Miracle-dz/UniFAR-FTUs huggingface dataset:
Signalling from TPA to MAP kinase requires protein kinase C, raf and MEK: reconstitution of the signalling pathway in vitro.

The phorbol ester PMA/TPA (phorbol 12-myristate 13-acetate) is a potent tumor promoter which mimics distinct intracellular signalling events triggered by activated growth factor receptors, e.g. the activation of MAP kinases. The largest known family of TPA-binding proteins comprise members of the protein kinase C (PKC) family although other TPA-binding proteins outside the PKC family have recently been identified. In this report we addressed the mechanism and the pathway by which TPA induces the activation of MAPkinases. Using recombinant proteins and in vitro phosphorylation reactions we identified the components in the signal transduction pathway from TPA to MAPkinase and we show that the activation of MAPkinase by TPA requires the presence of protein kinase C, c-raf and the MAPkinase activator MEK. We also find that the activation of raf autophosphorylation in vitro correlates with the ability of Raf to signal to MAPkinase. Thus the activation of Raf by PKC apparently can trigger the same signalling pathway as oncogenic Raf or Raf activation by ras in combination with tyrosine phosphorylation.
Lipopolysaccharide induction of indoleamine 2,3‐dioxygenase is mediated dominantly by an IFN‐γ‐independent mechanism

Indoleamine 2,3‐dioxygenase (IDO) is a rate‐limiting enzyme in the L‐tryptophan‐kynurenine pathway, which converts an essential amino acid, L‐tryptophan, to N‐formylkynurenine. It has been speculated that IFN‐γ is a dominant IDO inducer in vivo. The present study used IFN‐γ or TNF‐α gene‐disrupted mice and IFN‐γ antibody‐treated mice to demonstrate that lipopolysaccharide (LPS)‐induced systemic IDO is largely dependent on TNF‐α rather than IFN‐γ. IFN‐γ‐independent IDO induction was also demonstrated in vitro with LPS‐stimulated monocytic THP‐1 cells. These findings clearly indicate that there is an IFN‐γ‐independent mechanism of IDO induction in addition to the IFN‐γ‐dependent mechanism.
Phosphodiesterase‐3B‐cAMP Pathway of Leptin Signalling in the Hypothalamus is Impaired During the Development of Diet‐Induced Obesity in FVB/N Mice

The phosphodiesterase‐3B (PDE3B)‐cAMP pathway plays an important role in transducing the action of leptin in the hypothalamus. Obesity is usually associated with hyperleptinaemia and resistance to anorectic and body weight‐reducing effects of leptin. To determine whether the hypothalamic PDE3B‐cAMP pathway of leptin signalling is impaired during the development of diet‐induced obesity (DIO), we fed male FVB/N mice a high‐fat diet (HFD: 58% kcal as fat) or low‐fat diet (LFD: 6% kcal as fat) for 4 weeks. HFD fed mice developed DIO in association with hyperphagia, hyperleptinaemia and hyperinsulinaemia. Leptin (i.p.) significantly increased hypothalamic PDE3B activity and phosphorylated (p)‐Akt levels in LFD‐fed but not in HFD‐fed mice. However, basal p‐Akt levels in hypothalamus were increased in DIO mice. Additionally, amongst six‐microdissected brain nuclei examined, leptin selectively decreased cAMP levels in the arcuate nucleus (ARC) of LFD‐fed mice but failed to do so in HFD‐fed mice. We next tested whether both the PBE3B and Akt pathways of leptin signalling remained impaired in DIO mice on the HFD for 12 weeks (long‐term). DIO mice were hyperinsulinaemic and hyperleptinaemic in association with impaired glucose and insulin tolerance. Although, in LFD‐fed mice, leptin significantly increased PDE3B activity and p‐Akt levels in the hypothalamus, it failed to do so in HFD‐fed mice. Also, basal p‐Akt levels in the hypothalamus were increased in DIO mice and leptin had no further effect. Similarly, immunocytochemistry showed that leptin increased the number of p‐Akt‐positive cells in the ARC of LFD‐fed but not in HFD‐fed mice, and there was an increased basal number of p‐Akt positive cells in the ARC of DIO mice. These results suggest that the PDE3B‐cAMP‐ and Akt‐pathways of leptin signalling in the hypothalamus are impaired during the development of DIO. Thus, a defect in the regulation by leptin of the hypothalamic PDE3B‐cAMP pathway and Akt signalling may be one of the mechanisms of central leptin resistance and the development of DIO.
The therapeutic potential of skeletal muscle plasticity in Duchenne muscular dystrophy: phenotypic modifiers as pharmacologic targets

Duchenne muscular dystrophy (DMD) is a life‐limiting, neuromuscular disorder that causes progressive, severe muscle wasting in boys and young men. Although there is no cure, scientists and clinicians can leverage the fact that slower, more oxidative skeletal muscle fibers possess an enhanced degree of resistance to the dystrophic pathology relative to their faster, more glycolytic counterparts, and can thus use this knowledge when investigating novel therapeutic avenues. Several factors have been identified as powerful regulators of muscle plasticity. Some proteins, such as calcineurin, peroxisome proliferator‐activated receptor (PPAR) γ coactivator 1α (PGC‐1α), PPARβ/δ, and AMP‐activated protein kinase (AMPK), when chronically stimulated in animal models, remodel skeletal muscle toward the slow, oxidative myogenic program, whereas others, such as receptor‐interacting protein 140 (RIP140) and E2F transcription factor 1 (E2F1), repress this phenotype. Recent studies demonstrating that pharmacologic and physiological activation of targets that shift dystrophic muscle toward the slow, oxidative myogenic program provide appreciable molecular and functional benefits. This review surveys the rationale behind, and evidence for, the study of skeletal muscle plasticity in preclinical models of DMD and highlights the potential therapeutic opportunities in advancing a strategy focused on remodeling skeletal muscle in patients with DMD toward the slow, oxidative phenotype. —Ljubicic, V. , Burt, M. , Jasmin, B. J. The therapeutic potential of skeletal muscle plasticity in Duchenne muscular dystrophy: phenotypic modifiers as pharmacologic targets. FASEB J. 28, 548–568 (2014). www.fasebj. org
Impact of transport and drug properties on the local pharmacology of drug-eluting stents

Drugs released from stents are driven by physiological transport forces, principally solvent-driven flow (convection) and random molecular agitation (diffusion). The relative strength of these two forces determines drug penetration and distribution in the arterial wall. Drug physicochemical factors can induce critical modulations to the primary distribution, both transiently and at steady state. Hydrophobic interactions and nonspecific binding, for example, can both result in tissue drug concentrations severalfold above administered concentration. Drug interaction with native proteins may also interfere with drug transfer at the stent-artery interface. These transport forces and tissue interactions can induce local drug concentrations even at steady state to vary by one or more orders of magnitude over the span of a few cells. To account for significant local variations in drug concentrations following stent-based delivery, rational design of vascular delivery systems requires consideration of drug distribution and tissue interactions on a local, continuum basis. Continuum analysis adapts traditional pharmacokinetics to the local environment by supplementing discrete global parameters of drug content with continuous local values of concentration, transport and binding. The interplay of these parameters with local flux conditions and drug and tissue properties defines the local drug distribution in space and over time. This type of analysis may well become increasingly relevant given the trend toward stent-based drug therapy in cardiovascular care.
Failed medialization laryngoplasty: management by revision surgery.

OBJECTIVE The purpose of this study was to evaluate the cause of immediate and late medialization laryngoplasty failures and to describe their management. METHODS A retrospective analysis was performed in 20 patients who underwent revision surgery after failed medialization laryngoplasty. Analysis was based on preoperative spiral CT scan, preoperative and postoperative videostrobolaryngoscopy, and phonatory function measures. RESULTS Three major types of failures were identified. The most common problem was arytenoid rotation with a persistent posterior glottic gap (11 of 20). Malposition or wrong size of the implants resulted in a lateralized vocal fold or false vocal fold medialization (6 of 20). Three patients had implants that were extruding. Late atrophy and bowing resulted in a glottal gap (2 of 20). One patient had fibrosis around the implant requiring removal. Spiral CT scan of the larynx located the implant precisely and showed the degree of arytenoid rotation. Patients with arytenoid rotation and posterior gap had revision medialization combined with arytenoid adduction. Revision medialization was performed in 11 patients, arytenoid adduction in 12 patients, lipoinjection in 2 patients, and 4 implants were removed. The voice was improved in 15 patients. Improved voice was correlated with improved phonation time and reduced phonatory airflow rates. CONCLUSION Immediate and late failures of medialization laryngoplasty are due to several possible causes. Revision surgery is feasible and highly successful. To select between the surgical alternatives work up should include preoperative analysis of vocal function, videostrobolaryngoscopic analysis, and spiral CT of the larynx.
Sustained-release drug delivery of antimicrobials in controlling of supragingival oral biofilms

ABSTRACT Introduction: Dental caries, a bacterial biofilm-associated disease, is a prevalent oral health problem. It is a bacterial biofilm-associated disease. Conventional means of combating this disease involves oral hygiene, mostly tooth brushing. Supplementary means of prevention and treatment is often necessary. The use of sustained-release delivery systems, locally applied to the oral cavity appears to be one of the most acceptable avenues for the delivery of antimicrobial agents. Area covered: The development and current approaches of local sustained delivery technologies applied to the oral cavity for treatment and prevention of dental caries is discussed. The use of polymeric drug delivery systems, varnishes, liposomes and nanoparticles is presented. Expert opinion: The use of local sustained-release delivery systems applied to the oral cavity has numerous clinical, pharmacological and toxicological advantages over conventional means. Various sustained-release technologies have been suggested over the course of several years. The current research on oral diseases concentrates predominantly on improving the drug delivery. With progress in pharmaceutical technology, sophisticated controlled-release platforms are being developed. The sustained release concept is innovative and there are few products available for the benefit of all populations. Harmonizing academic research with the dental industry will surely expedite the development and commercialization of more products of such pharmacological nature.
A Retrospective Study of Causes of Low Vision in Saud Arabia, A Case of Eye World Medical Complex in Riyadh

Vision is the ability of seeing with a definite understanding of features, color and contrast, and to distinguish between objects visually. In the year 1999, the World Health Organization (WHO) and the International Agency for the Prevention of Blindness formulated a worldwide project for the eradication of preventable loss of sight with the subject of “Vision 2020: the Right to Sight”. This global program aims to eradicate preventable loss of sight by the year 2020. This study was conducted to determine the main causes of low vision in Saudi Arabia and also to assess their visual improvement after using low vision aids (LVD). The study is a retrospective study and was conducted in low vision clinic at Eye World Medical Complex in Riyadh, Saudi Arabia. The file medical record of 280 patients attending low vision clinics from February 2008 to June 2010 was included. A data sheet was filled which include: age, gender, cause of low vision, unassisted visual acuity for long distances and short distances, low vision devices needed for long distances and short distances that provides best visual acuity. The result shows that the main cause of low vision was Optic atrophy (28.9%). Retinitis pigmentosa was the second cause of low vision, accounting for 73 patients (26%) followed by Diabetic retinopathy and Macular degeneration with 44 patients (15.7%) and 16 patients (5.7%) respectively. Inter family marriage could be one of the main causes of low vision. Public awareness should be embarked on for enlightenment on ocular diseases result in consanguineous marriage. Also, it is an important issue to start establishing low vision clinics in order to improve the situation.
Requirements elicitation: Towards the unknown unknowns

Requirements elicitation research is reviewed using a framework categorising the relative `knowness' of requirements specification and Common Ground discourse theory. The main contribution of this survey is to review requirements elicitation from the perspective of this framework and propose a road map of research to tackle outstanding elicitation problems involving tacit knowledge. Elicitation techniques (interviews, scenarios, prototypes, etc.) are investigated, followed by representations, models and support tools. The survey results suggest that elicitation techniques appear to be relatively mature, although new areas of creative requirements are emerging. Representations and models are also well established although there is potential for more sophisticated modelling of domain knowledge. While model-checking tools continue to become more elaborate, more growth is apparent in NL tools such as text mining and IR which help to categorize and disambiguate requirements. Social collaboration support is a relatively new area that facilitates categorisation, prioritisation and matching collections of requirements for product line versions. A road map for future requirements elicitation research is proposed investigating the prospects for techniques, models and tools in green-field domains where few solutions exist, contrasted with brown-field domains where collections of requirements and products already exist. The paper concludes with remarks on the possibility of elicitation tackling the most difficult question of `unknown unknown' requirements.
Acute infectious diarrhoea in children: new insights in antisecretory treatment with racecadotril

In developing countries acute infectious diarrhoea remains one of the leading causes of death among young children, especially those under 1 year of age. In contrast, in industrialized nations the death rate is very low, although the disease is an important cause of morbidity and consumes substantial healthcare costs. A variety of viral, bacterial and parasitic organisms have been implicated in the pathogenesis of acute diarrhoea. The primary objectives of treatment of acute infectious diarrhoea are correction of dehydration with oral replacement therapy (ORT) and maintenance of good nutritional status via food intake. With regards drug therapy antimicrobial agents are not usually recommended since the disease is generally self‐limiting. Racecadotril is powerful and selective enkephalinase inhibitor and has emerged as a promising drug in the antisecretory therapy of acute infectious diarrhoea in children.
Experimental amblyopia in monkeys. I. Behavioral studies of stimulus deprivation amblyopia.

Rhesus monkeys were visually deprived unilaterally by surgical closure of the eyelids at different ages after birth. The animals were subsequently conditioned to respond to Landolt rings in different positions to determine visual acuity. After acuity thresholds were established for the nondeprived eye, it was surgically closed; the deprived eye was opened, and the acuity of the deprived eye was measured. The results reveal that severe visual impairment without recovery was caused by lid closure during the first four weeks of life. If lid closure was performed at three months or afterwards, the deprived eye showed rapid functional recovery when the lids were reopened. The electroretinograms in two monkeys with stimulus deprivation amblyopia were normal.
Novel Hemi-Staple for the Fusionless Correction of Pediatric Scoliosis: Influence on Intervertebral Disks and Growth Plates in a Porcine Model

Study Design:In vivo porcine model utilized to evaluate the influence of an intravertebral fusionless growth modulating device (hemi-staple) on intervertebral disks and growth plates. Objective:To evaluate the radiographic and histologic changes in disks and growth plates with the purpose of measuring influence of the explored hemi-staple. Summary of Background Data:Fusionless growth modulation for the early treatment of scoliosis should insure the long-term viability of the intervertebral disk and successfully reduce or arrest local growth. A novel hemi-staple that proved effective in the control of coronal spinal alignment warranted further analyses of its influence on the disk health and growth-plate morphology. Methods:A hemi-staple that inhibited local vertebral growth exclusive of the disk was introduced over T5–T8 in 4 immature pigs (16 vertebrae; experimental), whereas 3 underwent surgery without instrumentation (sham) and 2 had no intervention (control). Three-month follow-up before animal euthanasia provided radiographic (disk height and health) and histologic (growth plate morphology, disk health, and type X collagen distribution) analyses. Results:No postoperative complications were experienced. Radiographic data returned inverse disk wedging (greater disk height adjacent to device, 2.6±0.7 mm compared with the noninstrumented side, 1.8±0.5 mm) in experimental segments and suggested disk viability. Histologic data confirmed device growth modulation through significant local reduction of growth plate hypertrophic zone (125.64±16.61 &mgr;m and 61.16±8.25 &mgr;m in noninstrumented and instrumented sections, respectively) and cell height (16.14±1.87 &mgr;m and 9.22±1.57 &mgr;m in noninstrumented and instrumented sections, respectively). A variability of disk health, dependant of device insertion location, was observed. Type X collagen was consistently identified in experimental growth plates and absent from intervertebral disks. Conclusions:Hemi-staples decreased growth plate hypertrophic zone and cell height, and, depending on device insertion site, showed positive signs of disk health sustainability. Spinal growth modulation achieved exclusive of disk compression, as practiced by this method, offers unique advantages over other fusionless techniques. This technique may provide a suitable and attractive alternative for the early treatment of idiopathic scoliosis.
A CMOS bootstrapped switch with novel clock feed-through compensation

A new clock feed-through compensation configuration and corresponding bootstrapped switch are presented and designed optimally with UMC Mixed-Mode/RF 0. 18µm 1P6M P-Sub Twin-Well CMOS process by orientating and elaborate designing the switch MOSFETs that have influence on the delay path match of the clock boosting circuit. HSPICE simulation results show that the proposed clock feed-through compensation configuration can not only enhance the sampling accuracy under the variations of process, power supply voltage, temperature and capacitors but also decrease even harmonic, high-order odd harmonic and THD on the whole effectively.
Follow-up services for stroke survivors after hospital discharge-a randomized control study

Objective: To evaluate whether follow-up services for stroke survivors could improve functional outcome and reduce readmission rate. In this paper results of functional outcome are reported. Design: Randomized controlled trial allocating patients to one of three different types of aftercare: (1) follow-up home visits by a physician, (2) physiotherapist instruction in the patient's home, or (3) standard aftercare. Subjects: Stroke patients with persisting impairment and disability who, after completing inpatient rehabilitation, were discharged to their homes. Outcome measures: Six months after discharge, functional outcome was assessed with Functional Quality of Movement, Barthel Index, Frenchay Activity Index and Index of Extended Activites of Daily Living. Results: One-hundred and fifty-five stroke patients were included in the study. Fifty-four received follow-up home visits by a physician, 53 were given instructions by a physiotherapist in their home and 48 received standard aftercare only. No statistically signi cant differences in functional outcome six months after discharge were demonstrated between the three groups. However, all measurements showed a tendency towards higher scores indicating better function in both interventions groups compared with the control group. Conclusion: Follow-up services after stroke may be a way of improving functional outcome. The results of the present study should be evaluated in future trials. More research in this eld is needed, especially studies of how to support stroke survivors to resume social and leisure activities.
New problem formulation for optimal demand side response in hybrid AC/DC systems

This paper proposes a new problem formulation to simplify the mathematical representation for a hybrid AC/DC domestic energy system. Instead of building the formulation from a component level, the new formulation is built at the whole system level such that all power transfers between AC/DC or DC/AC are reflected in the AC power drawn from the main grid. This is achieved by assigning the AC power drawn from the grid as a piecewise function of local DC power, each slope in the function represents the conversion efficiency, making it flexible to consider a wide range of conversion efficiencies for different system components. The new formulation substantially reduces the number of variables/constraints, improves efficiency modelling accuracy and increases the search efficacy. The piecewise functions are directly solved by a mixed integer linear programming (MILP). The performance of the proposed formulation is illustrated by the hybrid AC/DC energy systems at a primary school in the UK. The results show that the proposed problem formulation and the MILP solution method provide an effective optimal control strategy for a mixed AC/DC domestic energy system in the presence of variable tariffs and differing conversion efficiency, achieved a cost saving of 24% increase in energy bills compared with the traditional approach.