bluuebunny/crossref_metadata_2025 huggingface dataset:
miR-24 triggers epidermal differentiation by controlling actin adhesion and cell migration
Authors: Amelio Ivano , Lena Anna Maria , Viticchiè Giuditta , Shalom-Feuerstein Ruby , Terrinoni Alessandro , Dinsdale David , Russo Giandomenico , Fortunato Claudia , Bonanno Elena , Spagnoli Luigi Giusto , Aberdam Daniel , Knight Richard Austen , Candi Eleonora , Melino Gerry
Published: October 2012

During keratinocyte differentiation and stratification, cells undergo extensive remodeling of their actin cytoskeleton, which is important to control cell mobility and to coordinate and stabilize adhesive structures necessary for functional epithelia. Limited knowledge exists on how the actin cytoskeleton is remodeled in epithelial stratification and whether cell shape is a key determinant to trigger terminal differentiation. In this paper, using human keratinocytes and mouse epidermis as models, we implicate miR-24 in actin adhesion dynamics and demonstrate that miR-24 directly controls actin cable formation and cell mobility. miR-24 overexpression in proliferating cells was sufficient to trigger keratinocyte differentiation both in vitro and in vivo and directly repressed cytoskeletal modulators (PAK4, Tks5, and ArhGAP19). Silencing of these targets recapitulated the effects of miR-24 overexpression. Our results uncover a new regulatory pathway involving a differentiation-promoting microribonucleic acid that regulates actin adhesion dynamics in human and mouse epidermis.
Haspin inhibitors reveal centromeric functions of Aurora B in chromosome segregation
Authors: Wang Fangwei , Ulyanova Natalia P. , Daum John R. , Patnaik Debasis , Kateneva Anna V. , Gorbsky Gary J. , Higgins Jonathan M.G.
Published: October 2012

Haspin phosphorylates histone H3 at threonine-3 (H3T3ph), providing a docking site for the Aurora B complex at centromeres. Aurora B functions to correct improper kinetochore–microtubule attachments and alert the spindle checkpoint to the presence of misaligned chromosomes. We show that Haspin inhibitors decreased H3T3ph, resulting in loss of centromeric Aurora B and reduced phosphorylation of centromere and kinetochore Aurora B substrates. Consequently, metaphase chromosome alignment and spindle checkpoint signaling were compromised. These effects were phenocopied by microinjection of anti-H3T3ph antibodies. Retargeting Aurora B to centromeres partially restored checkpoint signaling and Aurora B–dependent phosphorylation at centromeres and kinetochores, bypassing the need for Haspin activity. Haspin inhibitors did not obviously affect phosphorylation of histone H3 at serine-10 (H3S10ph) by Aurora B on chromosome arms but, in Aurora B reactivation assays, recovery of H3S10ph was delayed. Haspin inhibitors did not block Aurora B localization to the spindle midzone in anaphase or Aurora B function in cytokinesis. Thus, Haspin inhibitors reveal centromeric roles of Aurora B in chromosome movement and spindle checkpoint signaling.
Structure and conformational change of a replication protein A heterotrimer bound to ssDNA
Authors: Fan Jie , Pavletich Nikola P.
Published: October 2012

Replication protein A (RPA) is the main eukaryotic ssDNA-binding protein with essential roles in DNA replication, recombination, and repair. RPA maintains the DNA as single-stranded and also interacts with other DNA-processing proteins, coordinating their assembly and disassembly on DNA. RPA binds to ssDNA in two conformational states with opposing affinities for DNA and proteins. The RPA–protein interactions are compatible with a low DNA affinity state that involves DNA-binding domain A (DBD-A) and DBD-B but not with the high DNA affinity state that additionally engages DBD-C and DBD-D. The structure of the high-affinity RPA–ssDNA complex reported here shows a compact quaternary structure held together by a four-way interface between DBD-B, DBD-C, the intervening linker (BC linker), and ssDNA. The BC linker binds into the DNA-binding groove of DBD-B, mimicking DNA. The associated conformational change and partial occlusion of the DBD-A–DBA-B protein–protein interaction site establish a mechanism for the allosteric coupling of RPA–DNA and RPA–protein interactions.
An unexpected binding mode for a Pol II CTD peptide phosphorylated at Ser7 in the active site of the CTD phosphatase Ssu72
Authors: Xiang Kehui , Manley James L. , Tong Liang
Published: October 2012

Ssu72, an RNA polymerase II C-terminal domain (CTD) phospho-Ser5 (pSer5) phosphatase, was recently reported to have pSer7 phosphatase activity as well. We report here the crystal structure of a ternary complex of the N-terminal domain of human symplekin, human Ssu72, and a 10-mer pSer7 CTD peptide. Surprisingly, the peptide is bound in the Ssu72 active site with its backbone running in the opposite direction compared with a pSer5 peptide. The pSer7 phosphatase activity of Ssu72 is ∼4000-fold lower than its pSer5 phosphatase activity toward a peptide substrate, consistent with the structural observations.
A multidomain hub anchors the chromosome segregation and chemotactic machinery to the bacterial pole
Authors: Yamaichi Yoshiharu , Bruckner Raphael , Ringgaard Simon , Möll Andrea , Cameron D. Ewen , Briegel Ariane , Jensen Grant J. , Davis Brigid M. , Waldor Matthew K.
Published: October 2012

The cell poles constitute key subcellular domains that are often critical for motility, chemotaxis, and chromosome segregation in rod-shaped bacteria. However, in nearly all rods, the processes that underlie the formation, recognition, and perpetuation of the polar domains are largely unknown. Here, in Vibrio cholerae, we identified HubP (hub of the pole), a polar transmembrane protein conserved in all vibrios, that anchors three ParA-like ATPases to the cell poles and, through them, controls polar localization of the chromosome origin, the chemotactic machinery, and the flagellum. In the absence of HubP, oriCI is not targeted to the cell poles, chemotaxis is impaired, and a small but increased fraction of cells produces multiple, rather than single, flagella. Distinct cytoplasmic domains within HubP are required for polar targeting of the three ATPases, while a periplasmic portion of HubP is required for its localization. HubP partially relocalizes from the poles to the mid-cell prior to cell division, thereby enabling perpetuation of the polar domain in future daughter cells. Thus, a single polar hub is instrumental for establishing polar identity and organization.
Strategic logistics management
Authors: Sandelands Eric
Published: October 2012

We all talk of logistical problems as if they were something which can be left to others ‐ you know, those less creative than ourselves; the slightly dull sorts with
computer‐like brains who thrive on just this sort of basically mathematical problem. This may be an overstatement of the case, but how many senior executives regularly meet with the managers responsible for the movement of materials? And how often do the same executives physically visit the scenes of these activities? Often? Sometimes? Never? And how many equate the costs of logistics merely with warehouse rents plus road haulage or rail costs?
Strategic logistics management
Authors: Fojt Martin
Published: October 2012

It is all too easy in the hectic world of business to get too involved with the day‐to‐day managing of processes and events. When this happens it is difficult to see the wood for the trees and the automatic pilot syndrome takes over. This does not suggest that you do not know what you are doing ‐ on the contrary you are probably as switched on to whatever activity you are managing as anyone could be. What you could be missing, however, is the explanation as to why you are doing it. If this sounds familiar to you, what might be needed is a detached period from your work. By this I mean stay on the high ground for a while so you can get an overview of what you are doing and, more importantly, why you are doing it. How many managers, I wonder, get the opportunity to question what they are doing? If you allow yourself to slip into complacency then you and your organization will soon lose competitive advantage.
Experimentally testing the accuracy of an extinction estimator: Solow's optimal linear estimation model
Authors: Clements Christopher F. , Worsfold Nicholas T. , Warren Philip H. , Collen Ben , Clark Nick , Blackburn Tim M. , Petchey Owen L.
Published: October 2012

Mathematical methods for inferring time to extinction have been widely applied but poorly tested. Optimal linear estimation (also called the ‘Weibull’ or ‘Weibull extreme value’ model) infers time to extinction from a temporal distribution of species sightings. Previous studies have suggested optimal linear estimation provides accurate estimates of extinction time for some species; however, an in‐depth test of the technique is lacking.

The use of data from wild populations to gauge the error associated with estimations is often limited by very approximate estimates of the actual extinction date and poor sighting records. Microcosms provide a system in which the accuracy of estimations can be tested against known extinction dates, whilst incorporating a variety of extinction rates created by changing environmental conditions, species identity and species richness.

We present the first use of experimental microcosm data to exhaustively test the accuracy of one sighting‐based method of inferring time of extinction under a range of search efforts, search regimes, sighting frequencies and extinction rates.

Our results show that the accuracy of optimal linear estimation can be affected by both observer‐controlled parameters, such as change in search effort, and inherent features of the system, such as species identity. Whilst optimal linear estimation provides generally accurate and precise estimates, the technique is susceptible to both overestimation and underestimation of extinction date.

Microcosm experiments provide a framework within which the accuracy of extinction predictors can be clearly gauged. Variables such as search effort, search regularity and species identity can significantly affect the accuracy of estimates and should be taken into account when testing extinction predictors in the future.
Diet and phylogeny shape the gut microbiota of Antarctic seals: a comparison of wild and captive animals
Authors: Nelson Tiffanie M. , Rogers Tracey L. , Carlini Alejandro R. , Brown Mark V.
Published: October 2012

The gut microbiota of mammals underpins the metabolic capacity and health of the host. Our understanding of what influences the composition of this community has been limited primarily to evidence from captive and terrestrial mammals. Therefore, the gut microbiota of southern elephant seals, Mirounga leonina, and leopard seals, Hydrurga leptonyx, inhabiting Antarctica were compared with captive leopard seals. Each seal exhibited a gut microbiota dominated by four phyla: Firmicutes (41.5 ± 4.0%), Fusobacteria (25.6 ± 3.9%), Proteobacteria (17.0 ± 3.2%) and Bacteroidetes (14.1 ± 1.7%). Species, age, sex and captivity were strong drivers of the composition of the gut microbiota, which can be attributed to differences in diet, gut length and physiology and social interactions. Differences in particular prey items consumed by seal species could contribute to the observed differences in the gut microbiota. The longer gut of the southern elephant seal provides a habitat reduced in available oxygen and more suitable to members of the phyla Bacteroidetes compared with other hosts. Among wild seals, 16 ‘core’ bacterial community members were present in the gut of at least 50% of individuals. As identified between southern elephant seal mother–pup pairs, ‘core’ members are passed on via vertical transmission from a young age and persist through to adulthood. Our study suggests that these hosts have co‐evolved with their gut microbiota and core members may provide some benefit to the host, such as developing the immune system. Further evidence of their strong evolutionary history is provided with the presence of 18 shared ‘core’ members in the gut microbiota of related seals living in the Arctic. The influence of diet and other factors, particularly in captivity, influences the composition of the community considerably. This study suggests that the gut microbiota has co‐evolved with wild mammals as is evident in the shared presence of ‘core’ members.
Long‐term monitoring of the human intestinal microbiota composition
Authors: Rajilić‐Stojanović Mirjana , Heilig Hans G. H. J. , Tims Sebastian , Zoetendal Erwin G. , de Vos Willem M.
Published: October 2012

The microbiota that colonizes the human intestinal tract is complex and its structure is specific for each of us. In this study we expand the knowledge about the stability of the subject‐specific microbiota and show that this ecosystem is stable in short‐term intervals (< 1 year) but also during long periods of time (> 10 years). The faecal microbiota composition of five unrelated and healthy subjects was analysed using a comprehensive and highly reproducible phylogenetic microarray, the HITChip. The results show that the use of antibiotics, application of specific dietary regimes and distant travelling have limited impact on the microbiota composition. Several anaerobic genera, including Bifidobacterium and a number of genera within the Bacteroidetes and the Firmicutes phylum, exhibit significantly higher similarity than the total microbiota. Although the gut microbiota contains subject‐specific species, the presence of which is preserved throughout the years, their relative abundance changes considerably. Consequently, the recently proposed enterotype status appears to be a varying characteristic of the microbiota. Our data show that the intestinal microbiota contains a core community of permanent colonizers, and that environmentally introduced changes of the microbiota throughout adulthood are primarily affecting the abundance but not the presence of specific microbial species.
Is poor access to dental care why people outside capital cities have poor oral health?
Authors: Crocombe LA , Stewart JF , Brennan DS , Slade GD , Spencer AJ
Published: October 2012

Background : Why oral health status outside capital cities is poorer than that in capital cities has not been satisfactorily explained. The aim of this study was to determine if the reason was poorer access to dental care.

Methods : Data were obtained from the Australian National Survey of Adult Oral Health (2004–06). Oral health status was measured by DMFT Index, and numbers of decayed, missing and filled teeth. A two‐step analysis was undertaken: comparing the dependent variables by location, socio‐demographic confounders and preventive dental behaviours, and then including six access to dental care variables.

Results : Of the 14 123 people interviewed, 5505 were examined, and 4170 completed the questionnaire. With socio‐economic parameters in the first regression model, non‐capital city people had higher DMFT (regression coefficient = 1.15, p < 0.01), more decayed (0.42, p < 0.01) and missing teeth (0.85, p < 0.01), but not filled teeth (−0.11, p = 0.71), than capital city based people. In the second step analysis, non‐capital city people still had a greater DMFT (1.01, p < 0.01), more decayed (0.27, p = 0.03) and missing teeth (0.74, p < 0.01), but not filled teeth (0.00, p = 0.99) than capital city based people.

Conclusions : Access to dental care was not the only reason why people outside capital cities have poorer oral health than people living in capital cities.
Effectiveness of interventions for the prevention of small‐for‐gestational age fetuses and perinatal mortality: a review of systematic reviews
Authors: MORRIS RACHEL K. , OLIVER EMILY A. , MALIN GEMMA , KHAN KHALID S. , MEADS CATHERINE
Published: October 2012

Previous narrative reviews in this area have concluded that there are few interventions that are likely to be beneficial and that further high‐quality research is required. Our objective was to perform a review of systematic reviews of the effectiveness of interventions for the prevention of small‐for‐gestational age (SGA) fetuses and perinatal mortality, to summarize the most up‐to‐date evidence and assess quality. Searches were carried out by using Medline, Embase, Cochrane Library and DARE (inception to September 2011), by hand searching of journal and reference lists and by contact with experts. Systematic reviews of randomized controlled trials were selected. Two reviewers independently selected articles and assessed the methodological and reporting quality. Data were extracted on study characteristics, quality and results. Summary data were presented as relative risks (RRs) and 95% confidence intervals (CIs). There were 834 randomized controlled trials (>668 672 participants), reporting on 45 different interventions. The most effective interventions to prevent the SGA fetus were antiplatelets at <16 weeks in women at risk of pre‐eclampsia (RR 0.47; CI 0.30–0.74) and progesterone therapy for prevention of preterm birth (RR 0.64; CI 0.49–0.83). For the prevention of perinatal mortality in high‐risk women, antiplatelets (RR 0.69; CI 0.53–0.90) and antenatal corticosteroids (RR 0.77; CI 0.67–0.89) were effective interventions. It is concluded that effective interventions are available for reducing the occurrence of SGA fetuses and preventing related perinatal mortality. Some are effective in all women, while others target specific co‐morbidities. There is a need to consider a comprehensive approach to primary prevention that targets SGA along with pre‐eclampsia and preterm birth.
Impact of Clostridium difficile colitis on 5‐year health outcomes in patients with ulcerative colitis
Authors: Murthy S. K. , Steinhart A. H. , Tinmouth J. , Austin P. C. , Daneman N. , Nguyen G. C.
Published: October 2012

Background

Clostridium difficile colitis (CDC) is associated with an increased short‐term mortality risk in hospitalised ulcerative colitis (UC) patients. We sought to determine whether CDC also impacts long‐term risks of adverse health events in this population.

Aim

To determine whether CDC also impacts long‐term risks of adverse health events in this population.

Methods

A population‐based retrospective cohort study was conducted of UC patients hospitalised in Ontario, Canada between 2002 and 2008. Patients with and without CDC were compared on the rates of adverse health events. The primary outcomes were the 5‐year adjusted risks of colectomy and death.

Results

Among 181 patients with CDC and 1835 patients without CDC, the 5‐year cumulative colectomy rates were 44% and 33% (P = 0.0052) and the 5‐year cumulative mortality rates were 27% and 14% (P < 0.0001) respectively. CDC was associated with a higher adjusted 5‐year risk of mortality [adjusted hazard ratio (aHR) 2.40, 95% CI 1.37–4.20], but not of colectomy (aHR 1.18, 95% CI 0.90–1.54). CDC impacted mortality risk both during index hospitalisation (adjusted odds ratio 8.90, 95% CI 2.80–28.3) as well as over 5 years following hospital discharge among patients who recovered from their acute illness (aHR 2.41, 95% CI 1.37–4.22). Colectomy risk was not influenced by CDC in this cohort.

Conclusion

Clostridium difficile colitis is associated with increased short‐term and long‐term mortality risks among hospitalised ulcerative colitis patients. As colectomy risk is not similarly impacted by Clostridium difficile colitis, factors predictive of death among C. difficile‐infected ulcerative colitis patients require elucidation.
Pharmacokinetics and central nervous system effects of the novel dual NK1/NK3 receptor antagonist GSK1144814 in alcohol‐intoxicated volunteers
Authors: te Beek Erik T. , Hay Justin L. , Bullman Jonathan N. , Burgess Clare , Nahon Kimberly J. , Klaassen Erica S. , Gray Frank A. , van Gerven Joop M. A.
Published: October 2012

Aims

Antagonism of both NK1 and NK3 receptors may be an effective strategy in the pharmacotherapy of schizophrenia, drug addiction or depression. GSK1144814 is a novel selective dual NK1/NK3 receptor antagonist. The potential influence of GSK1144814 on the effects of alcohol was investigated.

Methods

In a blinded, randomized, placebo‐controlled, two period crossover study, the pharmacokinetics and central nervous system (CNS) effects of single oral doses of 200 mg GSK1144814 were evaluated in 20 healthy volunteers, using a controlled alcohol infusion paradigm to maintain stable alcohol concentrations with subsequent analysis of eye movements, adaptive tracking, body sway, visual analogue scales, Epworth sleepiness scale and the verbal visual learning test.

Results

Frequent adverse effects were mild somnolence, fatigue and headache. Plasma concentration of GSK1144814 in the presence of alcohol was maximal 1.5 h after dose administration. GSK1144814 did not affect alcohol pharmacokinetics. Co‐administration of GSK1144814 and alcohol impaired saccadic reaction time and peak velocity, adaptive tracking, alertness, sleepiness, word recognition and recognition reaction time compared with administration of alcohol alone, but the size of the interaction was small.

Conclusions

Administration of GSK1144814 in the presence of alcohol was generally well tolerated and not likely to produce clinically relevant additional impairments after alcohol consumption.
Anti‐tumour immunotherapy with Vγ9Vδ2 T lymphocytes: from the bench to the bedside
Authors: Braza Mounia S. , Klein Bernard
Published: October 2012

Gamma delta (γδ) Τ cells are non‐conventional T lymphocyte effectors that can interact with and eradicate tumour cells. Several data demonstrate that these T cells, which are implicated in the first line of defence against pathogens, have anti‐tumour activity against many cancers and suggest that γδ Τ cell‐mediated immunotherapy is feasible and might induce objective tumour responses. Due to the importance of γδ Τ lymphocytes in the induction and control of immunity, a complete understanding of their biology is crucial for the development of a potent cancer immunotherapy. This review discusses recent advances in γδ Τ basic research and data from clinical trials on the use of γδ Τ cells in the treatment of different cancers. It analyses how this knowledge might be applied to develop new strategies for the clinical manipulation and the potentiation of γδ Τ lymphocyte activity in cancer immunotherapy.
When does anxiety help or hinder cognitive test performance? The role of working memory capacity
Authors: Owens Matthew , Stevenson Jim , Hadwin Julie A. , Norgate Roger
Published: October 2012

Cognitive interference theories (e.g. attentional control theory, processing efficiency theory) suggest that high levels of trait anxiety predict adverse effects on the performance of cognitive tasks, particularly those that make high demands on cognitive resources. We tested an interaction hypothesis to determine whether a combination of high anxiety and low working memory capacity (WMC) would predict variance in demanding cognitive test scores. Ninety six adolescents (12‐ to 14‐years‐old) participated in the study, which measured self‐report levels of trait anxiety, working memory, and cognitive test performance. As hypothesized, we found that the anxiety‐WMC interaction explained a significant amount of variance in cognitive test performance (ΔR2 .07, p < .01). Trait anxiety was unrelated to cognitive test performance for those adolescents with average WMC scores (β = .13, p > .10). In contrast, trait anxiety was negatively related to test performance in adolescents with low WMC (β = −.35, p < .05) and positively related to test performance in those with high WMC (β = .49, p < .01). The results of this study suggest that WMC moderates the relationship between anxiety and cognitive test performance and may be a determinant factor in explaining some discrepancies found in the literature. Further research is needed to fully understand the mechanisms involved.
Diabetes mellitus and cancer risk: Review of the epidemiological evidence
Authors: Shikata Kentaro , Ninomiya Toshiharu , Kiyohara Yutaka
Published: October 2012

Diabetes mellitus and cancer are diseases of epidemic proportions across the globe. These diseases are influenced by many factors, both genetic and environmental. A possible association between diabetes and cancer risk has long been speculated. Increased incidence of several cancers has been observed in diabetes patients, notably pancreatic, hepatic, colorectal, breast, urinary tract, and endometrial cancers. In contrast, a decreased incidence of prostate cancer is observed in diabetes patients, implying a protective effect. Precise knowledge of the complex associations and interactions between these two conditions is of great importance for their prevention and treatment. Multiple potential mechanisms have been proposed, but they have tended to be site‐specific. Possible common mechanisms for a biological link between diabetes and cancer include hyperinsulinemia, hyperglycemia, and inflammation. Today, 366 million people live with diabetes globally, and this figure is expected to increase. Thus, if diabetes is associated with even a small increase in cancer risk, this may have important consequences at the population level. The aim of this review is to summarize recent epidemiological evidence of an association between diabetes and total cancer and specific sites of cancer, and to consider causal associations between these diseases. (Cancer Sci 2013; 104: 9–14)
Back to the Future: Can Physical Models of Passive Membrane Permeability Help Reduce Drug Candidate Attrition and Move Us Beyond QSPR?
Authors: Swift Robert V. , Amaro Rommie E.
Published: October 2012

It is widely recognized that adsorption, distribution, metabolism, excretion, and toxicology liabilities kill the majority of drug candidates that progress to clinical trials. The development of computational models to predict small molecule membrane permeability is therefore of considerable scientific and public health interest. Empirical qualitative structure permeability relationship models of permeability have been a mainstay in industrial applications, but lack a deep understanding of the underlying biologic physics. Others and we have shown that implicit solvent models to predict passive permeability for small molecules exhibit mediocre predictive performance when validated across experimental test sets. Given the vast increase in computer power, more efficient parallelization schemes, and extension of current atomistic simulation codes to general use graphical processing units, the development and application of physical models based on all‐atom simulations may now be feasible. Preliminary results from rigorous free energy calculations using all‐atom simulations indicate that performance relative to implicit solvent models may be improved, but many outstanding questions remain. Here, we review the current state‐of‐the‐art physical models for passive membrane permeability prediction and present a prospective look at promising new directions for all‐atom approaches.
Optimization of CD4/gp120 Inhibitors by Thermodynamic‐Guided Alanine‐Scanning Mutagenesis
Authors: Liu Yingyun , Schön Arne , Freire Ernesto
Published: October 2012

As protein/protein interactions usually trigger signalling processes, inhibitors of those interactions must preclude protein binding without eliciting the signalling process themselves. To accomplish those goals, small molecules need to target those protein residues that contribute the most to binding (binding hotspots) without disturbing those residues that initiate signalling processes (allosteric hotspots). The availability of a blueprint identifying binding and allosteric hotspots will significantly aid inhibitor design and optimization. In this study, we show that in some situations the blueprint can be constructed by combining the standard technique of alanine‐scanning mutagenesis with isothermal titration calorimetry (ITC). We demonstrate the approach by developing the combined binding and allosteric hotspots blueprint for CD4/gp120, the initial interaction leading to HIV‐1 cell infection. A major finding of these studies is that not all binding hotspots are allosteric hotspots opening the possibility for the rational design of inhibitors and antagonist or agonist modulators.
Design, Synthesis and Biological Evaluation of Cinnamic Acyl Shikonin Derivatives
Authors: Lin Hong‐Yan , Chen Wei , Shi Jing , Kong Wen‐Yao , Qi Jin‐Liang , Wang Xiao‐Ming , Yang Yong‐Hua
Published: October 2012

Inducing apoptosis is an important and promising therapeutic approach to overcome cancer. Here, we described a series of novel synthesized compounds, cinnamic acyl shikonin derivatives (1b–19b), which were synthesized starting from shikonin and cinnamic acids, which exhibit anticancer activity via inducing apoptosis in vitro. Our flow cytometry results showed that compound 8b((E)‐1‐(5,8‐dihydroxy‐1,4‐dioxo‐1,4‐dihydronaphthalen‐2‐yl)‐4‐methylpent ‐3‐enyl‐3‐(3‐(trifluoromethyl) phenyl)acrylate) (IC50 = 0.69, 0.65, 1.62 μm for human SW872‐s, A875 and A549 cell lines, respectively) exhibited conspicuous anticancer activities and has low cell toxicity in vitro. Therefore, we considered that compound 8b is potentially to be a candidate of anticancer agent. The proliferation inhibitory effect of compound 8b was associated with its apoptosis‐inducing effect by activating caspase‐3, caspase‐7, caspase‐9, and PARP. When the level of cleaved caspase‐3, cleaved caspase‐7, cleaved caspase‐9, and cleaved PARP are rise, apoptosis of cancer cells will be induced.
Alanine Scan of an Immunosuppressive Peptide (CP): Analysis of Structure–Function Relationships
Authors: Raguine Laura , Ali Marina , Bender Veronika , Diefenbach Eve , Doddareddy Munikumar Reddy , Hibbs David , Manolios Nicholas
Published: October 2012

Core peptide is a hydrophobic peptide, the sequence of which is derived from the T‐cell antigen receptor alpha‐chain transmembrane region. Previous studies have shown that core peptide can inhibit T‐cell‐mediated immune responses both in vitro and in vivo. Here, we report the role each constituent amino acid plays within core peptide using an alanine scan and the amino acid effect on function using a biological antigen presentation assay. The biophysical behaviour of these analogues in model membranes was analysed using surface plasmon resonance studies and then binding correlated with T‐cell function. Removal of any single hydrophobic amino acid between the two charged amino acids in core peptide (R, K) resulted in lower binding. Changing the overall net charge of core peptide, by removing either of the positively charged residues (R or K), had varying effects on peptide binding and IL‐2 production. There was a direct correlation (ρ = 0.718) between peptide binding to model membranes and peptide ability to inhibit IL‐2. Except for IL‐2 inhibition, production of other T‐cell cytokines such as GM‐CSF, IFN‐γ, IL‐1α, IL‐4, IL‐5, IL‐6, IL‐10, IL‐17 and T‐cell antigen receptor alpha‐chain was not detected using a fluorescent bead immunoassay. This study provides important structure–function relationships essential for further drug design.
Community dental clinics: providers' perspectives
Authors: Wallace Bruce B. , MacEntee Michael I. , Harrison Rosamund , Hole Rachelle , Mitton Craig
Published: October 2012

Objectives

Not‐for‐profit community dental clinics attempt to address the inequities of oral health care for disadvantaged communities, but there is little information about how they operate. The objective of this article is to explain from the perspective of senior staff how five community dental clinics in British Columbia, Canada, provide services.

Methods

The mixed‐methods case study included the five not‐for‐profit dental clinics with full‐time staff who provided a wide range of dental services. We conducted open‐ended interviews to saturation with eight senior administrative staff selected purposefully because of their comprehensive knowledge of the development and operation of the clinics and supplemented their information with a year's aggregated data on patients, treatments, and operating costs.

Results

The interview participants described the benefits of integrating dentistry with other health and social services usually within community health centres, although they doubted the sustainability of the clinics without reliable financial support from public funds. Aggregated data showed that 75% of the patients had either publically funded or no coverage for dental services, while the others had employer‐sponsored dental insurance. Financial subsidies from regional health authorities allowed two of the clinics to treat only patients who are economically vulnerable and provide all services at reduced costs. Clinics without government subsidies used the fees paid by some patients to subsidize treatment for others who could not afford treatment.

Conclusions

Not‐for‐profit dental clinics provide dental services beyond pain relief for underserved communities. Dental services are integrated with other health and community services and located in accessible locations. However, all of the participants expressed concerns about the sustainability of the clinics without reliable public revenues.
Protection against allergic airway inflammation during the chronic and acute phases of Trichinella spiralis infection
Authors: Aranzamendi C. , de Bruin A. , Kuiper R. , Boog C. J. P. , van Eden W. , Rutten V. , Pinelli E.
Published: October 2012

Background

Modulation of the host immune response by helminths has been reported to be essential for parasite survival and also to benefit the host by suppressing inflammatory diseases such as allergies. We have previously shown that excretory‐secretory products of Trichinella spiralis muscle larvae have immunomodulatory properties and induce in vitro the expansion of CD4+CD25+FOXP3+ Treg cells in a TGF‐β‐dependent manner.

Objective

We aimed at determining the effect of the acute (intestinal) and the chronic (muscle) phase of T. spiralis infection on experimental allergic airway inflammation (EAAI) to Ovalbumin (OVA) and the involvement of Treg cells.

Methods

The chronic phase was established before OVA‐sensitization/challenge and the acute phase at two‐time points, before and after OVA‐sensitization. Mice were infected with 400 T. spiralis larvae and after euthanasia different pathological features of EAAI were measured. Adoptive transfer of CD4+ T cells from Trichinella infected mice to OVA sensitized/challenged recipients was also performed.

Results

We found that the chronic as well as the acute phase of Trichinella infection suppress EAAI as indicated by reduction in airway inflammation, OVA‐specific IgE levels in sera, Th2‐cytokine production and eosinophils in bronchoalveolar lavage. This protective effect was found to be stronger during the chronic phase and to be associated with increased numbers of splenic CD4+CD25+FOXP3+ Treg cells with suppressive activity. Adoptive transfer of splenic CD4+ T cells from chronically infected mice with elevated numbers of Treg cells resulted in partial protection against EAAI.

Conclusions and Clinical Relevance

These results demonstrate that the protective effect of T. spiralis on EAAI increases as infection progresses from the acute to the chronic phase. Here, Treg cells may play an essential role in the suppression of EAAI. Elucidating the mechanisms and molecular helminth structures responsible for this regulatory process is relevant to develop alternative tools for preventing or treating allergic asthma.
Quality not quantity for transglutaminase antibody 2: the performance of an endomysial and tissue transglutaminase test in screening coeliac disease remains stable over time
Authors: Swallow K , Wild G , Sargur R , Sanders D S , Aziz I , Hopper A D , Egner W
Published: October 2012

National Institute of Clinical Excellence (NICE) and European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidance for the diagnosis of coeliac disease has been published. However, there is some controversy regarding the advice on the use of stratifying levels of immunoglobulin (IgA) tissue transglutaminase antibody (TG2) test positivity in the absence of test standardization and the vagueness of the indication to test equivocal samples. Using repeat service audit, we demonstrate that a combination of TG2 followed by IgA endomysial antibodies (EMA) is the best strategy for all degrees of mucosal abnormality using our test combination. Reliance upon immunoassay titre is not as effective, and cannot be applied consistently across populations in the absence of assay standardization. Guidelines advocating the use of tests should involve experts in laboratory diagnostics and external quality assurance to ensure that errors of generalization do not occur and that test performance is achievable in routine diagnostic use.
Immune mechanisms and the impact of the disrupted lung microbiome in chronic bacterial lung infection and bronchiectasis
Authors: Boyton R J , Reynolds C J , Quigley K J , Altmann D M
Published: October 2012

Recent studies analysing immunogenetics and immune mechanisms controlling susceptibility to chronic bacterial infection in bronchiectasis implicate dysregulated immunity in conjunction with chronic bacterial infection. Bronchiectasis is a structural pathological end-point with many causes and disease associations. In about half of cases it is termed idiopathic, because it is of unknown aetiology. Bronchiectasis is proposed to result from a ‘vicious cycle’ of chronic bacterial infection and dysregulated inflammation. Paradoxically, both immune deficiency and excess immunity, either in the form of autoimmunity or excessive inflammatory activation, can predispose to disease. It appears to be a part of the spectrum of inflammatory, autoimmune and atopic conditions that have increased in prevalence through the 20th century, attributed variously to the hygiene hypothesis or the ‘missing microbiota’. Immunogenetic studies showing a strong association with human leucocyte antigen (HLA)-Cw*03 and HLA-C group 1 homozygosity and combinational analysis of HLA-C and killer immunoglobulin-like receptors (KIR) genes suggests a shift towards activation of natural killer (NK) cells leading to lung damage. The association with HLA-DR1, DQ5 implicates a role for CD4 T cells, possibly operating through influence on susceptibility to specific pathogens. We hypothesize that disruption of the lung microbial ecosystem, by infection, inflammation and/or antibiotic therapy, creates a disturbed, simplified, microbial community (‘disrupted microbiota’) with downstream consequences for immune function. These events, acting with excessive NK cell activation, create a highly inflammatory lung environment that, in turn, permits the further establishment and maintenance of chronic infection dominated by microbial pathogens. This review discusses the implication of these concepts for the development of therapeutic interventions.
Efficacy and safety of long‐term, continuous subcutaneous octreotide infusion for patients with different subtypes of KATP‐channel hyperinsulinism
Authors: Yorifuji Tohru , Kawakita Rie , Hosokawa Yuki , Fujimaru Rika , Matsubara Kousaku , Aizu Katsuya , Suzuki Shigeru , Nagasaka Hironori , Nishibori Hironori , Masue Michiya
Published: October 2012

Objective

To evaluate the efficacy of long‐term, continuous, subcutaneous octreotide infusion for congenital hyperinsulinism caused by mutations in the KATP‐channel genes, KCNJ11 and ABCC8.

Patients

Fifteen Japanese patients with diazoxide‐unresponsive, KATP‐channel hyperinsulinism.

Methods

Molecular diagnoses were made by sequencing and multiple ligation‐dependent probe amplification analysis. In patients with paternally inherited, monoallelic mutations, 18F‐DOPA PET scans were performed to determine the location of the lesion. The patients were treated with continuous, subcutaneous octreotide infusion at a dosage of up to 25 μg/kg/day, using an insulin pump to maintain blood glucose levels higher than 3·33 mmol/l. Additional treatments (IV glucose, glucagon or enteral feeding) were administered as needed. The efficacy of the treatment was assessed in patients who received octreotide for 4 months to 5·9 years.

Results

Three patients had biallelic mutations, and 12 had monoallelic, paternally inherited mutations. Four patients with monoallelic mutations showed diffuse 18F‐DOPA uptake, whereas seven patients showed focal uptake. Octreotide was effective in all the patients. The patients with biallelic mutations required a higher dosage (17–25 μg/kg/day), and two patients required additional treatments. By contrast, the patients with monoallelic mutations required a lower dosage (0·5–21 μg/kg/day) irrespective of the PET results and mostly without additional treatments. Treatment was discontinued in three patients at 2·5, 3·3 and 5·9 years of age, without psychomotor delay. Except for growth deceleration at a higher dosage, no significant adverse effects were noted.

Conclusions

Long‐term, continuous, subcutaneous octreotide infusion is a feasible alternative to surgery especially for patients with monoallelic KATP‐channel mutations.
The effects of caloric restriction on Fetuin‐A and cardiovascular risk factors in rats and humans: a randomized controlled trial
Authors: Choi Kyung Mook , Han Kyung Ah , Ahn Hee Jung , Lee So Young , Hwang Soon Young , Kim Baek‐Hui , Hong Ho Cheol , Choi Hae Yoon , Yang Sae Jeong , Yoo Hye Jin , Baik Sei Hyun , Choi Dong Seop , Min Kyung Wan
Published: October 2012

Objectives

The liver‐secreted protein fetuin‐A is associated with insulin resistance, metabolic syndrome, type 2 diabetes and atherosclerosis. We examined the effect of caloric restriction (CR) on fetuin‐A levels and concomitant changes in hepatic steatosis and cardiovascular risk factors in rats and humans.

Design and Subjects

We performed a randomized, controlled clinical trial to examine circulating fetuin‐A levels and cardiovascular risk parameters including visceral fat area (VFA), atherogenic lipid profile, inflammatory markers, adipokines levels and brachial artery endothelial function in 76 overweight women with type 2 diabetes before and after 12 weeks of CR. In addition, the effects of CR on hepatic steatosis and fetuin‐A mRNA expression were evaluated in Otuska Long Evans Tokushima Fatty (OLETF) rats, an animal model of obesity and type 2 diabetes.

Results

Circulating fetuin‐A levels were significantly decreased after 12 weeks of CR and were accompanied by improvements in VFA, blood pressure, glucose, lipid profiles and liver function. The CR group also showed a significant decrease in apolipoprotein B, leptin and insulin resistance compared to those in the control group, although endothelial function was not different. Multiple regression analysis showed that the changes in fetuin‐A levels were independently associated with CR and changes in hsCRP and adiponectin (R2 = 0·156). Moreover, CR significantly reduced hepatic steatosis and fetuin‐A expression, as well as weight, glucose, total cholesterol and triglyceride levels, in OLETF rats.

Conclusion

Caloric restriction significantly reduced the hepatic expression of fetuin‐A and its circulating levels and improved several cardiovascular risk factors in obese rats and humans with type 2 diabetes.
Parental origin of mutation and the risk of breast cancer in a prospective study of women with a BRCA1 or BRCA2 mutation
Authors: Senst N , Llacuachaqui M , Lubinski J , Lynch H , Armel S , Neuhausen S , Ghadirian P , Sun P , Narod SA ,   the Hereditary Breast Cancer Study Group
Published: October 2012

The objective is to estimate the risk of breast cancer in women who carry a deleterious BRCA1 or BRCA2 mutation, according to parental origin of mutation. We conducted a cohort study of women with a BRCA1 mutation (n = 1523) or BRCA2 mutation (n = 369) who had not been diagnosed with breast or ovarian cancer. For each woman, the pedigree was reviewed and the origin of the mutation was assigned as probable paternal or maternal. The hazard ratio (HR) for developing breast cancer in the follow‐up period was estimated for women with a paternal mutation compared to a maternal mutation. The risk of breast cancer was modestly higher in women with a paternal BRCA1 mutation compared to women with a maternal BRCA1 mutation (HR = 1.46; 95% CI = 0.99–2.16) but the difference was not significant (p = 0.06). The parental mutation origin did not affect the risk in women with a BRCA2 mutation. Our results are consistent with the hypothesis that there is an increased risk of breast cancer among women with a paternally inherited BRCA1 mutation compared to a maternally inherited mutation. However, the data are not sufficiently compelling to justify different screening recommendations for the two subgroups.
Beckwith–Wiedemann syndrome and long QT syndrome due to familial‐balanced translocation t(11;17)(p15.5;q21.3) involving the KCNQ1 gene
Authors: Kaltenbach S , Capri Y , Rossignol S , Denjoy I , Soudée S , Aboura A , Baumann C , Verloes A
Published: October 2012

We report a child with Beckwith–Wiedemann syndrome (BWS) as the consequence of an apparently balanced, maternally inherited reciprocal translocation t(11;17)(p15.5;q21.3). His mother and aunt, who inherited the translocation from their father, did not have BWS. At birth, long QT syndrome (LQTS) was diagnosed in this child and, secondarily, among apparently healthy family members carrying the translocation. By FISH analysis, the breakpoint in 11p15.5 interrupts the KCNQ1 gene between exons 2 and 10 and causes a loss of methylation of the IC2 (and thus BWS) on the maternally inherited der(11) chromosome. To explain the presence of LQTS segregating with the t(11;17) translocation in this family, we hypothesize that the translocation that interrupts KCNQ1 allow translation of an abnormal short allele that interferes in a dominant negative way with the normal isoform 1 of KCNQ1 in the heart (where this allele is not subject to parental imprint). This appears to be the first report of BWS with congenital LQTS, which should be considered as a rare but serious complication to be searched systematically in patients with BWS due to 11p15 rearrangements.
Hereditary trichilemmal cysts: a proposal for the assessment of diagnostic clinical criteria
Authors: Seidenari S , Pellacani G , Nasti S , Tomasi A , Pastorino L , Ghiorzo P , Ruini C , Bianchi‐Scarrà G , Pollio A , Mandel VD , Ponti G
Published: October 2012

Trichilemmal cysts (TCs) can occur as sporadic lesions or in hereditary–familial settings with autosomal dominant transmission. These entities have not been widely analyzed in their peculiar aspects yet. The aim of this study was to describe a cohort of patients with diagnosis of TCs through a clinical and biomolecular characterization, intended to highlight some effective diagnostic criteria for their identification. Among 149 cases of this study, 24 cases of TCs (16.1%) arose in patients with at least one first‐degree relative with diagnosis of TCs. Peculiar findings concerning hereditary lesions included the multiple presentation with an early onset age. On the basis of clinical evaluation, we propose a panel of clinical and histologic criteria for the diagnosis of hereditary TCs, which includes: (i) the diagnosis of TCs in at least two first‐degree relatives or in three first‐ or second‐degree relatives in two consecutive generations; (ii) at least one of the patients with TCs diagnosed <45 years; and (iii) the diagnosis of multiple or giant (>5‐cm lesions) or rare histopathologic features (proliferating and ossifying) TCs.