Bora phosphorylation substitutes in trans for T-loop phosphorylation in Aurora A to promote mitotic entry.

Polo-like kinase 1 (Plk1) is instrumental for mitotic entry and progression. Plk1 is activated by phosphorylation on a conserved residue Thr210 in its activation segment by the Aurora A kinase (AURKA), a reaction that critically requires the co-factor Bora phosphorylated by a CyclinA/B-Cdk1 kinase. Here we show that phospho-Bora is a direct activator of AURKA kinase activity. We localize the key determinants of phospho-Bora function to a 100 amino acid region encompassing two short Tpx2-like motifs and a phosphoSerine-Proline motif at Serine 112, through which Bora binds AURKA. The latter substitutes in trans for the Thr288 phospho-regulatory site of AURKA, which is essential for an active conformation of the kinase domain. We demonstrate the importance of these determinants for Bora function in mitotic entry both in Xenopus egg extracts and in human cells. Our findings unveil the activation mechanism of AURKA that is critical for mitotic entry.

Are cuffless devices challenged enough? Design of a validation protocol for ambulatory blood pressure monitors at the wrist: the case of the Aktiia Bracelet.

The US and European guidelines for the diagnosis and management of hypertension recommend the introduction of systematic home and night Blood Pressure (BP) monitoring. Fully-automated wearable devices can address the needs of patients and clinicians by improving comfort while achieving measurement accuracy. Often located at the wrist and based on indirect BP measurements, these devices must address the challenges of ambulatory scenarios. New validation strategies are needed, but little guidance has been published so far.In this work, we propose an experimental protocol for the validation of cuffless wrist BP monitors that addresses ambulatory environment challenges in a controlled experimental setting. The protocol assesses the robustness of the measurement for different body postures, the ability of the device to track BP changes, and its ability to deal with hydrostatic pressure changes induced by different arm heights.Performance testing using Aktiia Bracelet is provided as an illustration. The results of this pilot study indicate that the Aktiia Bracelet can generate accurate BP estimates for sitting and lying positions and is not affected by hydrostatic pressure perturbations.Clinical Relevance- Automated cuffless BP monitoring is opening a new chapter in the way patients are being diagnosed and managed. This paper provides a guidance on how to assess the clinical utility of such devices when used in different body positions.

Randomised clinical trial: relief of upper gastrointestinal symptoms by an acid pocket-targeting alginate-antacid (Gaviscon Double Action) - a double-blind, placebo-controlled, pilot study in gastro-oesophageal reflux disease.

BACKGROUND: The alginate-antacid, Gaviscon Double Action (Gaviscon DA; Reckitt Benckiser, Slough, UK) suppresses reflux after meals by creating a gel-like barrier that caps and displaces the acid pocket distal to the oesophago-gastric junction. The effect of Gaviscon DA on reflux and dyspepsia symptoms has not yet been demonstrated with a modern trial design. AIM: A pilot study to assess the efficacy and safety of Gaviscon DA compared with matched placebo for decreasing upper gastrointestinal symptoms in symptomatic gastro-oesophageal reflux disease (GERD) patients. METHODS: A randomised, double-blind, parallel group study was performed in 110 patients with symptoms of GERD. Patients received Gaviscon DA or placebo tablets for 7 consecutive days. The primary endpoint compared the change in overall Reflux Disease Questionnaire (RDQ) symptom score (combined heartburn/regurgitation/dyspepsia). Secondary endpoints assessed individual dimensions, GERD dimension (heartburn and regurgitation) and overall treatment evaluation (OTE). RESULTS: There was a greater decrease in overall RDQ symptom score in the Gaviscon DA group compared with the placebo group (Least Squares Mean difference -0.55; P = 0.0033), and for each of the dimensions independently. Patients in the Gaviscon DA group evaluated their overall treatment response higher than patients in the placebo group [mean (standard deviation) OTE 4.1 (2.44) vs. 1.9 (3.34); P = 0.0005]. No differences in the incidence of adverse events were observed between treatment groups. CONCLUSIONS: Gaviscon DA decreases reflux and dyspeptic symptoms in GERD patients compared with matched placebo and has a favourable benefit-risk balance. Larger scale clinical investigations of medications targeting the acid pocket are warranted. (EudraCT, 2012-002188-84).

Psychodynamic factors contributing to esthetic dental failures.

Traditionally, dentistry has focused on biomedical and mechanotechnical approaches to patients' dental health care. Objective and quantifiable measurements, such as tooth form, occlusal function, color, and biological compatibility, are conventional indicators of success or failure. However, unlike most facets of dental practice, the attainment of an enhanced facial and dental appearance is influenced and measured by more abstract, psychological factors such as perception, ideal body image, self-image, and personal motivation. These complex concepts are affected by emotional and personality factors that develop during the life cycle. This article will explore a psychodynamic perspective of patients who are dissatisfied with the esthetics of their dental treatment, although the result may be functionally and esthetically acceptable.

[Falls in elderly patients in an institution].

Falls among the elderly are a major concern of those caring for them. We studied the incidence of falls in institutionalized elderly, as well as the characteristics of those who fell and the causes of the falls, to determine how to prevent falling. A 2-month survey was conducted in Mishan, an institution in Raanana, and included 144 falls in 108 patients (447 women and 162 men, mean age 84) out of a total of 609 elderly. The prevalence of falls was 1426 per 1000 per year. Most cases of falls were first seen in the emergency room or wards for demented patients. The prevalence of falls among those receiving physiotherapy was only 1/3 that of those who did not. Old institutionalized patients tend to fall mainly while getting in and out of bed. Falls may result from medication such as sleeping pills and psychotropic drugs, but not diuretics. Falls are not inevitable, and measures can be applied to prevent them and thus reduce their frequency.

Psychologic facets of esthetic dental health care: a developmental perspective.

A developmental perspective is presented to explore dental health and esthetics in dentistry and to describe the specific ways human behavior and various aspects of esthetic health care interrelate. An investigation of the fascinating links between mind and mouth over the life cycle are elucidated to explain how and why the oral cavity is so psychologically important. Clinical examples of how personality factors can influence dental treatment and its outcome are illustrated.

Effect of heart rate alterations produced by atrial pacing on the pattern of diastolic filling in normal subjects.

To determine the effect of heart rate alterations on diastolic timing intervals and filling parameters, 10 normal patients were paced from the right atrium at 30 and 50 beats/min above their baseline rates. M-mode echocardiograms of the aortic valve, mitral valve and left ventricle were obtained and digitized at baseline and with each pacing rate. With increased atrial pacing, left ventricular systolic time became an increasingly greater proportion of cycle length while the diastolic filling period occupied a lesser proportion of the cycle length. The time to peak filling rate and the rapid filling period occupied a greater proportion of the diastolic filling period. The peak filling rate increased progressively with increased atrial pacing (baseline 128 +/- 19 mm/s, first paced rate 146 +/- 27 mm/s, p less than 0.05 vs baseline; second paced rate 167 +/- 23 mm/s, p less than 0.01 vs baseline and first paced rate). The early diastolic filling fraction and rapid filling fraction also increased with pacing. Increasing the heart rate resulted in an alteration of the time course of diastolic filling and extent of diastolic filling during the rapid filling period. Interventions that improve diastolic filling and increase heart rate may in part be due to heart rate changes.

Photoaffinity labeling of opiate receptors using intrinsically photoactive 3H-opiates.

Opiate receptors in rat and cow brain membranes have been labeled irreversibly using the intrinsic photolability of 3H-opiates. Membranes were incubated with 3H-ligand and then irradiated with UV light of 254 nm. Nonspecific binding was determined in the presence of 10 microM unlabeled levallorphan. Irreversible binding was defined as binding which survived heat or acid denaturation of membranes. Specific incorporation of label into denatured samples was observed only when unbound or loosely bound 3H-ligand was washed free from the membranes prior to irradiation. There was a general correlation between photosensitivity of the 3H-ligand and its ability to photolabel receptors. Hence, photolabeling presumably results by covalent attachment of highly reactive species generated during photochemical decomposition of ligand. With 3H-etorphine, optimal irradiation time was 5 min. In addition to 3H-etorphine, receptors could be labeled irreversibly with 3H-oxymorphone, 3H-dihydromorphine, and 3H-ethylketocyclazocine. Of the specific binding present in irradiated, nondenatured samples, 45-60% remained attached to receptors upon denaturation. 3H-Ethylketocyclazocine exhibited an 86% yield of incorporation. Signal-to-noise levels of 50-80% could be achieved in denatured samples. Therefore, this method provides a means of covalently labeling opiate receptors in high yield and with high signal-to-noise ratios. The opioid peptides, 3-H-D-Ala2,D-Leu5-enkephalin, 3H-D-Ser2,Leu5,Thr6-enkephalin, 3H-D-Ala2,Met5-enkephalin amide, and 3H-D-Ala2,N-MePhe4,Gly-ol5-enkephalin, as well as the benzomorphan, 3H-bremazocine, apparently lack the structural characteristics which allow photolabeling. 3H-Etorphine was incorporated at high specific activity into a glycoprotein fraction of bovine brain membranes which was retained on wheat germ agglutinin affinity columns. Unretained proteins were essentially unlabeled. 3H-Etorphine was also incorporated at high specific activity into proteins of 17,000 and less than 13,700 Da and, at lower specific activity, into a protein of 2.4 X 10(6) Da in guinea pig brain membranes when kappa receptors were selectively labeled. This method therefore allows labeling of specific membrane proteins and will prove useful in molecular characterization of opiate receptors.

A bioequivalence study of three preparations of propranolol.

The bioequivalence of two different tablets and a solution, each containing 10 mg propranolol hydrochloride was studied in twelve healthy volunteers. Single oral doses of each preparation were administered at intervals of one week. Samples of blood for propranolol radioimmunoassay were taken up to 8 h after dosing. The plasma propranolol concentration at 0.5 h was significantly higher for the solution than for the two tablet formulations which did not differ significantly from each other at any sampling point. The area under the curve was similar for all three preparations. The study demonstrated that the three different preparations of propranolol were bioequivalent.

Almost All Roots of zeta(s) = a Are Arbitrarily Close to sigma = 1/2.

Let s = sigma + it. For any complex a, all but O(1/log log T) of the roots of zeta(s) = a in T < t < 2T lie in|sigma - 1/2| < (log log T)(2)/log T. The results extend easily to other functions satisfying a functional equation such as the Dirichlet L-functions, the Lerch functions, etc.

Deduction of Semi-Optimal Mollifier for Obtaining Lower Bound for N(0)(T) for Riemann's Zeta-Function.

A mollifier played a key role in showing N(0)(T) > 1/3N(T) for large T in ref. 1 [Levinson, N. (1974) Advan. Math. 13, 383-436]. A basic problem in ref. 1 was that of obtaining an upper bound for a sum of two terms, one larger than the other. Here a deductive procedure is given for finding a mollifier that actually minimizes the larger term. An Euler-Lagrange equation is obtained. (Optimization of the sum of both the major and minor terms appears to be formidable.) The actual improvement effected by the optimized mollifier over the ad hoc mollifier of ref. 1 is unfortunately only 1.4%. To obtain a usable mollifier it is necessary to blur the optimization procedure by smoothing at several stages of the deduction. The procedure is of more interest than the particular application because of the small improvement in this case.

Generalization of Recent Method Giving Lower Bound for N(o)(T) of Riemann's Zeta-Function.

Let h(s) = pi(-s/2)tau(s/2). Then, h(s)zeta(s) approximately h(s)H(s) + h(1 - s)H(1 - s) where H(s) = Sigma(1 - (log n)/log t/2pi)n(-s), n /= N(T)/3. Here the extension to H(s) approximately Sigma P (1 - (log n)/log t/2pi) n(-s) is made where P(x) is a polynomial such that P(0) = 0 and P(x) + P(1 - x) = 1. The earlier case is P(x) = x. The relevant formulas in the general case can be obtained explicitly by the earlier method used for P(x) = x, and, indeed, in some respects there is greater simplicity for the general case.

At Least One-Third of Zeros of Riemann's Zeta-Function are on sigma = (1/2).

Starting from the derivative of the functional equation of the zeta-function, it is shown that at least one-third of the zeros of the zeta-function are on the line sigma = (1/2).

Asymptotic Formula for the Coordinates of the Zeros of Sections of the Zeta Function, zeta(N)(s), Near s = 1.

The sum, Sigma1(N)n(-8) = zetaN(s), s = sigma + it, is called a section of the Riemann zeta function, zeta(s). Here an asymptotic formula, for large N, giving the location of the zeros of zetaN(s) near s = 1 will be demonstrated. In particular these zeros will lie in sigma < 1. Relationships between the location of the zeros of zetaN(s) and the zeros of zeta(s) were discovered by Turán. The location in sigma < 1 will also be demonstrated directly, without the asymptotic formula, together with results valid also when s - 1 is not small.