bluuebunny/crossref_metadata_2025 huggingface dataset:
Proposing a new framework
Authors: Lebo Franklin Barr
Published: May 2016

The Chinese experience following the Cultural Revolution (circa. 1966–1976) in adjusting from a period of great human suffering and civil chaos to one of relative normalcy deserves placement within the larger transitional justice literature. As an early example of conflict transformation and reconciliation that restored legitimacy to the Chinese Communist Party (CCP) through not only substantive reforms, but also history revision, controlled outlets for communal venting, and the scapegoating of outgoing officials, the Chinese case challenges scholarly assumptions that competent transition policies must be rooted exclusively in truth and justice. This article thus concludes with a new approach for evaluating reconciliation processes that accounts for the disparate array of national experiences including, amongst others, Germany, Rwanda, South Africa, Guatemala, China, Ecuador, and Spain. Such modeling is necessary to press the transitional justice literature toward a more theoretically driven evaluation of conflict transformation and reconciliation policies.
Advancing the Practice of Health Coaching
Authors: Huffman Melinda H.
Published: May 2016

The increasing demand for health coaches and wellness coaches in worksite health promotion and the marketplace has resulted in a plethora of training programs with wide variations in coaching definitions, content, attributes, and eligibility of those who may train. It is in the interest of public awareness and safety that those in clinical practice take the lead in this discussion and offer a reasonable contrast and comparison focusing on the risks and responsibilities of health coaching in particular. With the endorsement of the American Association of Occupational Health Nurses (AAOHN), the National Society of Health Coaches, whose membership is primarily nurses, discusses the issue and states its position here.
Food Malayan Berhad’s Intention to Grow Its Businesses
Authors: Tan Albert , Mitra Sumit
Published: May 2016

This case concerns and discusses how a company can shape its growth strategy, given the current competitive environment and increasing operating costs. The case will help students to realize the important of aligning its business objectives with its operations. The food industry is facing declining profit margins due to fierce competition internally and also from overseas competitors. It is, therefore, important to align its strategies with its operations to grow its revenue while reducing its operating costs.
The Communist Party of India (Marxist) and the Left Government in West Bengal, 1977–2011: Strains of Governance and Socialist Imagination
Authors: Löfgren Hans
Published: May 2016

This article appraises the role of the Communist Party of India (Marxist) (CPM) in West Bengal, where the CPM-led Left Front formed government uninterruptedly between 1977 and 2011. It identifies four phases of Left politics in West Bengal: the period during which communists built support for a programme of radical transformation; the post-1977 years when the Left Front introduced land reform and effective local government that produced a ‘party society’ in rural areas; a third stage when popular support was subverted through clientelism tinged with coercion and petty corruption; and the 1990s, when growth in agricultural output petered out, the proportion of landless labourers increased and employment in manufacturing stagnated. The Left had also not delivered significant progress in social policy. The CPM turned to corporate investments and special economic zones. This trajectory points to problems of party ideology and the imperative of renewal to devise an anti-capitalist strategy.
Review of Diagnosis-Related Group-Based Financing of Hospital Care
Authors: Mihailovic Natasa , Kocic Sanja , Jakovljevic Mihajlo
Published: May 2016

Since the 1990s, diagnosis-related group (DRG)-based payment systems were gradually introduced in many countries. The main design characteristics of a DRG-based payment system are an exhaustive patient case classification system (ie, the system of diagnosis-related groupings) and the payment formula, which is based on the base rate multiplied by a relative cost weight specific for each DRG. Cases within the same DRG code group are expected to undergo similar clinical evolution. Consecutively, they should incur the costs of diagnostics and treatment within a predefined scale. Such predictability was proven in a number of cost-of-illness studies conducted on major prosperity diseases alongside clinical trials on efficiency. This was the case with risky pregnancies, chronic obstructive pulmonary disease, diabetes, depression, alcohol addiction, hepatitis, and cancer. This article presents experience of introduced DRG-based payments in countries of western and eastern Europe, Scandinavia, United States, Canada, and Australia. This article presents the results of few selected reviews and systematic reviews of the following evidence: published reports on health system reforms by World Health Organization, World Bank, Organization for Economic Co-operation and Development, Canadian Institute for Health Information, Canadian Health Services Research Foundation, and Centre for Health Economics University of York. Diverse payment systems have different strengths and weaknesses in relation to the various objectives. The advantages of the DRG payment system are reflected in the increased efficiency and transparency and reduced average length of stay. The disadvantage of DRG is creating financial incentives toward earlier hospital discharges. Occasionally, such polices are not in full accordance with the clinical benefit priorities.
CHAMPION-1: a phase 1/2 study of once-weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma
Authors: Berenson James R. , Cartmell Alan , Bessudo Alberto , Lyons Roger M. , Harb Wael , Tzachanis Dimitrios , Agajanian Richy , Boccia Ralph , Coleman Morton , Moss Robert A. , Rifkin Robert M. , Patel Priti , Dixon Sandra , Ou Ying , Anderl Janet , Aggarwal Sanjay , Berdeja Jesus G.
Published: May 2016

Key Points

The CHAMPION-1 study is the first clinical trial to investigate carfilzomib on a once-weekly dosing schedule with dexamethasone. Once-weekly carfilzomib (30-minute infusion; 20 and 70 mg/m2) with dexamethasone is feasible and effective in relapsed/refractory MM.
Predictive and prognostic factors in patients with blood-culture-positive community-acquired pneumococcal pneumonia
Authors: Amaro Rosanel , Liapikou Adamantia , Cilloniz Catia , Gabarrus Albert , Marco Francesc , Sellares Jacobo , Polverino Eva , Garau Javier , Ferrer Miquel , Musher Daniel M. , Torres Antoni
Published: May 2016

In patients with pneumococcal community-acquired pneumonia (CAP), the risk factors for bacteraemia and its impact on outcomes are not fully elucidated. We aimed to compare characteristics of patients with blood-culture-positiveversusblood-culture-negative pneumococcal CAP, and to characterise bacteraemic serotypes.

We describe a prospective, observational study on nonimmunocompromised patients with pneumococcal CAP, from 1996 to 2013. We define severe pneumonia according to American Thoracic Society/Infectious Diseases Society of America guidelines.

Of a total of 917 patients with pneumococcal CAP, 362 had blood-culture-positive pneumococcal pneumonia (BCPPP; 39%). High C-reactive protein (CRP) (≥20 mg·dL−1) (odds ratio (OR) 2.36, 95% CI 1.45–3.85), pleural effusion (OR 2.03, 95% CI 1.13–3.65) and multilobar involvement (OR 1.69, 95% CI 1.02–2.79) were independently associated with bacteraemic CAP, while nursing home resident (OR 0.12, 95% CI 0.01–1.00) was found as a protective factor. Despite the clinical differences, BCPPP showed similar outcomes to blood-culture-negative pneumococcal pneumonia (BCNPP). 14% of the serotypes (period 2006–2013) causing bacteraemia are included in pneumococcal conjugate vaccine PVC7, 74% in pneumococcal conjugate vaccine PVC13 and 83% in pneumococcal polysaccharide vaccine PPSV23.

Pleural effusion, a high level of CRP and multilobar involvement predicted an increased risk of BCPPP. Although BCPPP patients were more severely ill at admission, mortality was not significantly greater than in BCNPP patients.
Incidence and familial risk of pleural mesothelioma in Sweden: a national cohort study
Authors: Ji Jianguang , Sundquist Jan , Sundquist Kristina
Published: May 2016

Familial clustering of pleural mesothelioma was reported previously, but none of the reports quantified the familial risk of mesothelioma or the association with other cancers. The contributions of shared environmental or genetic factors to the aggregation of mesothelioma were unknown.

We used a number of Swedish registers, including the Swedish Multigeneration Register and the Swedish Cancer Register, to examine the familial risk of mesothelioma in offspring. Standardised incidence ratios (SIRs) were used to calculate the risk. Age standardised incidence rates of mesothelioma were calculated from the Swedish Cancer Registry.

The incidence of mesothelioma reached its peak rate in 2000 and decreased thereafter. Risk of mesothelioma was significantly increased when parents or siblings were diagnosed with mesothelioma, with SIRs of 3.88 (95% CI 1.01–10.04) and 12.37 (95% CI 5.89–22.84), respectively. Mesothelioma was associated with kidney (SIR 2.13, 95% CI 1.16–3.59) and bladder cancers (SIR 2.09, 95% CI 1.32–3.14) in siblings. No association was found between spouses.

Family history of mesothelioma, including both parental and sibling history, is an important risk factor for mesothelioma. Shared genetic factors may contribute to the observed familial clustering of mesothelioma, but the contribution of shared environmental factors could not be neglected. The association with kidney and bladder cancers calls for further study to explore the underlying mechanisms.
Mediating pathways from central obesity to childhood asthma: a population-based longitudinal study
Authors: Chih An-Hsuan , Chen Yang-Ching , Tu Yu-Kang , Huang Kuo-Chin , Chiu Tai-Yuan , Lee Yungling Leo
Published: May 2016

The mediating pathways linking obesity and asthma are largely unknown. We aimed to investigate the mediating pathways and to search for the most prominent pathological mechanism between central obesity and childhood asthma.

In the Taiwan Children Health Study, we collected data on an open cohort of children aged 9–13 years. Children's respiratory outcomes, atopic conditions, obesity measures and pulmonary function were surveyed annually between 2010 and 2012. Exhaled nitric oxide fraction concentrations were recorded in 2012. Generalised estimating equations and general linear models were used to examine the associations between central obesity, possible mediators and asthma. Structural equation models were applied to investigate the pathways that mediate the link between central obesity and asthma.

Central obesity (waist-to-hip ratio) most accurately predicted childhood asthma. In the active asthma model, the percentage of mediation was 28.6% for pulmonary function, 18.1% for atopy and 5.7% for airway inflammation. The percentage of mediation for pulmonary function was 40.2% in the lifetime wheeze model. Pulmonary function was responsible for the greatest percentage of mediation among the three mediators in both models.

Decline in pulmonary function is the most important pathway in central obesity related asthma. Pulmonary function screening should be applied to obese children for asthma risk prediction.
Risk factors for lung cancer worldwide
Authors: Malhotra Jyoti , Malvezzi Matteo , Negri Eva , La Vecchia Carlo , Boffetta Paolo
Published: May 2016

Lung cancer is the most frequent malignant neoplasm in most countries, and the main cancer-related cause of mortality worldwide in both sexes combined.

The geographic and temporal patterns of lung cancer incidence, as well as lung cancer mortality, on a population level are chiefly determined by tobacco consumption, the main aetiological factor in lung carcinogenesis.

Other factors such as genetic susceptibility, poor diet, occupational exposures and air pollution may act independently or in concert with tobacco smoking in shaping the descriptive epidemiology of lung cancer. Moreover, novel approaches in the classification of lung cancer based on molecular techniques have started to bring new insights to its aetiology, in particular among nonsmokers. Despite the success in delineation of tobacco smoking as the major risk factor for lung cancer, this highly preventable disease remains among the most common and most lethal cancers globally.

Future preventive efforts and research need to focus on non-cigarette tobacco smoking products, as well as better understanding of risk factors underlying lung carcinogenesis in never-smokers.
Is ventilation heterogeneity related to asthma control?
Authors: Svenningsen Sarah , Nair Parameswaran , Guo Fumin , McCormack David G. , Parraga Grace
Published: May 2016

In asthma patients, magnetic resonance imaging (MRI) and the lung clearance index (LCI) have revealed persistent ventilation heterogeneity, although its relationship to asthma control is not well understood. Therefore, our goal was to explore the relationship of MRI ventilation defects and the LCI with asthma control and quality of life in patients with severe, poorly controlled asthma.

18 patients with severe, poorly controlled asthma (mean±sd46±12 years, six males/12 females) provided written informed consent to an ethics board approved protocol, and underwent spirometry, LCI and3He MRI during a single 2-h visit. Asthma control and quality of life were evaluated using the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ). Ventilation heterogeneity was quantified using the LCI and3He MRI ventilation defect percent (VDP).

All participants reported poorly controlled disease (mean±sdACQ score=2.3±0.9) and highly heterogeneous ventilation (mean±sdVDP=12±11% and LCI=10.5±3.0). While VDP and LCI were strongly correlated (r=0.86, p<0.0001), in a multivariate model that included forced expiratory volume in 1 s, VDP and LCI, VDP was the only independent predictor of asthma control (R2=0.38, p=0.01). There was also a significantly worse VDP, but not LCI in asthma patients with an ACQ score >2 (p=0.04) and AQLQ score <5 (p=0.04), and a trend towards worse VDP (p=0.053), but not LCI in asthma patients reporting ≥1 exacerbation in the past 6 months.

In patients with poorly controlled, severe asthma MRI ventilation, but not LCI was significantly worse in those with worse ACQ and AQLQ.
Effects of Usag-1 and Bmp7 deficiencies on murine tooth morphogenesis
Authors: Saito Kazuyuki , Takahashi Katsu , Asahara Masakazu , Kiso Honoka , Togo Yumiko , Tsukamoto Hiroko , Huang Boyen , Sugai Manabu , Shimizu Akira , Motokawa Masaharu , Slavkin Harold C. , Bessho Kazuhisa
Published: May 2016

Background

Wnt5a and Mrfzb1 genes are involved in the regulation of tooth size, and their expression levels are similar to that of Bmp7 during morphogenesis, including during the cap and early bell stages of tooth formation. We previously reported that Usag-1-deficient mice form supernumerary maxillary incisors. Thus, we hypothesized that BMP7 and USAG-1 signaling molecules may play important roles in tooth morphogenesis. In this study, we established double genetically modified mice to examine the in vivo inter-relationships between Bmp7 and Usag-1.

Results

We measured the volume and cross-sectional areas of the mandibular incisors using micro-computed tomography (micro-CT) in adult Bmp7- and Usag-1-LacZ knock-in mice and their F2 generation upon interbreeding. The mandibular incisors of adult Bmp7+/− mice were significantly larger than those of wild-type (WT) mice. The mandibular incisors of adult Usag-1−/− mice were the largest of all genotypes examined. In the F2 generation, the effects of these genes were additive; Bmp7+/− was most strongly associated with the increase in tooth size using generalized linear models, and the total area of mandibular supernumerary incisors of Usag-1−/−Bmp7+/− mice was significantly larger than that of Usag-1−/−Bmp7 +/+ mice. At embryonic day 15 (E15), BrdU assays demonstrated that the labeling index of Bmp7+/− embryos was significantly higher than that of WT embryos in the cervical loop. Additionally, the labeling index of Usag-1−/− embryos was significantly the highest of all genotypes examined in dental papilla.

Conclusions

Bmp7 heterozygous mice exhibited significantly increased tooth sizes, suggesting that tooth size was controlled by specific gene expression. Our findings may be useful in applications of regenerative medicine and dentistry.
The algorithm for Alzheimer risk assessment based on APOE promoter polymorphisms
Authors: Limon-Sztencel Anna , Lipska-Ziętkiewicz Beata S. , Chmara Magdalena , Wasag Bartosz , Bidzan Leszek , Godlewska Beata R. , Limon Janusz
Published: May 2016

Background

Over the past two decades, the APOE gene and its polymorphisms have been among the most studied risk factors of Alzheimer disease (AD) development; yet, there are discrepancies between various studies regarding their impact. For this reason, the evaluation of the APOE genotype has not been included in the current European Federation of Neurological Societies guidelines for AD diagnosis and management. This aim of this study was to add to this discussion by assessing the possible influence of multiple polymorphisms in the promoter region of the APOE gene and genotypes of its allele E on the risk for dementia.

Methods

We performed a comprehensive analysis of APOE gene polymorphisms, assessed the detected genotypes and correlated molecular findings with serum apolipoprotein E concentrations. The study comprised 110 patients with AD and 110 age-matched healthy individuals from the Polish population.

Results

Four polymorphisms of the APOE gene had minor allele frequency exceeding 5 % and were included in the analysis: −491A/T (rs449647), −427T/C (rs769446), −219T/G (rs405509) in the promoter region and +113G/C (rs440446) in intron 1. A protective effect of the −219G allele on AD development was observed. Also, the −491T and −219G alleles were found to be underrepresented in the carriers of the APOE E4 variant. On the basis of the genotype and linkage disequilibrium studies, a relative score was attributed to given genotypes with respect to the estimated probability of their protective effects against AD, giving rise to the ‘preventive score’. This ‘preventive score’, based on the total sums of the relative scores, expresses the protective effect deriving from the synergistic action of individual single-nucleotide polymorphisms. The ‘preventive score’ was identified as an independent predictive factor.

Conclusions

We propose a novel, more complex approach to AD risk assessment based on the additive effect of multiple polymorphic loci within the APOE promoter region, which on their own may have too weak an impact to reach the level of significance. This has potentially practical implications, as it may help to improve the informative potential of APOE testing in a clinical setting. Subsequent studies of the proposed system in large, multi-ethnic cohorts are necessary for its validation and to assess its potential practical value for clinical applications.
What happened to collective bargaining during the great recession?
Authors: Visser Jelle
Published: May 2016

Collective bargaining over labour conditions between unions and employers is a key labour market institution in democratic societies, guaranteed by international and national law. Its coverage, organization and impact have varied over time and across countries. Inclusive bargaining, conducted by employers’ associations with a mandate to bargain, and supported by the state, received a strong impulse during the interwar Depression. In the Great Recession a more exclusive version based on enterprise bargaining appears to have been favoured by governments and international agencies. How this relates to changes in bargaining coverage, multi-employer and multi-level bargaining, rules on extension and opening clauses is the subject of this paper, which surveys developments in 38 OECD and EU countries. A distinction is made between long-term and crisis-related changes, and between regulatory and non-regulatory changes during the Great Recession.
The cost of immigrants’ occupational mismatch and the effectiveness of postarrival policies in Canada
Authors: Aydede Yigit , Dar Atul
Published: May 2016

Using the 2006 Census, we create a continuous index that quantifies the relatedness between 1375 fields of study and 520 occupations for native-born workers and use it as the benchmark reflecting the “common” matching quality in Canadian labor markets that internationally educated immigrant workers could achieve in the long run. This allows us to approximate the cost of the occupational mismatch of immigrants by estimating the change in their earnings had they been distributed identically to the native born in terms of relatedness. Although the results show a significant and persistent poor matching quality for foreign-educated immigrants, their relative underutilization cost is negligible.

Jel codes: J6, J15, J61
Perspectives on Optimizing Care of Patients in Multidisciplinary Chronic Kidney Disease Clinics
Authors: Collister David , Russell Randall , Verdon Josee , Beaulieu Monica , Levin Adeera
Published: May 2016

Purpose of review:

To summarize a jointly held symposium by the Canadian Society of Nephrology (CSN), the Canadian Association of Nephrology Administrators (CANA), and the Canadian Kidney Knowledge Translation and Generation Network (CANN-NET) entitled “Perspectives on Optimizing Care of Patients in Multidisciplinary Chronic Kidney Disease (CKD) Clinics” that was held on April 24, 2015, in Montreal, Quebec.

Sources of information:

The panel consisted of a variety of members from across Canada including a multidisciplinary CKD clinic patient (Randall Russell), nephrology fellow (Dr. David Collister), geriatrician (Dr. Josee Verdon), and nephrologists (Dr. Monica Beaulieu, Dr. Adeera Levin).

Findings:

The objectives of the symposium were (1) to gain an understanding of the goals of care for CKD patients, (2) to gain an appreciation of different perspectives regarding optimal care for patients with CKD, (3) to examine the components required for optimal care including education strategies, structures, and tools, and (4) to describe a framework and metrics for CKD care which respect patient and system needs. This article summarizes the key concepts discussed at the symposium from a patient and physician perspectives. Key messages include (1) understanding patient values and preferences is important as it provides a framework as to what to prioritize in multidisciplinary CKD clinic and provincial renal program models, (2) barriers to effective communication and education are common in the elderly, and adaptive strategies to limit their influence are critical to improve adherence and facilitate shared decision-making, (3) the use of standardized operating procedures (SOPs) improves efficiency and minimizes practice variability among health care practitioners, and (4) CKD scorecards with standardized system processes are useful in approaching variability as well as measuring and improving patient outcomes.

Limitations:

The perspectives provided may not be applicable across centers given the differences in patient populations including age, ethnicity, culture, language, socioeconomic status, education, and multidisciplinary CKD clinic structure and function.

Implications:

Knowledge transmission by collaborative interprovincial and interprofessional networks may play a role in facilitating optimal CKD care. Validation of system and clinic models that improve outcomes is needed prior to disseminating these best practices.
Complete genome sequence of ‘Halanaeroarchaeum sulfurireducens’ M27-SA2, a sulfur-reducing and acetate-oxidizing haloarchaeon from the deep-sea hypersaline anoxic lake Medee
Authors: Messina Enzo , Sorokin Dimitry Y. , Kublanov Ilya V. , Toshchakov Stepan , Lopatina Anna , Arcadi Erika , Smedile Francesco , La Spada Gina , La Cono Violetta , Yakimov Michail M.
Published: May 2016

Strain M27-SA2 was isolated from the deep-sea salt-saturated anoxic lake Medee, which represents one of the most hostile extreme environments on our planet. On the basis of physiological studies and phylogenetic positioning this extremely halophilic euryarchaeon belongs to a novel genus ‘Halanaeroarchaeum’ within the family Halobacteriaceae. All members of this genus cultivated so far are strict anaerobes using acetate as the sole carbon and energy source and elemental sulfur as electron acceptor. Here we report the complete genome sequence of the strain M27-SA2 which is composed of a 2,129,244-bp chromosome and a 124,256-bp plasmid. This is the second complete genome sequence within the genus Halanaeroarchaeum. We demonstrate that genome of ‘Halanaeroarchaeum sulfurireducens’ M27-SA2 harbors complete metabolic pathways for acetate and sulfur catabolism and for de novo biosynthesis of 19 amino acids. The genomic analysis also reveals that ‘Halanaeroarchaeum sulfurireducens’ M27-SA2 harbors two prophage loci and one CRISPR locus, highly similar to that of Kulunda Steppe (Altai, Russia) isolate ‘H. sulfurireducens’ HSR2T. The discovery of sulfur-respiring acetate-utilizing haloarchaeon in deep-sea hypersaline anoxic lakes has certain significance for understanding the biogeochemical functioning of these harsh ecosystems, which are incompatible with life for common organisms. Moreover, isolations of Halanaeroarchaeum members from geographically distant salt-saturated sites of different origin suggest a high degree of evolutionary success in their adaptation to this type of extreme biotopes around the world.
A Quasi Experiment to Determine the Effectiveness of a “Partially Flipped” versus “Fully Flipped” Undergraduate Class in Genetics and Evolution
Authors: Adams Alison E. M. , Garcia Jocelyn , Traustadóttir Tinna
Published: May 2016

Two sections of Genetics and Evolution were taught by one instructor. One group (the fully flipped section) had the entire class period devoted to active learning (with background material that had to be watched before class), and the other group (the partially flipped section) had just a portion of class time spent on active learning (with the background material presented during class time). The same materials and assessments were used for both sections. Analysis of objective measures revealed that there was no significant difference between the learning outcomes of students in the two sections. There was no main effect of gender, major, or ethnicity on success in the whole cohort or in either section. There appeared to be a significant main effect of class standing, with freshmen performing significantly less well than sophomores, juniors, or seniors (who all performed equally well) in both sections (p < 0.01); however, this was a very preliminary observation, as there were very few freshmen in either section. The only predictor of success in the two sections was prior grade point average. An anonymous end-of-semester survey showed no significant difference between the two sections in interest in the subject matter.
To Cull or Not To Cull? Considerations for Studies of Endocrine-Disrupting Chemicals
Authors: Suvorov Alexander , Vandenberg Laura N.
Published: May 2016

The power of animal models is derived from the ability to control experimental variables so that observed effects may be unequivocally attributed to the factor that was changed. One variable that is difficult to control in animal experiments is the number and composition of offspring in a litter. To account for this variability, artificial equalization of the number of offspring in a litter (culling) is often used. The rationale for culling, however, has always been controversial. The Developmental Origins of Health and Disease concept provides a new context to evaluate the pros and cons of culling in laboratory animal studies, especially in the context of endocrine-disrupting chemicals. Emerging evidence indicates that culling, especially of large litters, can drastically change the feeding status of a pup, which can result in compensatory growth with long-term consequences for the animal, including increased risk of cardio-metabolic diseases. Similarly, culling of litters to intentionally bias sex ratios can alter the animal's behavior and physiology, with effects observed on a wide range of outcomes. Thus, in an attempt to control for variability in developmental rates, culling introduces an uncontrolled or confounding variable, which itself may affect a broad spectrum of health-related consequences. Variabilities in culling protocols could be responsible for differences in responses to endocrine-disrupting chemicals reported across studies. Because litter sex composition and size are vectors that can influence both prenatal and postnatal growth, they are essential considerations for the interpretation of results from laboratory animal studies.
Prolactin Suppression of Gonadotropin-Releasing Hormone Initiation of Mammary Gland Involution in Female Rats
Authors: Rieanrakwong Duangjai , Laoharatchatathanin Titaree , Terashima Ryota , Yonezawa Tomohiro , Kurusu Shiro , Hasegawa Yoshihisa , Kawaminami Mitsumori
Published: May 2016

It has been demonstrated that mammary gland involution after lactation is initiated by accumulation of milk in alveoli after weaning. Here, we report that involution is also dependent on mammary GnRH expression that is suppressed by PRL during lactation. Reduction of plasma prolactin (PRL) by the withdrawal of suckling stimuli increased GnRH and annexin A5 (ANXA5) expression in the mammary tissues after lactation with augmentation of epithelial apoptosis. Intramammary injection of a GnRH antagonist suppressed ANXA5 expression and apoptosis of epithelial cells after forcible weaning at midlactation, whereas local administration of GnRH agonist (GnRHa) caused apoptosis of epithelial cells with ANXA5 augmentation in lactating rats. The latter treatment also decreased mammary weight, milk production, and casein accumulation. Mammary mast cells were strongly immunopositive for GnRH and the number increased in the mammary tissues after weaning. GnRHa was shown to be a chemoattractant for mast cells by mammary local administration of GnRHa and Boyden chamber assay. PRL suppressed the mammary expression of both ANXA5 and GnRH mRNA. It also decreased mast cell numbers in the gland after lactation. These results are the first to demonstrate that GnRH, synthesized locally in the mammary tissues, is required for mammary involution after lactation. GnRH is also suggested to introduce mast cells into the regressing mammary gland and would be in favor of tissue remodeling. The suppression of these processes by PRL is a novel physiological function of PRL.
Cortistatin Is a Key Factor Regulating the Sex-Dependent Response of the GH and Stress Axes to Fasting in Mice
Authors: Cordoba-Chacón José , Gahete Manuel D. , Pozo-Salas Ana I. , de Lecea Luis , Castaño Justo P. , Luque Raúl M.
Published: May 2016

Cortistatin (CORT) shares high structural and functional similarities with somatostatin (SST) but displays unique sex-dependent pituitary actions. Indeed, although female CORT-knockout (CORT-KO) mice exhibit enhanced GH expression/secretion, Proopiomelanocortin expression, and circulating ACTH/corticosterone/ghrelin levels, male CORT-KO mice only display increased plasma GH/corticosterone levels. Changes in peripheral ghrelin and SST (rather than hypothalamic levels) seem to regulate GH/ACTH axes in CORT-KOs under fed conditions. Because changes in GH/ACTH axes during fasting provide important adaptive mechanisms, we sought to determine whether CORT absence influences GH/ACTH axes during fasting. Accordingly, fed and fasted male/female CORT-KO were compared with littermate controls. Fasting increased circulating GH levels in male/female controls but not in CORT-KO, suggesting that CORT can be a relevant regulator of GH secretion during fasting. However, GH levels were already higher in CORT-KO than in controls in fed state, which might preclude a further elevation in GH levels. Interestingly, although fasting-induced pituitary GH expression was elevated in both male/female controls, GH expression only increased in fasted female CORT-KOs, likely owing to specific changes observed in key factors controlling somatotrope responsiveness (ie, circulating ghrelin and IGF-1, and pituitary GHRH and ghrelin receptor expression). Fasting increased corticosterone levels in control and, most prominently, in CORT-KO mice, which might be associated with a desensitization to SST signaling and to an augmentation in CRH and ghrelin-signaling regulating corticotrope function. Altogether, these results provide compelling evidence that CORT plays a key, sex-dependent role in the regulation of the GH/ACTH axes in response to fasting.
Long-term drug administration in the adult zebrafish using oral gavage for cancer preclinical studies
Authors: Dang Michelle , Henderson Rachel E. , Garraway Levi A. , Zon Leonard I.
Published: May 2016

Zebrafish are a major model for chemical genetics, and most studies use embryos to find small molecules that cause interesting phenotypes or that can rescue disease models. Limited studies have dosed adults with small molecules, and relied on water-born exposure or injection techniques. Challenges in drug delivery-related trauma and anesthesia-related toxicity have prevented the adult zebrafish from long-term drug efficacy studies. Here we introduce a novel anesthetic combination of MS-222 and isoflurane to an oral gavage technique for a non-toxic, non-invasive and long-term drug administration platform. As a proof of principle, we established drug efficacy of the FDA-approved BRAFV600E inhibitor, Vemurafenib, in the adult zebrafish harboring BRAFV600E melanoma tumors. In the model, adult casper zebrafish intraperitoneally transplanted with a zebrafish melanoma cell line (ZMEL1) are exposed to daily sublethal dosing at 100 mg/kg of Vemurafenib for 2 weeks via oral gavage and resulted in an average 65% decrease in tumor burden and a 15% mortality rate. In contrast, Vemurafenib-resistant ZMEL1 cell lines, generated in culture from low-dose drug exposure for 4 months, did not respond to the oral gavage treatment regimen when transplanted into irradiated casper zebrafish. Similarly, caspers transplanted with primary BRAFV600E-mutant melanoma tumors resulted in a 65% decrease in tumor burden when gavaged daily with 100 mg/kg Vemurafenib for 2 weeks. This drug treatment regimen can be applied to adult transgenic zebrafish harboring primary melanoma tumors and resulted in a 70% decrease in tumor burden. Taken together, we developed an effective long-term drug treatment system in both a transplantation model using adult casper zebrafish and a primary melanoma model using adult transgenic zebrafish. This drug administration technique of oral gavage will allow adult zebrafish to be used to identify more effective anti-melanoma combination therapies and opens up possibilities for treating adult models of other diseases.
Dysfunction of intraflagellar transport-A causes hyperphagia-induced obesity and metabolic syndrome
Authors: Jacobs Damon T. , Silva Luciane M. , Allard Bailey A. , Schonfeld Michael P. , Chatterjee Anindita , Talbott George C. , Beier David R. , Tran Pamela V.
Published: May 2016

Primary cilia extend from the plasma membrane of most vertebrate cells and mediate signaling pathways. Ciliary dysfunction underlies ciliopathies, which are genetic syndromes that manifest multiple clinical features, including renal cystic disease and obesity. THM1 (also termed TTC21B or IFT139) encodes a component of the intraflagellar transport-A complex and mutations in THM1 have been identified in 5% of individuals with ciliopathies. Consistent with this, deletion of murine Thm1 during late embryonic development results in cystic kidney disease. Here we report that deletion of murine Thm1 during adulthood results in obesity, diabetes, hypertension and fatty liver disease, with gender differences in susceptibility to weight gain and metabolic dysfunction. Pair-feeding of Thm1 conditional knock-out mice relative to control littermates prevented the obesity and related disorders, indicating that hyperphagia caused the obese phenotype. Thm1 ablation resulted in increased localization of adenylyl cyclase III in primary cilia that were shortened with bulbous distal tips on neurons of the hypothalamic arcuate nucleus, an integrative center for signals that regulate feeding and activity. In pre-obese Thm1 conditional knock-out mice, expression of anorexogenic pro-opiomelanocortin was decreased by 50% in the arcuate nucleus, which likely caused the hyperphagia. Fasting of Thm1 conditional knock-out mice did not alter pro-opiomelanocortin nor orexogenic agouti-related peptide expression, suggesting impaired sensing of changes in peripheral signals. Together, these data indicate that the Thm1-mutant ciliary defect diminishes sensitivity to feeding signals, which alters appetite regulation and leads to hyperphagia, obesity and metabolic disease.
CYLD – a deubiquitylase that acts to fine-tune microtubule properties and functions
Authors: Yang Yunfan , Zhou Jun
Published: May 2016

Microtubules are dynamic structures that are crucially involved in a variety of cellular activities. The dynamic properties and functions of microtubules are regulated by various factors, such as tubulin isotype composition and microtubule-binding proteins. Initially identified as a deubiquitylase with tumor-suppressing functions, the protein cylindromatosis (CYLD) has recently been revealed to interact with microtubules, modulate microtubule dynamics, and participate in the regulation of cell migration, cell cycle progression, chemotherapeutic drug sensitivity and ciliogenesis. These findings have greatly enriched our understanding of the roles of CYLD in physiological and pathological conditions. Here, we focus on recent literature that shows how CYLD impacts on microtubule properties and functions in various biological processes, and discuss the challenges we face when interpreting results obtained from different experimental systems.
The Ca2+-activated Cl− channel Ano1 controls microvilli length and membrane surface area in the oocyte
Authors: Courjaret Raphael , Hodeify Rawad , Hubrack Satanay , Ibrahim Awab , Dib Maya , Daas Sahar , Machaca Khaled
Published: May 2016

Ca2+-activated Cl− channels (CaCCs) play important physiological functions in epithelia and other tissues. In frog oocytes the CaCC Ano1 regulates resting membrane potential and the block to polyspermy. Here, we show that Ano1 expression increases the oocyte surface, revealing a novel function for Ano1 in regulating cell morphology. Confocal imaging shows that Ano1 increases microvilli length, which requires ERM-protein-dependent linkage to the cytoskeleton. A dominant-negative form of the ERM protein moesin precludes the Ano1-dependent increase in membrane area. Furthermore, both full-length and the truncated dominant-negative forms of moesin co-localize with Ano1 to the microvilli, and the two proteins co-immunoprecipitate. The Ano1–moesin interaction limits Ano1 lateral membrane mobility and contributes to microvilli scaffolding, therefore stabilizing larger membrane structures. Collectively, these results reveal a newly identified role for Ano1 in shaping the plasma membrane during oogenesis, with broad implications for the regulation of microvilli in epithelia.
Solving Chance-Constrained Optimization Problems with Stochastic Quadratic Inequalities
Authors: Lejeune Miguel A. , Margot François
Published: May 2016

We propose a new and systematic reformulation and algorithmic approach to solve a complex class of stochastic programming problems involving a joint chance constraint with random technology matrix and stochastic quadratic inequalities. The method is general enough to apply to nonconvex as well as nonseparable quadratic terms. We derive two new reformulations and give sufficient conditions under which the reformulated problem is equivalent. The second reformulation provides a much sparser representation of the feasible set of the chance constraint and offers tremendous computational advantages. This new reformulation method can be used for linear stochastic inequalities and will also significantly improve the solution of such joint chance-constrained problems. We provide general and easily identifiable conditions under which the base reformulations can be linearized. We show that the size of the reformulated problems, in particular, their number of binary variables and quadratic mixed-integer terms, does not grow linearly with the number of scenarios used to represent uncertainty. We propose two new nonlinear branch-and-bound algorithms for the nonconvex quadratic integer reformulations. We present detailed empirical results, comparing the various reformulations and several algorithmic ideas that improve the performance of the mixed-integer nonlinear solver Couenne for solving these problems. Guidelines on how to tune the solver and to select reformulations are presented. The test instances are epidemiology and disaster management facility location models and cover the three types of stochastic quadratic inequalities, namely, product of two decision variables that are both binary, binary and continuous, or both continuous.
Robust Control of Partially Observable Failing Systems
Authors: Kim Michael Jong
Published: May 2016

This paper is concerned with optimal maintenance decision making in the presence of model misspecification. Specifically, we are interested in the situation where the decision maker fears that a nominal Bayesian model may be miss-specified or unrealistic, and would like to find policies that work well even when the underlying model is flawed. To this end, we formulate a robust dynamic optimization model for condition-based maintenance in which the decision maker explicitly accounts for distrust in the nominal Bayesian model by solving a worst-case problem against a second agent, “nature,” who has the ability to alter the underlying model distributions in an adversarial manner. The primary focus of our analysis is on establishing structural properties and insights that hold in the face of model miss-specification. In particular, we prove (i) an explicit characterization of nature’s optimal response through an analysis of the robust dynamic programming equation, (ii) convexity results for both the robust value function and the optimal robust stopping region, (iii) a general robustness result for the preventive maintenance paradigm, and (iv) the optimality of a robust control limit policy for the important subclass of Bayesian change point detection problems. We illustrate our theoretical result on a real-world application from the mining industry.
Online Collaborative Filtering on Graphs
Authors: Banerjee Siddhartha , Sanghavi Sujay , Shakkottai Sanjay
Published: May 2016

Existing approaches to designing recommendation systems with user feedback focus on settings where the number of items is small and/or admit some underlying structure. It is unclear, however, if these approaches extend to applications like social network news feeds and content-curation platforms, which have large and unstructured content pools and constraints on user-item recommendations. To this end, we consider the design of recommendation systems in content-rich setting—where the number of items and the number of item-views by users are of a similar order and an access graph constrains which user is allowed to see which item. In this setting, we propose recommendation algorithms that effectively exploit the access graph, and characterize how their performance depends on the graph topology. Our results demonstrate the importance of serendipity in exploration and how recommendation improves when the access graph has higher expansion; they also suggest reasons behind the success of simple algorithms like Twitter’s latest-first policy. From a technical perspective, our model presents a framework for studying explore-exploit trade-offs in large-scale settings, with potentially infinite number of items. We present algorithms with competitive-ratio guarantees under both finite-horizon and infinite-horizon settings; conversely, we demonstrate that naive policies can be highly suboptimal and also that in many settings, our results are orderwise optimal.
Inertia in Routines: A Hidden Source of Organizational Variation
Authors: Yi Sangyoon , Knudsen Thorbjørn , Becker Markus C.
Published: May 2016

Traditionally, routines have been perceived as a primary source of inertia, which slows down organizational change and hinders organizational adaptation. Advancing prior research on routine dynamics, this study examines how inertia in routines influences the process of organizational adaptation, both in the absence and presence of endogenous change of routines. Contrary to conventional wisdom, our analysis suggests an overlooked mechanism by which routine-level inertia may help, rather than hinder, organization-level adaptation. We demonstrate this mechanism by using a simple theoretical model in which the organization is characterized as a configuration of interdependent routines and study the process by which this configuration adapts to cope with its task environment. We find that inertia in routines may engender potentially useful variation in the process of organizational adaptation because reduced rates of routine-level changes may lead to temporal reordering when these changes are implemented. In our nuanced perspective, inertia is not only a consequence of adaptation or selection as perceived in prior research, but also a source of variation that turns out to be useful for adaptation. This logic is helpful to better understand why apparently inertial organizations keep surviving and from time to time exhibit outstanding performance. We conclude by discussing how this advanced understanding of the role of routines in organizational adaptation helps elaborate the theory of economic evolution.
Trace Element Contents in Bone Affected by Osteomyelitis
Authors: Zaichick Vladimir , Zaichick Sofia
Published: May 2016

To clarify the role of trace elements in the etiology and the pathogenesis of the osteomyelitis, a nondestructive neutron activation analysis with high resolution spectrometry of long-lived radionuclides were performed. The silver (Ag), cobalt (Co), chromium (Cr), iron (Fe), mercury (Hg), rubidium (Rb), antimony (Sb), selenium (Se), and zinc (Zn) mass fraction were estimated in normal bone samples from 27 patients with intact bone (12 females and 15 males, aged from 16 to 49 years), who had died from various non bone related causes, mainly unexpected from trauma, and in samples, obtained from open biopsies or after operation of 10 patients with osteomyelitis (3 females and 7 males, 9 to 21 years old). The reliability of difference in the results between intact bone and bone affected by osteomyelitis was evaluated by Student’s t-test. In the bone affected by osteomyelitis the mass fractions of Co, Cr, Fe, Se, and Zn are significantly higher than in normal bone tissues. In the inflamed bone tissue many correlations between trace elements found in the control group are no longer evident. In bone affected by osteomyelitis the trace element homeostasis is significantly disturbed.