bluuebunny/crossref_metadata_2025 huggingface dataset:
Caregiver Burden and Needs in Frontotemporal Dementia
Authors: Diehl-Schmid Janine , Schmidt Eva-Maria , Nunnemann Sabine , Riedl Lina , Kurz Alexander , Förstl Hans , Wagenpfeil Stefan , Cramer Barbara
Published: August 2013

Background:

It is well known that burden among caregivers of patients with frontotemporal dementia (FTD) is high. However, little is known about the specific problems, the factors that contribute to caregiver burden, and the needs of the FTD caregivers—particularly those needs that are accessible by external support strategies.

Objective:

We developed a standardized questionnaire that addressed burdens, problems, and the actual needs of FTD caregivers. A total of 94 caregivers were interviewed.

Results:

It appears that changes in the patients’ behavior and in the interpersonal relations between caregivers and patients are associated with caregiver depression. The most important needs and requests of the caregivers included information and psychosocial support through educated staff, financial support as well as the education of medical staff about the disease.

Conclusions:

Support strategies should focus on information and psychosocial support. Given the low prevalence of FTD, internet- and telephone-based strategies appear suitable.
Yuan: Towards an International Reserve Currency
Authors: Bhat T.P.
Published: August 2013

The emergence of China as a powerhouse of the world economy has added a new dimension to the global currency market. China’s impressive economic growth and phenomenal rise in exports have given considerable strength to its currency yuan in recent years. To what extent will China push to make the yuan the world’s reserve currency has become a burning issue. Currently, the share of yuan in total world reserves is hardly 1 per cent. The reasons are obvious. The yuan is not fully convertible, the capital market is shallow, the exchange rate is not flexible and international acceptance of yuan as a store of value is non-existent. In the face of these constraints, China is showing an inclination to make the yuan an international currency and to rival the US dollar and euro. Increase in the inflow of foreign direct investment as well as outflow of investment abroad is enabling China to move towards internationalisation of yuan in the near future. Regionalisation of the yuan is gaining importance with rise in its international trade in Asia. China has now allowed the commercial banks in Hong Kong to accept the yuan-denominated deposits. It is further extending loans in yuan to developing countries. Many steps are being taken towards making the yuan an international reserve currency. At the outset, it appears that the yuan would become an international currency in the foreseeable future.
Book Review: Diplomatic Channels
Authors: Sajjanhar Ambassador Ashok
Published: August 2013

Srinivasan, Krishnan, Diplomatic Channels (New Delhi: Manohar Publishers, 2012). Pp. 264, Price ₹750.
Optimum placement of actuators in structural and control design using Stackelberg games
Authors: Ali Arjumand , Ghotbi Ehsan , Dhingra Anoop K
Published: August 2013

Actuator placement has a significant impact on the dynamic response of actively controlled structures. Misplaced actuators and sensors often lead to controllability and observability problems, and the desired system performance may not be achieved with any choice of control law. This paper addresses the design of actively controlled structures wherein both the actuator placement and controller design aspects are addressed simultaneously. It is assumed that a hierarchical structure exists between the actuator placement and controller design objective functions with the actuator placement problem considered as being more important. The resulting multiobjective design problem is solved as a bi-level Stackelberg game. A computational procedure based on variable updating using response surface methods is developed for exchanging information between the two levels (leader and follower). The optimization problem has mixed discrete-continuous variables with discrete variables corresponding to actuator placement and continuous variables associated with the controller design problem. The solution approach includes a blend of genetic algorithms and sequential quadratic programming techniques and is applied to the design of a flexible truss structure. The proposed approach successfully designed an optimum controller while minimizing the weight of the structure and simultaneously maximizing the energy dissipated by the controller to bring the structure to its equilibrium position when subjected to an external disturbance.
Experimental study on the control of a novel vibration isolator via adaptive backstepping
Authors: Coppola Gianmarc , Liu Kefu , Liu Xiaoping , Zhang Dan
Published: August 2013

This study focuses on the control of a novel active vibration isolator using an adaptive backstepping approach. The developed active isolator is introduced and its dynamic model is presented. It is shown that the unknown nonlinear restoring force and damping parameter pose control challenges. The nonlinear restoring force is approximated as a polynomial with unknown coefficients. Adaptive control is chosen as a suitable approach to tackle the control challenges. An existing lower-order adaptive backstepping controller is modified in order to include the actuator dynamics and avoid the zero convergence of the estimated parameter vector. An extensive experimental study is conducted to test the effectiveness of the modified controller. The performance of the controller is compared with that of the lower-order controller. The results from several testing scenarios are presented and interpreted, and the issues related to parameter estimation and control performance are addressed.
Analytical study on in-plane free vibration of a cable network with straight alignment rigid cross-ties
Authors: Ahmad Javaid , Cheng Shaohong
Published: August 2013

Using cross-ties is one of the effective countermeasures to suppress unfavorable bridge stay cable vibrations. It has been successfully applied in the field. However, dynamic behavior of cable networks is still not clearly understood, which hinders the development of a more efficient design. The current paper aims at extending the existing analytical studies on in-plane free vibration of cable networks by developing closed-form modal solutions for a wider series of cases, in particular for general cable networks consisting of n horizontally laid main cables interconnected transversely with a single line of rigid cross-ties. The validity of these analytical modal solutions is verified by independent finite element simulations. These closed-form modal solutions offer a clear elucidation of the mechanics underlying various modal behaviors observed in cable networks of different layout and structural properties. In addition, based on the proposed analytical formulation, the important system parameters of cable networks are identified. The unique features associated with cable networks of a number of specific configurations are investigated and discussed.
A Statistical Analysis of the Role of Benefit–Cost Analysis in Awarding TIGER Grants
Authors: Homan Anthony C. , Adams Teresa M. , Marach Alex J.
Published: August 2013

As directed by the American Recovery and Reinvestment Act of 2009, the U.S. Department of Transportation (DOT) created the Transportation Investment Generating Economic Recovery (TIGER) discretionary grant program for surface transportation infrastructure projects. TIGER used a multistep competitive application process to award surface transportation funds. TIGER applications were initially screened by U.S. DOT’s staff of technical and economic experts and the final awardees were selected by a Review Team of Modal Administrators and DOT Office of the secretary-level officials. The purpose of the research was to determine if the most deserving projects, based on an applicant’s benefit–cost analysis and the likelihood that benefits exceeded costs, were more likely to receive grant funding. We base the findings on pair-wise comparisons and on logistic regression models. Based on these analyses, we found that the outcome of the benefit–cost analysis (both quality and expected net benefits) was not a statistically significant factor.
Collaboration for Innovation in Tourism Organizations
Authors: Zach Florian
Published: August 2013

Collaboration for innovation is a key contributor to successful innovations in the tourism industry. Research, however, has not fully understood how tourism organizations with less than 10 employees (also known as micro organizations) can foster collaboration for innovation. This study contributes to tourism research by successfully testing the effect of innovation formality, interorganizational communication, and leadership support on collaboration for innovation at destination marketing organizations with less than 10 employees. It was found that leadership support for both innovation and collaboration is the most important driver to collaborate with partners in the innovation process. Interorganizational communication and innovation formality were driven by leadership support but did not have a strong direct effect on collaboration for innovation. This suggests that micro destination marketing organizations need to identify and invest in leadership rather than develop or rely on organizational processes that are useful in large organizations.
How patients’ review sites will change health care
Authors: Hotopf Max
Published: August 2013

TripAdvisor has changed how the travel industry treats customers. Is the same likely to happen to health services? Review sites are growing fast across Europe, propelled by expansions in patient choice. What impact will they have on the medical profession and on providers, both public and private? How will they change the nature of health care? To address these questions, those at the forefront of developing review sites in Europe were interviewed.
Undocumented migration, use wear, and the materiality of habitual suffering in the Sonoran Desert
Authors: De León Jason
Published: August 2013

Since the late 1990s, unauthorized migrants attempting to cross the Sonoran Desert of Arizona have been relying on a unique set of material culture to evade Border Patrol, as well as prevent and treat injuries during the crossing process. Some media and academic attention has focused on the hundreds of migrants who die each year during desert border crossings, but little focus has been paid to the non-lethal injuries (e.g. blisters and dehydration) that hundreds of thousands of people sustain annually. Using a combination of ethnographic and archaeological data, the author argues that border-crossing artifacts both reflect and shape a way of being that is specific to the desert migration process. Expanding upon the archaeological concept of use wear, he demonstrates that modifications made to migrant goods provide evidence of border-crossing body techniques that are connected to widespread and routinized forms of corporeal suffering.
Turning the Wheels: The Cost Factor
Authors: Majumdar Mukul , Mukherjee Priya
Published: August 2013

Corruption scandals are increasingly becoming rampant, especially in developing countries. The recent corruption scandals in India, in particular, have led to calls for legislation to establish an independent Public Ombudsman, who will be able to initiate investigations into allegations of corruption. In this paper we consider a typical problem that such an Ombudsman might face — that of initiating an enquiry into an allegation of corruption involving a large body of public officials. Recognizing that such investigations may be costly, we draw from the literature on statistical sampling to get estimates of the possible costs of an initial investigation, and report numerical results comparing the classical approach with the sequential sampling approach of Wald (1947).
Comparative study on structural and optical properties of nitrogen rich InN on Si(110) and 6H-SiC
Authors: Amirhoseiny M , Hassan Z , Ng S S
Published: August 2013

Nitrogen rich indium nitride (InN) thin films were deposited on anisotropic silicon [Si(110)] and 6H-silicon carbide (6H-SiC) substrates by reactive radio frequency sputtering technique. The surface quality of the InN films on Si(110) substrate was compared to that deposited on 6H-SiC substrate. Both deposited films showed wurtzite nanocrystalline InN films with a (101) preferred growth orientation. One Raman active optical phonon of E2(high) and two Raman and infrared active modes of A1(LO) and E1(TO) of the wurtzite InN thin film were clearly observed for both samples. Morphological characteristics showed higher surface quality for InN grown on Si(110) compared to that on SiC substrate. Owing to the large lattice mismatch, it was found that the crystallinity of InN films grown on 6H-SiC substrate degraded as compared to that grown on Si(110).
Fuzzy approximation of Euler-Lagrange quadratic mappings
Authors: Kim Hark-Mahn , Rassias John M , Lee Juri
Published: August 2013

In this article, we consider the Hyers-Ulam stability of the Euler-Lagrange quadratic functional equation

f
(
k
x
+
l
y
)
+
f
(
k
x
−
l
y
)
=
k
l

[
f
(
x
+
y
)
+
f
(
x
−
y
)
]

+
2
(
k
−
l
)

[
k
f
(
x
)
−
l
f
(
y
)
]

in fuzzy Banach spaces, where k, l are nonzero rational numbers with

k
≠
l

.
Evaluation of estrogenic, antiestrogenic and genotoxic activity of nemorosone, the major compound found in brown Cuban propolis
Authors: Camargo Mariana S , Prieto Aline M , Resende Flavia A , Boldrin Paula K , Cardoso Cassia RP , Fernández Mariana F , Molina-Molina José Manuel , Olea Nicolás , Vilegas Wagner , Cuesta-Rubio Osmany , Varanda Eliana A
Published: August 2013

Background

Brown propolis is the major type of propolis found in Cuba; its principal component is nemorosone, the major constituent of Clusia rosea floral resins. Nemorosone has received increasing attention due to its strong in vitro anti-cancer action. The citotoxicity of nemorosone in several human cancer cell lines has been reported and correlated to the direct action it has on the estrogen receptor (ER). Breast cancer can be treated with agents that target estrogen-mediated signaling, such as antiestrogens. Phytoestrogen can mimic or modulate the actions of endogenous estrogens and the treatment of breast cancer with phytoestrogens may be a valid strategy, since they have shown anti-cancer activity.

Methods

The aim of the present investigation was to assess the capacity of nemorosone to interact with ERs, by Recombinant Yeast Assay (RYA) and E-screen assays, and to determine by comet assay, if the compound causes DNA-damaging in tumoral and non-tumoral breast cells.

Results

Nemorosone did not present estrogenic activity, however, it inhibited the 17-β-estradiol (E2) action when either of both methods was used, showing their antiestrogenicity. The DNA damage induced by the benzophenone in cancer and normal breast cells presented negative results.

Conclusion

These findings suggest that nemorosone may have therapeutic application in the treatment of breast cancer.
RACK(1) to the future – a historical perspective
Authors: Ron Dorit , Adams David R , Baillie George S , Long Aideen , O’Connor Rosemary , Kiely Patrick A
Published: August 2013

This perspective summarises the first and long overdue RACK1 meeting held at the University of Limerick, Ireland, May 2013, in which RACK1’s role in the immune system, the heart and the brain were discussed and its contribution to disease states such as cancer, cardiac hypertrophy and addiction were described. RACK1 is a scaffolding protein and a member of the WD repeat family of proteins. These proteins have a unique architectural assembly that facilitates protein anchoring and the stabilisation of protein activity. A large body of evidence is accumulating which is helping to define the versatile role of RACK1 in assembling and dismantling complex signaling pathways from the cell membrane to the nucleus in health and disease. In this commentary, we first provide a historical perspective on RACK1. We also address many of the pertinent and topical questions about this protein such as its role in transcription, epigenetics and translation, its cytoskeletal contribution and the merits of targeting RACK1 in disease.
Identification of prefoldin amplification (1q23.3-q24.1) in bladder cancer using comparative genomic hybridization (CGH) arrays of urinary DNA
Authors: López Virginia , González-Peramato Pilar , Suela Javier , Serrano Alvaro , Algaba Ferrán , Cigudosa Juan C , Vidal August , Bellmunt Joaquim , Heredero Oscar , Sánchez-Carbayo Marta
Published: August 2013

Background

Array-CGH represents a comprehensive tool to discover genomic disease alterations that could potentially be applied to body fluids. In this report, we aimed at applying array-CGH to urinary samples to characterize bladder cancer.

Methods

Urinary DNA from bladder cancer patients and controls were hybridized on 44K oligonucleotide arrays. Validation analyses of identified regions and candidates included fluorescent in situ hybridization (FISH) and immunohistochemistry in an independent set of bladder tumors spotted on custom-made tissue arrays (n = 181).

Results

Quality control of array-CGH provided high reproducibility in dilution experiments and when comparing reference pools. The most frequent genomic alterations (minimal recurrent regions) among bladder cancer urinary specimens included gains at 1q and 5p, and losses at 10p and 11p. Supervised hierarchical clustering identified the gain at 1q23.3-q24.1 significantly correlated to stage (p = 0.011), and grade (p = 0.002). The amplification and overexpression of Prefoldin (PFND2), a selected candidate mapping to 1q23.3-q24.1, correlated to increasing stage and tumor grade by means of custom-designed and optimized FISH (p = 0.013 and p = 0.023, respectively), and immunohistochemistry (p ≤0.0005 and p = 0.011, respectively), in an independent set of bladder tumors included in tissue arrays. Moreover, PFND2 overexpression was significantly associated with poor disease-specific survival (p ≤0.0005). PFND2 was amplified and overexpressed in bladder tumors belonging to patients providing urinary specimens where 1q23.3q24.1 amplification was detected by array-CGH.

Conclusions

Genomic profiles of urinary DNA mirrowed bladder tumors. Molecular profiling of urinary DNA using array-CGH contributed to further characterize genomic alterations involved in bladder cancer progression. PFND2 was identified as a tumor stratification and clinical outcome prognostic biomarker for bladder cancer patients.
Serum concentrations of 25-hydroxyvitamin D and immunoglobulins in an older Swiss cohort: results of the Senior Labor Study
Authors: Sakem Benjamin , Nock Cristina , Stanga Zeno , Medina Pedro , Nydegger Urs E , Risch Martin , Risch Lorenz
Published: August 2013

Background

Vitamin D and the components of humoral immunity play important roles in human health. Older people have lower 25-hydroxyvitamin D (25(OH)D) serum levels than younger adults. We aimed to determine the levels of 25(OH)D serum concentrations in healthy senior citizens and to study their relationship to the levels of components of humoral immunity.

Methods

A total of 1,470 healthy Swiss men and women, 60 years or older, were recruited for this study. A total of 179 subjects dropped out of the study because of elevated serum concentrations of C-reactive protein. Fasting blood sera were analyzed for 25(OH)D with the high-performance liquid chromatography (HPLC) and for parathyroid hormone (PTH), immunoglobulins and complement C4 and C3 concentrations with immunoassays. The percentage of participants in each of the four 25(OH)D deficiency groups - severely deficient (<10 ng/ml), deficient (10 to 20), insufficient (21 to 29 ng/ml) and normal (>=30 ng/ml) - were statistically compared. The relationship of the major components of the humoral system and age with 25(OH)D levels was also assessed.

Results

About 66% of the subjects had insufficient levels of 25(OH)D. Normal levels of 25(OH)D were found in 26.1% of the subjects of which 21% were males and 30.5% were females (total study population). Severely deficient levels of 25(OH)D were found in 7.98% of the total study population. Low levels of 25(OH)D were positively associated with IgG2 (P = 0.01) and with C4 (P = 0.02), yet were inversely related to levels of IgG1 and IgA (P < 0.05) and C3 (P = 0.01). Serum levels of total IgA, IgG, IgG2 and IgG4 peaked together with 25(OH)D during late summer.

Conclusions

Approximately two-thirds of the healthy, older Swiss population presented with Vitamin D insufficiency. The incremental shift in IgA and C3 levels might not necessarily reflect a deranged humoral immune defense; however, given the high prevalence of vitamin D deficiency, the importance of this condition in humoral immunity will be worth looking at more closely. This study supports the role of vitamin D in the competent immune system.
Combustion-derived flame generated ultrafine soot generates reactive oxygen species and activates Nrf2 antioxidants differently in neonatal and adult rat lungs
Authors: Chan Jackie KW , Charrier Jessica G , Kodani Sean D , Vogel Christoph F , Kado Sarah Y , Anderson Donald S , Anastasio Cort , Van Winkle Laura S
Published: August 2013

Background

Urban particulate matter (PM) has been epidemiologically correlated with multiple cardiopulmonary morbidities and mortalities, in sensitive populations. Children exposed to PM are more likely to develop respiratory infections and asthma. Although PM originates from natural and anthropogenic sources, vehicle exhaust rich in polycyclic aromatic hydrocarbons (PAH) can be a dominant contributor to the PM2.5and PM0.1fractions and has been implicated in the generation of reactive oxygen species (ROS).

Objectives

Current studies of ambient PM are confounded by the variable nature of PM, so we utilized a previously characterized ethylene-combusted premixed flame particles (PFP) with consistent and reproducible physiochemical properties and 1) measured the oxidative potential of PFP compared to ambient PM, 2) determined the ability of PFPs to generate oxidative stress and activate the transcription factor usingin vitroandex vivomodels, and 3) we correlated these responses with antioxidant enzyme expressionin vivo.

Methods

We compared oxidative stress response (HMOX1) and antioxidant enzyme (SOD1, SOD2, CAT, and PRDX6) expressionin vivoby performing a time-course study in 7-day old neonatal and young adult rats exposed to a single 6-hour exposure to 22.4 μg/m3PFPs.

Results

We showed that PFP is a potent ROS generator that induces oxidative stress and activates Nrf2. Induction of the oxidative stress responsive enzyme HMOX1in vitrowas mediated through Nrf2 activation and was variably upregulated in both ages. Furthermore, antioxidant enzyme expression had age and lung compartment variations post exposure. Of particular interest was SOD1, which had mRNA and protein upregulation in adult parenchyma, but lacked a similar response in neonates.

Conclusions

We conclude that PFPs are effective ROS generators, comparable to urban ambient PM2.5,that induce oxidative stress in neonatal and adult rat lungs. PFPs upregulate a select set of antioxidant enzymes in young adult animals, that are unaffected in neonates. We conclude that the inability of neonatal animals to upregulate the antioxidant response may, in part, explain enhanced their susceptibility to ultrafine particles, such as PFP.
Developmental changes in the transcriptome of the rat choroid plexus in relation to neuroprotection
Authors: Kratzer Ingrid , Liddelow Shane A , Saunders Norman R , Dziegielewska Kate M , Strazielle Nathalie , Ghersi-Egea Jean-Francois
Published: August 2013

Background

The choroid plexuses are the interface between the blood and the cerebrospinal fluid (CSF) contained within the ventricular spaces of the central nervous system. The tight junctions linking adjacent cells of the choroidal epithelium create a physical barrier to paracellular movement of molecules. Multispecific efflux transporters as well as drug-metabolizing and antioxidant enzymes functioning in these cells contribute to a metabolic barrier. These barrier properties reflect a neuroprotective function of the choroid plexus. The choroid plexuses develop early during embryogenesis and provide pivotal control of the internal environment throughout development when the brain is especially vulnerable to toxic insults. Perinatal injuries like hypoxia and trauma, and exposure to drugs or toxic xenobiotics can have serious consequences on neurogenesis and long-term development. The present study describes the developmental expression pattern of genes involved in the neuroprotective functions of the blood–CSF barrier.

Methods

The transcriptome of rat lateral ventricular choroid plexuses isolated from fifteen-day-old embryos, nineteen-day old fetuses, two-day old pups, and adults was analyzed by a combination of Affymetrix microarrays, Illumina RNA-Sequencing, and quantitative RT-PCR.

Results

Genes coding for proteins involved in junction formation are expressed early during development. Overall perinatal expression levels of genes involved in drug metabolism and antioxidant mechanisms are similar to, or higher than levels measured in adults. A similar developmental pattern was observed for multispecific efflux transporter genes of the Abc and Slc superfamilies. Expression of all these genes was more variable in choroid plexus from fifteen-day-old embryos. A large panel of transcription factors involved in the xenobiotic- or cell stress-mediated induction of detoxifying enzymes and transporters is also expressed throughout development.

Conclusions

This transcriptomic analysis suggests relatively well–established neuroprotective mechanisms at the blood-CSF barrier throughout development of the rat. The expression of many transcription factors early in development raises the possibility of additional protection for the vulnerable developing brain, should the fetus or newborn be exposed to drugs or other xenobiotics.
Individual differences effects on the psychological refractory period
Authors: Laguë-Beauvais Maude , Gagnon Christine , Castonguay Nathalie , Bherer Louis
Published: August 2013

The goal of this study was to assess the impact of individual neuropsychological differences on the ability to share attention between concurrent tasks. Participants (n = 20) were trained on six single task practice sessions and dual-task was assessed with reaction time performance on a psychological refractory period (PRP) paradigm. Neuropsychological test scores were also acquired. Furthermore, one of the known variables that can influence performances on neuropsychological tests is gender, which was added as a potential predictor. Results show that the small PRP group was associated with better performances in processing speed, inhibition, flexibility and working memory on neuropsychological tests. Gender also had an impact on the PRP, males having a lower PRP than females. A multiple regression was performed to determine which variables explained the most PRP duration, which showed that 49.1% of the variance of the PRP length could be explained by gender, reaction times of the PRP practice trials at the sixth session, the denomination and flexibility conditions of the Modified Stroop Task as well as results on the Symbol Search Test. Gender was the variable that explained the PRP variance the most (23%). Processing speed also seemed to be a great determinant of the PRP as well as the ability to alternate between task-sets as assessed by the Flexibility condition of the Modified Stroop Task. Thus, this study reveals that good performances on certain neuropsychological tests could predict one’s ease to manage two tasks simultaneously with a higher chance for males to perform better.
Dentoalveolar class III treatment using retromolar miniscrew anchorage
Authors: Poletti Laura , Silvera Aimara A , Ghislanzoni Luis T Huanca
Published: August 2013

In this article, we report the successful use of miniscrews in the distalization of the lower dentition to correct an Angle class III malocclusion with lower anterior crowding in a dolichofacial adult patient. Conventional intraoral and extraoral appliances have many disadvantages, including the need for patient cooperation, potential for anchorage loss, and vertical extrusion of upper molars and lower incisors. Extrusion should be prevented or minimized when treating long-faced patients with reduced overbite. After third molar extractions, miniscrews were placed in the retromolar area. A sliding jig was applied to distalize the lower molars, while the anterior teeth were bonded and retracted secondarily to avoid round tripping. After 18 months of treatment, molar and canine class I relationship with normal overjet and overbite were achieved. In addition, there was an esthetic improvement in the profile with only a small increase of the lower anterior facial height. These results remained stable at a 12-month follow-up.
A comparative phenotypic and genomic analysis of C57BL/6J and C57BL/6N mouse strains
Authors: Simon Michelle M , Greenaway Simon , White Jacqueline K , Fuchs Helmut , Gailus-Durner Valérie , Wells Sara , Sorg Tania , Wong Kim , Bedu Elodie , Cartwright Elizabeth J , Dacquin Romain , Djebali Sophia , Estabel Jeanne , Graw Jochen , Ingham Neil J , Jackson Ian J , Lengeling Andreas , Mandillo Silvia , Marvel Jacqueline , Meziane Hamid , Preitner Frédéric , Puk Oliver , Roux Michel , Adams David J , Atkins Sarah , Ayadi Abdel , Becker Lore , Blake Andrew , Brooker Debra , Cater Heather , Champy Marie-France , Combe Roy , Danecek Petr , di Fenza Armida , Gates Hilary , Gerdin Anna-Karin , Golini Elisabetta , Hancock John M , Hans Wolfgang , Hölter Sabine M , Hough Tertius , Jurdic Pierre , Keane Thomas M , Morgan Hugh , Müller Werner , Neff Frauke , Nicholson George , Pasche Bastian , Roberson Laura-Anne , Rozman Jan , Sanderson Mark , Santos Luis , Selloum Mohammed , Shannon Carl , Southwell Anne , Tocchini-Valentini Glauco P , Vancollie Valerie E , Westerberg Henrik , Wurst Wolfgang , Zi Min , Yalcin Binnaz , Ramirez-Solis Ramiro , Steel Karen P , Mallon Ann-Marie , de Angelis Martin Hrabě , Herault Yann , Brown Steve DM
Published: August 2013

Background

The mouse inbred line C57BL/6J is widely used in mouse genetics and its genome has been incorporated into many genetic reference populations. More recently large initiatives such as the International Knockout Mouse Consortium (IKMC) are using the C57BL/6N mouse strain to generate null alleles for all mouse genes. Hence both strains are now widely used in mouse genetics studies. Here we perform a comprehensive genomic and phenotypic analysis of the two strains to identify differences that may influence their underlying genetic mechanisms.

Results

We undertake genome sequence comparisons of C57BL/6J and C57BL/6N to identify SNPs, indels and structural variants, with a focus on identifying all coding variants. We annotate 34 SNPs and 2 indels that distinguish C57BL/6J and C57BL/6N coding sequences, as well as 15 structural variants that overlap a gene. In parallel we assess the comparative phenotypes of the two inbred lines utilizing the EMPReSSslim phenotyping pipeline, a broad based assessment encompassing diverse biological systems. We perform additional secondary phenotyping assessments to explore other phenotype domains and to elaborate phenotype differences identified in the primary assessment. We uncover significant phenotypic differences between the two lines, replicated across multiple centers, in a number of physiological, biochemical and behavioral systems.

Conclusions

Comparison of C57BL/6J and C57BL/6N demonstrates a range of phenotypic differences that have the potential to impact upon penetrance and expressivity of mutational effects in these strains. Moreover, the sequence variants we identify provide a set of candidate genes for the phenotypic differences observed between the two strains.
Phagocyte dysfunction in polymyalgia rheumatica and other age-related, chronic, inflammatory conditions
Authors: Álvarez-Rodríguez Lorena , López-Hoyos Marcos , Calvo-Alén Jaime , Aurrecoechea Elena , Villa Ignacio , Martínez-Taboada Víctor Manuel
Published: August 2013

This study was conducted to evaluate phagocyte function in patients with age-related chronic inflammatory conditions. It included 95 patients with PMR, 17 with GCA, 40 with EORA, and 25 age-matched HCs. Serum IL-8 was determined with a bead array. The chemotactic capacity, phagocytic ability, and oxidative burst activity of circulating leukocytes were determined with flow cytometry kits. Patients with active chronic inflammatory diseases showed a significant increase in circulating levels of IL-8 that remained elevated in patients with PMR or EORA, despite treatment. No correlation was found between circulating IL-8 and the migratoty capacity of neutrophils. Neutrophils from patients with active EORA without stimulus and after fMLP stimuli showed a higher capacity to migrate than those of the HCs (P=0.033). The phagocytic activity of granulocytes in the patients with GCA was significantly higher than in the HCs and the patients with PMR or EORA (P<0.05). The percentage and MFI of phagocytes that produce ROIs when stimulated with Escherichia coli was significantly reduced in neutrophils and monocytes from the patients with age-restricted inflammatory conditions. We concluded that the effector functions of phagocytes, determined to be chemotaxis, phagocytosis, and oxidative burst, are deregulated in age-restricted inflammatory disorders and may have a pathogenic role.
Editorial: Are all eotaxins created equal?
Authors: Pease James E , Williams Timothy J
Published: August 2013

Discussion of recent findings suggestive of alternative signaling via the eotaxin family of chemokines.
Military psychiatry – 100 words
Authors: Deahl Martin P.
Published: August 2013

Few have first-hand experience of military psychiatry. Military psychiatry, however, has had a substantial impact on us: WWI and ‘shell shock‘, the ‘Northfield experiments’ of WWII, engendering a sense of therapeutic optimism, helping fuel the ‘care in the community’ movement and development of modern psychotherapy. PTSD and ‘Gulf War’ illnesses have stimulated critical reappraisal of psychiatric diagnosis, nosology, Cartesian dualism and hysteria. Servicemen and veterans have served and suffered in our name. We, in turn, have a duty to respect their sacrifice and this intellectual legacy by better understanding their needs, so we, in turn, can serve them more effectively.
Cavum septum pellucidum and psychopathy
Authors: Toivonen Päivi , Könönen Mervi , Niskanen Eini , Vaurio Olli , Repo-Tiihonen Eila , Seppänen Allan , Aronen Hannu J. , Vanninen Ritva , Tiihonen Jari , Laakso Mikko P.
Published: August 2013

The presence of cavum septum pellucidum (CSP) has been reported to be a neurodevelopmental marker of psychopathy. We scanned 26 violent offenders and 25 controls; 2 offenders and 2 controls had CSP (8% in both groups). Thus, the presence of CSP is not a common or a unique feature of antisocial personality disorder or psychopathy.
Attention-deficit hyperactivity disorder and the shifting sands of psychiatric nosology
Authors: Faraone Stephen V.
Published: August 2013

Larsson et al provide epidemiological evidence for a genetic association between attention-deficit hyperactivity disorder (ADHD) and both bipolar disorder and schizophrenia and Hamshere and colleagues confirm the latter association with genome-wide data. Although a genetic link between ADHD and bipolar disorder has been hypothesised for over a decade, the association with schizophrenia fills a notable gap in the literature. This editorial discusses the implications of these findings for clinicians, who must address psychiatric comorbidity in their treatment formulations, and researchers who are learning that the discrete categorical diagnoses of our diagnostic systems may not be up to the task of clarifying the causes and cures of psychopathology.
Scottish psychiatrists' attitudes to electroconvulsive therapy: survey analysis
Authors: Martin Fiona , Elworthy Tim
Published: August 2013

Aims and method

Electroconvulsive therapy (ECT) prescription rates in Scotland are decreasing. This study aims to look for possible causes, in particular psychiatrists' attitudes. Ninety-one Scottish psychiatrists completed a survey in 2009 relating to demographics, training, current practice, National Institute for Health and Care Excellence (NICE) guidelines and attitudes.

Results

The mean number of times the psychiatrists had prescribed ECT in the past 2 years was twice. About 43% felt that their prescribing rates had decreased. Reasons for this included more effective medication, public and patient perception, and NICE guidelines. There was a significant correlation between doctors' gender and estimated prescription rates (P= 0.004), however, not with other prescription data. Almost all surveyed psychiatrists (97%) agreed that ECT has a place in current psychiatric practice.

Clinical implications

Despite generally positive attitudes to ECT shown by psychiatrists in this study, prescription rates were low and decreasing. With more effective medication the role of ECT in therapy appears to be changing.
New estimates of Hilbert–Kunz multiplicities for local rings of fixed dimension
Authors: Aberbach Ian M. , Enescu Florian
Published: August 2013

We present results on the Watanabe–Yoshida conjecture for the Hilbert–Kunz multiplicity of a local ring of positive characteristic. By improving on a “volume estimate” giving a lower bound for Hilbert–Kunz multiplicity, we obtain the conjecture when the ring has either Hilbert–Samuel multiplicity less than or equal to 5 or dimension less than or equal to 6. For nonregular rings with fixed dimension, a new lower bound for the Hilbert–Kunz multiplicity is obtained.
GDNF is required for neural colonization of the pancreas
Authors: Muñoz-Bravo José Luis , Hidalgo-Figueroa María , Pascual Alberto , López-Barneo José , Leal-Cerro Alfonso , Cano David A.
Published: August 2013

The mammalian pancreas is densely innervated by both the sympathetic and parasympathetic nervous systems, which control exocrine and endocrine secretion. During embryonic development, neural crest cells migrating in a rostrocaudal direction populate the gut, giving rise to neural progenitor cells. Recent studies in mice have shown that neural crest cells enter the pancreatic epithelium at E11.5. However, the cues that guide the migration of neural progenitors into the pancreas are poorly defined. In this study we identify glial cell line-derived neurotrophic factor (GDNF) as a key player in this process. GDNF displays a dynamic expression pattern during embryonic development that parallels the chronology of migration and differentiation of neural crest derivatives in the pancreas. Conditional inactivation of Gdnf in the pancreatic epithelium results in a dramatic loss of neuronal and glial cells and in reduced parasympathetic innervation in the pancreas. Importantly, the innervation of other regions of the gut remains unaffected. Analysis of Gdnf mutant mouse embryos and ex vivo experiments indicate that GDNF produced in the pancreas acts as a neurotrophic factor for gut-resident neural progenitor cells. Our data further show that exogenous GDNF promotes the proliferation of pancreatic progenitor cells in organ culture. In summary, our results point to GDNF as crucial for the development of the intrinsic innervation of the pancreas.
TEAD4 establishes the energy homeostasis essential for blastocoel formation
Authors: Kaneko Kotaro J. , DePamphilis Melvin L.
Published: August 2013

It has been suggested that during mouse preimplantation development, the zygotically expressed transcription factor TEAD4 is essential for specification of the trophectoderm lineage required for producing a blastocyst. Here we show that blastocysts can form without TEAD4 but that TEAD4 is required to prevent oxidative stress when blastocoel formation is accompanied by increased oxidative phosphorylation that leads to the production of reactive oxygen species (ROS). Both two-cell and eight-cell Tead4-/- embryos developed into blastocysts when cultured under conditions that alleviate oxidative stress, and Tead4-/- blastocysts that formed under these conditions expressed trophectoderm-associated genes. Therefore, TEAD4 is not required for specification of the trophectoderm lineage. Once the trophectoderm was specified, Tead4 was not essential for either proliferation or differentiation of trophoblast cells in culture. However, ablation of Tead4 in trophoblast cells resulted in reduced mitochondrial membrane potential. Moreover, Tead4 suppressed ROS in embryos and embryonic fibroblasts. Finally, ectopically expressed TEAD4 protein could localize to the mitochondria as well as to the nucleus, a property not shared by other members of the TEAD family. These results reveal that TEAD4 plays a crucial role in maintaining energy homeostasis during preimplantation development.
Cell fate respecification and cell division orientation drive intercalary regeneration in Drosophila wing discs
Authors: Repiso Ada , Bergantiños Cora , Serras Florenci
Published: August 2013

To understand the cellular parameters that govern Drosophila wing disc regeneration, we genetically eliminated specific stripes of the wing disc along the proximodistal axis and used vein and intervein markers to trace tissue regeneration. We found that veins could regenerate interveins and vice versa, indicating respecification of cell fates. Moreover, respecification occurred in cells close to the wound. The newly generated domains were intercalated to fill in the missing parts. This intercalation was driven by increased proliferation, accompanied by changes in the orientation of the cell divisions. This reorientation depended on Fat (Ft) and Crumbs (Crb), which acted, at least partly, to control the activity of the effector of the Hippo pathway, Yorkie (Yki). Increased Yki, which promotes proliferation, affected the final shape and size. Heterozygous ft or crb, which normally elicit size and shape defects in regenerated wings, could be rescued by yki heterozygosity. Thus, Ft and Crb act as sensors to drive cell orientation during intercalary regeneration and control Yki levels to ensure a proper balance between proliferation and cell reorientation. We propose a model based on intercalation of missing cell identities, in which a coordinated balance between orientation and proliferation is required for normal organ shape and size.
Phosphorylation of RNA polymerase II is independent of P-TEFb in the C. elegans germline
Authors: Bowman Elizabeth Anne , Bowman Christopher Ray , Ahn Jeong H. , Kelly William G.
Published: August 2013

RNA polymerase II (Pol II) elongation in metazoans is thought to require phosphorylation of serine 2 (Ser2-P) of the Pol II C-terminal domain (CTD) by the P-TEFb complex, CDK-9/cyclin T. Another Ser2 kinase complex, CDK-12/cyclin K, which requires upstream CDK-9 activity has been identified in Drosophila and human cells. We show that regulation of Ser2-P in C. elegans soma is similar to other metazoan systems, but Ser2-P in the germline is independent of CDK-9, and largely requires only CDK-12. The observed differences are not due to differential tissue expression as both kinases and their cyclin partners are ubiquitously expressed. Surprisingly, loss of CDK-9 from germ cells has little effect on Ser2-P, yet CDK-9 is essential for germline development. By contrast, loss of CDK-12 and Ser2-P specifically from germ cells has little impact on germline development or function, although significant loss of co-transcriptional H3K36 trimethylation is observed. These results show a reduced requirement for Pol II Ser2-P in germline development and suggest that generating Ser2-P is not the essential role of CDK-9 in these cells. Transcriptional elongation in the C. elegans germline thus appears to be uniquely regulated, which may be a novel facet of germline identity.
Abdominal-B and caudal inhibit the formation of specific neuroblasts in the Drosophila tail region
Authors: Birkholz Oliver , Vef Olaf , Rogulja-Ortmann Ana , Berger Christian , Technau Gerhard M.
Published: August 2013

The central nervous system of Drosophila melanogaster consists of fused segmental units (neuromeres), each generated by a characteristic number of neural stem cells (neuroblasts). In the embryo, thoracic and anterior abdominal neuromeres are almost equally sized and formed by repetitive sets of neuroblasts, whereas the terminal abdominal neuromeres are generated by significantly smaller populations of progenitor cells. Here we investigated the role of the Hox gene Abdominal-B in shaping the terminal neuromeres. We show that the regulatory isoform of Abdominal-B (Abd-B.r) not only confers abdominal fate to specific neuroblasts (e.g. NB6-4) and regulates programmed cell death of several progeny cells within certain neuroblast lineages (e.g. NB3-3) in parasegment 14, but also inhibits the formation of a specific set of neuroblasts in parasegment 15 (including NB7-3). We further show that Abd-B.r requires cooperation of the ParaHox gene caudal to unfold its full competence concerning neuroblast inhibition and specification. Thus, our findings demonstrate that combined action of Abdominal-B and caudal contributes to the size and composition of the terminal neuromeres by regulating both the number and lineages of specific neuroblasts.
Trafficking of the EGFR ligand Spitz regulates its signaling activity in polarized tissues
Authors: Steinhauer Josefa , Liu Hui Hua , Miller Eli , Treisman Jessica E.
Published: August 2013

Epidermal growth factor receptor (EGFR) ligands undergo a complex series of processing events during their maturation to active signaling proteins. Like its mammalian homologs, the predominant Drosophila EGFR ligand Spitz is produced as a transmembrane pro-protein. In the secretory pathway, Spitz is cleaved within its transmembrane domain to release the extracellular signaling domain. This domain is modified with an N-terminal palmitate group that tethers it to the plasma membrane. We found that the pro-protein can reach the cell surface in the absence of proteolysis, but that it fails to activate the EGFR. To address why the transmembrane pro-protein is inactive, whereas membrane association through the palmitate group promotes activity, we generated a panel of chimeric constructs containing the Spitz extracellular region fused to exogenous transmembrane proteins. Although the orientation of the EGF domain and its distance from the plasma membrane varies in these chimeras, they are all active in vivo. Thus, tethering Spitz to the membrane via a transmembrane domain at either terminus does not prevent activity. Conversely, removing the N-terminal palmitate group from the C-terminally tethered pro-protein does not render it active. Furthermore, we show that the Spitz transmembrane pro-protein can activate the EGFR in a tissue culture assay, indicating that its failure to signal in vivo is not due to structural features. In polarized imaginal disc cells, unprocessed Spitz pro-protein localizes to apical puncta, whereas the active chimeric Spitz constructs are basolaterally localized. Taken together, our data support the model that localized trafficking of the pro-protein restricts its ability to activate the receptor in polarized tissues.