFECTIONS AND BIOLOGICAL CHARACTERIZATION OF LOCAL STRAINS

Background & objectives: Pseudomonas aeruginosa is an important nosocomial pathogen since it can survive in minimal medium. There is a global emergence of multidrug resistant strains of Pseudomonas. These strains are the main causes of nosocomial infections causing morbidity and mortality as these infections are difficult to eradicate. The objective of the present study was to determine the prevalence of strains of P. aeruginosa in hospital environment, its incidence, clinical infections caused and to detect source of nosocomial infection by characterization of the Pseudomonas isolates. Methods: A total of 613 strains of Pseudomonas were isolated from different clinical specimens. 68 strains were isolated from environmental sites like Intensive Care Unit, Operation Theatre and Wards. Strains were identified by standard methods. Antibiogram and Pyocin typing was carried out for further characterization. Genotyping was performed by Pulsed Field Gel Electrophoresis. Results: Highest percentage of P. aeruginosa was from urine samples, followed by pus, tracheal secretions and sputa. Prevalence of the organism was highest in Intensive Care Unit followed by Intensive Care Medical Unit. The antibiogram showed maximum sensitivity to Piperacillin/Tazobactum, followed by Carbenicillin. About 47% of the strains belonged to pyocin type 10, 2.04% belonged to type 33 and 49% could not be typed. Two PFGE patterns were found among the isolates designated as SP and SP1. Out of 47, 44 isolates showing SP pattern were of pyocin type 10 and resistant to Septran, Lomefloxacin, Colistin, PolymyxinB, Ampicillin and Augmentin. The rest 3 isolates showing SP1 pattern were resistant to Gentamycin, Amikacin, Netilmycin, Carbenicillin, Ciprofloxacin and Chloramphenicol in addition to those mentioned earlier. Interpretation & conclusions: Majority of clinical and environmental strains showed a single PFGE pattern and a similar antimicrobial susceptibility pattern. Thus it is presumed that the strains of P. aeruginosa have a common origin. Out of 545 strains, 221 were isolated from post-operative cases. It can be concluded that patients acquired these infections from the hospital.
SECONDARY OCULAR HYPERTENSION AFTER INTRAVITREAL INJECTION OF 4 MG OF TRIAMCINOLONE ACETONIDE: Incidence and Risk Factors

Purpose: To analyze the incidence of secondary ocular hypertension (SOH) after intravitreal triamcinolone acetonide (IVTA) injection and its risk predictors. Methods: Retrospective review of charts for 219 consecutive patients receiving a 4-mg IVTA injection. Results: One hundred fifty eyes of 150 patients who were followed for at least 3 months and met inclusion criteria were considered. Main indications for IVTA injection were neovascular age-related macular degeneration (79 eyes [52.7%]), choroidal neovascularization due to other etiologies (22 eyes [14.7%]), diabetic macular edema (14 eyes [9.3%]), central retinal vein occlusion (12 eyes [8.0%]), and branch retinal vein occlusion (8 eyes [5.3%]). SOH defined as intraocular pressure (IOP) of ≥21 mmHg was recorded for 32.0% of injected eyes at some point during a mean follow-up of 7.7 months. There was no association between SOH and age, sex, arterial hypertension, diabetes mellitus, indication for IVTA injection, prior cataract surgery, or concurrent photodynamic therapy. Although previous pars plana vitrectomy did not influence risk, peak IOP was lower in vitrectomized eyes (P = 0.044). Prior diagnosis of glaucoma was a significant risk factor for SOH (relative risk = 2.17; P = 0.004). In nonglaucomatous eyes, baseline IOP of ≥16 mmHg was associated with a higher risk of SOH (relative risk = 2.31; P = 0.003). Baseline IOPs of <12 mmHg, 12–14 mmHg, 15–17 mmHg, 18–20 mmHg, and >20 mmHg were associated with incidences of SOH of 11.1%, 25.4%, 40.0%, 46.2%, and 50.0% (P = 0.01), respectively. Conclusions: A 4-mg IVTA injection was associated with SOH in 32.0% of treated eyes. The risk of SOH was higher in eyes with previous glaucoma and higher baseline IOP. Peak IOP after IVTA injection was lower in vitrectomized eyes. Risk factor analysis may permit better individualization of the risk–benefit ratio for IVTA injection.
Dysregulated expression of Slug, vimentin, and E‐cadherin correlates with poor clinical outcome in patients with basal‐like breast cancer

Among the different types of breast cancer, basal‐like breast cancer (BLBC) has an extremely poor prognosis due to its high rate of recurrence and metastasis. The present study aimed to investigate the correlation between the expression of Slug, E‐cadherin, and vimentin, and the clinicopathological characteristics and prognosis of patients with BLBC. We further inferred from these findings whether Slug leads to a poor prognosis in patients with BLBC through epithelial–mesenchymal transition (EMT).
Crystal structure of 4-amino-5-fluoro-2-oxo-2,3-dihydropyrimidin-1-ium 3-hydroxypyridine-2-carboxylate

The protonated N atom and 2-amine group of the 5-fluorocytosinium (5FC) cation interact with the 3-hydroxypicolinate (3HAP) anion through a pair of nearly-parallel N—H⋯O hydrogen bonds, forming a robust (8) ring motif. The ions are further linked by N—H⋯N, O—H⋯O, N—H⋯O and C—H⋯O hydrogen bonds, leading to supramolecular wave-like sheets and the crystal structure is further stabilized by C—H⋯π interactions, generating a three-dimensional architecture.
Moving Horizon H∞ Tracking Control of Wheeled Mobile Robots With Actuator Saturation

This brief considers the dynamic tracking control of wheeled mobile robots (WMR), in the presence of both actuator saturations and external disturbances. A computationally tractable moving horizon H infin tracking scheme is presented, where a constrained H infin control problem is solved at each sampling time with the update of not only the initial condition but also the prediction model. Closed-loop tracking properties inclusive of L 2 disturbance attenuation are discussed in the framework of dissipation theory. Simulation results are given.
Editorial : Scoring and Other Assessments of Plaque Morphology and Pathology

Coronary plaque burden, as determined by coronary computed tomography angiography (CCTA), has been shown to be a measure of the extent of coronary artery disease (CAD) and to have prognostic value. From a measurement of total plaque score (TPS) as the total number of coronary segments with at least some atherosclerotic plaque, Ayoub et al have proposed a new extended measurement which they refer to as percentage of TPS adjusted for age (%TPS/age). This appears to be a simple targeted assessment of cardiovascular (CV) risk. This editorial discusses various atherosclerotic plaque evaluations and how measurements such as %TPS/age may be valuable.
Health, education, and retirement over the prolonged life cycle: a selective survey of recent research

This issue of the Vienna Yearbook of Population Research contains a selection of papers that were presented at the conference ‘Health, Education, and Retirement over the Prolonged Life Cycle’, which was organised by the Vienna Institute of Demography of the Austrian Academy of Sciences and held in Vienna in November 2013. The conference was devoted to the socio-economic causes and consequences at both the individual and the societal level of the unprecedented increase in life expectancy over the past few decades. At the micro level, a better understanding is needed regarding the extent to which the increase in human life expectancy has been shaped by individual health behaviour, rather than by other socio-economic influences, and through which channels this happened. Conversely, it is important to understand better how the prolongation of the life cycle will shape individual behaviour. The conference focused on behaviour relating to health, education, and the supply of labour. Although generally perceived as a positive development, the increase in life expectancy also poses policy challenges for social security and the cohesion of society, given that different social groups benefit from rising longevity to varying degrees. Important questions have been raised about the macro consequences of the prolongation of the individual life cycle, not least because having an understanding of the underlying mechanisms will be crucial for assessing the extent to which retirement, health, and educational policies need to be reformed. The recognition that the design of reforms should be guided by an awareness of the potential effects
Do genes allow inflammation to kill or not to kill?

Cardiovascular disease is principally responsible for the high mortality in patients with ESRD.1 Extending to dialysis patients therapies proven successful in the general population has thus far been of limited success,2 indicating the critical need for alternative interventions in this patient population. The metabolic complexity of renal failure encourages a variety of processes that increase cardiovascular complications and mortality. One such mechanism is enhanced chronic inflammation brought on, in part, by low GFR and, of course, various dialysis-specific proinflammatory signals.3 Inflammation initiates and propagates atherosclerosis4 through chemokines that mobilize inflammatory cell influx and proliferation during atherosclerotic plaque formation.5 Chemokines—the word itself stemming from an abbreviation of chemoattractant cytokines—are small (8 to 14 kD) proteins that regulate leukocyte trafficking, cell adhesion, phagocytosis, cytokine secretion, cell activation, proliferation, apoptosis, and angiogenesis during inflammation.6 Chemokines are classified into four groups on the basis of the number and position of conserved cysteine residues in their amino acid structure (CC, XC, CXC, and CX3C), and their receptors are accordingly designated as CCR, XCR, CXCR, or CX3CR followed by a number corresponding to the chronological order in which they were identified.5 One chemokine receptor attracting substantial interest is CCR5,7 because it also serves as …
Prior antipsychotic prescribing in patients currently receiving clozapine: a case note review.

BACKGROUND Clozapine is indicated for the treatment of resistant schizophrenia, which is usually defined as failure to respond to adequate trials of 2 antipsychotics. It is thought that only clozapine is likely to be effective in such cases and that other drugs are ineffective. We sought to discover prior patterns of antipsychotic prescribing in schizophrenic patients eventually prescribed clozapine. METHOD Prescribing histories were obtained from prescription charts and case notes for all inpatients prescribed clozapine in 4 hospitals in southeast London during April 2001. RESULTS 120 patients were identified, of whom 112 had been diagnosed with schizophrenia or schizoaffective disorder and whose data were analyzed. The mean duration of illness was 15.1 years. Subjects had experienced a mean of 9.2 (range, 2-35) episodes of antipsychotic prescription before clozapine was first used, with 5.7 (range, 0-25) episodes constituting adequate trials (drug used at therapeutic dose for 6 weeks). The mean number of different antipsychotics used was 5.5 (range, 1-13), with a mean of 4.0 (range, 0-12) given an adequate trial. Ninety percent of patients (N = 101) had received an atypical antipsychotic before first use of clozapine, and 65% (N = 73) had previously received antipsychotic polypharmacy. The mean maximum theoretical delay in using clozapine was 5.0 years (range, 0-11.1 years). Longer delay was significantly (p <.05) associated with being aged over 30 years at the time of the study, being diagnosed with psychotic illness before the introduction of clozapine, and completing adequate trials of 2 different antipsychotics before the introduction of clozapine or risperidone. CONCLUSION Clozapine treatment was quite likely delayed for longer than is clinically desirable. This delay may have important effects on quality of life, clinical outcome, and health resource utilization.