bluuebunny/crossref_metadata_2025 huggingface dataset:
The Impact of Global Financial Crisis and Policy Responses
Authors: Mitra Pradeep K.
Published: May 2010

The global economic crisis of 2008–09 was transmitted to the Caucasus, Central Asia, and Mongolia through the decline in prices of commodity exports and a slowdown in destination countries—principally the Russian Federation—which buy their exports and employ migrant workers. Unlike the other countries, however, Kazakhstan, which is well-integrated into global financial markets, experienced a sudden stop in capital flows in 2007. Fiscal stimuli have supported weakening economies, and have been financed through official borrowing by energy importers (Armenia, Georgia, the Kyrgyz Republic, Mongolia, Tajikistan) to the extent pre-crisis imbalances and the resulting debt dynamics allow and by stabilization funds in energy exporters (Azerbaijan, Kazakhstan, Turkmenistan, Uzbekistan). But more concessional financing will be needed to moderate the tradeoff between stimulus and sustainable debt levels in the event of a global recovery, which is weaker than expected. Distress in the banking sectors has been contained through liquidity support and deposit guarantees but regulatory forbearance should be avoided and proactive bank restructuring undertaken so as not to impede financial intermediation and economic recovery. Means-tested safety net programs, which can be scaled up to cushion the poorest households from the effects of the crisis, are in general better developed in the Caucasus than in Central Asia and Mongolia, where significant reform within existing fiscal envelopes and, in some cases, introduction of new programs is called for. Structural reforms to stay competitive in a post-crisis environment, where capital flows to developing countries are likely to be lower, should prioritize infrastructure and labor skills, which have emerged as the tightest bottlenecks to growth.
Prioritizing Quality Improvement in Vascular Surgery
Authors: Schilling Peter L. , Dimick Justin B. , Birkmeyer John D.
Published: May 2010

Background: Despite growing interest in quality improvement, there remains uncertainty about which procedures offer the most room for improvement in vascular surgery. To inform ongoing quality improvement initiatives, this study assessed the relative contribution of different procedures to overall morbidity, mortality, and excess length of stay in vascular surgery. Study design: Using data from ACS-NSQIP, all patients undergoing a vascular surgery operation in 2005 and 2006 (N = 16 096) were identified. Patients were placed in 29 distinct procedure categories based on CPT codes. First, we examined the procedures according to their relative contribution to overall morbidity and mortality. Then the procedures were assessed according to their contribution to overall excess length of stay. Results: Four procedure types alone accounted for 72% of adverse events, 68% of excess hospital days, and 77% of the cases in the cohort. Lower extremity bypass graft accounted for the greatest share of adverse events (29%), followed by abdominal aortic reconstruction (20%), lower extremity amputation (16%), and carotid endarterectomy (8%). The remaining 25 procedure categories accounted for only 28% of adverse events and 23% of the cases in the cohort. Conclusions: A small number of procedure types account for a disproportionately large share of morbidity, mortality, and excess hospital stay in vascular surgery, primarily because top ranked procedure types are also the most commonly performed operations in the field. These procedure types represent obvious targets for ACS-NSQIP and other efforts aimed at measuring and improving the quality of vascular surgery.
Denture hygiene care for residents in nursing homes in North Wales
Authors: Gately Fleur , Jagger Robert G. , Waylen Andrea , Jagger Daryll C.
Published: May 2010

Many elderly people who reside in nursing homes are dependent on care staff for all aspects of care, including oral health and denture hygiene. The aim of this study was to investigate the provision of one aspect of oral care, denture hygiene, in nursing homes in North Wales. Out of the 20 nursing homes identified for inclusion in the study, 10 nursing homes agreed to participate. The results of the study showed that denture hygiene care for elderly residents was still far from ideal. Perceived barriers to the provision of care include lack of training and a poor understanding of the importance of denture hygiene. In general the carers were keen to have training in oral and denture hygiene. This study has highlighted that one fundamental and important aspect of oral care for elderly residents, denture hygiene, is still a problem. This vulnerable group of individuals are not receiving essential care required to enhance their quality of life.
Cortisol is a potent modulator of lipopolysaccharide-induced interferon signaling in macrophages
Authors: Billing Anja M. , Fack Fred , Turner Jonathan D. , Muller Claude P.
Published: May 2010

The effects of cortisol (CORT) on resting and lipopolysaccharide (LPS)-activated monocyte-derived THP-1 macrophages were investigated by proteomics. Forty-seven proteins were found to be modulated, 20 by CORT, 11 by LPS, and 16 by CORT and LPS. Cortisol-sensitive chaperones and cytoskeletal proteins were mostly repressed. HCLS1, MGN, and MX1 were new proteins identified to be under the transcriptional control of this steroid and new CORT-sensitive variants of MX1, SYWC and IFIT3 were found. FKBP51, a known CORT target gene, showed the strongest response to CORT and synergism with LPS. In resting THP-1 macrophages, 18 proteins were modulated by CORT, with 15 being down-regulated. Activation of macrophages by LPS was associated with enhanced expression of immune response and metabolic proteins. In activated macrophages, CORT had a more equilibrated effect and almost all metabolism-related proteins were up-regulated, whereas immune response proteins were mostly down-regulated. The majority of the LPS up-regulated immune response-related proteins are known interferon (IFN) target genes (IFIT3, MX1, SYWC, PSME2) suggesting activation of the IRF3 signaling pathway. They were all suppressed by CORT. This is the first proteomics study to investigate the effects of CORT on activated immune cells.
Cytokine-activated NK cells inhibit PMN apoptosis and preserve their functional capacity
Authors: Bhatnagar Nupur , Hong Henoch S. , Krishnaswamy Jayendra K. , Haghikia Arash , Behrens Georg M. , Schmidt Reinhold E. , Jacobs Roland
Published: May 2010

Natural killer (NK) cells and polymorphonuclear cells (PMNs) play a critical role in the first line of defense against microorganisms. Upon host infection, PMNs phagocytose invading pathogens with subsequent killing by oxidative or nonoxidative mechanisms. NK cells are known to have immunoregulatory effects on T cells, B cells, dendritic cells (DCs), and monocytes through secretion of various soluble products and cell-cell contact. However, their impact on PMN survival and function is not well known. We found that soluble factors derived from cytokine-activated NK cells delay PMN apoptosis and preserve their ability to perform phagocytosis and produce reactive oxygen species (ROS). The expression patterns of CD11b and CD62L on PMNs differed according to the cytokine combination used for NK-cell stimulation. Irrespective of the NK-cell treatment, however, PMN survival was prolonged with sustained functional capacity. We found that interferon γ, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor α produced by NK cells upon stimulation with cytokines played a crucial role in NK cell–mediated effects on PMNs. Our study demonstrates that soluble factors derived from cytokine-activated NK cells send survival signals to PMNs, which would promote their accumulation and function at the site of inflammation in vivo.
Molecular characterization of Staphylococcus aureus isolates causing skin and soft tissue infections (SSTIs)
Authors: Yao Dan , Yu Fang-you , Qin Zhi-qiang , Chen Chun , He Su-su , Chen Zeng-qiang , Zhang Xue-qing , Wang Liang-xing
Published: May 2010

Background

Staphylococcus aureus, particularly methicillin-resistant S. aureus (MRSA), is an important cause of pyogenic skin and soft tissue infections (SSTIs). The aim of present study is to investigate the molecular characteristic of Staphylococcus aureus isolates isolated from the pus samples from the patients with purulent skin and soft tissue infections in Wenzhou, China.

Methods

Between December 2002 and June 2008, a total of 111 nonduplicate S. aureus isolates were collected from the pus samples of the patients with SSTIs in a teaching hospital in Wenzhou, China. All the tested isolates were confirmed as S. aureus using a Staph SPA agglutination kit, Gram's stain and a Vitek-60 microbiology analyzer. The homology among the tested isolates was determined by pulsed-field gel electrophoresis (PFGE). Multilocus sequence typing (MLST) was used to determine the sequence types (STs) of the selected isolates. The genotypes of SCCmec were determined by a multiplex PCR in the MRSA isolates. Panton-Valentine leukocidin (PVL) genes and mecA were also determined by another multiplex PCR.

Results

Among the 111 S. aureus isolates, 48 and 63 isolates were community-acquired and hospital-acquired respectively. Sixty isolates were confirmed as MRSA harboring mecA detected by PCR. A total of 32 PFGE clonal types were obtained by PFGE, with 10 predominant patterns (types A to J). Twenty-five different STs including ST398 and three novel STs were found among 51 selected isolates. The main STs were ST239, ST1018, ST59, ST7 and ST88. Of 60 MRSA isolates, SCCmec II, III, IV and SCCmec V were found in three, 50, three and two isolates, respectively. The positive rates of PVL genes in overall isolates, HA-isolates, CA-isolates, MRSA isolates and MSSA isolates were 23.4% (26/111), 20.6% (13/63), 27.1% (13/48), 21.7% (13/60) and 25.5% (13/51), respectively. Eight (33.3%, 8/24) of 24 CA-MRSA isolates and 5 (13.9%, 5/36) of 36 HA-MRSA isolates were positive for PVL genes. ST239-MRSA-SCCmecIII and ST1018-MRSA-SCCmecIII clones were found to be main clones and spread between community and hospital.

Conclusion

S. aureus isolates causing SSTIs showed considerable molecular heterogeneity and harbored high prevalence of PVL genes. Clonal spread was responsible for the dissemination of the isolates of S. aureus associated with SSTIs.
Copeptin is associated with mortality and outcome in patients with acute intracerebral hemorrhage
Authors: Zweifel Christian , Katan Mira , Schuetz Philipp , Siegemund Martin , Morgenthaler Nils G , Merlo Adrian , Mueller Beat , Christ-Crain Mirjam
Published: May 2010

Background

Spontaneous intracerebral hemorrhage (ICH) accounts for a high mortality and morbidity. Early prediction of outcome is crucial for optimized care and treatment decision. Copeptin, the C-terminal part of provasopressin, has emerged as a new prognostic marker in a variety of diseases, but its prognostic value in ICH is unknown.

Methods

In 40 consecutive patients who were admitted to the hospital within 72 hours after a spontaneous ICH, the plasma copeptin level was measured with a sandwich immunoassay upon admission. The prognostic value of copeptin to predict 30 day mortality and functional outcome after 90 days was assessed. A favorable outcome was defined as a Barthel score above 85 and a score below 3 on the Modified Rankin Scale.

Results

Copeptin correlated positively with hematoma volume (r = 0.32, p < 0.05) and negatively with the Glasgow Coma Scale (GCS) on admission (r = -0.35, p < 0.05). Copeptin levels were higher in patients who died within 30 days than in 30-day survivors (179.0 pmol/l (IQR 33.7- 566.0) vs. 12.9 pmol/l (IQR 5.2 - 42.8), p = 0.003). Copeptin levels were also higher in patients with an unfavorable functional outcome at 90 days compared to patients with a favorable outcome (32.4 pmol/l (IQR 9.5-97.8) vs. 11.9 pmol/l (IQR 3.2-19.8), p = 0.04). For the prediction of death, receiver-operating-characteristics analysis revealed an area under the curve (AUC) for copeptin of 0.88 (95%CI 0.75-1.00). The predictive value of the copeptin concentration was thus similar to that of GCS (AUC 0.82 (95%CI 0.59-1.00) p = 0.53), of the ICH Score (AUC 0.89, (95%CI 0.76-1.00), p = 0.94) and the ICH Grading Scale (AUC 0.86 (95%CI 0.69-1.00), p = 0.81).

Conclusions

Copeptin is a new prognostic marker in patients with an ICH. If this finding can be confirmed in larger studies, copeptin might be an additional valuable tool for risk stratification and decision-making in the acute phase of ICH.

Trial Registration

(Clinical Trial Registration: ISCTRN00390962)
Healthcare costs associated with progressive diabetic retinopathy among National Health Insurance enrollees in Taiwan, 2000-2004
Authors: Woung Lin-Chung , Tsai Ching-Yao , Chou Hsin-Kai , Tsai Ming-Tsu , Tsai Wei-Her , Chou Pesus , Shen Shih-Tsuo
Published: May 2010

Background

Diabetic retinopathy is one of the most common microvascular complications of diabetes and one of the major causes of adult visual impairment in national surveys in Taiwan. This study aimed to identify the healthcare costs of Taiwan's National Health Insurance program on behalf of diabetic patients with stable or progressive retinopathy.

Methods

A retrospective cohort study was conducted with 4,988 medication-using diabetic retinopathy subjects ≥ 40 years of age under National Health Insurance Program coverage between 2000 and 2004. Study cohort subjects were recorded as having diabetic retinopathy according to ICD-9-CM codes. States of diabetic retinopathy were strategically divided into stable and progressive categories according to subjects' conditions at follow-up in 2004. Expenditures were calculated and compared for the years 2000 and 2004.

Results

During the 4-year follow-up (2000 through 2004), 4,116 subjects (82.5%) of 4,988 diabetic subjects were in the stable category, and 872 (17.5%) were in the progressive category. Average costs of those in the normal category increased by US $48 from US $1921 in 2000 to US $1969 in 2004 (p = 0.594), whereas costs for those progressing from normal to non-proliferative diabetic retinopathy (NPDR) or proliferative diabetic retinopathy (PDR) increased by US $1760, from US $1566 in 2000 to US $3326 in 2004 (p < 0.001). The PDR category had the highest average costs at US $3632 in 2000. The NPDR-to-PDR category experienced the greatest increase in costs at US $3482, from US $2723 in 2000 to US $6204 in 2004 (p = 0.042), and the greatest percentage of increase at 2.3% (2.2% when adjusted by comparing to normal category).

Conclusions

This large-scale longitudinal study provides evidence that increased healthcare costs are associated with progressive diabetic retinopathy among diabetic NHI enrollees in Taiwan.
Decreased paraoxonase-1 activity is associated with alterations of high-density lipoprotein particles in chronic liver impairment
Authors: Marsillach Judit , Aragonès Gerard , Mackness Bharti , Mackness Michael , Rull Anna , Beltrán-Debón Raúl , Pedro-Botet Juan , Alonso-Villaverde Carlos , Joven Jorge , Camps Jordi
Published: May 2010

Background

Paraoxonase-1 (PON1), a lactonase synthesized by the liver, circulates in blood bound to high-density lipoproteins (HDL). This enzyme is thought to degrade oxidized phospholipids and play an important role in the organism's antioxidant and anti-inflammatory system. Chronic liver diseases are characterized by decreased serum PON1 activity. The aim of the present study was to investigate the compositional changes in HDL that could influence PON1 activity in liver impairment.

Methods

The study was performed in samples from five patients with advanced liver cirrhosis and with preserved renal function, chosen on the basis of having low serum PON1 activity and high serum PON1 concentration. As a control group, we accessed five healthy volunteers from among our hospital staff. Lipid and protein compositional analysis of lipoprotein particles were done by high-performance liquid chromatography, gel electrophoresis, and Western-Blot.

Results

HDL particles from cirrhotic patients had an increased phospholipid content that was inversely correlated to PON1 activity. The HDL particles contained high levels of PON1 that corresponded, in part, to an immunoreactive protein of high molecular weight (55 kDa) not present in control subjects. This protein was identified as glycosylated PON1 and was also present in biopsies from patients with steatosis and from rats with CCl4-induced hepatic impairment. These changes were associated with an increased plasma concentration of markers of oxidative stress, inflammation and fibrogenesis.

Conclusion

Abnormalities in the composition of lipids and proteins of HDL particles, including PON1 glycosylation, are associated with the decrease in serum PON1 activity in patients with liver disease. These alterations may adversely affect the protective role of HDL against oxidative stress and inflammation in these patients.
Changes in the SF-8 scores among healthy non-smoking school teachers after the enforcement of a smoke-free school policy: a comparison by passive smoke status
Authors: Kiyohara Kosuke , Itani Yuri , Kawamura Takashi , Matsumoto Yoshitaka , Takahashi Yuko
Published: May 2010

Background

The effects of the enforcement of a smoke-free workplace policy on health-related quality of life (HRQOL) among a healthy population are poorly understood. The present study was undertaken to examine the effects of the enforcement of a smoke-free school policy on HRQOL among healthy non-smoking schoolteachers with respect to their exposure to passive smoke.

Methods

Two self-reported questionnaire surveys were conducted, the first before and the second after the enforcement of a total smoke-free public school policy in Nara City. A total of 1534 teachers were invited from 62 schools, and their HRQOL was assessed using six domains extracted from the Medical Outcomes Survey Short Form-8 questionnaire (SF-8): general health perception (GH), role functioning-physical (RP), vitality (VT), social functioning (SF), mental health (MH), and role functioning-emotional (RE). The participants were divided into two groups according to their exposure to environmental tobacco smoke (ETS) at baseline: participants not exposed to ETS at school (non-smokers), and participants exposed to ETS at school (passive smokers). Changes in each SF-8 score were evaluated using paired t-tests for each group, and their inter-group differences were evaluated using multiple linear regression analyses adjusted for sex, age, school type, managerial position, and attitude towards a smoke-free policy.

Results

After ineligible subjects were excluded, 689 teachers were included in the analyses. The number of non-smokers and passive smokers was 447 and 242, respectively. Significant changes in SF-8 scores were observed for MH (0.9; 95% confidence interval [CI], 0.2-1.5) and RE (0.7; 95% CI, 0.0-1.3) in non-smokers, and GH (2.2; 95% CI, 1.2-3.1), VT (1.8; 95% CI, 0.9-2.7), SF (2.7; 95% CI, 1.6-3.8), MH (2.0; 95% CI, 1.0-2.9), and RE (2.0; 95% CI, 1.2-2.8) in passive smokers. In the multiple linear regression analyses, the net changes in the category scores of GH (1.8; 95% CI, 0.7-2.9), VT (1.4, 95% CI, 0.3-2.5), SF (2.5; 95% CI, 1.1-3.9), MH (1.2; 95% CI, 0.1-2.4) and RE (1.6; 95% CI, 0.5-2.7) in passive smokers significantly exceeded those in non-smokers.

Conclusions

A smoke-free school policy would improve the HRQOL of healthy non-smoking teachers who are exposed to ETS.
Fishing for Allergens: Bloodworm-Induced Asthma
Authors: Wu Keith CP , Räsänen Katja , Hudson Thomas J
Published: May 2010

Hypersensitivity to bloodworms (chironomid larvae) leading to asthma and other related allergic disorders is becoming common in individuals who keep or work with fish due to the increased use of bloodworms as fish food or bait.
Subcutaneous Immunoglobulin-G Replacement Therapy with Preparations Currently Available in the United States for Intravenous or Intramuscular Use: Reasons and Regimens
Authors: Chouksey Akhilesh , Duff Kimberly , Wasserbauer Nancy , Berger Melvin
Published: May 2010

For patients who require replacement therapy for primary immunodeficiency, subcutaneous infusions of immunoglobulin G (IgG) may be preferable to intravenous infusions for several reasons. However, at present, there is no preparation marketed for use by this route in North America. In this article, we describe the reasons patients have selected this route of therapy and the range of treatment regimens used. Approximately 20% of our patients have chosen the subcutaneous route, mainly because of adverse effects from intravenous (IV) infusions or difficulties with venous access. Unit dose regimens using whole bottles of currently available 16% intramuscular preparations or sucrose-containing lyophilized preparations intended for IV use but reconstituted to 15% IgG for subcutaneous administration were individually tailored to each patient. In most cases, self-infusions or home infusions were administered once or twice a week, most commonly requiring two subcutaneous sites and 2 to 3 hours per infusion. On average, patients took 0.18 mL of IgG per kilogram of body weight per site per hour. There were no systemic adverse effects. In patients for whom comparative data were available, trough serum IgG levels were higher with subcutaneous therapy than with IV therapy.
Proteome changes of lungs artificially infected with H-PRRSV and N-PRRSV by two-dimensional fluorescence difference gel electrophoresis
Authors: Xiao Shuqi , Wang Qiwei , Jia Jianyu , Cong Peiqing , Mo Delin , Yu Xiangchun , Qin Limei , Li Anning , Niu Yuna , Zhu Kongju , Wang Xiaoying , Liu Xiaohong , Chen Yaosheng
Published: May 2010

Background

Porcine reproductive and respiratory syndrome with PRRS virus (PRRSV) infection, which causes significant economic losses annually, is one of the most economically important diseases affecting swine industry worldwide. In 2006 and 2007, a large-scale outbreak of highly pathogenic porcine reproductive and respiratory syndrome (PRRS) happened in China and Vietnam. However little data is available on global host response to PRRSV infection at the protein level, and similar approaches looking at mRNA is problematic since mRNA levels do not necessarily predict protein levels. In order to improve the knowledge of host response and viral pathogenesis of highly virulent Chinese-type PRRSV (H-PRRSV) and Non-high-pathogenic North American-type PRRSV strains (N-PRRSV), we analyzed the protein expression changes of H-PRRSV and N-PRRSV infected lungs compared with those of uninfected negative control, and identified a series of proteins related to host response and viral pathogenesis.

Results

According to differential proteomes of porcine lungs infected with H-PRRSV, N-PRRSV and uninfected negative control at different time points using two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) and mass spectrometry identification, 45 differentially expressed proteins (DEPs) were identified. These proteins were mostly related to cytoskeleton, stress response and oxidation reduction or metabolism. In the protein interaction network constructed based on DEPs from lungs infected with H-PRRSV, HSPA8, ARHGAP29 and NDUFS1 belonged to the most central proteins, whereas DDAH2, HSPB1 and FLNA corresponded to the most central proteins in those of N-PRRSV infected.

Conclusions

Our study is the first attempt to provide the complex picture of pulmonary protein expression during H-PRRSV and N-PRRSV infection under the in vivo environment using 2D-DIGE technology and bioinformatics tools, provides large scale valuable information for better understanding host proteins-virus interactions of these two PRRSV strains.
Caveolin-1 influences human influenza A virus (H1N1) multiplication in cell culture
Authors: Sun Lijing , Hemgård Gun-Viol , Susanto Sony A , Wirth Manfred
Published: May 2010

Background

The threat of recurring influenza pandemics caused by new viral strains and the occurrence of escape mutants necessitate the search for potent therapeutic targets. The dependence of viruses on cellular factors provides a weak-spot in the viral multiplication strategy and a means to interfere with viral multiplication.

Results

Using a motif-based search strategy for antiviral targets we identified caveolin-1 (Cav-1) as a putative cellular interaction partner of human influenza A viruses, including the pandemic influenza A virus (H1N1) strains of swine origin circulating from spring 2009 on. The influence of Cav-1 on human influenza A/PR/8/34 (H1N1) virus replication was determined in inhibition and competition experiments. RNAi-mediated Cav-1 knock-down as well as transfection of a dominant-negative Cav-1 mutant results in a decrease in virus titre in infected Madin-Darby canine kidney cells (MDCK), a cell line commonly used in basic influenza research as well as in virus vaccine production. To understand the molecular basis of the phenomenon we focussed on the putative caveolin-1 binding domain (CBD) located in the lumenal, juxtamembranal portion of the M2 matrix protein which has been identified in the motif-based search. Pull-down assays and co-immunoprecipitation experiments showed that caveolin-1 binds to M2. The data suggest, that Cav-1 modulates influenza virus A replication presumably based on M2/Cav-1 interaction.

Conclusion

As Cav-1 is involved in the human influenza A virus life cycle, the multifunctional protein and its interaction with M2 protein of human influenza A viruses represent a promising starting point for the search for antiviral agents.
Mathematical modeling of translation initiation for the estimation of its efficiency to computationally design mRNA sequences with desired expression levels in prokaryotes
Authors: Na Dokyun , Lee Sunjae , Lee Doheon
Published: May 2010

Background

Within the emerging field of synthetic biology, engineering paradigms have recently been used to design biological systems with novel functionalities. One of the essential challenges hampering the construction of such systems is the need to precisely optimize protein expression levels for robust operation. However, it is difficult to design mRNA sequences for expression at targeted protein levels, since even a few nucleotide modifications around the start codon may alter translational efficiency and dramatically (up to 250-fold) change protein expression. Previous studies have used ad hoc approaches (e.g., random mutagenesis) to obtain the desired translational efficiencies for mRNA sequences. Hence, the development of a mathematical methodology capable of estimating translational efficiency would greatly facilitate the future design of mRNA sequences aimed at yielding desired protein expression levels.

Results

We herein propose a mathematical model that focuses on translation initiation, which is the rate-limiting step in translation. The model uses mRNA-folding dynamics and ribosome-binding dynamics to estimate translational efficiencies solely from mRNA sequence information. We confirmed the feasibility of our model using previously reported expression data on the MS2 coat protein. For further confirmation, we used our model to design 22 luxR mRNA sequences predicted to have diverse translation efficiencies ranging from 10-5 to 1. The expression levels of these sequences were measured in Escherichia coli and found to be highly correlated (R

2
= 0.87) with their estimated translational efficiencies. Moreover, we used our computational method to successfully transform a low-expressing DsRed2 mRNA sequence into a high-expressing mRNA sequence by maximizing its translational efficiency through the modification of only eight nucleotides upstream of the start codon.

Conclusions

We herein describe a mathematical model that uses mRNA sequence information to estimate translational efficiency. This model could be used to design best-fit mRNA sequences having a desired protein expression level, thereby facilitating protein over-production in biotechnology or the protein expression-level optimization necessary for the construction of robust networks in synthetic biology.
Electrical muscle stimulation prevents critical illness polyneuromyopathy: a randomized parallel intervention trial
Authors: Routsi Christina , Gerovasili Vasiliki , Vasileiadis Ioannis , Karatzanos Eleftherios , Pitsolis Theodore , Tripodaki Elli , Markaki Vasiliki , Zervakis Dimitrios , Nanas Serafim
Published: May 2010

Introduction

Critical illness polyneuromyopathy (CIPNM) is a common complication of critical illness presenting with muscle weakness and is associated with increased duration of mechanical ventilation and weaning period. No preventive tool and no specific treatment have been proposed so far for CIPNM. Electrical muscle stimulation (EMS) has been shown to be beneficial in patients with severe chronic heart failure and chronic obstructive pulmonary disease. Aim of our study was to assess the efficacy of EMS in preventing CIPNM in critically ill patients.

Methods

One hundred and forty consecutive critically ill patients with an APACHE II score ≥ 13 were randomly assigned after stratification to the EMS group (n = 68) (age:61 ± 19 years) (APACHE II:18 ± 4, SOFA:9 ± 3) or to the control group (n = 72) (age:58 ± 18 years) (APACHE II:18 ± 5, SOFA:9 ± 3). Patients of the EMS group received daily EMS sessions. CIPNM was diagnosed clinically with the medical research council (MRC) scale for muscle strength (maximum score 60, <48/60 cut off for diagnosis) by two unblinded independent investigators. Duration of weaning from mechanical ventilation and intensive care unit (ICU) stay were recorded.

Results

Fifty two patients could be finally evaluated with MRC; 24 in the EMS group and 28 in the control group. CIPNM was diagnosed in 3 patients in the EMS group as compared to 11 patients in the control group (OR = 0.22; CI: 0.05 to 0.92, P = 0.04). The MRC score was significantly higher in patients of the EMS group as compared to the control group [58 (33 to 60) vs. 52 (2 to 60) respectively, median (range), P = 0.04). The weaning period was statistically significantly shorter in patients of the EMS group vs. the control group [1 (0 to 10) days vs. 3 (0 to 44) days, respectively, median (range), P = 0.003].

Conclusions

This study suggests that daily EMS sessions prevent the development of CIPNM in critically ill patients and also result in shorter duration of weaning. Further studies should evaluate which patients benefit more from EMS and explore the EMS characteristics most appropriate for preventing CIPNM.

Trial Registration Number

ClinicalTrials.gov NCT00882830
Phospholipase C Signaling via the Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Is Essential for Normal Bone Responses to PTH
Authors: Guo Jun , Liu Minlin , Yang Dehong , Bouxsein Mary L. , Thomas Clare C. , Schipani Ernestina , Bringhurst F. Richard , Kronenberg Henry M.
Published: May 2010

We have previously shown that differentiation of hypertrophic chondrocytes is delayed in mice expressing a mutated PTH/PTHrP receptor (PTHR) (called DSEL here) that stimulates adenylyl cyclase normally but fails to activate phospholipase C (PLC). To better understand the role of PLC signaling via the PTHR in skeletal and mineral homeostasis, we examined these mice fed a normal or calcium-deficient diet. On a standard diet, DSEL mice displayed a modest decrease in bone mass. Remarkably, when fed a low-calcium diet or infused with PTH, DSEL mice exhibited strikingly curtailed peritrabecular stromal cell responses and attenuated new bone formation when compared with Wt mice. Attenuated in vitro colony formation was also observed in bone marrow cells derived from DSEL mice fed a low-calcium diet. Furthermore, PTH stimulated proliferation and increased mRNAs encoding cyclin D1 in primary osteoblasts derived from Wt but not from DSEL mice. Our data indicate that PLC signaling through the PTHR is required for skeletal homeostasis.
Molecular characterization ofnumr-1andnumr-2: genes that increase both resistance to metal-induced stress and lifespan inCaenorhabditis elegans
Authors: Tvermoes Brooke E. , Boyd Windy A. , Freedman Jonathan H.
Published: May 2010

To define the mechanisms involved in the molecular response to the carcinogenic metal cadmium, two novel metal-inducible genes from C. elegans were characterized: numr-1 and numr-2 (nuclear localized metal responsive). numr-1 and numr-2 sequences and cellular patterns of expression are identical, indicating that these are functionally equivalent genes. Constitutive transcription of numr-1 and numr-2 is developmentally regulated and occurs in the intestine, in head and tail neurons, and vulva muscles. Exposure to metals induces numr-1 and numr-2 transcription in pharyngeal and intestinal cells. Other environmental stressors do not affect transcription, indicating that these are metal-specific, stress-responsive genes. NUMR-1 and NUMR-2 target to nuclei and colocalize with HSF-1, suggesting that they may be components of nuclear stress granules. Nematodes overexpressing NUMR-1 and NUMR-2 are resistant to stress and live longer than control animals; likewise reducing expression increases sensitivity to metals and decreases neuromuscular functions. Upstream regulatory regions of both genes contain potential binding sites for DAF-16 and SKN-1, which are components of the insulin-IGF-like signaling pathway. This pathway regulates longevity and stress responses in C. elegans. NUMR-1 and NUMR-2 may function to promote resistance to environmental stressors and longevity, which is mediated by the insulin-IGF-like signaling pathway.
Glucocorticoid-dependent transdifferentiation of pancreatic progenitor cells into hepatocytes is dependent on transient suppression of WNT signalling
Authors: Wallace Karen , Marek Carylyn J. , Hoppler Stefan , Wright Matthew C.
Published: May 2010

Developmentally, the pancreas and liver are closely related and pathological conditions – including elevated glucocorticoid levels – result in the appearance of hepatocytes in the pancreas. The role of the WNT signalling pathway in this process has been examined in the model transdifferentiating pancreatic acinar AR42J-B-13 (B-13) cell. Glucocorticoid treatment resulted in a transient loss of constitutive WNT3a expression, phosphorylation and depletion of β-catenin, loss of β-catenin nuclear localisation, and significant reductions in T-cell factor/lymphoid enhancer factor (Tcf/Lef) transcriptional activity before overt changes in phenotype into hepatocyte-like (B-13/H) cells. A return to higher Tcf/Lef transcriptional activity correlated with the re-expression of WNT3a in B-13/H cells. β-catenin knock down alone substituted for and enhanced glucocorticoid-dependent transdifferentiation. Overexpression of a mutant β-catenin (pt-Xβ-cat) protein that blocked glucocorticoid-dependent suppression of Tcf/Lef activity resulted in inhibition of transdifferentiation. A small-molecule activator of Tcf/Lef transcription factors blocked glucocorticoid-dependent effects, as observed with pt-Xβ-cat expression. Quercetin – a Tcf/Lef inhibitor – did not promote transdifferentiation into B-13/H cells, but did potentiate glucocorticoid-mediated transdifferentiation. These data demonstrate that the transdifferentiation of B-13 cells into hepatocyte-like cells in response to glucocorticoid was dependent on the repression of constitutively active WNT signalling.
Acetylation of Microtubules Influences Their Sensitivity to Severing by Katanin in Neurons and Fibroblasts
Authors: Sudo Haruka , Baas Peter W.
Published: May 2010

Here we investigated whether the sensitivity of microtubules to severing by katanin is regulated by acetylation of the microtubules. During interphase, fibroblasts display long microtubules with discrete regions rich in acetylated tubulin. Overexpression of katanin for short periods of time produced breaks preferentially in these regions. In fibroblasts with experimentally enhanced or diminished microtubule acetylation, the sensitivity of the microtubules to severing by katanin was increased or decreased, respectively. In neurons, microtubules are notably more acetylated in axons than in dendrites. Experimental manipulation of microtubule acetylation in neurons yielded similar results on dendrites as observed on fibroblasts. However, under these experimental conditions, axonal microtubules were not appreciably altered with regard to their sensitivity to katanin. We hypothesized that this may be attributable to the effects of tau on the axonal microtubules, and this was validated by studies in which overexpression of tau caused microtubules in dendrites and fibroblasts to be more resistant to severing by katanin in a manner that was not dependent on the acetylation state of the microtubules. Interestingly, none of these various findings apply to spastin, because the severing of microtubules by spastin does not appear to be strongly influenced by either the acetylation state of the microtubules or tau. We conclude that sensitivity to microtubule severing by katanin is regulated by a balance of factors, including the acetylation state of the microtubules and the binding of tau to the microtubules. In the neuron, this contributes to regional differences in the microtubule arrays of axons and dendrites.
Synergistic Interactions between Aβ, Tau, and α-Synuclein: Acceleration of Neuropathology and Cognitive Decline
Authors: Clinton Lani K. , Blurton-Jones Mathew , Myczek Kristoffer , Trojanowski John Q. , LaFerla Frank M.
Published: May 2010

Alzheimer's disease (AD), the most prevalent age-related neurodegenerative disorder, is characterized pathologically by the accumulation of β-amyloid (Aβ) plaques and tau-laden neurofibrillary tangles. Interestingly, up to 50% of AD cases exhibit a third prevalent neuropathology: the aggregation of α-synuclein into Lewy bodies. Importantly, the presence of Lewy body pathology in AD is associated with a more aggressive disease course and accelerated cognitive dysfunction. Thus, Aβ, tau, and α-synuclein may interact synergistically to promote the accumulation of each other. In this study, we used a genetic approach to generate a model that exhibits the combined pathologies of AD and dementia with Lewy bodies (DLB). To achieve this goal, we introduced a mutant human α-synuclein transgene into 3xTg-AD mice. As occurs in human disease, transgenic mice that develop both DLB and AD pathologies (DLB-AD mice) exhibit accelerated cognitive decline associated with a dramatic enhancement of Aβ, tau, and α-synuclein pathologies. Our findings also provide additional evidence that the accumulation of α-synuclein alone can significantly disrupt cognition. Together, our data support the notion that Aβ, tau, and α-synuclein interactin vivoto promote the aggregation and accumulation of each other and accelerate cognitive dysfunction.
Setdb1 Histone Methyltransferase Regulates Mood-Related Behaviors and Expression of the NMDA Receptor Subunit NR2B
Authors: Jiang Yan , Jakovcevski Mira , Bharadwaj Rahul , Connor Caroline , Schroeder Frederick A. , Lin Cong L. , Straubhaar Juerg , Martin Gilles , Akbarian Schahram
Published: May 2010

Histone methyltransferases specific for the histone H3-lysine 9 residue, including Setdb1 (Set domain, bifurcated 1)/Eset/Kmt1e are associated with repressive chromatin remodeling and expressed in adult brain, but potential effects on neuronal function and behavior remain unexplored. Here, we report that transgenic mice with increased Setdb1 expression in adult forebrain neurons show antidepressant-like phenotypes in behavioral paradigms for anhedonia, despair, and learned helplessness. Chromatin immunoprecipitation in conjunction with DNA tiling arrays (ChIP-chip) revealed that genomic occupancies of neuronal Setdb1 are limited to <1% of annotated genes, which include the NMDA receptor subunitNR2B/Grin2Band other ionotropic glutamate receptor genes. Chromatin conformation capture and Setdb1-ChIP revealed a loop formation tethering theNR2B/Grin2bpromoter to the Setdb1 target site positioned 30 kb downstream of the transcription start site. In hippocampus and ventral striatum, two key structures in the neuronal circuitry regulating mood-related behaviors, Setdb1-mediated repressive histone methylation atNR2B/Grin2bwas associated with decreased NR2B expression and EPSP insensitivity to pharmacological blockade of NR2B, and accelerated NMDA receptor desensitization consistent with a shift in NR2A/B subunit ratios. In wild-type mice, systemic treatment with the NR2B antagonist, Ro25-6981 [R-(R,S)-α-(4-hydroxyphenyl)-β-methyl-4-(phenylmethyl)-1-piperidine propranol], and hippocampal small interfering RNA-mediated NR2B/Grin2b knockdown resulted in behavioral changes similar to those elicited by theSetdb1transgene. Together, these findings point to a role for neuronal Setdb1 in the regulation of affective and motivational behaviors through repressive chromatin remodeling at a select set of target genes, resulting in altered NMDA receptor subunit composition and other molecular adaptations.
The Therapeutic Mode of Action of 4-Aminopyridine in Cerebellar Ataxia
Authors: Alviña Karina , Khodakhah Kamran
Published: May 2010

Episodic ataxia type 2 (EA2) is a hereditary cerebellar ataxia associated with mutations in the P/Q-type voltage-gated calcium (Ca2+) channels. Therapeutic approaches for treatment of EA2 are very limited. Presently, the potassium (K+) channel blocker 4-aminopyridine (4-AP) constitutes the most promising treatment, although its mechanism of action is not understood. Here we show that, in contrast to what is commonly believed, therapeutic concentrations of 4-AP do not increase the inhibitory drive of cerebellar Purkinje cells. Instead, 4-AP restores the severely diminished precision of pacemaking in Purkinje cells of EA2 mutant mice by prolonging the action potential and increasing the action potential afterhyperpolarization. Consistent with this mode of action, the therapeutic efficacy of 4-AP was comparable, and not additive, to chlorzoxazone, an activator of Ca2+-dependent K+channels that also restores the precision of Purkinje cell pacemaking. The likely target of 4-AP at the concentrations used are the Kv1 family of K+channels, possibly the Kv1.5 subtype. Because at higher concentrations 4-AP blocks a large array of K+channels and is a proconvulsant, use of selective Kv1 channel blockers is likely to be a safer substitute for treatment of cerebellar ataxia.
Dendritic Calcium Signaling in ON and OFF Mouse Retinal Ganglion Cells
Authors: Margolis David J. , Gartland Andrew J. , Euler Thomas , Detwiler Peter B.
Published: May 2010

Retinal ganglion cells (RGCs) are the output cells of the retina; they convert synaptic input into spike output that carries visual information to the brain. Synaptic inputs are received, integrated and communicated to the spike initiation zone of the axon by dendrites whose properties are poorly understood. Here simultaneous patch-clamp recording and 2-photon Ca2+imaging are used to study voltage- and light-evoked Ca2+signals in the dendrites of identified types of mouse RGCs from parallel ON and OFF pathways, which encode the onset and offset of light, respectively. The results show pathway-specific differences in voltage-dependent Ca2+signaling. While both ON and OFF cells express high-voltage-activated (HVA) Ca2+channels, only OFF RGCs also express low-voltage-activated (LVA) Ca2+channels. LVA Ca2+channels in OFF cells are deinactivated by hyperpolarization from the resting potential and give rise to rebound excited Ca2+spikes at the termination of a step of either hyperpolarizing current or light. This suggests that the differential expression of voltage-gated Ca2+channels in ON and OFF RGC dendrites contributes to differences in the way the two cell types process visual stimuli.
Determinants of IGF1 and GH across the weight spectrum: from anorexia nervosa to obesity
Authors: Brick D J , Gerweck A V , Meenaghan E , Lawson E A , Misra M , Fazeli P , Johnson W , Klibanski A , Miller K K
Published: May 2010

Context

Chronic starvation is characterized by GH resistance, and obesity is characterized by decreased GH secretion. In both extremes, IGF1 levels may be low and androgen levels may be abnormal.

Objective

To investigate the determinants of IGF1 and GH across the weight spectrum in women.

Design

Cross-sectional study.

Setting

Clinical research center.

Study participants

In total, 32 women had participated in the study: 11 women with anorexia nervosa (AN), 11 normal-weight women, and 10 obese women of comparable mean age.

Intervention

None.

Main outcome measures

Pooled hourly overnight serum samples assayed for IGF1, GH, estradiol (E2), testosterone, SHBG, insulin, free fatty acids, and trunk fat.

Results

Free testosterone was higher in obese women and lower in women with AN than in normal-weight women, and was the only independent (and positive) predictor of IGF1 levels, accounting for 14% of the variability (P=0.032) in the group as a whole. This relationship was stronger when obese women were excluded, with free testosterone accounting for 36% of the variability (P=0.003). Trunk fat accounted for 49% of the variability (P<0.0001) of GH, with an additional 7% of the variability attributable to E2 (P=0.042) in the group as a whole, but was not a significant determinant of GH secretion when obese women were excluded.

Conclusions

Free testosterone is a significant determinant of IGF1 levels in women across the body weight spectrum. In contrast, GH secretion is differentially regulated at the extremes of the weight spectrum.
Genomic imprinting in germ cells: imprints are under control
Authors: Arnaud Philippe
Published: May 2010

Thecis-acting regulatory sequences of imprinted gene loci, called imprinting control regions (ICRs), acquire specific imprint marks in germ cells, including DNA methylation. These epigenetic imprints ensure that imprinted genes are expressed exclusively from either the paternal or the maternal allele in offspring. The last few years have witnessed a rapid increase in studies on how and when ICRs become marked by and subsequently maintain such epigenetic modifications. These novel findings are summarised in this review, which focuses on the germline acquisition of DNA methylation imprints and particularly on the combined role of primary sequence specificity, chromatin configuration, non-histone proteins and transcriptional events.
Transformation and catching-up issues in Hungary — From a network alignment perspective
Authors: Szalavetz A.
Published: May 2010

Awareness about the growing role of networks in economic activity keeps rapidly increasing as reflected by the number of publications in international academic literature. This literature is, however, concerned with the
advantages
of network-based cooperation, while analyses of network failure and inferior-to-expectations outcomes remain scarce. This paper adds to the accumulating evidence that network formation and network integration are no panacea: similarly to the much-researched and analysed phenomena of market failure or government (state) failure, there is such thing as
network failure
.Combining theoretical arguments with Hungarian fieldwork experience originating from the author’s past investigations, cases of network failure and network misalignment both within the innovation system and within producer networks are examined. Another focus of this paper is institutional and policy (mis)alignment, i.e. the question, how the institutional set-up facilitates or works against achieving developmental goals in Hungary. We claim that though networks have an impact on development outcomes, the effectiveness of networks, i.e. their developmental role and the value of network ties are continuously shaped by network actors’ capabilities and behaviour.