A loss-of-function screen reveals SNX5 and SNX6 as potential components of the mammalian retromer

The mammalian retromer is a multimeric protein complex involved in mediating endosome-to-trans-Golgi-network retrograde transport of the cation-independent mannose-6-phosphate receptor. The retromer is composed of two subcomplexes, one containing SNX1 and forming a membrane-bound coat, the other comprising VPS26, VPS29 and VPS35 and being cargo-selective. In yeast, an additional sorting nexin--Vps17p--is a component of the membrane bound coat. It remains unclear whether the mammalian retromer requires a functional equivalent of Vps17p. Here, we have used an RNAi loss-of-function screen to examine whether any of the other 30 mammalian sorting nexins are required for retromer-mediated endosome-to-trans-Golgi-network retrieval of the cation-independent mannose-6-phosphate receptor. Using this screen, we identified two proteins, SNX5 and SNX6, that, when suppressed, induced a phenotype similar to that observed upon suppression of known retromer components. Whereas SNX5 and SNX6 colocalised with SNX1 on early endosomes, in immunoprecipitation experiments only SNX6 appeared to exist in a complex with SNX1. Interestingly, suppression of SNX5 and/or SNX6 resulted in a significant loss of SNX1, an effect that seemed to result from post-translational regulation of the SNX1 level. Such data suggest that SNX1 and SNX6 exist in a stable, endosomally associated complex that is required for retromer-mediated retrieval of the cation-independent mannose-6-phosphate receptor. SNX5 and SNX6 may therefore constitute functional equivalents of Vps17p in mammals.

Increased expression of proteasome subunits in skeletal muscle of cancer patients with weight loss

Atrophy of skeletal muscle is common in patients with cancer and results in increased morbidity and mortality. In order to design effective therapy the mechanism by which this occurs needs to be elucidated. Most studies suggest that the ubiquitin-proteasome proteolytic pathway is most important in intracellular proteolysis, although there have been no reports on the activity of this pathway in patients with different extents of weight loss. In this report the expression of the ubiquitin-proteasome pathway in rectus abdominis muscle has been determined in cancer patients with weight loss of 0-34% using a competitive reverse transcriptase polymerase chain reaction to measure expression of mRNA for proteasome subunits C2 and C5, while protein expression has been determined by western blotting. Overall, both C2 and C5 gene expression was increased by about three-fold in skeletal muscle of cachectic cancer patients (average weight loss 14.5 ± 2.5%), compared with that in patients without weight loss, with or without cancer. The level of gene expression was dependent on the amount of weight loss, increasing maximally for both proteasome subunits in patients with weight loss of 12-19%. Further increases in weight loss reduced expression of mRNA for both proteasome subunits, although it was still elevated in comparison with patients with no weight loss. There was no evidence for an increase in expression at weight losses less than 10%. There was a good correlation between expression of proteasome 20Sα subunits, detected by western blotting, and C2 and C5 mRNA, showing that increased gene expression resulted in increased protein synthesis. Expression of the ubiquitin conjugating enzyme, E214k, with weight loss followed a similar pattern to that of proteasome subunits. These results suggest variations in the expression of key components of the ubiquitin-proteasome pathway with weight loss of cancer patients, and suggest that another mechanism of protein degradation must be operative for patients with weight loss less than 10%. © 2004 Elsevier Ltd. All rights reserved.

Weight loss strategies, stress, and cognitive function:supervised versus unsupervised dieting

The early stages of dieting to lose weight have been associated with neuro-psychological impairments. Previous work has not elucidated whether these impairments are a function solely of unsupported or supported dieting. Raised cortico-steroid levels have been implicated as a possible causal mechanism. Healthy, overweight, pre-menopausal women were randomised to one of three conditions in which they dieted either as part of a commercially available weight loss group, dieted without any group support or acted as non-dieting controls for 8 weeks. Testing occurred at baseline and at 1, 4 and 8 weeks post baseline. During each session, participants completed measures of simple reaction time, motor speed, vigilance, immediate verbal recall, visuo-spatial processing and (at Week 1 only) executive function. Cortisol levels were gathered at the beginning and 30 min into each test session, via saliva samples. Also, food intake was self-recorded prior to each session and fasting body weight and percentage body fat were measured at each session. Participants in the unsupported diet condition displayed poorer vigilance performance (p=0.001) and impaired executive planning function (p=0.013) (along with a marginally significant trend for poorer visual recall (p=0.089)) after 1 week of dieting. No such impairments were observed in the other two groups. In addition, the unsupported dieters experienced a significant rise in salivary cortisol levels after 1 week of dieting (p<0.001). Both dieting groups lost roughly the same amount of body mass (p=0.011) over the course of the 8 weeks of dieting, although only the unsupported dieters experienced a significant drop in percentage body fat over the course of dieting (p=0.016). The precise causal nature of the relationship between stress, cortisol, unsupported dieting and cognitive function is, however, uncertain and should be the focus of further research. © 2005 Elsevier Ltd. All rights reserved.

Visual field severity indices demonstrate dose-dependent visual loss from Vigabatrin therapy

Purpose: The aims of this study were to develop an algorithm to accurately quantify Vigabatrin (VGB)-induced central visual field loss and to investigate the relationship between visual field loss and maximum daily dose, cumulative dose and duration of dose. Methods: The sample comprised 31 patients (mean age 37.9 years; SD 14.4 years) diagnosed with epilepsy and exposed to VGB. Each participant underwent standard automated static visual field examination of the central visual field. Central visual field loss was determined using continuous scales quantifying severity in terms of area and depth of defect and additionally by symmetry of defect between the two eyes. A simultaneous multiple regression model was used to explore the relationship between these visual field parameters and the drug predictor variables. Results: The regression model indicated that maximum VGB dose was the only factor to be significantly correlated with individual eye severity (right eye: p = 0.020; left eye: p = 0.012) and symmetry of visual field defect (p = 0.024). Conclusions: Maximum daily dose was the single most reliable indicator of those patients likely to exhibit visual field defects due to VGB. These findings suggest that high maximum dose is more likely to result in visual field defects than high cumulative doses or those of long duration.

Age-related striatal BOLD changes without changes in behavioral loss aversion

Loss aversion (LA), the idea that negative valuations have a higher psychological impact than positive ones, is considered an important variable in consumer research. The literature on aging and behavior suggests older individuals may show more LA, although it is not clear if this is an effect of aging in general (as in the continuum from age 20 and 50 years), or of the state of older age (e.g., past age 65 years). We also have not yet identified the potential biological effects of aging on the neural processing of LA. In the current study we used a cohort of subjects with a 30 year range of ages, and performed whole brain functional MRI (fMRI) to examine the ventral striatum/nucleus accumbens (VS/NAc) response during a passive viewing of affective faces with model-based fMRI analysis incorporating behavioral data from a validated approach/avoidance task with the same stimuli. Our a priori focus on the VS/NAc was based on (1) the VS/NAc being a central region for reward/aversion processing; (2) its activation to both positive and negative stimuli; (3) its reported involvement with tracking LA. LA from approach/avoidance to affective faces showed excellent fidelity to published measures of LA. Imaging results were then compared to the behavioral measure of LA using the same affective faces. Although there was no relationship between age and LA, we observed increasing neural differential sensitivity (NDS) of the VS/NAc to avoidance responses (negative valuations) relative to approach responses (positive valuations) with increasing age. These findings suggest that a central region for reward/aversion processing changes with age, and may require more activation to produce the same LA behavior as in younger individuals, consistent with the idea of neural efficiency observed with high IQ individuals showing less brain activation to complete the same task.

Rutting-induced permeability loss of open graded friction course mixtures

Functionality of an open graded friction course (OGFC) depends on the high interconnected air voids or pores of the OGFC mixture. The authors' previous study indicated that the pores in the OGFC mixture were easily clogged by rutting deformation. Such a deformation-related clogging can cause a significant rutting-induced permeability loss in the OGFC mixture. The objective of this study was to control and reduce the rutting-induced permeability loss of the OGFC based on mixture design and layer thickness. Eight types of the OGFC mixtures with different air void contents, gradations, and nominal maximum aggregate sizes were fabricated in the laboratory. Wheel-tracking rutting tests were conducted on the OGFC slabs to simulate the deformation-related clogging. Permeability tests after different wheel load applications were performed on the rutted OGFC slabs using a falling head permeameter developed in the authors' previous study. The relationships between permeability loss and rutting depth as well as dynamic stability were developed based on the eight OGFC mixtures' test results. The thickness effects of the single-layer and the two-layer OGFC slabs were also discussed in terms of deformation-related clogging and the rutting-induced permeability loss. Results showed that the permeability coefficient decreases linearly with an increasing rutting depth of the OGFC mixtures. Rutting depth was recommended as a design index to control permeability loss of the OGFC mixture rather than the dynamic stability. Permeability loss due to deformation-related clogging can be effectively reduced by using a thicker single-layer OGFC or two-layer OGFC.

Regularity analysis of nocturnal oximetry recordings to assist in the diagnosis of sleep apnoea syndrome

The relationship between sleep apnoea–hypopnoea syndrome (SAHS) severity and the regularity of nocturnal oxygen saturation (SaO2) recordings was analysed. Three different methods were proposed to quantify regularity: approximate entropy (AEn), sample entropy (SEn) and kernel entropy (KEn). A total of 240 subjects suspected of suffering from SAHS took part in the study. They were randomly divided into a training set (96 subjects) and a test set (144 subjects) for the adjustment and assessment of the proposed methods, respectively. According to the measurements provided by AEn, SEn and KEn, higher irregularity of oximetry signals is associated with SAHS-positive patients. Receiver operating characteristic (ROC) and Pearson correlation analyses showed that KEn was the most reliable predictor of SAHS. It provided an area under the ROC curve of 0.91 in two-class classification of subjects as SAHS-negative or SAHS-positive. Moreover, KEn measurements from oximetry data exhibited a linear dependence on the apnoea–hypopnoea index, as shown by a correlation coefficient of 0.87. Therefore, these measurements could be used for the development of simplified diagnostic techniques in order to reduce the demand for polysomnographies. Furthermore, KEn represents a convincing alternative to AEn and SEn for the diagnostic analysis of noisy biomedical signals.

The value of tablets as reading aids for individuals with central visual field loss:an evaluation of eccentric reading with static and scrolling text

Purpose: Technological devices such as smartphones and tablets are widely available and increasingly used as visual aids. This study evaluated the use of a novel app for tablets (MD_evReader) developed as a reading aid for individuals with a central field loss resulting from macular degeneration. The MD_evReader app scrolls text as single lines (similar to a news ticker) and is intended to enhance reading performance using the eccentric viewing technique by both reducing the demands on the eye movement system and minimising the deleterious effects of perceptual crowding. Reading performance with scrolling text was compared with reading static sentences, also presented on a tablet computer. Methods: Twenty-six people with low vision (diagnosis of macular degeneration) read static or dynamic text (scrolled from right to left), presented as a single line at high contrast on a tablet device. Reading error rates and comprehension were recorded for both text formats, and the participant’s subjective experience of reading with the app was assessed using a simple questionnaire. Results: The average reading speed for static and dynamic text was not significantly different and equal to or greater than 85 words per minute. The comprehension scores for both text formats were also similar, equal to approximately 95% correct. However, reading error rates were significantly (p=0.02) less for dynamic text than for static text. The participants’ questionnaire ratings of their reading experience with the MD_evReader were highly positive and indicated a preference for reading with this app compared with their usual method. Conclusions: Our data show that reading performance with scrolling text is at least equal to that achieved with static text and in some respects (reading error rate) is better than static text. Bespoke apps informed by an understanding of the underlying sensorimotor processes involved in a cognitive task such as reading have excellent potential as aids for people with visual impairments.

Comparison of weight loss outcomes between obese patients with and without Type 2 diabetes attending a weight management focused structured educational group

Aims: Specialist lifestyle management (SLiM) is a medically supported dietetically led structured group education and self-management programme focusing on weight management. Obese patients with Type 2 diabetes are perceived to find it more difficult to lose weight compared with those without diabetes. We aimed to compare the weight loss achieved by obese patients with or without Type 2 diabetes completing the SLiM programme. Methods: A prospective analysis of patients attending SLiM between 2009 and 2013 was conducted. Results: There were 454 obese patients (mean age 49.1 ± 11.6years, women 72.5%, body mass index 49.8 ± 9.3kg/m2, weight137.3 ± 28kg). 152/454 patients (33%) had Type 2 diabetes of which 31 (20.4%) were insulin treated. Patients with Type 2diabetes were older (52.4 ± 11.3 vs 47.5 ± 11.4 years, p < 0.001). SLiM resulted in significant weight loss in patients with (136.5 ± 27 vs 130.2 ± 25.3, p < 0.001) or without (137.6 ± 29 vs 132.6 ± 28.4, p < 0.001) Type 2 diabetes. Weight loss was comparable between patients with and without Type 2 diabetes (6.1 ± 7.9 vs5.1 ± 7kg, p = 0.2). The proportion of patients achieving ≥ 10%weight loss was similar between patients with and without Type 2diabetes (10.5% vs 9.9%, p = 0.4). Insulin-treated patients lost similar weight to those not treated with insulin (6.3 ± 9.4 vs 6.1 ± 7.6kg, p = 0.9). After adjustment for age, sex, referral weight and medications, Type 2 diabetes did not predict weight change during the SLiM programme (b = 0.3, p = 0.5). Conclusions: Attending the SLiM groups produces a significant weight loss in patients with Type 2 diabetes which is comparable to those without Type 2 diabetes. Insulin-treated patients lost similar weight to those not on insulin. Weight gain with Type 2 diabetes and insulin treatment is not ‘unavoidable’ if patients receive the appropriate support and education.

HYBRID TCP/UDP video transport for H.264/AVC content delivery in burst loss networks

In this paper we propose a hybrid TCP/UDP transport, specifically for H.264/AVC encoded video, as a compromise between the delay-prone TCP and the loss-prone UDP. When implementing the hybrid approach, we argue that the playback at the receiver often need not be 100% perfect, provided that a certain level of quality is assured. Reliable TCP is used to transmit and guarantee delivery of the most important packets. This allows use of additional features in the H.264/AVC standard which simultaneously provide an enhanced playback quality, in addition to a reduction in throughput. These benefits are demonstrated through experimental results using a test-bed to emulate the hybrid proposal. We compare the proposed system with other protection methods, such as FEC, and in one case show that for the same bandwidth overhead, FEC is unable to match the performance of the hybrid system in terms of playback quality. Furthermore, we measure the delay associated with our approach, and examine its potential for use as an alternative to the conventional methods of transporting video by either TCP or UDP alone. © 2011 IEEE.

In vitro assessment of the combined effect of eicosapentaenoic acid, green tea extract and curcumin C3 on protein loss in C2C12 myotubes

EPA has been clinically shown to reduce muscle wasting during cancer cachexia. This study investigates whether curcumin or green tea extract (GTE) enhances the ability of low doses of eicosapentaenoic acid (EPA) to reduce loss of muscle protein in an in vitro model. A low dose of EPA with minimal anti-cachectic activity was chosen to evaluate any potential synergistic effect with curcumin or GTE. Depression of protein synthesis and increase in degradation was determined in C2C12 myotubes in response to tumour necrosis factor-α (TNF-α) and proteolysis-inducing factor (PIF). EPA (50 μM) or curcumin (10 μg ml−1) alone had little effect on protein degradation caused by PIF but the combination produced complete inhibition, as did the combination with GTE (10 μg ml−1). In response to TNF-α (25 ng ml−1)-induced protein degradation, EPA had a small, but not significant effect on protein degradation; however, when curcumin and GTE were combined with EPA, the effect was enhanced. EPA completely attenuated the depression of protein synthesis caused by TNF-α, but not that caused by PIF. The combination of EPA with curcumin produced a significant increase in protein synthesis to both agents. GTE alone or in combination with EPA had no effect on the depression of protein synthesis by TNF-α, but did significantly increase protein synthesis in PIF-treated cells. Both TNF-α and PIF significantly reduced myotube diameter from 17 to 13 μm for TNF-α (23.5%) and 15 μm (11.8%) for PIF However the triple combination of EPA, curcumin and GTE returned diameters to values not significantly different from the control. These results suggest that either curcumin or GTE or the combination could enhance the anti-catabolic effect of EPA on lean body mass.

A qualitative investigation of decision making during help-seeking for adult hearing loss

Objective: The Any Qualified Provider framework in the National Health Service has changed the way adult audiology services are offered in England. Under the new rules, patients are being offered a choice in geographical location and audiology provider. This study aimed to explore how choices in treatment are presented and to identify what information patients need when they are seeking help with hearing loss. Design: This study adopted qualitative methods of ethnographic observations and focus group interviews to identify information needed prior to, and during, help-seeking. Observational data and focus group data were analysed using the constant comparison method of grounded theory. Study sample: Participants were recruited from a community Health and Social Care Trust in the west of England. This service incorporates both an Audiology and a Hearing Therapy service. Twenty seven participants were involved in focus groups or interviews. Results: Participants receive little information beyond the detail of hearing aids. Participants report little information that was not directly related to uptake of hearing aids. Conclusions: Participant preferences were not explored and limited information resulted in decisions that were clinician-led. The gaps in information reflect previous data on clinician communication and highlight the need for consistent information on a range of interventions to manage hearing loss.

Európai Unió: túlélés vagy távlati tervezés – az állam változó szerepei (European Union – survival or long term planning?)

Az EU-ban, a mai állapotok szerint, csak „transzferunióról” beszélhetünk és nem egységes piacról. Az eurós pénzfolyamatok eltorzítva közvetítik a versenyképességet is: mind az árukban és vagyontárgyakban, mind – főleg – a pénzügyi eszközökben megtestesült munkákat/teljesítményeket rosszul árazzák. Egy ilyen keretben különösen könnyen alakul ki az, amit potyautas-problémának nevezünk, vagyis ahol tényleges vagy mérhető teljesítményleadás, vagy éppen fizetés nélkül lehet fogyasztani, és túl olcsón lehet szabad forrásokhoz jutni. Az eurózóna számos közvetítő mechanizmusában is tökéletlen. A sok, szuverénadósság-présbe került tagország között van kicsi, közepes és nagy is. Ez a tény, valamint az általános növekedési és munkapiaci problémák, egyértelműen „rendszerszintű zavarokat” jeleznek, amelyeket ebben a dolgozatban teljesítmény közvetítési-átviteli problémának hívunk, és ezért egy szokatlan, ám annál beszédesebb, elektromosenergia-átviteli rendszeranalógiával segítünk értelmezni. Megmutatjuk, hogy egy jó nagyvállalat miért jobb pénzügyi tervező, mint egy azonos méretű állam. _____ Why are ill-defined transfer mechanisms diverting valuable assets and resources to the wrong destination within the EU? Why do we witness ongoing pressure in the EU banking sector and in government finances? We offer an unusual answer to these questions: we apply an analogy from physics (from an electric generation and distribution network) to show the transmission inefficiency and waste, respectively, of the EU distribution mechanisms. We demonstrate that there are inherent flaws in both the measurement and in the distribution of assets and resources amongst the key EU markets: goods, money and factor markets. In addition, we find that when international equalizer mechanism is at work (cohesion funds allocated), many of these equity functions are at risk with respect to their reliable measurement. Especially are at risk the metered load factors, likewise the loss/waste factors. The map of desired outcomes does not match the real outcome, since EUtransfers in general are put to work with low efficiency.

The influence of spirituality, race/ethnicity and religion on parent grief and mental health at one and three months after their infant's/child's death in the neonatal or pediatric intensive care unit

The death of an infant/child is one of the most devastating experiences for parents and immediately throws them into crisis. Spiritual and religious coping strategies may help parents with their loss. The purposes of this longitudinal study were to: (1) describe differences in bereaved parents' use of spiritual coping strategies across racial/ethnic and religious groups, mother/father dyads, and time—one (T1) and three (T2) months after the infant's/child's death in the neonatal (NICU) or pediatric intensive care unit (PICU), and (2) test the relationship between spiritual coping strategies and grief, mental health, and personal growth for mothers and fathers at T1 and T2. A sample of 126 Hispanic, Black/African American, and White parents of 119 deceased children completed the Spiritual Coping Strategies scale, Beck Depression Inventory-II, Impact of Events-Revised, Hogan Grief Reaction Checklist, and a demographic form at T1 and T2. Controlling for race and religion, spiritual coping was a strong predictor of lower grief, better mental health, and greater personal growth for mothers at T1 and T2 and lower grief for fathers at T1. The findings of this study will guide bereaved parents to effective strategies to help them cope with their early grief.

"Unfair'' Restaurant Reviews:To Sue Or Not To Sue

In their discussion entitled - “Unfair” Restaurant Reviews: To Sue Or Not To Sue - by John Schroeder and Bruce Lazarus, Assistant Professors, Department of Restaurant, Hotel and Institutional Management at Purdue University, the authors initially state: “Both advantages and disadvantages exist on bringing lawsuits against restaurant critics who write “unfair” reviews. The authors, both of whom have experience with restaurant criticism, offer practical advice on what realistically can be done by the restaurateur outside of the courtroom to combat unfair criticism.” Well, this is going to be a sticky wicket no matter how you try to defend it, reviews being what they are; very subjective pieces of opinionated journalism, especially in the food industry. And, of course, unless you can prove malicious intent there really is no a basis for a libel suit. So, a restaurateur is at the mercy of written opinion and the press. “Libel is the written or published form of slander which is the statement of false remarks that may damage the reputation of others. It also includes any false and malicious publication which may damage a person's business, trade, or employment,” is the defined form of the law provided by the authors. Anecdotally, Schroeder and Lazarus offer a few of the more scathing pieces reviewers have written about particular eating establishments. And, yes, they can be a bit comical, unless you are the owner of an establishment that appears in the crosshairs of such a reviewer. A bad review can kneecap even a popular eatery. “Because of the large readership of restaurant reviews in the publication (consumer dining out habits indicate that nearly 50 percent of consumers read a review before visiting a new restaurant) your business begins a very dangerous downward tailspin,” the authors reveal, with attribution. “Many restaurant operators contend that a bad review can cost them an immediate trade loss of upward of 50 percent,” Schroeder and Lazarus warn. “The United States Supreme Court has ruled that a restaurant owner can collect damages only if he proves that the statement or statements were made with “actual malice,” even if the statements were untrue,” the authors say by way of citation. And that last portion of the statement cannot be over-emphasized. The first amendment to the U.S. Constitution does wield a heavy hammer, indeed, and it should. So, what recourse does a restaurateur have? The authors cautiously give a guarded thumbs-up to a lawsuit, but you better be prepared to prove a misstatement of fact, as opposed to the distinguishable press protected right of opinion. For the restaurateur the pitfalls are many, the rewards few and far between, Schroeder and Lazarus will have you know. “…after weighing the advantages and disadvantages of a lawsuit against a critic...the disadvantages are overwhelming,” the authors say. “Chicago restaurant critic James Ward said that someone dumped a load of manure on his yard accompanied by a note that read - Stop writing that s--t! - after he wrote a review of a local restaurant.” Such is a novel if not legally measurable tack against an un-mutual review.