bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation of magnesium intake with metabolic parameters, depression and physical activity in elderly type 2 diabetes patients: a cross-sectional study
Authors: Huang Jui-Hua , Lu Yi-Fa , Cheng Fu-Chou , Lee John Ning-Yuean , Tsai Leih-Ching
Published: June 2012

Background

Type 2 diabetes mellitus is a major global public health problem in the worldwide and is increasing in aging populations. Magnesium intake may be one of the most important factors for diabetes prevention and management. Low magnesium intake may exacerbate metabolic abnormalities. In this study, the relationships of magnesium intake with metabolic parameters, depression and physical activity in elderly patients with type 2 diabetes were investigated.

Methods

This cross-sectional study involved 210 type 2 diabetes patients aged 65 years and above. Participants were interviewed to obtain information on lifestyle and 24-hour dietary recall. Assessment of depression was based on DSM-IV criteria. Clinical variables measured included anthropometric measurements, blood pressure, and biochemical determinations of blood and urine samples. Linear regression was applied to determine the relationships of magnesium intake with nutritional variables and metabolic parameters.

Results

Among all patients, 88.6% had magnesium intake which was less than the dietary reference intake, and 37.1% had hypomagnesaemia. Metabolic syndromes and depression were associated with lower magnesium intake (p < 0.05). A positive relationship was found between magnesium intake and HDL-cholesterol (p = 0.005). Magnesium intake was inversely correlated with triglyceride, waist circumference, body fat percent and body mass index (p < 0.005). After controlling confounding factor, HDL-cholesterol was significantly higher with increasing quartile of magnesium intake (pfor trend = 0005). Waist circumference, body fat percentage, and body mass index were significantly lower with increase quartile of magnesium intake (pfor trend < 0.001). The odds of depression, central obesity, high body fat percentage, and high body mass index were significantly lower with increasing quartile of magnesium intake (pfor trend < 0.05). In addition, magnesium intake was related to high physical activity level and demonstrated lower serum magnesium levels. Serum magnesium was not significantly associated with metabolic parameters.

Conclusions

The majority of elderly type 2 diabetes who have low magnesium intake may compound this deficiency with metabolic abnormalities and depression. Future studies should determine the effects of increased magnesium intake or magnesium supplementation on metabolic control and depression in elderly people with type 2 diabetes.
Alcohol use in a military population deployed in combat areas: a cross sectional study
Authors: Hanwella Raveen , de Silva Varuni Asanka , Jayasekera Nicholas E L W
Published: June 2012

Background

Alcohol misuse is more prevalent among military populations. Association between PTSD and heavy drinking have been reported in many studies. Most of the studies on alcohol use among military personnel are from US and UK. Aim of this study is to describe alcohol consumption patterns among military personnel in Sri Lanka, a country where the alcohol consumption among the general population are very different to that in US and UK.

Methods

Cross sectional study consisting of representative samples of Sri Lanka Navy Special Forces and regular forces deployed in combat areas continuously during a one year period was carried out. Data was collected using a self report questionnaire. Alcohol Use Disorder Identification Test (AUDIT) was used to assess alcohol consumption.

Results

Sample consisted of 259 Special Forces and 412 regular navy personnel. The median AUDIT score was 2.0 (interquartile range 6.0). Prevalence of current drinking was 71.2 %. Of the current users 54.81 % were infrequent users (frequency ≤ once a month) while 37.87 % of users consumed 2–4 times a month. Prevalence of hazardous drinking (AUDIT ≥ 8) was 16.69 % and binge drinking 14.01 %. Five (0.75 %) had AUDIT total ≥20. There was no significant difference between Special Forces and regular forces in hazardous drinking or binge drinking. Total AUDIT score ≥16 were associated with difficulty performing work.

Conclusions

High rates of hazardous drinking and binge drinking described among military personnel in US and UK were not seen among SLN personnel deployed in combat areas. This finding contrasts with previously reported association between combat exposure and hazardous alcohol use among military personnel. Alcohol use among military personnel may be significantly influenced by alcohol consumption patterns among the general population, access to alcohol and attitudes about alcohol use. Similar to findings from other countries, heavy alcohol use was associated with poorer psychological health and functional impairment.
Frequency-based time-series gene expression recomposition using PRIISM
Authors: Rosa Bruce A , Jiao Yuhua , Oh Sookyung , Montgomery Beronda L , Qin Wensheng , Chen Jin
Published: June 2012

Background

Circadian rhythm pathways influence the expression patterns of as much as 31% of the Arabidopsis genome through complicated interaction pathways, and have been found to be significantly disrupted by biotic and abiotic stress treatments, complicating treatment-response gene discovery methods due to clock pattern mismatches in the fold change-based statistics. The PRIISM (Pattern Recomposition for the Isolation of Independent Signals in Microarray data) algorithm outlined in this paper is designed to separate pattern changes induced by different forces, including treatment-response pathways and circadian clock rhythm disruptions.

Results

Using the Fourier transform, high-resolution time-series microarray data is projected to the frequency domain. By identifying the clock frequency range from the core circadian clock genes, we separate the frequency spectrum to different sections containing treatment-frequency (representing up- or down-regulation by an adaptive treatment response), clock-frequency (representing the circadian clock-disruption response) and noise-frequency components. Then, we project the components’ spectra back to the expression domain to reconstruct isolated, independent gene expression patterns representing the effects of the different influences.

By applying PRIISM on a high-resolution time-series Arabidopsis microarray dataset under a cold treatment, we systematically evaluated our method using maximum fold change and principal component analyses. The results of this study showed that the ranked treatment-frequency fold change results produce fewer false positives than the original methodology, and the 26-hour timepoint in our dataset was the best statistic for distinguishing the most known cold-response genes. In addition, six novel cold-response genes were discovered. PRIISM also provides gene expression data which represents only circadian clock influences, and may be useful for circadian clock studies.

Conclusion

PRIISM is a novel approach for overcoming the problem of circadian disruptions from stress treatments on plants. PRIISM can be integrated with any existing analysis approach on gene expression data to separate circadian-influenced changes in gene expression, and it can be extended to apply to any organism with regular oscillations in gene expression patterns across a large portion of the genome.
Design, conduct, and analysis of a multicenter, pharmacogenomic, biomarker study in matched patients with severe sepsis treated with or without drotrecogin Alfa (activated)
Authors: Annane Djillali , Mira Jean Paul , Ware Lorraine B , Gordon Anthony C , Sevransky Jonathan , Stüber Frank , Heagerty Patrick J , Wellman Hugh F , Neira Mauricio , Mancini Alexandra DJ , Russell James A
Published: June 2012

Background

A genomic biomarker identifying patients likely to benefit from drotrecogin alfa (activated) (DAA) may be clinically useful as a companion diagnostic. This trial was designed to validate biomarkers (improved response polymorphisms (IRPs)). Each IRP (A and B) contains two single nucleotide polymorphisms that were associated with a differential DAA treatment effect.

Methods

DAA is typically given to younger patients with greater disease severity; therefore, a well-matched control group is critical to this multicenter, retrospective, controlled, outcome-blinded, genotype-blinded trial. Within each center, DAA-treated patients will be matched to controls treated within 24 months of each other taking into account age, APACHE II, cardiovascular, respiratory, renal, and hematologic dysfunction, mechanical ventilation status, medical/surgical status, and infection site. A propensity score will estimate the probability that a patient would have received DAA given their baseline characteristics. Two-phase data transfer will ensure unbiased selection of matched controls. The first transfer will be for eligibility and matching data and the second transfer for outcomes and genotypic data. The primary analysis will compare the effect of DAA in IRP + and IRP − groups on in-hospital mortality through day 28.

Discussion

A design-based approach matching DAA-free to DAA-treated patients in a multicenter study of patients who have severe sepsis and high risk of death will directly compare control to DAA-treated groups for mortality by genotype. Results, which should be available in 2012, may help to identify the group of patients who would benefit from DAA and may provide a model for future investigation of sepsis therapies.
Age-related increase in amyloid plaque burden is associated with impairment in conditioned fear memory in CRND8 mouse model of amyloidosis
Authors: Hanna Amanda , Iremonger Kayleigh , Das Pritam , Dickson Dennis , Golde Todd , Janus Christopher
Published: June 2012

Introduction

The current pathological confirmation of the diagnosis of Alzheimer's disease (AD) is still based on postmortem identification of parenchymal amyloid beta (Aβ) plaques, intra-neuronal neurofibrillary tangles, and neuronal loss. The memory deficits that are present in the early stages of AD are linked to the dysfunction of structures in the entorhinal cortex and limbic system, especially the hippocampus and amygdala. Using the CRND8 transgenic mouse model of amyloidosis, which over-expresses a mutant human amyloid precursor protein (APP) gene, we evaluated hippocampus-dependent contextual and amygdala-dependent tone fear conditioned (FC) memory, and investigated the relationship between the fear memory indices and Aβ plaque burden.

Methods

Mice were tested at three, six, and 12 months of age, which corresponds to early, mild, and severe Aβ plaque deposition, following a cross-sectional experimental design. We used a delay version of the fear conditioning paradigm in which tone stimulus was co-terminated with foot-shocks during exploration of the training chamber. The Aβ plaque burden was evaluated at each age after the completion of the behavioral tests.

Results

CRDN8 mice showed context fear memory comparable to control mice at three and six months, but were significantly impaired at 12 months of age. In contrast, the tone fear memory was significantly impaired in the model at each age of testing. The Aβ plaque burden significantly increased with age, and was correlated with the overall impairment in context and tone fear memory in the CRND8 mice within the studied age.

Conclusions

Our data extend previous studies showing that other APP mouse models exhibit impairment in fear conditioned memory, by demonstrating that this impairment is progressive and correlates well with an overall increase in Aβ burden. Also, the demonstrated greater sensitivity of the tone conditioning test in the identification of age dependent differences between CRND8 and control mice suggests that this paradigm might be particularly suitable in studies evaluating potential therapeutics related to memory improvement in mouse models of amyloidosis.
Semaphorin 3A is a marker for disease activity and a potential immunoregulator in systemic lupus erythematosus
Authors: Vadasz Zahava , Haj Tharwat , Halasz Katalin , Rosner Itzhak , Slobodin Gleb , Attias Dina , Kessel Aharon , Kessler Ofra , Neufeld Gera , Toubi Elias
Published: June 2012

Introduction

Semaphorin 3A (sema3A) and neuropilin-1 (NP-1) play a regulatory role in immune responses and have a demonstrated effect on the course of collagen induced arthritis. This study was undertaken to evaluate the role of sema3A and NP-1 in the pathogenesis of systemic lupus erythematosus (SLE) and the specific effect of sema3A on the auto-reactive properties of B cells in SLE patients.

Methods

Thirty two SLE and 24 rheumatoid arthritis (RA) patients were assessed and compared with 40 normal individuals. Sema3A serum levels were measured and correlated with SLE disease activity. The in vitro effect of sema3A in reducing Toll-like receptor 9 (TLR-9) expression in B cells of SLE patients was evaluated.

Results

Sema3A serum levels in SLE patients were found to be significantly lower than in RA patients (55.04 ± 16.30 ng/ml versus 65.54 ± 14.82 ng/ml, P = 0.018) and lower yet than in normal individuals (55.04 ± 16.30 ng/ml versus 74.41 ± 17.60 ng/ml, P < 0.0001). Altered serum sema3A levels were found to be in inverse correlation with SLE disease activity, mainly with renal damage. The expression of both sema3A and NP-1 on B cells from SLE patients was significantly different in comparison with normal healthy individuals. Finally, when sema3A was co-cultured with cytosine-phosphodiester-guanine oligodeoxynucleotides (CpG-ODN)-stimulated B cells of SLE patients, their TLR-9 expression was significantly reduced, by almost 50% (P = 0.001).

Conclusions

This is the first study in which a reduced serum level of sema3A was found in association with SLE disease activity. It also raises the possibility that sema3A may have a regulatory function in SLE.
Determining sensitivity and specificity of HER2 testing in breast cancer using a tissue micro-array approach
Authors: Dekker Tim JA , Borg Susan Ter , Hooijer Gerrit KJ , Meijer Sybren Lf , Wesseling Jelle , Boers James E , Schuuring Ed , Bart Jos , van Gorp Joost , Mesker Wilma E , Kroep Judith R , Smit Vincent THBM , van de Vijver Marc J
Published: June 2012

Introduction

Overexpression of the human epidermal growth factor receptor 2 (HER2) as a result of HER2 gene amplification is associated with a relatively poor prognosis in breast cancer and is predictive of HER2-targeting therapy response. False-positive rates of up to 20% for HER2 testing have been described. HER2-testing laboratories are therefore encouraged to participate in external quality control schemes in order to improve HER2-testing standardization.

Methods

This study investigated the feasibility of retesting large numbers of invasive breast cancers for HER2 status on tissue micro-array (TMA) as part of a quality control scheme. For this assessment different HER2 testing methods were used including HER2 detecting antibodies SP3, 4B5, Herceptest and mono color silver in situ hybridization (SISH) and dual color SISH. Final HER2 status for each tumor on the TMA was compared to the local testing result for the same tumor. Discordances between these two results were investigated further by staining whole tumor sections.

Results

For this study, 1,210 invasive breast carcinomas of patients treated in six hospitals between 2006 and 2008 were evaluated. Results from the three immunohistochemistry (IHC) and two in situ hybridization (ISH) assays performed on the TMAs were compared. The final HER2 status on TMA was determined with SP3, 4B5 and mono color SISH. Concordance between local HER2 test results and TMA retesting was 98.0%. Discordant results between local and TMA retesting were found in 20 tumors (2.0%). False positive HER2 IHC results were identified in 13 (1.3%) tumors; false negative IHC results in seven (0.7%) tumors.

Conclusions

Retesting large volumes of HER2 classified breast carcinomas was found to be feasible and can be reliably performed by staining TMAs with SP3, 4B5 and mono color SISH in combination with full-sized slides for discordant cases. The frequency of false-positive results was lower than previously reported in the literature. This method is now offered to other HER2-testing laboratories.
γ-Secretase inhibition promotes cell death, Noxa upregulation, and sensitization to BH3 mimetic ABT-737 in human breast cancer cells
Authors: Séveno Céline , Loussouarn Delphine , Bréchet Sophie , Campone Mario , Juin Philippe , Barillé-Nion Sophie
Published: June 2012

Introduction

Inappropriate Notch signaling, downstream of γ-secretase activity, is understood to have tumor-promoting function and to be associated with poor outcome in cancer, of the breast in particular. The molecular basis of antitumoral effects of its inhibitors, however, remains poorly characterized. Moreover, the effects of their combination with the pro-apoptotic pharmacologic inhibitor of Bcl-2/Bcl-xL, ABT-737, have never been evaluated. In this study, we thus specifically addressed the biologic consequences of targeting γ-secretase and Bcl-2/Bcl-xL, alone or simultaneously, in breast cancer cell lines as well as in a novel human breast cancer ex vivo assay.

Methods

By using in vitro 2D or 3D cultures of breast cancer cells plus a novel preclinical short-term ex vivo assay that correctly maintains human mammary tissue integrity and preserves tumor microenvironment, we tested the effects of the pharmacologic γ-secretase inhibitor GSIXII used as a single agent or in combination with ABT-737.

Results

We show herein that the γ-secretase inhibitor, GSIXII, efficiently induces apoptosis in breast cancer cell lines by a process that relies on the induction of Noxa, a pro-apoptotic Bcl2-homology 3 domain (BH3)-only protein of the Bcl-2 family that functions as an inhibitor of antiapoptotic Mcl1. GSIXII also targets mammary cancer stem-like cells because it dramatically prevents in vitro mammosphere formation. Moreover, combining GSIXII treatment with ABT-737, a BH3-mimetic inhibitor of additional antiapoptotic proteins, such as Bcl-2 and Bcl-xL, leads to both a synergistic apoptotic response in breast cancer cells and to an inhibitory effect on mammosphere formation. These effects are also found when a Notch transcriptional inhibitor, SAHM1, is used. Finally, we evaluated individual human tumor responses to γ-secretase inhibition alone or in combination with ABT-737 in ex vivo assays. Analysis of a series of 30 consecutive tumors indicated that a majority of tumors are sensitive to apoptosis induction by GSIXII and that association of GSIXII with ABT-737 leads to an enhanced induction of apoptosis in tumor cells.

Conclusions

We thus provide evidence that γ-secretase, and downstream Notch signaling, are relevant targets in breast cancer. GSIXII, used as single agent or in combination with clinically relevant BH3-mimetics, is a promising innovative proapoptotic strategy to treat mammary tumors.
The importance of colonization pressure in multiresistant Acinetobacter baumannii acquisition in a Greek intensive care unit
Authors: Arvaniti Kostoula , Lathyris Dimitrios , Ruimy Raymond , Haidich Anna-Bettina , Koulourida Vasiliki , Nikolaidis Pavlos , Matamis Dimitrios , Miyakis Spiros
Published: June 2012

Introduction

We investigated the role of colonization pressure on multiresistant Acinetobacter baumannii acquisition and defined patient-related predictors for carriage at admission and acquisition during hospitalization in intensive care unit (ICU) patients.

Methods

This was a 12-month, prospective, cohort study of all patients admitted to a single ICU of a tertiary hospital. Screening samples were collected at ICU admission to identify imported carriers, and weekly during hospitalization to identify acquisition. Colonization pressure (carriers' patient-days × 100/all patients' patient-days) and the absolute number of carriers were calculated weekly, and the statistical correlation between these parameters and acquisition was explored. Multivariable analysis was performed to identify predictors for A. baumannii carriage at admission and acquisition during hospitalization. A. baumannii isolates were genotyped by repetitive-extragenic-palindromic polymerase chain reaction (PCR; rep-PCR).

Results

At ICU admission, 284 patients were screened for carriage. A. baumannii was imported in 16 patients (5.6%), and acquisition occurred in 32 patients (15.7%). Acquisition was significantly correlated to weekly colonization pressure (correlation coefficient, 0.379; P = 0.004) and to the number of carriers per week (correlation coefficient, 0.499; P < 0.001). More than one carrier per week significantly increased acquisition risk (two to three carriers, odds ratio (OR), 12.66; P = 0.028; more than four carriers, OR, 25.33; P = 0.004). Predictors of carriage at admission were infection at admission (OR, 11.03; confidence interval (CI), 3.56 to 34.18; P < 0.01) and hospitalization days before ICU (OR, 1.09; CI, 1.01 to 1.16; P = 0.02). Predictors of acquisition were a medical reason for ICU admission (OR, 5.11; CI, 1.31 to 19.93; P = 0.02), duration of antibiotic administration in the unit (OR, 1.24; CI, 1.12 to 1.38; P < 0.001), and duration of mechanical ventilation (OR, 1.08; CI, 1.04 to 1.13; P = 0.001). All strains were multiresistant. Rep-PCR analysis showed one dominant cluster.

Conclusions

Acquisition of multiresistant A. baumannii in ICU patients is strongly correlated to colonization pressure. High levels of colonization pressure and more than two carriers per week independently increase acquisition risk. Patient-related factors, such as infection at admission and long hospitalization before the ICU, can identify imported A. baumannii carriers. Medical patients with extended administration of antibiotics and long duration of mechanical ventilation in the ICU were the most vulnerable to acquisition.
Should lower respiratory tract secretions from intensive care patients be systematically screened for influenza virus during the influenza season?
Authors: Giannella Maddalena , Rodríguez-Sánchez Belen , Roa Paula López , Catalán Pilar , Muñoz Patricia , de Viedma Darío García , Bouza Emilio ,   the Gregorio Marañón Task Force for Pneumonia (GANG)
Published: June 2012

Introduction

Influenza is easily overlooked in intensive care units (ICUs), particularly in patients with alternative causes of respiratory failure or in those who acquire influenza during their ICU stay.

Methods

We performed a prospective study of patients admitted to three adult ICUs of our hospital from December 2010 to February 2011. All tracheal aspirate (TA) samples sent to the microbiology department were systematically screened for influenza. We defined influenza as unsuspected if testing was not requested and the patient was not receiving empirical antiviral therapy after sample collection.

Results

We received TA samples from 105 patients. Influenza was detected in 31 patients and was classified as unsuspected in 15 (48.4%) patients, and as hospital acquired in 13 (42%) patients. Suspected and unsuspected cases were compared, and significant differences were found for age (53 versus 69 median years), severe respiratory failure (68.8% versus 20%), surgery (6.3% versus 60%), median days of ICU stay before diagnosis (1 versus 4), nosocomial infection (18.8% versus 66.7%), cough (93.8% versus 53.3%), localized infiltrate on chest radiograph (6.3% versus 40%), median days to antiviral treatment (2 versus 9), pneumonia (93.8% versus 53.3%), and acute respiratory distress syndrome (75% versus 26.7%). Multivariate analysis showed admission to the surgical ICU (odds ratio (OR), 37.1; 95% confidence interval (CI), 2.1 to 666.6; P = 0.01) and localized infiltrate on chest radiograph (OR, 27.8; 95% CI, 1.3 to 584.1; P = 0.03) to be independent risk factors for unsuspected influenza. Overall mortality at 30 days was 29%. ICU admission for severe respiratory failure was an independent risk factor for poor outcome.

Conclusion

During the influenza season, almost one third of critical patients with suspected lower respiratory tract infection had influenza, and in 48.4%, the influenza was unsuspected. Lower respiratory samples from adult ICUs should be systematically screened for influenza during seasonal epidemics.
Assessment of candidemia-attributable mortality in critically ill patients using propensity score matching analysis
Authors: González de Molina Francisco J , León Cristóbal , Ruiz-Santana Sergio , Saavedra Pedro ,   the CAVA I Study Group
Published: June 2012

Introduction

Candidemia in critically ill patients is usually a severe and life-threatening condition with a high crude mortality. Very few studies have focused on the impact of candidemia on ICU patient outcome and attributable mortality still remains controversial. This study was carried out to determine the attributable mortality of ICU-acquired candidemia in critically ill patients using propensity score matching analysis.

Methods

A prospective observational study was conducted of all consecutive non-neutropenic adult patients admitted for at least seven days to 36 ICUs in Spain, France, and Argentina between April 2006 and June 2007. The probability of developing candidemia was estimated using a multivariate logistic regression model. Each patient with ICU-acquired candidemia was matched with two control patients with the nearest available Mahalanobis metric matching within the calipers defined by the propensity score. Standardized differences tests (SDT) for each variable before and after matching were calculated. Attributable mortality was determined by a modified Poisson regression model adjusted by those variables that still presented certain misalignments defined as a SDT > 10%.

Results

Thirty-eight candidemias were diagnosed in 1,107 patients (34.3 episodes/1,000 ICU patients). Patients with and without candidemia had an ICU crude mortality of 52.6% versus 20.6% (P < 0.001) and a crude hospital mortality of 55.3% versus 29.6% (P = 0.01), respectively. In the propensity matched analysis, the corresponding figures were 51.4% versus 37.1% (P = 0.222) and 54.3% versus 50% (P = 0.680). After controlling residual confusion by the Poisson regression model, the relative risk (RR) of ICU- and hospital-attributable mortality from candidemia was RR 1.298 (95% confidence interval (CI) 0.88 to 1.98) and RR 1.096 (95% CI 0.68 to 1.69), respectively.

Conclusions

ICU-acquired candidemia in critically ill patients is not associated with an increase in either ICU or hospital mortality.
Artificial immune-based self-organizing maps for seismic-facies analysis
Authors: Saraswat Puneet , Sen Mrinal K.
Published: June 2012

Seismic facies, combined with well-log data and other seismic attributes such as coherency, curvature, and AVO, play an important role in subsurface geological studies, especially for identification of depositional structures. The effectiveness of any seismic facies analysis algorithm depends on whether or not it is driven by local geologic factors, the absence of which may lead to unrealistic information about subsurface geology, depositional environment, and lithology. This includes proper identification of number of classes or facies existing in the data set. We developed a hybrid waveform classification algorithm based on an artificial immune system and self-organizing maps (AI-SOM), that forms the class of unsupervised classification or automatic facies identification followed by facies map generation. The advantage of AI-SOM is that, unlike, a stand-alone SOM, it is more robust in the presence of noise in seismic data. Artificial immune system (AIS) is an excellent data reduction technique providing a compact representation of the training data; this is followed by clustering and identification of number of clusters in the data set. The reduced data set from AIS processing serves as an excellent input to SOM processing. Thus, facies maps generated from AI-SOM are less affected by noise and redundancy in the data set. We tested the effectiveness of our algorithm with application to an offshore 3D seismic volume from F3 block in the Netherlands. The results confirmed that we can better interpret an appropriate number of facies in the seismic data using the AI-SOM approach than with a conventional SOM. We also examined the powerful data-reduction capabilities of AIS and advantages the of AI-SOM over SOM when data under consideration were noisy and redundant.
Putting together the psoriasis puzzle: an update on developing targeted therapies
Authors: Johnson-Huang Leanne M. , Lowes Michelle A. , Krueger James G.
Published: June 2012

Psoriasis vulgaris is a chronic, debilitating skin disease that affects millions of people worldwide. There is no mouse model that accurately reproduces all facets of the disease, but the accessibility of skin tissue from patients has facilitated the elucidation of many pathways involved in the pathogenesis of psoriasis and highlighted the importance of the immune system in the disease. The pathophysiological relevance of these findings has been supported by genetic studies that identified polymorphisms in genes associated with NFκB activation, IL-23 signaling and T helper 17 (Th17)-cell adaptive immune responses, and in genes associated with the epidermal barrier. Recently developed biologic agents that selectively target specific components of the immune system are highly effective for treating psoriasis. In particular, emerging therapeutics are focused on targeting the IL-23–Th17-cell axis, and several agents that block IL-17 signaling have shown promising results in early-phase clinical trials. This review discusses lessons learned about the pathogenesis of psoriasis from mouse-and patient-based studies, emphasizing how the outcomes of clinical trials with T-cell-targeted and cytokine-blocking therapies have clarified our understanding of the disease.
Understanding cardiovascular disease: a journey through the genome (and what we found there)
Authors: Lara-Pezzi Enrique , Dopazo Ana , Manzanares Miguel
Published: June 2012

Cardiovascular disease (CVD) is a major cause of mortality and hospitalization worldwide. Several risk factors have been identified that are strongly associated with the development of CVD. However, these explain only a fraction of cases, and the focus of research into the causes underlying the unexplained risk has shifted first to genetics and more recently to genomics. A genetic contribution to CVD has long been recognized; however, with the exception of certain conditions that show Mendelian inheritance, it has proved more challenging than anticipated to identify the precise genomic components responsible for the development of CVD. Genome-wide association studies (GWAS) have provided information about specific genetic variations associated with disease, but these are only now beginning to reveal the underlying molecular mechanisms. To fully understand the biological implications of these associations, we need to relate them to the exquisite, multilayered regulation of protein expression, which includes chromatin remodeling, regulatory elements, microRNAs and alternative splicing. Understanding how the information contained in the DNA relates to the operation of these regulatory layers will allow us not only to better predict the development of CVD but also to develop more effective therapies.
Maple syrup urine disease: new insights from a zebrafish model
Authors: Roberts Nathan B.
Published: June 2012

Summary and comment on a recent Disease Models & Mechanisms paper entitled ‘Mutation of zebrafish dihydrolipoamide branched-chain transacylase E2 results in motor dysfunction and models maple syrup urine disease’ (Friedrich et al., 2012).
P2Y2 receptor inhibits EGF-induced MAPK pathway to stabilise keratinocyte hemidesmosomes.
Authors: Faure Emilie , Garrouste Françoise , Parat Fabrice , Monferran Sylvie , Leloup Ludovic , Pommier Gilbert , Kovacic Hervé , Lehmann Maxime
Published: June 2012

α6β4 integrin is the main component of hemidesmosomes (HD) that stably anchor the epithelium to the underlying basement membrane. Epithelial cell migration requires HD remodelling which can be promoted by epidermal growth factor (EGF). We previously showed that extracellular nucleotides inhibit growth factor-induced keratinocyte migration. Here, we investigate the effect of extracellular nucleotides on α6β4 integrin localisation in HD during EGF-induced cell migration. Using a combination of pharmacological inhibition and gene silencing approaches, we report that UTP activates the P2Y2 purinergic receptor and Gαq protein to inhibit EGF/ERK1/2-induced cell migration in keratinocytes. Using a keratinocyte cell line expressing an inducible form of the Raf kinase, we show that UTP inhibits the EGF-induced ERK1/2 pathway activation downstream of Raf. Moreover, we establish that ERK1/2 activation by EGF leads to the mobilization of α6β4 integrin from HD. Importantly, activation of P2Y2R and Gαq by UTP promotes HD formation and protects these structures from EGF-triggered dissolution as revealed by confocal analysis of the distribution of α6β4 integrin, plectin, BPAG1, BPAG2 and CD151 in keratinocytes. Finally, we show that the activation of p90RSK, downstream of ERK1/2, is sufficient to promote EGF-mediated HD dismantling and that UTP does not stabilise HD in cells expressing an activated form of p90RSK. Our data underline an unexpected role of P2Y2R and Gαq in the inhibition of ERK1/2 signalling pathway and in the modulation of hemidesmosome dynamics and keratinocyte migration.
Flightless, secreted through a late endosome/lysosome pathway, binds LPS and dampens cytokine secretion
Authors: Lei Nazi , Franken Linda , Ruzehaji Nadira , Offenhäuser Carolin , Cowin Allison J. , Murray Rachael Z.
Published: June 2012

Flightless (Flii) is upregulated in response to wounding and has been shown to function in wound closure and scarring. In macrophages intracellular Flii negatively modulates TLR signalling and dampens cytokine production. We now show that Flii is constitutively secreted from macrophages and fibroblasts and is present in human plasma. Secretion from fibroblasts is upregulated in response to scratch wounding and LPS-activated macrophages also temporally upregulate their secretion of Flii. Using siRNA, wild-type and mutant proteins we show that Flii is secreted via a late endosomal/lysosomal pathway that is regulated by Rab7 and Stx11. Flii contains 11 leucine rich repeat (LRR) domains in its N-terminus that have nearly 50% similarity to those in the extracellular pathogen binding portion of Toll-like receptor 4 (TLR4). We show secreted Flii can also bind LPS and has the ability to alter macrophage activation. LPS activation of macrophages in Flii depleted conditioned media leads to enhanced macrophage activation and increased TNF secretion compared to cells activated in the presence of Flii. These results show secreted Flii binds to LPS and in doing so alters macrophage activation and cytokine secretion, suggesting that like the intracellular pool of Flii, secreted Flii also has the ability to alter inflammation.
Heat shock induces rapid resorption of primary cilia
Authors: Prodromou Natalia V. , Thompson Clare , Osborn Daniel P. S. , Cogger Kathryn F. , Ashworth Rachel , Knight Martin M. , Beales Philip L. , Chapple J. Paul
Published: June 2012

Primary cilia are involved in important developmental and disease pathways, such as regulation of neurogenesis and tumorigenesis. They function as sensory antennae and are essential in the regulation of key extracellular signalling systems. Here we investigate the effects of cell stress on primary cilia. Exposure of mammalian cells in vitro, and zebrafish cells in vivo, to elevated temperature resulted in the rapid loss of cilia by resorption. In mammalian cells cilia loss correlated with a reduction in hedgehog signalling. Heat shock dependent loss of cilia was decreased in cells where histone deacetylases (HDACs) were inhibited, suggesting resorption is mediated by the axoneme localised tubulin deacetylase HDAC6. In thermotolerant cells the rate of ciliary resorption was reduced. This implies a role for molecular chaperones in primary cilia maintenance. The cytosolic chaperone Hsp90 localises to the ciliary axoneme and its inhibition resulted in cilia loss. In the cytoplasm of unstressed cells, Hsp90 is known to exist in a complex with HDAC6. Moreover, immediately after heat shock Hsp90 levels were reduced in remaining cilia. We hypothesise ciliary resorption serves to attenuate cilia mediated signalling pathways in response to extracellular stress and that this mechanism is regulated in part by HDAC6 and Hsp90.
Notch-Rbpj signaling is required for the development of noradrenergic neurons in mouse locus coeruleus
Authors: Shi Ming , Hu Ze-Lan , Zheng Min-Hua , Song Ning-Ning , Huang Ying , Zhao Gang , Han Hua , Ding Yu-Qiang
Published: June 2012

The locus coeruleus (LC) is the main source of noradrenaline in the brain and is implicated in a broad spectrum of physiological and behavioral processes. However, genetic pathways controlling the development of noradrenergic neurons in the mammalian brain are largely unknown. We report here that Rbpj, a key nuclear effector in Notch signaling pathway, plays an essential role in the LC neuron development in the mouse. Conditional inactivation of Rbpj in the dorsal rhombomere (r) 1, where LC neurons are born, resulted in a dramatic increase in the number of Phox2a- and Phox2b-expressing early-differentiating LC neurons, and dopamine-β-hydroxylase- and tyrosine hydroxylase-expressing late-differentiating LC neurons. In contrast, other neuronal populations derived from the dorsal r1 were either reduced or unchanged. In addition, a drastic upregulation of Ascl1, an essential factor for noradrenergic neurogenesis, was observed in the dorsal r1 of the conditional knockout mice. Through genomic sequence analysis and EMSA and ChIP assays, a conserved Rbpj-binding motif was identified within the Ascl1 promoter. Luciferase reporter assay revealed that Rbpj per se could induce Ascl1 transactivation but this effect was counteracted by its downstream-targeted gene Hes1. Moreover, our in vitro gene transfection and in ovo electroporation assays showed that Rbpj upregulated Ascl1 expression when Hes1 expression was knocked down, though it also exerted a repressive effect on Ascl1 expression in the presence of Hes1. Thus, our results provide the first evidence that Rbpj functions as a key modulator of LC neuron development via regulating Ascl1 expression in a direct manner and as well as via an indirect way mediated by its targeted gene Hes1.
Cadherin-dependent mechanotransduction depends on ligand identity but not affinity
Authors: Tabdili Hamid , Langer Matthew , Shi Quanming , Poh Yeh-Chuin , Wang Ning , Leckband Deborah
Published: June 2012

This study investigates the relationship between classical cadherin binding affinities and mechanotransduction through cadherin-mediated adhesions. The mechanical properties of cadherin-dependent intercellular junctions are generally attributed to differences in the binding affinities of classical cadherin subtypes that contribute to cohesive energies between cells. However, cell mechanics and mechanotransduction may also regulate intercellular contacts. Here, micropipette measurements quantified the two-dimensional affinities of cadherins at the cell surface, and two complementary mechanical measurements assessed ligand-dependent mechanotransduction through cadherin adhesions. At the cell surface, the classical cadherins investigated in this study form both homophilic and heterophilic bonds with two-dimensional affinities that differ by less than three fold. In contrast, mechanotransduction via cadherin adhesions is strongly ligand-dependent such that homophilic, but not heterophilic ligation mediates mechanotransduction, independent of the cadherin binding affinity. These findings suggest that ligand-selective mechanotransduction may supersede differences in cadherin binding affinities in regulating intercellular contacts.
The Nup155-mediated Organization of Inner Nuclear Membrane Proteins is Independent of Nup155 Anchoring to the Metazoan Nuclear Pore Complex
Authors: Busayavalasa Kiran , Chen Xin , Farrants Ann-Kristin Östlund , Wagner Nicole , Sabri Nafiseh
Published: June 2012

The nuclear envelope (NE), an important barrier between the nucleus and the cytoplasm, is composed of three structures: The outer nuclear membrane (ONM), which is continuous with the ER, the inner nuclear membrane (INM), which interfaces with chromatin, and nuclear pore complexes (NPCs), which are essential for the exchange of macromolecules between the two compartments. The NPC protein Nup155 has an evolutionarily conserved role in the metazoan NE formation; but the in vivo analysis of Nup155 has been severely hampered by the essential function of this protein in cell viability. Here, we take advantage of the hypomorphicity of RNAi systems and use a combination of protein binding and rescue assays to map the interaction sites of two neigbouring NPC proteins Nup93 and Nup53 on Nup155, and to define the requirement of these interactions in INM protein organization. We show that different parts of Drosophila Nup155 have distinct functions: The Nup155 β-propeller anchors the protein to the NPC, while the α-solenoid part of Nup155 is essential for the correct localization of INM proteins LBR and otefin. Using chromatin extracts from semi-synchronized cells, we also provide evidence that the Nup155 α-solenoid has a chromatin-binding activity that is stronger at the end of mitosis. Our results argue that the role of Nup155 in INM protein localization is not mediated through the NPC anchoring activity of the protein and suggest that regions other than Nup155 β-propeller are necessary for the targeting of proteins to the INM.
FOR20, a conserved centrosomal protein, is required for assembly of the transition zone and basal body docking at the cell surface
Authors: Aubusson-Fleury Anne , Lemullois Michel , de Loubresse Nicole Garreau , Laligné Chloé , Cohen Jean , Rosnet Olivier , Jerka-Dziadosz Maria , Beisson Janine , Koll France
Published: June 2012

Within the FOP family of centrosomal proteins, the conserved FOR20 protein has been implicated in the control of primary cilium assembly in human cells. To ascertain its role in ciliogenesis, we have investigated the function of its ortholog, PtFOR20p, in a multiciliated unicellular organism, Paramecium. By a combined functional and cytological analysis, we found that PtFOR20p specifically localizes at basal bodies and is required to build the transition zone, a prerequisite to their maturation and docking at the cell surface, hence to ciliogenesis. We also found that PtCen2p (one of the two basal body specific centrins, ortholog of HsCen2) is required to recruit PtFOR20p at the developing basal body and to control its length. In contrast, the other basal body specific centrin, PtCen3p, is not needed for assembly of the transition zone, but is required downstream, for basal body docking. Comparison of the structural defects induced by depletion of PtFOR20p, PtCen2p or PtCen3p respectively illustrates the dual role of the transition zone in the biogenesis of the basal body and in cilium assembly. The multiple potential roles of the transition zone during basal body biogenesis and the evolutionary conserved function of the FOP proteins in microtubule membrane interactions are discussed.
Flow structure and transport characteristics of feeding and exchange currents generated by upside-down Cassiopea jellyfish
Authors: Santhanakrishnan Arvind , Dollinger Makani , Hamlet Christina L. , Colin Sean P. , Miller Laura A.
Published: June 2012

Quantifying the flows generated by the pulsations of jellyfish bells is crucial for understanding the mechanics and efficiency of their swimming and feeding. Recent experimental and theoretical work has focused on the dynamics of vortices in the wakes of swimming jellyfish with relatively simple oral arms and tentacles. The significance of bell pulsations for generating feeding currents through elaborate oral arms and the consequences for particle capture are not as well understood. To isolate the generation of feeding currents from swimming, the pulsing kinematics and fluid flow around the benthic jellyfish Cassiopea spp. were investigated using a combination of videography, digital particle image velocimetry and direct numerical simulation. During the rapid contraction phase of the bell, fluid is pulled into a starting vortex ring that translates through the oral arms with peak velocities that can be of the order of 10 cm s–1. Strong shear flows are also generated across the top of the oral arms throughout the entire pulse cycle. A coherent train of vortex rings is not observed, unlike in the case of swimming oblate medusae such as Aurelia aurita. The phase-averaged flow generated by bell pulsations is similar to a vertical jet, with induced flow velocities averaged over the cycle of the order of 1–10 mm s–1. This introduces a strong near-horizontal entrainment of the fluid along the substrate and towards the oral arms. Continual flow along the substrate towards the jellyfish is reproduced by numerical simulations that model the oral arms as a porous Brinkman layer of finite thickness. This two-dimensional numerical model does not, however, capture the far-field flow above the medusa, suggesting that either the three-dimensionality or the complex structure of the oral arms helps to direct flow towards the central axis and up and away from the animal.
Body size is not critical for criticalPO2 in scarabaeid and tenebrionid beetles
Authors: Lease Hilary M. , Klok Cornelis J. , Kaiser Alexander , Harrison Jon F.
Published: June 2012

Constraints on oxygen delivery potentially limit animal body size. Because diffusion rates are highly distance dependent, and because tracheal length increases with size, gas exchange was traditionally thought to be more difficult for larger insects. As yet the effect of body size on critical oxygen partial pressure (Pcrit) has not been measured for any clade of insect species for which there are interspecific data on tracheal scaling. We addressed this deficiency by measuring Pcrit over a 4150-fold mass range (ratio of largest to smallest species mean) of two families of Coleoptera (Tenebrionidae and Scarabaeidae). We exposed adult beetles to progressively lower oxygen levels and measured their ability to maintain CO2 release rates. Absolute metabolic rates increased hypometrically with beetle body mass (M) at both normoxic (M0.748) and hypoxic (M0.846) conditions. Pcrit, however, was independent of body size. Maximum overall conductances for oxygen from air to mitochondria (GO2,max) matched metabolic rates as insects became larger, likely enabling the similar Pcrit values observed in large and small beetles. These data suggest that current atmospheric oxygen levels do not limit body size of insects because of limitations on gas exchange. However, increasing relative investment in the tracheal system in larger insects may produce trade-offs or meet spatial limits that constrain insect size.