Motor learning without physical practice: The effects of combined action observation and motor imagery practice on cup-stacking speed.

In this study we explored training effects for combined action observation and motor imagery (AO + MI) instructions on a complex cup-stacking task, without physical practice. Using a Graeco-Latin Square design, we randomly assigned twenty-six participants into four groups. This counterbalanced the within-participant factor of practice condition (AO + MI, AO, MI, Control) across four cup-stacking tasks, which varied in their complexity. On each of the three consecutive practice days participants experienced twenty trials under each of the three mental practice conditions. On each trial, a first-person perspective video depicted bilateral cup-stacking performed by an experienced model. During AO, participants passively observed this action, responding only to occasional colour cues. For AO + MI, participants imagined performing the observed action and synchronised their concurrent MI with the display. For MI, a sequence of pictures cued imagery of each stage of the task. Analyses revealed a significant main effect of practice condition both at the 'surprise' post-test (Day 3) and at the one-week retention test. At both time points movement execution times were significantly shorter for AO + MI compared with AO, MI and the Control. Execution times were also shorter overall at the retention compared with the post-test. These results demonstrate that a complex novel motor task can be acquired without physical training. Practitioners can therefore use AO + MI practice to supplement physical practice and optimise skill learning.

The Effects of Biofeedback on Performance and Technique of the Boxing Jab.

A growing body of research has addressed the application of movement-based biofeedback techniques for improving sports performers' gross motor skills. Unlike in previous research, we aimed in this study to quantify the effects of this "external" biofeedback on selected performance and technique variables for the boxing jab among both novices and experts. The technical setup included two inertial measurement units linked wirelessly to a video game system with audio output. The units were configured to provide auditory external biofeedback, based on the peak acceleration of the bag (i.e., biofeedback with an external attentional focus). Sixteen participants (8 novices and 8 experts) performed boxing jabs against the bag in blocked phases of biofeedback. When compared to baseline, the acute effects of externally focused biofeedback on peak bag acceleration were possibly positive in both retention phases for novices (d = 0.29; d = 0.41) and likely positive for experts (d = 0.41; d = 0.30), respectively. The experts' performance improvements were accompanied by substantive increases in trunk rotation, though this was not true for the novices. Thus, technique improvements can be promoted indirectly via externally focused biofeedback, but only when these actions are within the performers' motor repertoire. Overall, biofeedback via inertial sensors appears to be a potent technique for modifying human movement patterns in both experts and novices. This low-cost technology could be used to support training across sports, rehabilitation and human-computer interactions.

EEG and behavioural correlates of different forms of motor imagery during action observation in rhythmical actions.

Recent studies show that participants can engage in motor imagery (MI) and action observation (AO) simultaneously (AO+MI), indicating a capacity for dual action simulation. Here we studied the electrophysiological correlates and behavioural outcomes of two forms of AO+MI, along with pure MI and pure AO control conditions. In synchronised AO+MI, participants imagined performing a rhythmical action in synchrony with an observed distractor action. In contrast in static AO+MI, where the imagery served to conflict with AO, participants imagined holding a static hand posture during AO. Following synchronised AO+MI, rhythmical execution was strongly biased toward the cycle time of the previously observed rhythm ('imitation bias'), whereas a weaker bias was found following pure MI, and particularly for static AO+MI. In line with these findings, event-related desynchronisation (ERD) in primary sensorimotor and parietal regions was more pronounced in synchronised AO+MI compared to both pure AO and pure MI. These ERD amplitudes were, however, highly similar for static and synchronised AO+MI; suggesting that, regardless of co-represented content, both AO+MI states produced stronger motor activations than single action simulation. In contrast, synchronised AO+MI produced significantly stronger ERD in rostral prefrontal cortex compared to the other three conditions. This specific rostral prefrontal involvement most likely reflected additional cognitive processing for aligning dual action simulations. Together these results provide an important empirical validation of different AO+MI states, in that the imitation bias was strongly modulated by the content of the AO+MI instructions, and that synchronised AO+MI produced stronger behavioural and neurophysiological effects compared to pure AO or MI.

MAF mediates crosstalk between Ras-MAPK and mTOR signaling in NF1.

Mutations in the neurofibromatosis type 1 (NF1) tumor suppressor gene are common in cancer and can cause resistance to therapy. Using transcriptome analysis we identified MAF as an NF1- regulated transcription factor and verified MAF regulation through RAS/MAPK/AP-1 signaling in malignant peripheral nerve sheath tumor (MPNST) cell lines. MAF was also downregulated in human MPNST. Acute re-expression of MAF promoted expression of glial differentiation markers in MPNST cells in vitro, decreased self-renewal of embryonic precursors and transiently affected tumor cell phenotypes in vitro by increasing MPNST cell death and reducing metabolic activity and anchorage-independent growth. Paradoxically, chronic MAF overexpression enhanced MPNST cell tumor growth in vivo, correlating with elevated pS6 in vitro and in vivo. RAD001 blocked MAF-mediated tumor growth, and MAF regulated the mTOR pathway through DEPTOR. MAPK inhibition with NF1 loss of function is predicted to show limited efficacy due to reactivation of mTOR signaling via MAF.

EGFR-STAT3 signaling promotes formation of malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumors (MPNSTs) develop sporadically or in the context of neurofibromatosis type 1. Epidermal growth factor receptor (EGFR) overexpression has been implicated in MPNST formation, but its precise role and relevant signaling pathways remain unknown. We found that EGFR overexpression promotes mouse neurofibroma transformation to aggressive MPNST (GEM-PNST). Immunohistochemistry demonstrated phosphorylated STAT3 (Tyr705) in both human MPNST and mouse GEM-PNST. A specific JAK2/STAT3 inhibitor FLLL32 delayed MPNST formation in an MPNST xenograft nude mouse model. STAT3 knockdown by shRNA prevented MPNST formation in vivo. Finally, reducing EGFR activity strongly reduced pSTAT3 in vivo. Thus, an EGFR-STAT3 pathway is necessary for MPNST transformation and establishment of MPNST xenografts growth but not for tumor maintenance. Efficacy of the FLLL32 pharmacological inhibitor in delaying MPNST growth suggests that combination therapies targeting JAK/STAT3 might be useful therapeutics.

Upregulated vimentin suggests new areas of neurodegeneration in a model of an alcohol use disorder.

Excessive alcohol intake, characteristic of an alcohol use disorder (AUD), results in neurodegeneration as well as cognitive deficits that may recover in abstinence. Neurodegeneration in psychiatric disorders such as AUDs is due to various effects on tissue integrity. Several groups report that alcohol-induced neurodegeneration and recovery include a role for adult neurogenesis. Therefore, the initial purpose of this study was to investigate the effect of alcohol on the temporal profile of neural progenitor cells using the radial glia marker, vimentin, in a model of an AUD. However, striking vimentin expression throughout corticolimbic regions led, instead, to the discovery of a significant gliosis response in this model. Adult male rats were subjected to a 4-day binge model of an AUD and brains harvested for immunohistochemistry at 0, 2, 4, 7, 14, and 28 days following the last dose of ethanol. A prominent increase in vimentin immunoreactivity was apparent at 4 and 7 days post binge that returned to control levels by 14 days in the corticolimbic regions examined. Vimentin-positive cells co-labeled with glial fibrillary acidic protein (GFAP), which suggested that cells were reactive astrocytes. A second experiment supported that increased vimentin was not primarily due to alcohol withdrawal seizures and is more likely due to alcohol-induced cell death. As this gliosis was remarkably distinct in regions where cell death had not previously been reported in this model, adjacent tissue sections were processed for FluoroJade B staining for cell death. FluoroJade B-positive cells were evident immediately following the last ethanol dose as expected, but were significantly elevated in the hippocampal dentate gyrus and CA3 regions and corticolimbic regions from 2 to 7 days post binge. Intriguingly, vimentin labeling of astrogliosis is more widespread than FluoroJade B labeling of cell death, which suggests that 4-day binge ethanol consumption is more damaging than originally realized.

The Escherichia coli CcmG protein fulfils a specific role in cytochrome c assembly.

In Escherichia coli K-12, c-type cytochromes are synthesized only during anaerobic growth with trimethylamine-N-oxide, nitrite or low concentrations of nitrate as the terminal electron acceptor. A thioredoxin-like protein, CcmG, is one of 12 proteins required for their assembly in the periplasm. Its postulated function is to reduce disulphide bonds formed between correctly paired cysteine residues in the cytochrome c apoproteins prior to haem attachment by CcmF and CcmH. We report that loss of CcmG synthesis by mutation was not compensated by a second mutation in disulphide-bond-forming proteins, DsbA or DsbB, or by the chemical reductant, 2-mercaptoethanesulphonic acid. An anti-CcmG polyclonal antibody was used in Western-blot analysis to probe the redox state of CcmG in mutants defective in the synthesis of other proteins essential for cytochrome c assembly. The oxidized form of CcmG accumulated not only in trxA or dipZ mutants defective in the transfer of electrons from the cytoplasm for disulphide isomerization and reduction reactions in the periplasm, but also in ccmF and ccmH mutants. The requirement of both CcmF and CcmH for the reduction of the disulphide bond in CcmG indicates that CcmG functions later than CcmF and CcmH in cytochrome c assembly, rather than in electron transfer from the membrane-associated DipZ (also known as DsbD) to CcmH. The data support a model proposed by others in which CcmG catalyses one of the last reactions specific to cytochrome c assembly.

An examination of the concept of equity and the implications for health policy if equity is re-asserted as one of the key government objectives for the National Health Service.

AIM: To gain a full understanding of the concept of equity and means of promoting and monitoring a more equitable healthservice. BACKGROUND: With previous policy decisions having sidelined equity, a new government is likely to wish to reverse this trend. ORIGINS OF INFORMATION: Government and expert opinion. DATA ANALYSIS: A critical approach to previous literature. KEY ISSUES: Equity is not a unitary concept and so it is explored and dissected using the framework of: Distribution of Resources, Access and Uptake of Healthcare, Standards and Outcomes of Healthcare, Health Status. Means of improving and monitoring equity in these four areas are suggested. CONCLUSIONS: There are a number of ways of considering the concept of equity and for any fruitful discussion to occur there needs to be an agreed working definition. Specific topics are discussed where equity is lacking and a plan of action is suggested which is likely to improve equity in the areas identified.

The CcmE protein from Escherichia coli is a haem-binding protein.

We previously reported that a 17.5-kDa haem-binding polypeptide accumulates in Escherichia coli K-12 mutants defective in an essential gene for cytochrome c assembly, ccmF, and speculated that this polypeptide is either CcmE or CcmG. The haem-containing polypeptide, which is associated with the cytoplasmic membrane, has now been identified by N-terminal sequencing to be CcmE. The haem-dependent peroxidase activity of CcmE is clearly visible not only in a ccmF mutant, but also in ccmG and ccmH mutants, implying that CcmE functions either before or in the same step as CcmF, CcmG and CcmH in cytochrome c maturation. A trxA mutant, like the dipZ mutant, was unable to assemble c-type cytochromes or catalyse formate-dependent nitrite reduction: both activities were restored in the trxA and dipZ, but not ccmG, mutants by the reducing agent, 2-mercaptoethanesulphonic acid. Our data suggest that haem transferred across the cytoplasmic membrane by the CcmABCD complex becomes associated with CcmE, possibly by a labile covalent bond, before it is transferred to the cytochrome c apoproteins by the periplasmic haem lyase encoded by ccmF and ccmH. We further propose that CcmG is essential to reduce the disulphide bonds formed in cytochrome c apoproteins by DsbA, before haem is attached by the haem lyase. Electrons for disulphide bond reduction are supplied from thioredoxin in the cytoplasm via DipZ in the membrane, but can be replaced by the chemical reductant, 2-mercaptoethanesulphonic acid. According to this model, CcmG is the last protein in the reducing pathway which interacts stereospecifically with the apoprotein.

Involvement of products of the nrfEFG genes in the covalent attachment of haem c to a novel cysteine-lysine motif in the cytochrome c552 nitrite reductase from Escherichia coli.

Cytochrome c552 is the terminal component of the formate-dependent nitrite reduction pathway of Escherichia coli. In addition to four 'typical' haem-binding motifs, CXXCH-, characteristic of c-type cytochromes, the N-terminal region of NrfA includes a motif, CWSCK. Peptides generated by digesting the cytochrome from wild-type bacteria with cyanogen bromide followed by trypsin were analysed by on-line HPLC MS/MS in parent scanning mode. A strong signal at mass 619, corresponding to haem, was generated by fragmentation of a peptide of mass 1312 that included the sequence CWSCK. Neither this signal nor the haem-containing peptide of mass 1312 was detected in parallel experiments with cytochrome that had been purified from a transformant unable to synthesize NrfE, NrfF and NrfG: this is consistent with our previous report that NrfE and NrfG (but not NrfF) are essential for formate-dependent nitrite reduction. Redox titrations clearly revealed the presence of high and low mid-point potential redox centres. The best fit to the experimental data is for three n=1 components with mid-point redox potentials (pH 7.0) of +45 mV (21% of the total absorbance change), -90 mV (36% of the total) and -210mV (43% of the total). Plasmids in which the lysine codon of the cysteine-lysine motif, AAA, was changed to the histidine codon CAT (to create a fifth 'typical' haem c-binding motif), or to the isoleucine and leucine codons, ATT and CTT, were unable to transform a Nrf deletion mutant to Nrf+ or to restore formate-dependent nitrite reduction to the transformants. The presence of a 50 kDa periplasmic c-type cytochrome was confirmed by staining proteins separated by SDS-PAGE for covalently bound haem, but the methyl-viologen-dependent nitrite reductase activities associated with the mutated proteins, although still detectable, were far lower than that of the native protein. The combined data establish not only that there is a haem group bound covalently to the cysteine-lysine motif of cytochrome c552 but also that one or more products of the last three genes of the nrf operon are essential for the haem ligation to this motif.

The product of the molybdenum cofactor gene mobB of Escherichia coli is a GTP-binding protein.

The mob mutants of Escherichia coli are pleiotropically defective in molybdoenzyme activities because they are unable to catalyse the conversion of molybdopterin guanine dinucleotide, the active form of the molybdenum cofactor. The mob locus comprises two genes. The product of mobA, protein FA, has previously been purified to homogeneity and is able to restore molybdoenzyme activities following incubation with cell extracts of mob strains. The mobB gene, although not essential for the biosynthesis of active molybdoenzymes, encodes a protein which, sequence analysis strongly suggests, contains a nucleotide-binding site. We have overproduced the products of both the mobA and mobB genes in engineered E. coli strains and purified each to homogeneity. The preparation of protein FA (MobA) is simpler than that previously published and produces a much greater yield of active protein. The isolated MobB protein, which is dimeric in solution, acts in the presence of protein FA, to enhance the level of nitrate reductase activation achieved on incubation with mob cell extracts. Equilibrium dialysis experiments show that purified MobB binds 0.83 mol GTP/mol protein with a Kd of 2.0 microM. Isolated MobB also catalyses a low GTPase activity (turnover number of 3 x 10(-3) min-1) with a K(m) for GTP to GDP of 7.5 microM. Under the conditions tested, protein FA did not affect the GTP-binding or GTPase activity of MobB. Intrinsic (tryptophan) protein fluorescence measurements show that MobB also binds the nucleotides ATP, TTP and GDP, but with lower affinity than GTP. These results are consistent with a model whereby MobB binds the guanine nucleotide which is attached to molybdopterin during the biosynthesis of the molybdenum cofactor.

Involvement of the narJ and mob gene products in distinct steps in the biosynthesis of the molybdoenzyme nitrate reductase in Escherichia coli.

The Escherichia coli mob locus is required for synthesis of active molybdenum cofactor, molybdopterin guanine dinucleotide. The mobB gene is not essential for molybdenum cofactor biosynthesis because a deletion of both mob genes can be fully complemented by just mobA. Inactive nitrate reductase, purified from a mob strain, can be activated in vitro by incubation with protein FA (the mobA gene product), GTP, MgCl2, and a further protein fraction, factor X. Factor X activity is present in strains that lack MobB, indicating that it is not an essential component of factor X, but over-expression of MobB increases the level of factor X. MobB, therefore, can participate in nitrate reductase activation. The narJ protein is not a component of mature nitrate reductase but narJ mutants cannot express active nitrate reductase A. Extracts from narJ strains are unable to support the in vitro activation of purified mob nitrate reductase: they lack factor X activity. Although the mob gene products are necessary for the biosynthesis of all E. coli molybdoenzymes as a result of their requirement for molybdopterin guanine dinucleotide, NarJ action is specific for nitrate reductase A. The inactive nitrate reductase A derivative in a narJ strain can be activated in vitro following incubation with cell extracts containing the narJ protein. NarJ acts to activate nitrate reductase after molybdenum cofactor biosynthesis is complete.

Suicide following homicide in the family.

Previous research has established that perpetrators of homicide-suicide share more characteristics with those who commit suicide than they do with those who commit homicide without suicide. This article examines the characteristics of victims, perpetrators and the circumstances leading to the homicide of a sample of familial homicide-suicides and familial homicides in southwest British Columbia. A familial homicide was defined as one in which the victim and perpetrator were related directly or indirectly through blood or an intimate relationship. Suicide only occurred following the killing of an intimate partner and/or offspring. Consistent with an evolutionary perspective, homicides followed by suicide were most often attributable to male proprietariness (manifested by killing former intimate partners or offspring following an intimate separation) or mental illness. By contrast, none of the murders which occurred as a result of violence by the victim, child abuse, family conflict, or financial/criminal motives was followed by suicide.

Mental health research in the criminal justice system: The need for common approaches and international perspectives.

There is a need for researchers and policy makers in the area of mental health and law to collaborate and develop common methods of approach to research. Although we have learned a great deal about the prevalence and needs of mentally ill offenders in jails and prisons, there are a number of research questions that remain. If the "second generation" of research is to be fruitful--and useful to policy makers--we need to be sure that the methods we employ are valid and that the findings we obtain are reliable. By collaborating with colleagues in other jurisdictions, we can begin to learn whether some of the existing findings are of a general nature, or dependent upon the system in which they were found. Similarly, while the first-generation research has alerted us to the needs of mentally ill offenders in jails and prisons, second-generation research is needed to help identify factors that may help prevent the "revolving door phenomenon," which results in mentally ill people being volleyed among mental health, criminal justice, and community settings. One area that has received embarrassingly little attention has been the need for considering the relationship between substance abuse and mental disorders. In our own work, we have found an alarmingly high degree of substance abuse among offenders, including mentally ill offenders. We have come to realize the importance of considering the role that substance abuse coupled with other mental disorders may play in the criminal justice system. As a result of this concern, the Surrey Mental Health Project recently hired a full-time drug and alcohol counselor whose job it is to work with inmates with substance abuse disorders while in the jail, and to help arrange continuing treatment resources upon their release. As Wilson et al. (1995) discuss, intensive case management projects may be particularly useful at targeting the unique needs of mentally ill offenders with multiple problems. Much of the research conducted with mentally ill offenders to date has focused primarily upon psychological and psychiatric questions--questions that are, as Hodgins (1995) indicates, epidemiological in nature. More attention must be paid to that research by policy makers and others who work with mentally ill offenders in the criminal justice system. As Hoyer et al. (1995) and Gould (1995) make clear, a number of unique policy questions arise when considering mentally ill offenders in the legal system.(ABSTRACT TRUNCATED AT 400 WORDS)