bluuebunny/crossref_metadata_2025 huggingface dataset:
An autoethnography on shifting relationships between a daughter, her mother and Alzheimer’s dementia (in any order)
Authors: Malthouse Marina
Published: May 2011

This is an autoethnography written by a daughter whose mother developed Alzheimer’s dementia a few years ago. In the writing, a shifting nature of relationships is described between the daughter, her mother and the dementia. As a form of self-narrative where the author is placed within a social context, the writing within the autoethnography follows Ellis (1999) who suggests seeing through a wide-angled lens. This lens has been focused outwards and inwards with the aim of creating an evocative text about shifting relationships and dementia. In its construction, meaning has been extracted from these experiences that help the author to stay aware of these relationships that can shift even further as her mother’s dementia moves on in time.
‘Happiness being like a blooming flower’: An action research of rural social work in an ethnic minority community of Yunnan Province, PRC
Authors: Ku Benjamin Hok-Bun
Published: May 2011

The effects of rural reform and China’s integration into the global capitalist market have increased the vulnerability of the rural poor to financial hardship, loss of cultural identity, and other deprivations. In response to this situation, we initiated a pilot action research project in 2005 in an ethnic minority community in the Yunnan province of China. It encouraged local women to form a handicraft group to preserve and develop indigenous cultural artefacts and crafts which are available for market consumption. It aims, through capacity building, enhance the women’s income, promote a new form of collectivism, protect the Zhuang ethnic minority traditional culture, and strengthen local cultural identity and confidence. This article first describes the dilemma of China’s rural development and introduces our theoretical perspective. Then it demonstrates how we invigorated the community participation and facilitated the rural social work step by step.
Sleep opportunities and periodic light exposures: Impact on biomarkers, performance and sleepiness
Authors: Figueiro MG , Rea MS
Published: May 2011

A within-subjects study investigated the impact of sleep opportunities and periodic light exposures on biomarkers, performance and sleepiness over 27-hour sessions. Ten subjects experienced three experimental sleep sessions: No sleep; sleep for 3 hours; and sleep for 7 hours. Subjects remained in dim red light for every experimental session, except when they were exposed to 40 lux of 470-nm light at the cornea for 50 minutes. Saliva samples for biomarker assays, performance scores on psychomotor vigilance tests and self-reports of sleepiness were collected just prior to and at the end of the light exposures. All measures follow circadian patterns that mark the transitions between daytime and nighttime, but they have different forms and are differentially affected by light exposure, sleep and circadian time.
Safety and efficacy of saxagliptin in combination with submaximal sulphonylurea versus up-titrated sulphonylurea over 76 weeks
Authors: Chacra Antonio R , Tan Gerry H , Ravichandran Shoba , List James , Chen Roland ,   CV181040 Investigators
Published: May 2011

To assess the long-term efficacy and safety of saxagliptin in patients with type 2 diabetes mellitus inadequately controlled on sulphonylurea monotherapy, 768 patients were randomised to saxagliptin 2.5 or 5 mg in combination with glyburide 7.5 mg versus placebo added to up-titrated glyburide over 76 weeks (24 weeks plus 52-week extension) in this phase 3, double-blind, placebo-controlled trial; 557 patients completed the study, 142 without being rescued. At 76 weeks, adjusted mean changes from baseline HbA1C (repeated measures model) (95% confidence interval) for saxagliptin 2.5 mg, saxagliptin 5 mg, and up-titrated glyburide were 0.11% (-0.05, 0.27), 0.03% (-0.14, 0.19), and 0.69% (0.47, 0.92), respectively (post hoc and nominal p < 0.0001 for saxagliptin 2.5 and 5 mg vs. up-titrated glyburide). Adverse event frequency was similar in all treatment groups; reported hypoglycaemia event rates were 24.2%, 22.9%, and 20.6% with saxagliptin 2.5 mg, saxagliptin 5 mg, and up-titrated glyburide, respectively. Saxagliptin plus glyburide provided sustained incremental efficacy compared with up-titrated glyburide over 76 weeks, and was generally well tolerated.
Achievement of recommended lipid and lipoprotein levels with combined ezetimibe/statin therapy versus statin alone in patients with and without diabetes
Authors: Guyton John R , Betteridge D John , Farnier Michel , Leiter Lawrence A , Jianxin Lin  , Shah Arvind , Johnson-Levonas Amy O , Brudi Philippe
Published: May 2011

Treatment guidelines identify low-density lipoprotein cholesterol (LDL-C) as the primary target of therapy with secondary targets of non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (apoB). Data were pooled from 27 randomised, double-blind, active or placebo-controlled trials in 21,794 adult hypercholesterolaemic patients (LDL-C 1.81—6.48 mmol/L) receiving ezetimibe/statin or statin for 4—24 weeks. Percentages of patients achieving various targets were calculated among diabetes ( n = 6541) and non-diabetes ( n = 15,253) subgroups. Significantly more patients with and without diabetes achieved specified levels of LDL-C (< 2.59, < 1.99, < 1.81 mmol/L), non-HDL-C (< 3.37, < 2.59 mmol/L) and apoB (< 0.9, < 0.8 g/L) with ezetimibe/statin versus statin. Patients with diabetes had larger mean per cent reductions in LDL-C and non-HDL-C than non-diabetes patients. A greater percentage of patients achieved both the LDL-C and apoB targets and all three LDL-C, apoB, and non-HDL-C targets with ezetimibe/statin versus statin in both subgroups. Patients with diabetes benefitted at least as much as, and sometimes more than, non-diabetes patients following treatment with ezetimibe/statin.
Job Stress and Incivility
Authors: Roberts Sara J. , Scherer Lisa L. , Bowyer Casey J.
Published: May 2011

Uncivil behaviors are costly to organizations due to their resulting decrease in health, performance, and attendance among employees. The purpose of the present study is to examine whether job stress increases one’s tendency to display uncivil behaviors and whether psychological capital moderates this relationship. A total of 390 working adults completed a questionnaire assessing the level of stress at their current job, their level of psychological capital, and the extent to which they display uncivil behaviors at work. Results indicated that psychological capital buffers the effect of job stress on incivility.
Total testosterone in young men is more closely associated than free testosterone with prostate cancer disparities
Authors: Alvarado Louis Calistro
Published: May 2011

Introduction: Early adulthood has been suggested as the most relevant time to determine the influence of testosterone on prostate carcinogenesis. For a more detailed assessment of this hypothesis, the present study examined whether serum total or free testosterone in young men was more closely associated with prostate cancer disparities.

Methods: A literature search was conducted for studies that reported both total and free testosterone levels for population samples of young men, along with prostate cancer incidences for the populations from which study populations were sampled. A previously developed analytical method was used to standardize the hormone levels of 19 population samples gathered from nine studies, and these standardized values were compared with disparities in prostate cancer incidence.

Results: Population differences in total testosterone levels were significantly associated with prostate cancer disparities, r = 0.833, p = 0.001, as were population differences in free testosterone, r = 0.661, p = 0.027. After controlling for age differences, total and free testosterone remained associated with prostate cancer disparities, partial r = 0.888, p < 0.001, and partial r = 0.657, p = 0.039, respectively. A marginally significant difference existed in the strength of relationships between total and free testosterone with respect to prostate cancer disparities, with total testosterone exhibiting a stronger association, T2 = 1.573, p = 0.077.

Conclusions: Across analyses, total testosterone demonstrated a more robust relationship than free testosterone with cancer disparities, which may suggest that total testosterone is the more sensitive biomarker for evaluating androgenic stimulation of the prostate gland.
Implementing public health in secondary care: A Rotherham perspective on strategy development and implementation
Authors: Al-alawy Khamis , Roche Teresa , Alwali Walid
Published: May 2011

Aims: This paper reports an approach to develop and implement a public health strategy in secondary care and uses smoking cessation as a means for measuring success.

Methods: Rotherham Foundation Hospital Trust recognized its unique role to promote, prevent and protect health and well-being in Rotherham. Following consultation across key departments, the trust developed a public health strategy encompassing five priorities.

Results: We report ongoing commitment and engagement following the launch of the public health strategy. Over a period of one year (April 2008 to March 2009) 269 front-line staff were trained on smoking cessation brief interventions. We report 890 referrals to smoking cessation, resulting in 414 setting a quit date and 143 four-week quitters (35% conversion rate). Despite progress in implementing smoking cessation, more communication is required to ensure that GPs and hospital staff continue to maximize patient outcomes through brief interventions.

Conclusions: The paper provides an approach to implement public health in secondary care. The Commissioning for Quality and Innovation (CQUIN) payment framework would be a useful tool to ensure key public health areas such as smoking cessation are systemized in secondary care.
Planning to innovate. Designing change or caught up in a game?
Authors: Mowles Chris
Published: May 2011

In this article I engage with some orthodox theories of the management of innovation and change, which take for granted the idea that they can be predicted and controlled. Organizations are thought to be systems with boundaries, which managers acting as engineers, or doctors, can ‘diagnose’ and restore to ‘health’, or order differently. As an alternative, and by drawing on an experience of working with health service managers, I argue instead that change and innovation arise as a result of the interweaving of everyone’s intentions. Organizations are sites of intense political interaction and contestation, and exactly what emerges is unpredictable and unplannable, even by the most powerful individuals and groups.
GP consortia: Navigating ambiguity to produce greater public value?
Authors: Holbeche Linda
Published: May 2011

The UK’s NHS is about to be significantly remodelled according to a white paper published in July 20101 that outlines the devolution of commissioning responsibilities away from strategic health authorities and primary care trusts to consortia of GPs, which are to be established at local level. Details of how the new GP consortia will operate are as yet unclear, but in essence they will be strategic alliances and it is likely that they will develop more or less formal arrangements between consortia partners, such as those of a commercial joint venture.

This article draws on primary research into strategic alliances between organizations in all sectors. It suggests that there can be significant challenges for those working within strategic alliances, given that these tend to be beset by ambiguity and political tensions. In a context of ever greater transparency and accountability, it will be crucial to attend to the human aspects of strategic alliances since these represent significant risk if neglected. Conversely, alliances also offer the opportunity to develop the synergy of people, organizations and communities to deliver greater public value.

Successful collaborations need to get three things right: governance, operations and behaviours. Relationships between consortia partners have a significant bearing on their ability to deliver desired outcomes. They must be able to build and maintain trust. Consortia partners will need sophisticated negotiating and stakeholder management skills and must be able to engage the public in setting the strategic goals for which they will be accountable. They also need strategic and operational management skills and must be able to cope with ambiguity and manage complexity.

This paper argues that specific forms of leadership are needed in collaborative arrangements to mobilize people for positive action. People must work together by willingly and effectively pooling their initiative and expertise, and create a product or energy that is greater than the sum of their parts. The nature of leadership required to produce such high performance outcomes is likely to supersede leadership that is the result of structural relationships or of individual action. In particular, distributed leadership is likely to be relevant.
Spend to save: Synergy and innovation in public health
Authors: Varey Philippa
Published: May 2011

As public health budgets become ever tighter, an innovative approach in another public service sector could bring huge savings. Philippa Varey, Managing Director of Oriel Marketing, looks at what can be achieved if local authorities are allowed to take a holistic approach to spending
Innovation and the new landscape for public health
Authors: Hughes Liam
Published: May 2011

Liam Hughes, National Adviser for Healthy Communities, looks at the opportunity for innovation now granted to councils.
Efficacy and safety of novel anticoagulants compared with established agents
Authors: Rybak Iwona , Ehle Michael , Buckley Leo , Fanikos John
Published: May 2011

Dabigatran, rivaroxaban, and apixaban are novel oral anticoagulants that offer major advantages over existing agents. The onset of the anticoagulant effect of these agents is rapid. Each agent has a predictable anticoagulant response that eliminates the need for monitoring. Clinical trials have been completed with all three agents in the prevention and treatment of the three leading causes of cardiovascular death: myocardial infarction, stroke, and venous thromboembolism (VTE). Novel agents have shown reduced or similar rates of thrombosis, major bleeding, and adverse events when weighed against either low molecular weight heparin or warfarin. Additional trials are underway and more agents are in development. As a result, novel anticoagulants may impact physician prescribing practices and warrant consideration in patients requiring thrombosis management.
Airway reflux, cough and respiratory disease
Authors: Molyneux Ian D. , Morice Alyn H.
Published: May 2011

It is increasingly accepted that the effects of gastro-oesophageal reflux are not limited to the gastrointestinal tract. The adjacent respiratory structures are also at risk from material ejected from the proximal oesophagus as a result of the failure of anatomical and physiological barriers. There is evidence of the influence of reflux on several respiratory and otorhinological conditions and although in many cases the precise mechanism has yet to be elucidated, the association alone opens potential novel avenues of therapy to clinicians struggling to treat patients with apparently intractable respiratory complaints. This review provides a description of the airway reflux syndrome, its effects on the lung and current and future therapeutic options.
Pharmacy interventions on prescribing in nursing homes: from evidence to practice
Authors: Hughes Carmel M. , Lapane Kate L.
Published: May 2011

Prescribing of medicines for older people who live in nursing homes is a very common intervention. Undoubtedly, medicines have contributed to longevity and improved health outcomes in the population, but they are not without their side effects and can give rise to adverse events. The nursing home population is particularly at risk as residents have multiple comorbidities and receive multiple medications. Moreover, the quality of prescribing has been criticised with long-standing concerns about inappropriate prescribing, particularly overuse of medications which are not clinically indicated or which are no longer required. It has been suggested that pharmacists could use their skills to improve prescribing in the nursing home population and this review paper outlines the evidence for this type of intervention. The studies which have been included were rigorously designed and conducted. A number of interventions consisted of medication reviews, which often focused on specific drugs, notably antipsychotics, hypnotics and anxiolytics. In some cases, the pharmacist was solely responsible for the delivery of the intervention while in others a multidisciplinary approach was taken involving other key healthcare professionals. A number of outcome measures were employed to assess the impact of the intervention, ranging from a change in the number of inappropriate medications to differences in hospitalizations or health-related quality of life. Owing to the variation across studies, it is difficult to be definitive about the impact of pharmacy interventions in this setting. In an older, frail population such as nursing home residents, consideration needs to be given to appropriate and relevant outcome measures including a reduction in inappropriate prescribing, optimization of prescribing, reduced costs and improved health-related quality of life. Pharmacists and other healthcare professionals should continue to strive to meet these challenges in this particular demographic.
JeffHOPE
Authors: Hemba Kenneth E. , Plumb James
Published: May 2011

Established in 1992, JeffHOPE (Health Opportunities, Prevention and Education) of Jefferson Medical College in Philadelphia, Pennsylvania, is one of the largest and most robust Student-Run Clinics (SRCs) in the country. It operates 5 weekly clinics at 6 locations throughout Philadelphia, sees over 2000 patient visits annually, and has a staff of over 60 medical student volunteers. This case study describes JeffHOPE’s origins, mission, services, organizational structure, and funding. Pertinent SRC topics from the literature are examined, revealing potential areas of research, growth and development for the organization. Finally, suggestions are made as to how JeffHOPE can apply a framework to better fulfill its mission, providing a template for reflection and planning internally and for SRCs nationwide.
Implementation of force distribution analysis for molecular dynamics simulations
Authors: Stacklies Wolfram , Seifert Christian , Graeter Frauke
Published: May 2011

Background

The way mechanical stress is distributed inside and propagated by proteins and other biopolymers largely defines their function. Yet, determining the network of interactions propagating internal strain remains a challenge for both, experiment and theory. Based on molecular dynamics simulations, we developed force distribution analysis (FDA), a method that allows visualizing strain propagation in macromolecules.

Results

To be immediately applicable to a wide range of systems, FDA was implemented as an extension to Gromacs, a commonly used package for molecular simulations. The FDA code comes with an easy-to-use command line interface and can directly be applied to every system built using Gromacs. We provide an additional R-package providing functions for advanced statistical analysis and presentation of the FDA data.

Conclusions

Using FDA, we were able to explain the origin of mechanical robustness in immunoglobulin domains and silk fibers. By elucidating propagation of internal strain upon ligand binding, we previously also successfully revealed the functionality of a stiff allosteric protein. FDA thus has the potential to be a valuable tool in the investigation and rational design of mechanical properties in proteins and nano-materials.
Analysis of Gene expression in soybean (Glycine max) roots in response to the root knot nematode Meloidogyne incognita using microarrays and KEGG pathways
Authors: Ibrahim Heba MM , Hosseini Parsa , Alkharouf Nadim W , Hussein Ebtissam HA , Gamal El-Din Abd El Kader Y , Aly Mohammed AM , Matthews Benjamin F
Published: May 2011

Background

Root-knot nematodes are sedentary endoparasites that can infect more than 3000 plant species. Root-knot nematodes cause an estimated $100 billion annual loss worldwide. For successful establishment of the root-knot nematode in its host plant, it causes dramatic morphological and physiological changes in plant cells. The expression of some plant genes is altered by the nematode as it establishes its feeding site.

Results

We examined the expression of soybean (Glycine max) genes in galls formed in roots by the root-knot nematode, Meloidogyne incognita, 12 days and 10 weeks after infection to understand the effects of infection of roots by M. incognita. Gene expression was monitored using the Affymetrix Soybean GeneChip containing 37,500 G. max probe sets. Gene expression patterns were integrated with biochemical pathways from the Kyoto Encyclopedia of Genes and Genomes using PAICE software. Genes encoding enzymes involved in carbohydrate and cell wall metabolism, cell cycle control and plant defense were altered.

Conclusions

A number of different soybean genes were identified that were differentially expressed which provided insights into the interaction between M. incognita and soybean and into the formation and maintenance of giant cells. Some of these genes may be candidates for broadening plants resistance to root-knot nematode through over-expression or silencing and require further examination.
Long-term follow-up of nonspecific small bowel ulcers with a benign course and no requirement for surgery: is this a distinct group?
Authors: Wang Weifeng , Wang Zhanbo , Yang Yunsheng , Linghu Enqiang , Lu Zhongsheng
Published: May 2011

Background

Nonspecific small bowel ulcers are rare and surgical intervention is often believed to be elective. Since the extensive investigation of the small bowel in the 1990s, there have been limited reports of these ulcers and the updates have been unsatisfactory. The aim of this study was to explore the clinical features and natural histories of nonspecific small bowel ulcers through prospective observational study.

Methods

We reviewed the medical records of all patients who had undergone ileocolonoscopy or enteroscopy between 2000 and 2005 in a tertiary referral hospital. Seven patients with small bowel ulcers of unknown cause were identified. These patients were prospectively followed in a prolonged observation until March 2010.

Results

All seven patients (mean age: 54.7 years) presented with mild gastrointestinal symptoms, including chronic diarrhea and/or abdominal pain/discomfort, except for one who was asymptomatic when surveyed for colon polyps. Most patients were suspected of having functional bowel disorders for a long time (4.4 years) before small bowel ulcers were demonstrated on ileoscopy. The ulcers were characteristically multiple, superficial, and small (3-6 mm), locating at the terminal ileum and/or ileocecal valve. Various empirical treatments were applied, and most patients felt partly improved, even relieved. However the gastrointestinal symptoms did not always correlate with the presence of ulcers, and the ulcers tended to be either persistent (4 patients) or recurrent (1 patient). Ileocolonoscopy was repeated 4.1 times during follow-up, even after the lesions had healed. The characteristics of the ulcers, if still present during follow-up, were similar to their earlier characteristics. No patient experienced exacerbation or complications, such as intestinal obstruction, perforation, or bleeding. All patient survived and no surgical intervention was involved during the prolonged follow-up (7.0 years).

Conclusion

The reported patients with nonspecific small bowel ulcers experienced benign courses, inconsistent with previous reports. Without extensive investigation, this disease can be confused with functional bowel disorders.
A cross-sectional study of HIV and syphilis infections among male students who have sex with men (MSM) in northeast China: implications for implementing HIV screening and intervention programs
Authors: Xu Jun-Jie , Reilly Kathleen Heather , Lu Chun-Ming , Ma Ning , Zhang Min , Chu Zhen-Xing , Wang Jun-Jie , Yun Ke , Shang Hong
Published: May 2011

Background

China has 76.2 million high school and college students, in which the number of reported HIV/AIDS cases is increasing rapidly. Most of these cases are attributed to male-to-male sexual contact. Few studies have explored HIV prevalence and behavioural characteristics of Chinese male students who have sex with men (MSM).

Methods

A cross-sectional study of MSM high school and college students in Liaoning Province was conducted. Data were collected through face-to-face interviews and blood specimens were obtained and tested for HIV and syphilis.

Results

There were 436 eligible participants. HIV and syphilis prevalence was 3.0% and 5.0%, respectively. In multivariate analysis, sexual orientation known by family members (OR: 7.3; 95% CI: 1.5-34.6), HIV/AIDS information obtained from clinical doctors (OR: 6.7; 95% CI: 1.7-25.9), HIV/AIDS information obtained through free educational services and materials such as voluntary counseling and testing (VCT) and condom distribution services (OR: 0.2; 95% CI: 0.4-1.0), inconsistent condom use (OR: 5.7; 95%: 1.3-25.3), sexual partner experienced anal bleeding after insertive anal intercourse (OR: 6.8; 95% CI: 1.6-28.4), and history of illegal drug use (OR: 18.9; 95% CI: 2.2-165.3) were found to be significantly associated with HIV infection.

Conclusions

Greater effort should be made towards stemming the HIV and syphilis epidemics among Chinese student MSM. Immediate screening and comprehensive interventions towards student MSM should be implemented in order to curb the spread of HIV. Family and school-based interventions should be considered to target this educated, yet vulnerable, population.
Local Activation of Cannabinoid CB1 Receptors in the Urinary Bladder Reduces the Inflammation-Induced Sensitization of Bladder Afferents
Authors: Walczak Jean-Sébastien , Cervero Fernando
Published: May 2011

Background:

Systemic administration of cannabinoid agonists is known to reduce pain induced by bladder inflammation and to modulate cystometric parameters in vivo. We have previously reported that intravesical administration of a cannabinoid agonist reduces the electrical activity of bladder afferents under normal conditions. However, the effects of local activation of bladder cannabinoid receptors on afferent activity during inflammation are unknown. This study was aimed to assess the effects of intravesical administration of a cannabinoid agonist on the discharges of afferent fibers in inflamed bladders ex vivo. We also characterized the expression of CB1 receptors in the bladder and their localization and co-expression with TRPV1, a marker of nociceptive afferents.

Results:

Compared to untreated animals, afferent fiber activity in inflamed bladders was increased for intravesical pressures between 10 and 40 mmHg. Local treatment with a non selective cannabinoid agonist (AZ12646915) significantly reduced the afferent activity at intravesical pressures above 20 mmHg. This effect was blocked by AM251 but not by AM630 (selective for CB1 and CB2 respectively). Finally, CB1 was co-expressed with TRPV1 in control and inflamed bladders.

Conclusion:

These results demonstrate that sensitization of bladder afferents induced by inflammation is partly suppressed by intravesical activation of cannabinoid receptors, an effect that appears to be mediated by CB1 receptors. Also, TRPV1 positive fibers were found to co-express CB1, supporting the hypothesis of a direct action of the cannabinoid agonist on nociceptive afferents. Taken together, these results indicate a peripheral modulation by the cannabinoid system of bladder hypersensitivity during inflammation.
Nav1.7 is the Predominant Sodium Channel in Rodent Olfactory Sensory Neurons
Authors: Ahn Hye-Sook , Black Joel A , Zhao Peng , Tyrrell Lynda , Waxman Stephen G , Dib-Hajj Sulayman D
Published: May 2011

Background:

Voltage-gated sodium channel Nav1.7 is preferentially expressed in dorsal root ganglion (DRG) and sympathetic neurons within the peripheral nervous system. Homozygous or compound heterozygous loss-of-function mutations in SCN9A, the gene which encodes Nav1.7, cause congenital insensitivity to pain (CIP) accompanied by anosmia. Global knock-out of Nav1.7 in mice is neonatal lethal reportedly from starvation, suggesting anosmia. These findings led us to hypothesize that Nav1.7 is the main sodium channel in the peripheral olfactory sensory neurons (OSN, also known as olfactory receptor neurons).

Methods:

We used multiplex PCR-restriction enzyme polymorphism, in situ hybridization and immunohistochemistry to determine the identity of sodium channels in rodent OSNs.

Results:

We show here that Nav1.7 is the predominant sodium channel transcript, with low abundance of other sodium channel transcripts, in olfactory epithelium from rat and mouse. Our in situ hybridization data show that Nav1.7 transcripts are present in rat OSNs. Immunostaining of Nav1.7 and Nav1.6 channels in rat shows a complementary accumulation pattern with Nav1.7 in peripheral presynaptic OSN axons, and Nav1.6 primarily in postsynaptic cells and their dendrites in the glomeruli of the olfactory bulb within the central nervous system.

Conclusions:

Our data show that Nav1.7 is the dominant sodium channel in rat and mouse OSN, and may explain anosmia in Nav1.7 null mouse and patients with Nav1.7-related CIP.
Similarities and differences in structure, expression, and functions of VLDLR and ApoER2
Authors: Reddy Sunil S , Connor Teal E , Weeber Edwin J , Rebeck William
Published: May 2011

Very Low Density Lipoprotein Receptor (VLDLR) and Apolipoprotein E Receptor 2 (ApoER2) are important receptors in the brain for mediating the signaling effects of the extracellular matrix protein Reelin, affecting neuronal function in development and in the adult brain. VLDLR and ApoER2 are members of the low density lipoprotein family, which also mediates the effects of numerous other extracellular ligands, including apolipoprotein E. Although VLDLR and ApoER2 are highly homologous, they differ in a number of ways, including structural differences, expression patterns, alternative splicing, and binding of extracellular and intracellular proteins. This review aims to summarize important aspects of VLDLR and ApoER2 that may account for interesting recent findings that highlight the unique functions of each receptor.
A modulated empirical Bayes model for identifying topological and temporal estrogen receptor α regulatory networks in breast cancer
Authors: Shen Changyu , Huang Yiwen , Liu Yunlong , Wang Guohua , Zhao Yuming , Wang Zhiping , Teng Mingxiang , Wang Yadong , Flockhart David A , Skaar Todd C , Yan Pearlly , Nephew Kenneth P , Huang Tim HM , Li Lang
Published: May 2011

Background

Estrogens regulate diverse physiological processes in various tissues through genomic and non-genomic mechanisms that result in activation or repression of gene expression. Transcription regulation upon estrogen stimulation is a critical biological process underlying the onset and progress of the majority of breast cancer. Dynamic gene expression changes have been shown to characterize the breast cancer cell response to estrogens, the every molecular mechanism of which is still not well understood.

Results

We developed a modulated empirical Bayes model, and constructed a novel topological and temporal transcription factor (TF) regulatory network in MCF7 breast cancer cell line upon stimulation by 17β-estradiol stimulation. In the network, significant TF genomic hubs were identified including ER-alpha and AP-1; significant non-genomic hubs include ZFP161, TFDP1, NRF1, TFAP2A, EGR1, E2F1, and PITX2. Although the early and late networks were distinct (<5% overlap of ERα target genes between the 4 and 24 h time points), all nine hubs were significantly represented in both networks. In MCF7 cells with acquired resistance to tamoxifen, the ERα regulatory network was unresponsive to 17β-estradiol stimulation. The significant loss of hormone responsiveness was associated with marked epigenomic changes, including hyper- or hypo-methylation of promoter CpG islands and repressive histone methylations.

Conclusions

We identified a number of estrogen regulated target genes and established estrogen-regulated network that distinguishes the genomic and non-genomic actions of estrogen receptor. Many gene targets of this network were not active anymore in anti-estrogen resistant cell lines, possibly because their DNA methylation and histone acetylation patterns have changed.
The Expression and Regulation of Adrenomedullin in the Human Endometrium: A Candidate for Endometrial Repair
Authors: Maybin Jacqueline A. , Battersby Sharon , Hirani Nikhil , Nikitenko Leonid L. , Critchley Hilary O. D. , Jabbour Henry N.
Published: May 2011

After menstruation, the endometrium has a remarkable capacity for repair, but the factors involved remain undefined. We hypothesize adrenomedullin (AM) plays a role in this process. Premenstrually progesterone levels decline, stimulating prostaglandin (PG) synthesis, vasoconstriction, and hypoxia. This study aimed to determine 1) AM expression throughout the menstrual (M) cycle and 2) its regulation by PG and hypoxia. Human endometrial biopsies (n = 51) were collected with ethical approval and consent. AM mRNA expression was examined by quantitative RT-PCR and was found to be selectively elevated in endometrium from the menstrual (M) phase (P < 0.001). AM immunohistochemical staining was maximal in M and proliferative (P) endometrium. Culture of secretory, but not P, explants with 100 nm PGF2α or hypoxia (0.5% O2) increased AM mRNA (P < 0.05). P explants were induced to increase AM expression using in vitro progesterone withdrawal but required the presence of hypoxia (P < 0.05). Short hairpin sequences against hypoxia-inducible factor-1α (HIF-1α) inhibited AM hypoxic up-regulation but did not alter PGF2α-induced expression. The AM receptor was immunolocalized to endothelial cells in both lymphatic and blood vessels. Conditioned medium from PGF2α-treated cells increased endothelial cell proliferation and branching (P < 0.05). This was abolished by AM receptor antagonists. In conclusion, AM is elevated at the time of endometrial repair and induces both angiogenesis and lymphangiogenesis by stimulating endothelial cell proliferation and tube formation. In the human endometrium, AM expression is up-regulated by two mechanisms: a HIF-1α-mediated hypoxic induction and a HIF-1α-independent PGF2α pathway. These physiological mechanisms may provide novel therapeutic targets for disorders such as heavy menstrual bleeding.
Glucocorticoids Facilitate Astrocytic Amyloid-β Peptide Deposition by Increasing the Expression of APP and BACE1 and Decreasing the Expression of Amyloid-β-Degrading Proteases
Authors: Wang Yanyan , Li Maoquan , Tang Jun , Song Min , Xu Xueqing , Xiong Jiaxiang , Li Junxia , Bai Yun
Published: May 2011

In most cases, the molecular mechanism underlying the pathogenesis of sporadic Alzheimer's disease (AD) is unknown. Elevated basal cortisol levels in AD patients suggest that glucocorticoids (GC) may contribute to the development and/or maintenance of AD. Amyloid plaques are the hallmark of AD, and they are considered to play an early role in the AD process. However, little is known about how their formation is regulated by stress and GC. Astrocyte accumulation is one of the earliest neuropathological changes in AD. Here, we report that GC elevated amyloid-β (Aβ) production in primary cultures of astrocytes by increasing amyloid precursor protein (APP) and β-site APP-cleaving enzyme 1 gene expression. Notably, GC administered to normal, middle-aged mice promoted the expression of APP and β-site APP-cleaving enzyme 1 in astrocytes, as determined by double immunofluorescence. Additionally, confocal microscopy and ELISA revealed that GC markedly reduced Aβ degradation and clearance by astrocytes in vitro, indicating a decreased neuroprotective capacity of the astrocytes. This may have been due to the decrease of several Aβ-degrading proteases, such as insulin-degrading enzyme and matrix metalloproteinase-9. These effects occurred through the activation of GC receptors. Taken together, our results demonstrate that GC can enhance the production of Aβ, reduce its degradation in astrocytes, and provide a molecular mechanism linking stress factors to AD. Our study suggests that GC can facilitate AD pathogenesis and that reducing GC in the elderly and early AD patients would be beneficial.
Regulation of Notch1 signaling by the APP intracellular domain facilitates degradation of the Notch1 intracellular domain and RBP-Jk
Authors: Kim Mi-Yeon , Mo Jung-Soon , Ann Eun-Jung , Yoon Ji-Hye , Jung Jane , Choi Yun-Hee , Kim Su-Man , Kim Hwa-Young , Ahn Ji-Seon , Kim Hangun , Kim Kwonseop , Hoe Hyang-Sook , Park Hee-Sae
Published: May 2011

The Notch1 receptor is a crucial controller of cell fate decisions, and is also a key regulator of cell growth and differentiation in a variety of contexts. In this study, we have demonstrated that the APP intracellular domain (AICD) attenuates Notch1 signaling by accelerated degradation of the Notch1 intracellular domain (Notch1-IC) and RBP-Jk, through different degradation pathways. AICD suppresses Notch1 transcriptional activity by the dissociation of the Notch1-IC–RBP-Jk complex after processing by γ-secretase. Notch1-IC is capable of forming a trimeric complex with Fbw7 and AICD, and AICD enhances the protein degradation of Notch1-IC through an Fbw7-dependent proteasomal pathway. AICD downregulates the levels of RBP-Jk protein through the lysosomal pathway. AICD-mediated degradation is involved in the preferential degradation of non-phosphorylated RBP-Jk. Collectively, our results demonstrate that AICD functions as a negative regulator in Notch1 signaling through the promotion of Notch1-IC and RBP-Jk protein degradation.
Cyclosporin-A-induced prion protein aggresomes are dynamic quality-control cellular compartments
Authors: Ben-Gedalya Tziona , Lyakhovetsky Roman , Yedidia Yifat , Bejerano-Sagie Michal , Kogan Natalya M. , Karpuj Marcela Viviana , Kaganovich Daniel , Cohen Ehud
Published: May 2011

Despite the activity of cellular quality-control mechanisms, subsets of mature and newly synthesized polypeptides fail to fold properly and form insoluble aggregates. In some cases, protein aggregation leads to the development of human neurodegenerative maladies, including Alzheimer's and prion diseases. Aggregates of misfolded prion protein (PrP), which appear in cells after exposure to the drug cyclosporin A (CsA), and disease-linked PrP mutants have been found to accumulate in juxtanuclear deposition sites termed ‘aggresomes’. Recently, it was shown that cells can contain at least two types of deposition sites for misfolded proteins: a dynamic quality-control compartment, which was termed ‘JUNQ’, and a site for terminally aggregated proteins called ‘IPOD’. Here, we show that CsA-induced PrP aggresomes are dynamic structures that form despite intact proteasome activity, recruit chaperones and dynamically exchange PrP molecules with the cytosol. These findings define the CsA–PrP aggresome as a JUNQ-like dynamic quality-control compartment that mediates the refolding or degradation of misfolded proteins. Together, our data suggest that the formation of PrP aggresomes protects cells from proteotoxic stress.
Interplay between FGF2 and BMP controls the self-renewal, dormancy and differentiation of rat neural stem cells
Authors: Sun Yirui , Hu Jin , Zhou Liangfu , Pollard Steven M. , Smith Austin
Published: May 2011

Mouse and human central nervous system progenitor cells can be propagated extensively ex vivo as stem cell lines. For the rat, however, in vitro expansion has proven to be problematic owing to proliferation arrest and differentiation. Here, we analyse the establishment, in adherent culture, of undifferentiated tripotent neural stem (NS) cell lines derived from rat foetal brain and spinal cord. Rat NS cells invariably undergo growth arrest and apparent differentiation after several passages; however, conditioned medium from proliferating cultures can overcome this block, enabling continuous propagation of undifferentiated rat NS cells. We found that dormancy is induced by autocrine production of bone morphogenetic proteins (BMPs). Accordingly, the BMP antagonist noggin can replace conditioned medium to sustain continuous self-renewal. Noggin can also induce dormant cells to re-enter the cell cycle, upon which they reacquire neurogenic potential. We further show that fibroblast growth factor 2 (FGF2) is required to suppress terminal astrocytic differentiation and maintain stem cell potency during dormancy. These findings highlight an extrinsic regulatory network, comprising BMPs, BMP antagonists and FGF2 signals, that governs the proliferation, dormancy and differentiation of rat NS cells and which can be manipulated to enable long-term clonogenic self-renewal.
A hydrodynamic sensory antenna used by killifish for nocturnal hunting
Authors: Schwarz Jason S. , Reichenbach Tobias , Hudspeth A. J.
Published: May 2011

The perception of sensory stimuli by an animal requires several steps, commencing with the capture of stimulus energy by an antenna that, as the interface between the physical world and the nervous system, modifies the stimulus in ways that enhance the animal's perception. The mammalian external ear, for example, collects sound and spectrally alters it to increase sensitivity and improve the detection of directionality. In view of the morphological diversity of the lateral-line system across species and its accessibility to observation and experimental intervention, we sought to investigate the role of antennal structures on the response characteristics of the lateral line. The surface-feeding killifish Aplocheilus lineatus is able to hunt in darkness by detecting surface capillary waves with the lateral-line system atop its head. This cephalic lateral line consists of a stereotyped array of 18 mechanosensitive neuromasts bordered by fleshy ridges. By recording microphonic potentials, we found that each neuromast has a unique receptive field defined by its sensitivity to stimulation of the water's surface. The ridges help determine these receptive fields by altering the flow of water over each neuromast. Modification of the hydrodynamic environment by the addition of a supplemental ridge changes the pattern of water movement, perturbs the receptive fields of adjacent neuromasts and impairs the fish's localization ability. On the basis of electrophysiological, hydrodynamic and behavioral evidence, we propose that the ridges constitute a hydrodynamic antenna for the cephalic lateral line.
Origins of variation in muscle cytochrome c oxidase activity within and between fish species
Authors: Bremer Katharina , Moyes Christopher D.
Published: May 2011

Mitochondrial content, central to aerobic metabolism, is thought to be controlled by a few transcriptional master regulators, including nuclear respiratory factor 1 (NRF-1), NRF-2 and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). Though well studied in mammals, the mechanisms by which these factors control mitochondrial content have been less studied in lower vertebrates. We evaluated the role of these transcriptional regulators in seasonal changes in white muscle cytochrome c oxidase (COX) activity in eight local fish species representing five families: Centrarchidae, Umbridae, Esocidae, Gasterosteidae and Cyprinidae. Amongst centrarchids, COX activity was significantly higher in winter for pumpkinseed (2-fold) and black crappie (1.3-fold) but not bluegill or largemouth bass. In esociforms, winter COX activity was significantly higher in central mudminnow (3.5-fold) but not northern pike. COX activity was significantly higher in winter-acclimatized brook stickleback (2-fold) and northern redbelly dace (3-fold). Though mudminnow COX activity increased in winter, lab acclimation to winter temperatures did not alter COX activity, suggesting a role for non-thermal cues. When mRNA was measured for putative master regulators of mitochondria, there was little evidence for a uniform relationship between COX activity and any of NRF-1, NRF-2α or PGC-1α mRNA levels Collectively, these studies argue against a simple temperature-dependent mitochondrial response ubiquitous in fish, and suggest that pathways which control mitochondrial content in fish may differ in important ways from those of the better studied mammals.
The distribution and expression of CFTR restricts electrogenic anion secretion to the ileum of the brushtail possum, Trichosurus vulpecula
Authors: Gill Mike , Bartolo Ray C. , Demmers Kristy , Harfoot Natalie , Fan Shujun , Butt Grant
Published: May 2011

In eutherian mammals, fluid secretion is essential for intestinal function. This is driven by electrogenic Cl– secretion, which involves a NaK2Cl cotransporter (NKCC1) in the enterocyte basolateral membrane and the cystic fibrosis transmembrane conductance regulator (CFTR) in the apical membrane. However, in the possum ileum, NKCC1 expression is low and secretagogues stimulate electrogenic HCO3– secretion driven by a basolateral NaHCO3 cotransporter (pNBCe1). Here we investigated whether electrogenic anion secretion occurs in possum duodenum and jejunum and determined the role of CFTR in possum intestinal anion secretion. Prostaglandin E2 (PGE2) and forskolin stimulated a large increase in ileal short-circuit current (Isc), consistent with electrogenic HCO3– secretion, but had little effect on the duodenal and jejunal Isc. Furthermore, 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) and N-(2-naphthalenyl)-[(3,5-dibromo-2,4-dihydroxyphenyl)methylene]glycine hydrazide (GlyH101) inhibited cloned possum CFTR in cultured cells and the PGE2-stimulated ileal Isc, implicating CFTR in ileal HCO3– secretion. Consistent with this, CFTR is expressed in the apical membrane of ileal crypt and lower villous cells, which also express pNBCe1 in the basolateral membrane. In contrast, duodenal and jejunal CFTR expression is low relative to the ileum. Jejunal pNBCe1 expression is also low, whereas duodenal and ileal pNBCe1 expression are comparable. All regions have low NKCC1 expression. These results indicate that cAMP-dependent electrogenic Cl– secretion does not occur in the possum small intestine because of the absence of CFTR and NKCC1. Furthermore, CFTR functions as the apical anion conductance associated with HCO3– secretion and its distribution limits electrogenic HCO3– secretion to the ileum.
Rhodium-catalyzed Oxidative Coupling of Benzylamines with Alkynes through Dehydrogenation and Dehydrogenative Cyclization
Authors: Morimoto Keisuke , Hirano Koji , Satoh Tetsuya , Miura Masahiro
Published: May 2011

Oxidative coupling of benzylamines with internal alkynes accompanied by dehydrogenation and dehydrogenative cyclization proceeds efficiently under rhodium catalysis to selectively give the corresponding 3,4-substituted isoquinoline derivatives. The procedure is also applicable to the reactions of (1-naphthylmethyl)amine with diaryl- and dialkylacetylenes to construct benzo[h]isoquinoline and benzo[e]isoindole frameworks, respectively.