Influence of Action-Effect Associations Acquired by Ideomotor Learning on Imitation

According to the ideomotor theory, actions are represented in terms of their perceptual effects, offering a solution for the correspondence problem of imitation (how to translate the observed action into a corresponding motor output). This effect-based coding of action is assumed to be acquired through action-effect learning. Accordingly, performing an action leads to the integration of the perceptual codes of the action effects with the motor commands that brought them about. While ideomotor theory is invoked to account for imitation, the influence of action-effect learning on imitative behavior remains unexplored. In two experiments, imitative performance was measured in a reaction time task following a phase of action-effect acquisition. During action-effect acquisition, participants freely executed a finger movement (index or little finger lifting), and then observed a similar (compatible learning) or a different (incompatible learning) movement. In Experiment 1, finger movements of left and right hands were presented as action-effects during acquisition. In Experiment 2, only right-hand finger movements were presented during action-effect acquisition and in the imitation task the observed hands were oriented orthogonally to participants’ hands in order to avoid spatial congruency effects. Experiments 1 and 2 showed that imitative performance was improved after compatible learning, compared to incompatible learning. In Experiment 2, although action-effect learning involved perception of finger movements of right hand only, imitative capabilities of right- and left-hand finger movements were equally affected. These results indicate that an observed movement stimulus processed as the effect of an action can later prime execution of that action, confirming the ideomotor approach to imitation. We further discuss these findings in relation to previous studies of action-effect learning and in the framework of current ideomotor approaches to imitation.     

Sex,gender, and pharmaceutical politics: From drug development to marketing

Background: Biological sex differences and sociocultural gender norms affect the provision of health care products and services, but there has been little explicit analysis of the impact of sex differences and gender norms on the regulation of pharmaceutical development and marketing.Objectives: This article provides an overview of the regulation of pharmaceuticals and examines the ways that regulatory agencies account for sex and gender in their review of scientific data and marketing materials.Methods: The primary focus is on the US context, but information is also included about regulatory models in Europe, Canada, and Japan for comparative purposes. Specific examples show how sex differences and gender norms influence scientific and policy decisions about pharmaceuticals.Results: The United States and Canada were found to be the only countries that have explicit requirements to include women in clinical trials and to perform sex-based subgroup analysis on study results. The potential influence of politics on regulatory decisions may have led to an uneven application of standards, as seen through the examples of mifepristone (for abortion) and sildenafil citrate (for erectile dysfunction). Three detailed case studies illustrate the importance of considering sex and gender in pharmaceutical development and marketing: Phase I clinical trials; human papillomavirus quadrivalent vaccine; and tegaserod, a drug for irritable bowel syndrome.Conclusions: Sex and gender play important roles in pharmaceutical regulation, from the design of clinical trials and the approval of new drugs to advertising and postmarketing surveillance. However, regulatory agencies pay insufficient attention to both biological sex differences and sociocultural gender norms. This disregard perpetuates inequalities by ignoring drug safety problems that predominate in women and by allowing misleading drug marketing that reinforces gender stereotypes. Recommendations have been made to improve the regulation of pharmaceuticals in regard to sex and gender.     

The formin FMNL3 assembles plasma membrane protrusions that participate in cell–cell adhesion

FMNL3 is a vertebrate-specific formin protein previously shown to play a role in angiogenesis and cell migration. Here we define the cellular localization of endogenous FMNL3, the dynamics of GFP-tagged FMNL3 during cell migration, and the effects of FMNL3 suppression in mammalian culture cells. The majority of FMNL3 localizes in a punctate pattern, with >95% of these puncta being indistinguishable from the plasma membrane by fluorescence microscopy. A small number of dynamic cytoplasmic FMNL3 patches also exist, which enrich near cell–cell contact sites and fuse with the plasma membrane at these sites. These cytoplasmic puncta appear to be part of larger membranes of endocytic origin. On the plasma membrane, FMNL3 enriches particularly in filopodia and membrane ruffles and at nascent cell–cell adhesions. FMNL3-containing filopodia occur both at the cell–substratum interface and at cell–cell contacts, with the latter being 10-fold more stable. FMNL3 suppression by siRNA has two major effects: decrease in filopodia and compromised cell–cell adhesion in cells migrating as a sheet. Overall our results suggest that FMNL3 functions in assembly of actin-based protrusions that are specialized for cell–cell adhesion.     

Weight Change in Adult Life and Health Outcomes

Objective: To investigate the relationship between weight change in adult life and subsequent mortality and cancer incidence in women. Research Methods and Procedures: In 1994 to 1995, all women (age range, 42 to 81) still under general practitioner observation in the United Kingdom's Royal College of General Practitioners Oral Contraception Study (n = 12 303) were sent a health survey asking about health and lifestyle issues, including current weight and weight at age 30. The main outcome measures were 6‐year all‐cause mortality and cancer incidence among different weight change deciles. Cox regression was used to calculate hazard ratios that were adjusted for: social class at recruitment, BMI at age 30, and age group, parity, smoking status, and hormone replacement therapy status in 1995. Results: Women who had been obese at age 30 were more likely to die and significantly more likely to develop cancer in the 6 years after the health survey than non‐obese respondents. Women reporting weight gains between age 30 and 1995 were significantly less likely to die during the 6 years after the health survey than those with a stable weight, whereas those with weight loss did not fare any better than those in the stable‐weight group. Discussion: Although obesity at young age was associated with subsequent mortality and cancer incidence, weight gain over a time period of 12 to 51 years appeared to be beneficial when compared with women with stable weight over the same time period. Further research is needed to confirm or refute our findings and to allow detailed examination of potential explanations for them.     

Association of an MHC Class II Haplotype with Increased Risk of Polymyositis in Hungarian Vizsla Dogs

A breed-specific polymyositis is frequently observed in the Hungarian Vizsla. Beneficial clinical response to immunosuppressive therapies has been demonstrated which points to an immune-mediated aetiology. Canine inflammatory myopathies share clinical and histological similarities with the human immune-mediated myopathies. As MHC class II associations have been reported in the human conditions we investigated whether an MHC class II association was present in the canine myopathy seen in this breed. 212 Hungarian Vizsla pedigree dogs were stratified both on disease status and degree of relatedness to an affected dog. This generated a group of 29 cases and 183 “graded” controls: 93 unaffected dogs with a first degree affected relative, 44 unaffected dogs with a second degree affected relative, and 46 unaffected dogs with no known affected relatives. Eleven DLA class II haplotypes were identified, of which, DLA-DRB1*02001/DQA1*00401/DQB1*01303, was at significantly raised frequency in cases compared to controls (OR = 1.92, p = 0.032). When only control dogs with no family history of the disease were compared to cases, the association was further strengthened (OR = 4.08, p = 0.00011). Additionally, a single copy of the risk haplotype was sufficient to increase disease risk, with the risk substantially increasing for homozygotes. There was a trend of increasing frequency of this haplotype with degree of relatedness, indicating low disease penetrance. These findings support the hypothesis of an immune-mediated aetiology for this canine myopathy and give credibility to potentially using the Hungarian Vizsla as a genetic model for comparative studies with human myositis.     

The status of the freshwater pearl mussel <Emphasis Type="Italic">Margaritifera margaritifera</Emphasis> in Scotland: extent of change since 1990s,threats and management implications

All known rivers in Scotland with recent records of freshwater pearl mussels Margaritifera margaritifera were surveyed in 2013–2015 using a standard methodology. Freshwater pearl mussel populations were classed as: (i) apparently extinct in 11 rivers, (ii) not successfully recruiting in 44 rivers, and (iii) evidence of recent successful recruitment in 71 rivers. On a regional basis, a high proportion of extant populations were located in North and West Scotland. In all regions extant populations were characterised by low pearl mussel densities, with 97 of 115 extant Scottish populations defined as ‘rare’ (0.1–0.9 mussels per 1 m ²) or ‘scarce’ (1.0–9.9 mussels per 1 m ²). Only 18 Scottish rivers now hold pearl mussel populations in densities that are considered to be ‘common’ (10–19.9 mussels per 1 m ²) or ‘abundant’ (>20 mussels per 1 m ²). Based on survey evidence, the number of apparently extinct pearl mussel populations in Scottish rivers is now 73. The decline is particularly pronounced in the West Highlands and Western Isles strongholds. The key threats are: (i) pearl fishing, (ii) low host fish densities, (iii) pollution/water quality, (iv) climate change and habitat loss, (v) hydrological management/river engineering and (vi) ‘other factors’, such as non-native invasive species. Over the last 100 years this endangered species has been lost from much of its former Holarctic range. Scotland’s extant M. margaritifera populations continue to be of international importance, but their continued decline since the first national survey in 1998 is of great concern.     

The pectic disaccharides lepidimoic acid and β-d-xylopyranosyl-(1→3)-d-galacturonic acid occur in cress-seed exudate but lack allelochemical activity

Background and aims Cress-seed (Lepidium sativum) exudate exerts an allelochemical effect, promoting excessive hypocotyl elongation and inhibiting root growth in neighbouring Amaranthus caudatus seedlings. We investigated acidic disaccharides present in cress-seed exudate, testing the proposal that the allelochemical is an oligosaccharin—lepidimoic acid (LMA; 4-deoxy-β-l-threo-hex-4-enopyranuronosyl-(1→2)-l-rhamnose).Methods Cress-seed exudate was variously treated [heating, ethanolic precipitation, solvent partitioning, high-voltage paper electrophoresis and gel-permeation chromatography (GPC)], and the products were bioassayed for effects on dark-grown Amaranthus seedlings. Two acidic disaccharides, including LMA, were isolated and characterized by electrophoresis, thin-layer chromatography (TLC) and nuclear magnetic resonance (NMR) spectroscopy, and then bioassayed.Key Results Cress-seed exudate contained low-M_r, hydrophilic, heat-stable material that strongly promoted Amaranthus hypocotyl elongation and inhibited root growth, but that separated from LMA on electrophoresis and GPC. Cress-seed exudate contained ∼250 µm LMA, whose TLC and electrophoretic mobilities, susceptibility to mild acid hydrolysis and NMR spectra are reported. A second acidic disaccharide, present at ∼120 µm, was similarly characterized, and shown to be β-d-xylopyranosyl-(1→3)-d-galacturonic acid (Xyl→GalA), a repeat unit of xylogalacturonan. Purified LMA and Xyl→GalA when applied at 360 and 740 µm, respectively, only slightly promoted Amaranthus hypocotyl growth, but equally promoted root growth and thus had no effect on the hypocotyl:root ratio, unlike total cress-seed exudate.Conclusions LMA is present in cress seeds, probably formed by rhamnogalacturonan lyase action on rhamnogalacturonan-I during seed development. Our results contradict the hypothesis that LMA is a cress allelochemical that appreciably perturbs the growth of potentially competing seedlings. Since LMA and Xyl→GalA slightly promoted both hypocotyl and root elongation, their effect could be nutritional. We conclude that rhamnogalacturonan-I and xylogalacturonan (pectin domains) are not sources of oligosaccharins with allelochemical activity, and the biological roles (if any) of the disaccharides derived from them are unknown. The main allelochemical principle in cress-seed exudate remains to be identified.     

CaMKK2 facilitates Golgi-associated vesicle trafficking to sustain cancer cell proliferation

Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) regulates cell and whole-body metabolism and supports tumorigenesis. The cellular impacts of perturbing CAMKK2 expression are, however, not yet fully characterised. By knocking down CAMKK2 levels, we have identified a number of significant subcellular changes indicative of perturbations in vesicle trafficking within the endomembrane compartment. To determine how they might contribute to effects on cell proliferation, we have used proteomics to identify Gemin4 as a direct interactor, capable of binding CAMKK2 and COPI subunits. Prompted by this, we confirmed that CAMKK2 knockdown leads to concomitant and significant reductions in δ-COP protein. Using imaging, we show that CAMKK2 knockdown leads to Golgi expansion, the induction of ER stress, abortive autophagy and impaired lysosomal acidification. All are phenotypes of COPI depletion. Based on our findings, we hypothesise that CAMKK2 sustains cell proliferation in large part through effects on organelle integrity and membrane trafficking.Subject terms: Prostate cancer, Golgi     

Use of auditory learning to manage listening problems in children

This paper reviews recent studies that have used adaptive auditory training to address communication problems experienced by some children in their everyday life. It considers the auditory contribution to developmental listening and language problems and the underlying principles of auditory learning that may drive further refinement of auditory learning applications. Following strong claims that language and listening skills in children could be improved by auditory learning, researchers have debated what aspect of training contributed to the improvement and even whether the claimed improvements reflect primarily a retest effect on the skill measures. Key to understanding this research have been more circumscribed studies of the transfer of learning and the use of multiple control groups to examine auditory and non-auditory contributions to the learning. Significant auditory learning can occur during relatively brief periods of training. As children mature, their ability to train improves, but the relation between the duration of training, amount of learning and benefit remains unclear. Individual differences in initial performance and amount of subsequent learning advocate tailoring training to individual learners. The mechanisms of learning remain obscure, especially in children, but it appears that the development of cognitive skills is of at least equal importance to the refinement of sensory processing. Promotion of retention and transfer of learning are major goals for further research.     

MHC class II polymorphism is associated with a canine SLE-related disease complex

Nova Scotia duck tolling retrievers are predisposed to a SLE-related disease complex including immune-mediated rheumatic disease (IMRD) and steroid-responsive meningitis–arteritis (SRMA). IMRD involves symptoms that resemble those seen in systemic autoimmune rheumatic diseases, such as systemic lupus erythematosus, SLE, or SLE-related diseases, in humans. This disease complex involves persistent lameness, stiffness, mainly after resting, and palpable pain from several joints of extremities. The majority of affected dogs display antinuclear autoantibody (ANA)-reactivity. SRMA is manifested in young dogs with high fever and neck stiffness and can be treated with corticosteroids. We have investigated the possible role of MHC class II as a genetic risk factor in IMRD and SRMA etiology. We performed sequence-based typing of the DLA-DRB1, -DQA1, and -DQB1 class II loci in a total of 176 dogs including 51 IMRD (33 ANA-positive), 49 SRMA cases, and 78 healthy controls (two dogs were both IMRD- and SRMA-affected). Homozygosity for the risk haplotype DRB1*00601/DQA1*005011/DQB1*02001 increased the risk for IMRD (OR?=?4.9; ANA-positive IMRD: OR?=?7.2) compared with all other genotypes. There was a general heterozygote advantage, homozygotes had OR?=?4.4 (ANA-positive IMRD: OR?=?8.9) compared with all heterozygotes. The risk haplotype contains the five amino acid epitope RARAA, known as the shared epitope for rheumatoid arthritis. No association was observed for SRMA. We conclude that DLA class II is a highly significant genetic risk factor for ANA-positive IMRD. The results indicate narrow diversity of DLA II haplotypes and identify an IMRD-related risk haplotype, which becomes highly significant in homozygous dogs.