Cargo adaptors regulate stepping and force generation of mammalian dynein-dynactin.

Cytoplasmic dynein is an ATP-driven motor that transports intracellular cargos along microtubules. Dynein adopts an inactive conformation when not attached to a cargo, and motility is activated when dynein assembles with dynactin and a cargo adaptor. It was unclear how active dynein-dynactin complexes step along microtubules and transport cargos under tension. Using single-molecule imaging, we showed that dynein-dynactin advances by taking 8 to 32-nm steps toward the microtubule minus end with frequent sideways and backward steps. Multiple dyneins collectively bear a large amount of tension because the backward stepping rate of dynein is insensitive to load. Recruitment of two dyneins to dynactin increases the force generation and the likelihood of winning against kinesin in a tug-of-war but does not directly affect velocity. Instead, velocity is determined by cargo adaptors and tail-tail interactions between two closely packed dyneins. Our results show that cargo adaptors modulate dynein motility and force generation for a wide range of cellular functions

The stimulating effects of ethanol on ventral tegmental area dopamine neurons projecting to the ventral pallidum and medial prefrontal cortex in female Wistar rats: regional difference and involvement of serotonin-3 receptors

RATIONALE: The ventral tegmental area (VTA) mediates the local stimulating effects of ethanol (EtOH) in a region-dependent manner, with EtOH administration in the posterior but not anterior VTA stimulating the mesolimbic system. The serotonin-3 (5-HT(3)) receptor has been involved in the effects of EtOH on the mesolimbic system. OBJECTIVES: The current study tested the hypothesis that EtOH would stimulate mesopallidal and mesocortical dopamine neurons in the posterior but not anterior VTA and that the stimulating effects of EtOH in the VTA would involve activation of local 5-HT(3) receptors. METHODS: Wistar female rats were surgically implanted with two cannulae, one in one sub-region of the VTA for microinjection and the other in the ventral pallidum (VP) or medial prefrontal cortex (mPFC) for microdialysis. Artificial cerebrospinal fluid or EtOH (200 mg%; 44 mM) was microinjected in the anterior or posterior VTA, and extracellular dopamine was measured in the VP or mPFC with microdialysis-HPLC. RESULTS: EtOH injections in the posterior but not anterior VTA significantly increased extracellular dopamine levels in the VP and mPFC. Co-injections of the 5-HT(3) receptor antagonist ICS-205,930 with EtOH in the posterior VTA significantly reduced the effects of EtOH on extracellular dopamine levels in the VP and mPFC. CONCLUSIONS: The results indicate that posterior VTA dopamine neurons projecting to the VP and mPFC are stimulated by local administration of EtOH and that the local stimulating effects of EtOH are mediated, at least in part, by 5-HT(3) receptors

CB1 Receptors Regulate Alcohol-Seeking Behavior and Alcohol Self-administration of Female Alcohol-Preferring (P) Rats

Rationale The endogenous cannabinoid (CB) system mediates a number of behaviors associated with drug-seeking and drug self-administration. In this study the effects of CB1 receptor manipulations on operant ethanol (EtOH) responding during EtOH-seeking, EtOH- relapse as well as on-going EtOH self-administration were determined. Methods Alcohol-preferring (P) rats were trained in 2-lever operant chambers to self-administer 15% EtOH (v/v) and water on a concurrent fixed-ratio 5 – fixed-ratio 1 (FR5-FR1) schedule of reinforcement in daily 1-hr sessions. After 10 weeks, rats underwent 7 extinction sessions, followed by 2 weeks in their home cages without access to EtOH or operant chambers. Rats were then returned to the operant chambers for testing of EtOH-seeking behavior (no EtOH present) for 4 sessions. After a week in their home cages following the EtOH-seeking test, rats were returned to the operant chambers with access to EtOH and water (relapse). Rats were then maintained in the operant chambers for daily 1-hr sessions with access to 15% EtOH and water for several weeks. Results The CB1 receptor antagonist (SR141716A), at doses of 1 and 2 mg/kg, i.p. reduced EtOH-seeking and transiently reduced EtOH self-administration during relapse and maintenance. Conversely, treatment with the CB1 receptor agonist CP, 55-940, at doses of 1 and 10 μg/kg i.p., increased EtOH-seeking and EtOH self-administration during relapse. Conclusions The results of this study demonstrate that activation of CB1 receptors are involved in regulating EtOH-seeking as well as the reinforcing effects of EtOH under relapse and on-going self-administration conditions

Effects of Alcohol and Saccharin Deprivations on Concurrent Ethanol and Saccharin Operant Self-Administration by Alcohol-Preferring (P) Rats

Consumption of sweet solutions has been associated with a reduction in withdrawal symptoms and alcohol craving in humans. The objective of the present study was to determine the effects of EtOH and saccharin (SACC) deprivations on operant oral self-administration. P rats were allowed to lever press concurrently self-administer EtOH (15% v/v) and SACC (0.0125% g/v) for 8 weeks. Rats were then maintained on daily operant access (non-deprived), deprived of both fluids (2 weeks), deprived of SACC and given 2 ml of EtOH daily, or deprived of EtOH and given 2 ml of SACC daily. All groups were then given two weeks of daily operant access to EtOH and SACC, followed by an identical second deprivation period. P rats responded more for EtOH than SACC. All deprived groups increased responding on the EtOH lever, but not on the SACC lever. Daily consumption of 2 ml EtOH decreased the duration of the ADE. Home cage access to 2 ml SACC also decreased the ADE but to a lesser extent than access to EtOH. A second deprivation period further increased and prolonged the expression of an ADE. These results show EtOH is a more salient reinforcer than SACC. With concurrent access to EtOH and SACC, P rats do not display a saccharin deprivation effect. Depriving P rats of both EtOH and SACC had the most pronounced effect on the magnitude and duration of the ADE, suggesting that there may be some interactions between EtOH and SACC in their CNS reinforcing effects

Nicotine Modulates Alcohol-Seeking and Relapse by Alcohol-Preferring (P) Rats in a Time Dependent Manner

Background— Alcohol is frequently co-abused with smoking. In humans, nicotine use can increase alcohol craving and consumption. The objectives of the current study were to assess the acute effects of nicotine on alcohol seeking and relapse at two different time points. Method— Adult female alcohol-preferring (P) rats were trained in 2-lever operant chambers to self-administer 15% EtOH (v/v) and water on a concurrent fixed-ratio 5 – fixed-ratio 1 (FR5-FR1) schedule of reinforcement in daily 1-hr sessions. Following 10 weeks of daily 1-hr sessions, rats underwent 7 extinction sessions, followed by 2 weeks in their home cages. Rats were then returned to the operant chambers without EtOH or water being present for 4 sessions (Pavlovian Spontaneous Recovery [PSR]). Rats were then given a week in their home cage before being returned to the operant chambers with access to EtOH and water (relapse). Nicotine (0, 0.1, 0.3, or 1.0 mg/kg) was injected s.c. immediately or 4-hr prior to PSR or relapse testing. Results— Injections of nicotine immediately prior to testing reduced (5–10 responses PSR; 50– 60 responses relapse), whereas injections of nicotine 4-hr prior to testing increased (up to 150 responses for PSR; up to 400 responses for relapse with 1.0 mg/kg dose) responses on the EtOH lever during PSR and relapse tests. Discussion— The results of this study demonstrate that acute effects of nicotine on EtOH- seeking and relapse behaviors may be time-dependent, with the immediate effects being a result of nicotine possibly acting as a substitute for EtOH whereas, with a delay of 4-hr, priming effects of nicotine alterations in nicotinic receptors, and/or the effects of nicotine’s metabolites (i.e., cotinine, nornicotine) may enhance the expression of EtOH-seeking and relapse behaviors

An Application of a Service-oriented System to Support ArrayAnnotation in Custom Chip Design for Epigenomic Analysis

We present the implementation of an application using caGrid, which is the service-oriented Grid software infrastructure of the NCI cancer Biomedical Informatics Grid (caBIGTM), to support design and analysis of custom microarray experiments in the study of epigenetic alterations in cancer. The design and execution of these experiments requires synthesis of information from multiple data types and datasets. In our implementation, each data source is implemented as a caGrid Data Service, and analytical resources are wrapped as caGrid Analytical Services. This service-based implementation has several advantages. A backend resource can be modified or upgraded, without needing to change other components in the application. A remote resource can be added easily, since resources are not required to be collected in a centralized infrastructure

Schoolgirls’ experience and appraisal of menstrual absorbents in rural Uganda: a cross-sectional evaluation of reusable sanitary pads

BACKGROUND: Governments, multinational organisations, and charities have commenced the distribution of sanitary products to address current deficits in girls’ menstrual management. The few effectiveness studies conducted have focused on health and education outcomes but have failed to provide quantitative assessment of girls’ preferences, experiences of absorbents, and comfort. Objectives of the study were, first, to quantitatively describe girls’ experiences with, and ratings of reliability and acceptability of different menstrual absorbents. Second, to compare ratings of freely-provided reusable pads (AFRIpads) to other existing methods of menstrual management. Finally, to assess differences in self-reported freedom of activity during menses according to menstrual absorbent. // METHODS: Cross-sectional, secondary analysis of data from the final survey of a controlled trial of reusable sanitary padand puberty education provision was undertaken. Participants were 205 menstruating schoolgirls from eight schools in rural Uganda. 72 girls who reported using the intervention-provided reusable pads were compared to those using existing improvised methods (predominately new or old cloth). // RESULTS: Schoolgirls using reusable pads provided significantly higher ratings of perceived absorbent reliability across activities, less difficulties changing absorbents, and less disgust with cleaning absorbents. There were no significant differences in reports of outside garment soiling (OR 1.00 95%CI 0.51–1.99), or odour (0.84 95%CI 0.40–1.74) during the last menstrual period. When girls were asked if menstruation caused them to miss daily activities there were no differences between those using reusable pads and those using other existing methods. However, when asked about activities avoided during menstruation, those using reusable pads participated less in physical sports, working in the field, fetching water, and cooking. // CONCLUSIONS: Reusable pads were rated favourably. This translated into some benefits for self-reported involvement in daily activities, although reports of actual soiling and missing activities due to menstruation did not differ. More research is needed comparing the impact of menstrual absorbents on girls’ daily activities, and validating outcome measures for menstrual management research

GridIMAGE: A Novel Use of Grid Computing to Support Interactive Human and Computer-Assisted Detection Decision Support

This paper describes a Grid-aware image reviewing system (GridIMAGE) that allows practitioners to (a) select images from multiple geographically distributed digital imaging and communication in medicine (DICOM) servers, (b) send those images to a specified group of human readers and computer-assisted detection (CAD) algorithms, and (c) obtain and compare interpretations from human readers and CAD algorithms. The currently implemented system was developed using the National Cancer Institute caGrid infrastructure and is designed to support the identification of lung nodules on thoracic computed tomography. However, the infrastructure is general and can support any type of distributed review. caGrid data and analytical services are used to link DICOM image databases and CAD systems and to interact with human readers. Moreover, the service-oriented and distributed structure of the GridIMAGE framework enables a flexible system, which can be deployed in an institution (linking multiple DICOM servers and CAD algorithms) and in a Grid environment (linking the resources of collaborating research groups). GridIMAGE provides a framework that allows practitioners to obtain interpretations from one or more human readers or CAD algorithms. It also provides a mechanism to allow cooperative imaging groups to systematically perform image interpretation tasks associated with research protocols

Menstruation and the cycle of poverty: a cluster quasi-randomised control trial of sanitary pad and puberty education provision in Uganda

BACKGROUND: Poor menstrual knowledge and access to sanitary products have been proposed as barriers to menstrual health and school attendance. In response, interventions targeting these needs have seen increasing implementation in public and private sectors. However, there has been limited assessment of their effectiveness. // OBJECTIVES: Assess the impact of providing reusable sanitary pads and puberty education on girls’ school attendance and psychosocial wellbeing outcomes. // METHODS: A cluster quasi-randomised controlled trial was conducted across 8 schools, including 1124 girls, in rural Uganda. Schools were allocated to one of four conditions: the provision of puberty education alone; reusable sanitary pads alone; puberty education and reusable sanitary pads; and a control (no intervention). The primary outcome was school attendance. Secondary outcomes reflected psychosocial wellbeing. // RESULTS: At follow-up, school attendance had worsened for girls across all conditions. Per-protocol analysis revealed that this decline was significantly greater for those in the control condition d = 0.52 (95%CI 0.26–0.77), with those in control schools having a 17.1% (95%CI: 8.7–25.5) greater drop in attendance than those in any intervention school. There were no differences between the intervention conditions. High rates of school drop-out and transfer meant the trial suffered from substantial participant drop-out. Intention-to-treat analyses using two different imputation strategies were consistent with the main results, with mean differences of 5.2% attendance in best-case and 24.5% in worst-case imputations. Results were robust to adjustments for clustering. There was no impact of the interventions on girls’ self-reported shame or insecurity during menstruation. // CONCLUSION: Results of the trial support the hypothesised positive impact of providing sanitary pads or puberty education for girls’ school attendance in a developing country context. Findings must be interpreted with caution in light of poor participant retention, intervention fidelity, and the attendance measures used

'The girl with her period is the one to hang her head' Reflections on menstrual management among schoolgirls in rural Kenya

<p>Abstract</p> <p>Background</p> <p>The onset of menstruation is a landmark event in the life of a young woman. Yet the complications and challenges that can accompany such an event have been understudied, specifically in resource-poor settings. As interventions aim to improve female attendance in schools, it is important to explore how menstruation is perceived and navigated by girls in the school setting. This research conveys rural Kenyan schoolgirls' perceptions and practices related to menstruation</p> <p>Methods</p> <p>Data were collected at six rural schools in the Nyanza Province of Western Kenya. Using focus group discussions, in-depth interviews, and field notes from observations, researchers collected information from 48 primary schoolgirls and nine teachers. Systematic analysis began with a reading of transcripts and debriefing notes, followed by manual coding of the narratives.</p> <p>Results</p> <p>Focus group discussions became opportunities for girls to share thoughts on menstruation, instruct one another on management practices and advise one another on coping mechanisms. Girls expressed fear, shame, distraction and confusion as feelings associated with menstruation. These feelings are largely linked to a sense of embarrassment, concerns about being stigmatized by fellow students and, as teachers explained, a perception that the onset of menstruation signals the advent of a girl's sexual status. Among the many methods for managing their periods, girls most frequently said they folded, bunched up or sewed cloth, including cloth from shirts or dresses, scraps of old cloth, or strips of an old blanket. Cloth was reported to frequently leak and cause chafing, which made school attendance difficult particularly as the day progressed. Attitudes and practices of girls toward menstruation have been arranged into personal, environmental and behavioural factors.</p> <p>Conclusion</p> <p>Further research on menstrual management options that are practical, sustainable and culturally acceptable must be conducted to inform future programs and policies that aim to empower young girls as they transition into womanhood. Stakeholders working within this and similar contexts must consider systematic mechanisms to explain to young girls what menstruation is and how to manage it. Providing sanitary supplies or guiding girls on how to create supplies serve as critical components for future interventions.</p