bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural analysis of Brucella abortus RicA substitutions that do not impair interaction with human Rab2 GTPase
Authors: Nkengfac Bernard , Pouyez Jenny , Bauwens Emilie , Vandenhaute Jean , Letesson Jean-Jacques , Wouters Johan , De Bolle Xavier
Published: August 2012

Background

Protein-protein interactions are at the basis of many cellular processes, and they are also involved in the interaction between pathogens and their host(s). Many intracellular pathogenic bacteria translocate proteins called effectors into the cytoplasm of the infected host cell, and these effectors can interact with one or several host protein(s). An effector named RicA was recently reported in Brucella abortus to specifically interact with human Rab2 and to affect intracellular trafficking of this pathogen.

Results

In order to identify regions of the RicA protein involved in the interaction with Rab2, RicA was subjected to extensive random mutagenesis using error prone polymerase chain reaction. The resulting allele library was selected by the yeast two-hybrid assay for Rab2-interacting clones that were isolated and sequenced, following the “absence of interference” approach. A tridimensional model of RicA structure was used to position the substitutions that did not affect RicA-Rab2 interaction, giving a “negative image” of the putative interaction region. Since RicA is a bacterial conserved protein, RicA homologs were also tested against Rab2 in a yeast two-hybrid assay, and the C. crescentus homolog of RicA was found to interact with human Rab2. Analysis of the RicA structural model suggested that regions involved in the folding of the “beta helix” or an exposed loop with the IGFP sequence could also be involved in the interaction with Rab2. Extensive mutagenesis of the IGFP loop suggested that loss of interaction with Rab2 was correlated with insolubility of the mutated RicA, showing that “absence of interference” approach also generates surfaces that could be necessary for folding.

Conclusion

Extensive analysis of substitutions in RicA unveiled two structural elements on the surface of RicA, the most exposed β-sheet and the IGFP loop, which could be involved in the interaction with Rab2 and protein folding. Our analysis of mutants in the IGFP loop suggests that, at least for some mono-domain proteins such as RicA, protein interaction analysis using allele libraries could be complicated by the dual effect of many substitutions affecting both folding and protein-protein interaction.
Analyzes of genome-wide association follow-up study for calving traits in dairy cattle
Authors: Höglund Johanna K , Guldbrandtsen Bernt , Lund Mogens S , Sahana Goutam
Published: August 2012

Background

There is often a pronounced disagreement between results obtained from different genome-wide association studies in cattle. There are multiple reasons for this disagreement. Particularly the presence of false positives leads to a need to validate detected QTL before they are optimally incorporated or weighted in selection decisions or further studied for causal gene. In dairy cattle progeny testing scheme new data is routinely accumulated which can be used to validate previously discovered associations. However, the data is not an independent sample and the sample size may not be sufficient to have enough power to validate previous discoveries. Here we compared two strategies to validate previously detected QTL when new data is added from the same study population. We compare analyzing a combined dataset (COMB) including all data presently available to only analyzing a validation dataset (VAL) i.e. a new dataset not previously analyzed as an independent replication. Secondly, we confirm SNP detected in the Reference population (REF) (i.e. previously analyzed dataset consists of older bulls) in the VAL dataset.

Results

Clearly the results from the combined (COMB) dataset which had nearly twice the sample size of other two subsets allowed the detection of far more significant associations than the two smaller subsets. The number of significant SNPs in REF (older bulls) was about four times higher compare to VAL (younger bulls) though both had similar sample sizes, 2,219 and 2,039 respectively. A total of 424 SNP-trait combinations on 22 chromosomes showed genome-wide significant association involving 284 unique SNPs in the COMB dataset. In the REF data set 101 associations (73 unique SNPs) and in the VAL 24 associations (18 unique SNPs) were found genome-wide significant. Sixty-eight percent of the SNPs in the REF dataset could be confirmed in the VAL dataset. Out of 469 unique SNPs showing chromosome-wide significant association with calving traits in the REF dataset 321 could be confirmed in the VAL dataset at P < 0.05.

Conclusions

The follow-up study for GWAS in cattle will depend on the aim of the study. If the aim is to discover novel QTL, analyses of the COMB dataset is recommended, while in case of identification of the causal mutation underlying a QTL, confirmation of the discovered SNPs are necessary to avoid following a false positive.
Optimizing de novo common wheat transcriptome assembly using short-read RNA-Seq data
Authors: Duan Jialei , Xia Chuan , Zhao Guangyao , Jia Jizeng , Kong Xiuying
Published: August 2012

Background

Rapid advances in next-generation sequencing methods have provided new opportunities for transcriptome sequencing (RNA-Seq). The unprecedented sequencing depth provided by RNA-Seq makes it a powerful and cost-efficient method for transcriptome study, and it has been widely used in model organisms and non-model organisms to identify and quantify RNA. For non-model organisms lacking well-defined genomes, de novo assembly is typically required for downstream RNA-Seq analyses, including SNP discovery and identification of genes differentially expressed by phenotypes. Although RNA-Seq has been successfully used to sequence many non-model organisms, the results of de novo assembly from short reads can still be improved by using recent bioinformatic developments.

Results

In this study, we used 212.6 million pair-end reads, which accounted for 16.2 Gb, to assemble the hexaploid wheat transcriptome. Two state-of-the-art assemblers, Trinity and Trans-ABySS, which use the single and multiple k-mer methods, respectively, were used, and the whole de novo assembly process was divided into the following four steps: pre-assembly, merging different samples, removal of redundancy and scaffolding. We documented every detail of these steps and how these steps influenced assembly performance to gain insight into transcriptome assembly from short reads. After optimization, the assembled transcripts were comparable to Sanger-derived ESTs in terms of both continuity and accuracy. We also provided considerable new wheat transcript data to the community.

Conclusions

It is feasible to assemble the hexaploid wheat transcriptome from short reads. Special attention should be paid to dealing with multiple samples to balance the spectrum of expression levels and redundancy. To obtain an accurate overview of RNA profiling, removal of redundancy may be crucial in de novo assembly.
Pediatric first aid knowledge and attitudes among staff in the preschools of Shanghai, China
Authors: Li Feng , Jiang Fan , Jin Xingming , Qiu Yulan , Shen Xiaoming
Published: August 2012

Background

Unintentional injury remains the leading cause of morbidity and mortality among children worldwide. The aims of this study were to assess a baseline level of first aid knowledge and overall attitudes regarding first aid among staff members in Shanghai preschools.

Methods

A cross-sectional study was carried out among the staff members at selected preschools. A stratified random sampling method was first used to identify suitable subjects. Data were obtained using a multiple-choice questionnaire. A standardized collection of demographics was performed and participants were given the aforementioned questionnaire to indicate knowledge of and attitudes toward first aid.

Results

1067 subjects completed the questionnaire. None of the surveyed employees answered all questions correctly; only 39 individuals (3.7%) achieved passing scores. The relative number of correct answers to specific questions ranged from 16.5% to 90.2%. In particular, subjects lacked knowledge regarding first aid for convulsive seizures (only 16.5% answered correctly), chemical injuries to the eye (23%), inhaled poison (27.6%), and choking and coughing (30.1%). A multiple linear regression analysis showed scores were significantly higher among staff members with more education, those who had received first aid training before or were already healthcare providers, younger employees, and staff members from rural districts. Most employees agreed that giving first aid was helpful; the vast majority felt that it was important and useful for them to learn pediatric first aid.

Conclusions

The level of first-aid knowledge among preschool staffs in Shanghai was low. There is an urgent need to educate staff members regarding first aid practices and the various risk factors relating to specific injuries.
Income-related inequality in health insurance coverage: analysis of China Health and Nutrition Survey of 2006 and 2009
Authors: Liu Jinan , Shi Lizheng , Meng Qingyue , Khan M Mahmud
Published: August 2012

Introduction

China introduced the urban resident basic medical insurance (URBMI) in 2007 to cover children and urban unemployed adults, in addition to the new cooperative medical scheme (NCMS) for rural residents in 2003 and the basic health insurance scheme (BHIS) for urban employees in 1998. This study examined whether the overall income-related inequality in health insurance coverage improved during 2006 and 2009 in China.

Methods

The China Health and Nutrition Survey (CHNS) data of 2006 and 2009 were used to create the concentration curve and the concentration index. GEE logistic regression was used to model the health insurance coverage as dependent variable and household income per capita as independent variable, controlling for individuals' age, gender, marital status, educational attainment, employment status, year 2009 (Y2009), household size, retirement status, and geographic variations. The change in the income-related inequality in 2009 was estimated using the interaction term of income*Y2009.

Results

In 2006, 49.7% (4,712/9,476) respondents had health insurance: 13.4% with BHIS and 28.4% with NCMS. In 2009, 90.8% (8,964/9,863) had health insurance: 10.1% with URBMI, 18.3% with BHIS, and 57.6% with NCMS. The BHIS, URBMI, and NCMS programs had different patterns of population coverage over 10 income deciles. The concentration index was 0.15 in 2006 and 0.04 in 2009. The dominance test showed that the concentration curves were significantly different between 2006 and 2009 (p < 0.05). An income increase per capita by 10,000 RMB was associated with 25.5% more likely to have health insurance coverage (odds ratio = 1.255, 95% confidence interval: [1.130-1.393]). In 2009, there was significant improvement in the income-related inequality (p < 0.001).

Discussions

Comparing 2009 to 2006, the income inequality in health insurance coverage was largely corrected in China through rapid expansion of CHNS in rural areas and initiation of URBMI in urban areas.
Obesity, Inflammation and Acute Myocardial Infarction - Expression of leptin, IL-6 and high sensitivity-CRP in Chennai based population
Authors: Rajendran Karthick , Devarajan Nalini , Ganesan Manohar , Ragunathan Malathi
Published: August 2012

Background

Obesity, characterised by increased fat mass and is currently regarded as a pro-inflammatory state and often associated with increased risk of cardiovascular diseases (CVD) including Myocardial infarction. There is an upregulation of inflammatory markers such as interleukin-6, interleukin-6 receptor and acute phase protein CRP in Acute Myocardial Infarction (AMI) patients but the exact mechanism linking obesity and inflammation is not known. It is of our interest to investigate if serum leptin (ob gene product) is associated with AMI and correlated with inflammatory proteins namely Interleukin-6 (IL-6) and high sensitivity - C reactive protein (hs-CRP).

Results

Serum leptin levels were significantly higher in AMI patients when compared to Non-CVD controls. IL-6 and hs-CRP were also elevated in the AMI group and leptin correlated positively with IL-6 and hs-CRP. Incidentally this is the first report from Chennai based population, India.

Conclusions

The strong correlation between serum levels of leptin and IL-6 implicates an involvement of leptin in the upregulation of inflammatory cytokines during AMI. We hypothesise that the increase in values of IL-6, hs-CRP and their correlation to leptin in AMI patients could be due to participation of leptin in the signaling cascade after myocardial ischemia.
Throughput and reliability analysis of a scalable broadcast MAC for distributed wireless networks
Authors: Pudasaini Subodh , Shin Seokjoo , Kim Kiseon
Published: August 2012

In carrier-sense-multiple-access-based distributed wireless networks, the legacy mechanism of arbitrating the access attempts of multiple broadcast users (using a fixed-size temporal contention window consisting of multiple contention slots having uniform selection probability) has been well understood to be inefficient in avoiding collisions, especially when the network is large. Recently, it has been found that this inefficiency can be mitigated by exploiting an additional degree of freedom (DoF) over the contention window, referred to as contention slot selection distribution (CSSD). In this article, the authors examine how the additional DoF contributes to enhancing network performance and quantify the performance gains that the network can achieve in terms of easily understandable performance indicators like network throughput efficiency and broadcast reliability. A discrete-time Markov chain is formulated to characterize the access arbitration process involving a reverse exponential CSSD and its steady-state solution is fed to a renewal-reward process-based network model to estimate the performances of interest. Validated numerical results are presented which confirm that this new channel access arbitration mechanism can significantly enhance the scalability of distributed broadcast networks.
TWIST1 associates with NF-κB subunit RELA via carboxyl-terminal WR domain to promote cell autonomous invasion through IL8 production
Authors: Li Shan , Kendall Stephen E , Raices Raquel , Finlay James , Covarrubias Maricela , Liu Zheng , Lowe Gina , Lin Yu-Huey , Teh Yuan Han , Leigh Victoria , Dhillon Simi , Flanagan Steven , Aboody Karen S , Glackin Carlotta A
Published: August 2012

Background

Metastasis is the primary cause of death for cancer patients. TWIST1, an evolutionarily conserved basic helix-loop-helix (bHLH) transcription factor, is a strong promoter of metastatic spread and its expression is elevated in many advanced human carcinomas. However, the molecular events triggered by TWIST1 to motivate dissemination of cancer cells are largely unknown.

Results

Here we show that TWIST1 induces the production of interleukin 8 (IL8), which activates matrix metalloproteinases and promotes invasion of breast epithelial and cancer cells. In this novel mechanism, TWIST1-mediated IL8 transcription is induced through the TWIST1 carboxy-terminal WR (Trp-Arg) domain instead of the classic DNA binding bHLH domain. Co-immunoprecipitation analyses revealed that the WR domain mediates the formation of a protein complex comprised of TWIST1 and the nuclear factor-kappaB (NF-κB) subunit RELA (p65/NF-κB3), which synergistically activates the transcriptional activity of NF-κB. This activation leads to increased DNA binding affinity of RELA to the IL8 promoter and thus induces the expression of the cytokine. Blockage of IL8 signaling by IL8 neutralizing antibodies or receptor inhibition reduced the invasiveness of both breast epithelial and cancer cells, indicating that TWIST1 induces autonomous cell invasion by establishing an IL8 antocrine loop.

Conclusions

Our data demonstrate that the TWIST1 WR domain plays a critical role in TWIST1-induced IL8 expression through interactions with and activation of NF-κB. The produced IL8 signals through an autocrine loop and promotes extracellular matrix degradation to enable cell invasion across the basement membrane.
Complement activation in the injured central nervous system: another dual-edged sword?
Authors: Brennan Faith H , Anderson Aileen J , Taylor Stephen M , Woodruff Trent M , Ruitenberg Marc J
Published: August 2012

The complement system, a major component of the innate immune system, is becoming increasingly recognised as a key participant in physiology and disease. The awareness that immunological mediators support various aspects of both normal central nervous system (CNS) function and pathology has led to a renaissance of complement research in neuroscience. Various studies have revealed particularly novel findings on the wide-ranging involvement of complement in neural development, synapse elimination and maturation of neural networks, as well as the progression of pathology in a range of chronic neurodegenerative disorders, and more recently, neurotraumatic events, where rapid disruption of neuronal homeostasis potently triggers complement activation. The purpose of this review is to summarise recent findings on complement activation and acquired brain or spinal cord injury, i.e. ischaemic-reperfusion injury or stroke, traumatic brain injury (TBI) and spinal cord injury (SCI), highlighting the potential for complement-targeted therapeutics to alleviate the devastating consequences of these neurological conditions.
Female attractiveness affects paternal investment: experimental evidence for male differential allocation in blue tits
Authors: Mahr Katharina , Griggio Matteo , Granatiero Michela , Hoi Herbert
Published: August 2012

Introduction

The differential allocation hypothesis (DAH) predicts that individuals should adjust their parental investment to their current mate’s quality. Although in principle the DAH holds for both sexes, male adjustment of parental investment has only been tested in a few experimental studies, revealing contradictory results. We conducted a field experiment to test whether male blue tits (Cyanistes caeruleus) allocate their parental effort in relation to female ornamentation (ultraviolet colouration of the crown), as predicted by the DAH.

Results

We reduced the UV reflectance in a sample of females and compared parental care by their mates with that of males paired to sham-manipulated control females. As predicted by the DAH our results demonstrate that males paired with UV-reduced females invested less in feeding effort but did not defend the chicks less than males paired with control females.

Conclusions

To our knowledge, this is one of the first studies providing support for male differential allocation in response to female ornamentation.
Suppression of dynamin GTPase decreases α-synuclein uptake by neuronal and oligodendroglial cells: a potent therapeutic target for synucleinopathy
Authors: Konno Masatoshi , Hasegawa Takafumi , Baba Toru , Miura Emiko , Sugeno Naoto , Kikuchi Akio , Fiesel Fabienne C , Sasaki Tsutomu , Aoki Masashi , Itoyama Yasuto , Takeda Atsushi
Published: August 2012

Background

The intracellular deposition of misfolded proteins is a common neuropathological hallmark of most neurodegenerative disorders. Increasing evidence suggests that these pathogenic proteins may spread to neighboring cells and induce the propagation of neurodegeneration.

Results

In this study, we have demonstrated that α-synuclein (αSYN), a major constituent of intracellular inclusions in synucleinopathies, was taken up by neuronal and oligodendroglial cells in both a time- and concentration-dependent manner. Once incorporated, the extracellular αSYN was immediately assembled into high-molecular-weight oligomers and subsequently formed cytoplasmic inclusion bodies. Furthermore, αSYN uptake by neurons and cells of the oligodendroglial lineage was markedly decreased by the genetic suppression and pharmacological inhibition of the dynamin GTPases, suggesting the involvement of the endocytic pathway in this process.

Conclusions

Our findings shed light on the mode of αSYN uptake by neuronal and oligodendroglial cells and identify therapeutic strategies aimed at reducing the propagation of protein misfolding.
L166P mutant DJ-1 promotes cell death by dissociating Bax from mitochondrial Bcl-XL
Authors: Ren Haigang , Fu Kai , Mu Chenchen , Zhen Xuechu , Wang Guanghui
Published: August 2012

Background

Mutations or deletions in DJ-1/PARK7 gene are causative for recessive forms of early onset Parkinson’s disease (PD). Wild-type DJ-1 has cytoprotective roles against cell death through multiple pathways. The most commonly studied mutant DJ-1(L166P) shifts its subcellular distribution to mitochondria and renders cells more susceptible to cell death under stress stimuli. We previously reported that wild-type DJ-1 binds to Bcl-XLand stabilizes it against ultraviolet B (UVB) irradiation-induced rapid degradation. However, the mechanisms by which mitochondrial DJ-1(L166P) promotes cell death under death stimuli are largely unknown.

Results

We show that DJ-1(L166P) is more prone to localize in mitochondria and it binds to Bcl-XLmore strongly than wild-type DJ-1. In addition, UVB irradiation significantly promotes DJ-1(L166P) translocation to mitochondria and binding to Bcl-XL. DJ-1(L166P) but not wild-type DJ-1 dissociates Bax from Bcl-XL, thereby leading to Bax enrichment at outer mitochondrial membrane and promoting mitochondrial apoptosis pathway in response to UVB irradiation.

Conclusion

Our findings suggest that wild-type DJ-1 protects cells and DJ-1(L166P) impairs cells by differentially regulating mitochondrial Bax/Bcl-XLfunctions.
Compatibility of SYTO 13 and Hoechst 33342 for longitudinal imaging of neuron viability and cell death
Authors: Hubbard Kyle S , Gut Ian M , Scheeler Stephen M , Lyman Megan E , McNutt Patrick M
Published: August 2012

Background

Simultaneous use of cell-permeant and impermeant fluorescent nuclear dyes is a common method to study cell viability and cell death progression. Although these assays are usually conducted as end-point studies, time-lapse imaging offers a powerful technique to distinguish temporal changes in cell viability at single-cell resolution. SYTO 13 and Hoechst 33342 are two commonly used cell-permeant nuclear dyes; however their suitability for live imaging has not been well characterized. We compare end-point assays with time-lapse imaging studies over a 6 h period to evaluate the compatibility of these two dyes with longitudinal imaging, using both control neurons and an apoptotic neuron model.

Findings

In longitudinal assays of untreated neurons, SYTO 13 addition caused acute necrosis within 3 h, whereas neurons imaged with Hoechst remained viable for at least 6 h. In a staurosporine-induced apoptotic model of neurotoxicity, determinations of the mode of cell death and measurements of nuclear size were identical between longitudinal studies using Hoechst and end-point assays. Alternatively, longitudinal studies using 500 nM or 5 nM SYTO 13 were not consistent with end-point assays.

Conclusions

SYTO 13 is acutely neurotoxic and when used in longitudinal studies, masked end-stage morphologic evidence of apoptotic cell death. In contrast, a single application of Hoechst evoked no evidence of toxicity over a 6 h period, and was consistent with end-point characterizations of cell viability and nuclear morphology. For longitudinal characterization of acute cell death, Hoechst is a superior option.
Uncommon cavernous malformation of the optic chiasm: a case report
Authors: Ning Xianbin , Xu Kan , Luo Qi , Qu Limei , Yu Jinlu
Published: August 2012

Cavernous malformation (CM) is a vascular malformation disorder characterized by a berry-like mass of expanded blood vessels. CM, originating from the optic chiasm. usually leads to chiasma syndrome presenting with bitemporal hemianopsia. We report a 28-year-old male presenting with left homonymous hemianopsia. Magnetic resonance imaging (MRI) revealed an occupied lesion located in the right side of the optic chiasm, and a clinical diagnosis of chiasmal CM was made. Microsurgical excision was performed via anterolateral pterional craniotomy. The patient showed good recovery with slight improvement of the visual field deficits after the operation. No CM recurrence was discovered during the follow-up MRI scans.
Persistence of disseminated tumor cells after neoadjuvant treatment for locally advanced breast cancer predicts poor survival
Authors: Mathiesen Randi R , Borgen Elin , Renolen Anne , Løkkevik Erik , Nesland Jahn M , Anker Gun , Østenstad Bjørn , Lundgren Steinar , Risberg Terje , Mjaaland Ingvil , Kvalheim Gunnar , Lønning Per Eystein , Naume Bjørn
Published: August 2012

Introduction

Presence of disseminated tumor cells (DTCs) in bone marrow (BM) and circulating tumor cells (CTC) in peripheral blood (PB) predicts reduced survival in early breast cancer. The aim of this study was to determine the presence of and alterations in DTC- and CTC-status in locally advanced breast cancer patients undergoing neoadjuvant chemotherapy (NACT) and to evaluate their prognostic impact.

Methods

Bone marrow and peripheral blood were collected before NACT (BM1: n = 231/PB1: n = 219), at surgery (BM2: n = 69/PB2: n = 71), and after 12 months from start of NACT (BM3: n = 162/PB3: n = 141). Patients were included from 1997 to 2003 and followed until 2009 (or ten years follow-up). DTC- and CTC-status were determined by morphological evaluation of immunocytochemically detected cytokeratin-positive cells. The prognostic significance of DTCs/CTCs was assessed by univariate and multivariate Cox-regression analyses.

Results

Before NACT, DTCs and CTCs were detected in 21.2% and 4.9% of the patients, respectively. At surgery, 15.9% and 1.4% had DTC- and CTC-presence, compared to 26.5% and 4.3% at 12 months from start of NACT. Of patients for whom DTC results both before NACT and at 12 months were available, concordant results were observed in 68%, and 14 out of 65 had positive DTC-status at both time points. Presence of ≥ 1 DTC 12 months from start of NACT, but not at other time points, predicted reduced disease-free survival (DFS; HR 2.3, p = 0.003), breast cancer-specific survival (BCSS; HR 3.0, p < 0.001) and overall survival (OS; HR 2.8, p < 0.001). Before NACT, presence of ≥ 3 DTCs was also associated with unfavorable outcome, and reduced BCSS was observed for CTC-positive patients (HR 2.2, p = 0.046). In multivariate analysis, DTC status (</≥ 1 DTC) at 12 months after start of NACT remained as a prognostic factor for both DFS (HR 2.2, p = 0.005), BCSS (HR 2.6, p = 0.002) and OS (HR 2.6, p = 0.002). The survival for patients with change in DTC-status was determined by the DTC-status at 12 months.

Conclusion

Presence of DTCs after NACT indicated high risk for relapse and death, irrespective of the DTC-status before treatment. The results supports the potential use of DTC analysis as a monitoring tool during follow up, for selection of patients to secondary treatment intervention within clinical trials.
Prognostic utility and characterization of cell-free DNA in patients with severe sepsis
Authors: Dwivedi Dhruva J , Toltl Lisa J , Swystun Laura L , Pogue Janice , Liaw Kao-Lee , Weitz Jeffrey I , Cook Deborah J , Fox-Robichaud Alison E , Liaw Patricia C ,   the Canadian Critical Care Translational Biology Group
Published: August 2012

Introduction

Although sepsis is the leading cause of death in noncoronary critically ill patients, identification of patients at high risk of death remains a challenge. In this study, we examined the incremental usefulness of adding multiple biomarkers to clinical scoring systems for predicting intensive care unit (ICU) mortality in patients with severe sepsis.

Methods

This retrospective observational study used stored plasma samples obtained from 80 severe sepsis patients recruited at three tertiary hospital ICUs in Hamilton, Ontario, Canada. Clinical data and plasma samples were obtained at study inclusion for all 80 patients, and then daily for 1 week, and weekly thereafter for a subset of 50 patients. Plasma levels of cell-free DNA (cfDNA), interleukin 6 (IL-6), thrombin, and protein C were measured and compared with clinical characteristics, including the primary outcome of ICU mortality and morbidity measured with the Multiple Organ Dysfunction (MODS) score and Acute Physiology and Chronic Health Evaluation (APACHE) II scores.

Results

The level of cfDNA in plasma at study inclusion had better prognostic utility than did MODS or APACHE II scores, or the biomarkers measured. The area under the receiver operating characteristic (ROC) curves for cfDNA to predict ICU mortality is 0.97 (95% CI, 0.93 to 1.00) and to predict hospital mortality is 0.84 (95% CI, 0.75 to 0.94). We found that a cfDNA cutoff value of 2.35 ng/μl had a sensitivity of 87.9% and specificity of 93.5% for predicting ICU mortality. Sequential measurements of cfDNA suggested that ICU mortality may be predicted within 24 hours of study inclusion, and that the predictive power of cfDNA may be enhanced by combining it with protein C levels or MODS scores. DNA-sequence analyses and studies with Toll-like receptor 9 (TLR9) reporter cells suggests that the cfDNA from sepsis patients is host derived.

Conclusions

These studies suggest that cfDNA provides high prognostic accuracy in patients with severe sepsis. The serial data suggest that the combination of cfDNA with protein C and MODS scores may yield even stronger predictive power. Incorporation of cfDNA in sepsis risk-stratification systems may be valuable for clinical decision making or for inclusion into sepsis trials.
Vasopressin and terlipressin in adult vasodilatory shock: a systematic review and meta-analysis of nine randomized controlled trials
Authors: Serpa Neto Ary , Nassar Antônio P , Cardoso Sérgio O , Manetta José A , Pereira Victor GM , Espósito Daniel C , Damasceno Maria CT , Russell James A
Published: August 2012

Introduction

Catecholamines are the most used vasopressors in vasodilatory shock. However, the development of adrenergic hyposensitivity and the subsequent loss of catecholamine pressor activity necessitate the search for other options. Our aim was to evaluate the effects of vasopressin and its analog terlipressin compared with catecholamine infusion alone in vasodilatory shock.

Methods

A systematic review and meta-analysis of publications between 1966 and 2011 was performed. The Medline and CENTRAL databases were searched for studies on vasopressin and terlipressin in critically ill patients. The meta-analysis was limited to randomized controlled trials evaluating the use of vasopressin and/or terlipressin compared with catecholamine in adult patients with vasodilatory shock. The assessed outcomes were: overall survival, changes in the hemodynamic and biochemical variables, a decrease of catecholamine requirements, and adverse events.

Results

Nine trials covering 998 participants were included. A meta-analysis using a fixed-effect model showed a reduction in norepinephrine requirement among patients receiving terlipressin or vasopressin infusion compared with control (standardized mean difference, -1.58 (95% confidence interval, -1.73 to -1.44); P < 0.0001). Overall, vasopressin and terlipressin, as compared with norepinephrine, reduced mortality (relative risk (RR), 0.87 (0.77 to 0.99); P = 0.04). Vasopressin compared with norepinephrine decreased mortality in adult patients (RR, 0.87 (0.76 to 1.00); P = 0.05) and in patients with septic shock (42.5% vs. 49.2%, respectively; RR, 0.87 (0.75 to 1.00); P = 0.05; number needed to treat, 1 to 15). There was no difference in adverse events between the vasopressin and control groups (RR, 0.98 (0.65 to 1.47); P = 0.92).

Conclusions

Vasopressin use in vasodilatory shock is safe, associated with reduced mortality, and facilitates weaning of catecholamines. In patients with septic shock, use of vasopressin compared with norepinephrine may also decrease mortality.
Anti-inflammatory treatment induced regenerative oligodendrogenesis in parkinsonian mice
Authors: Worlitzer Maik MA , Bunk Eva C , Hemmer Kathrin , Schwamborn Jens C
Published: August 2012

Introduction

The adult mammalian brain retains niches for neural stem cells (NSCs), which can generate glial and neuronal components of the brain tissue. However, it is barely established how chronic neuroinflammation, as it occurs in neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, affects adult neurogenesis and, therefore, modulates the brain's potential for self-regeneration.

Methods

Neural stem cell culture techniques, intraventricular tumor necrosis factor (TNF)-α infusion and the 6-hydroxydopamine mouse model were used to investigate the influence of neuroinflammation on adult neurogenesis in the Parkinson's disease background. Microscopic methods and behavioral tests were used to analyze samples.

Results

Here, we demonstrate that differences in the chronicity of TNF-α application to cultured NSCs result in opposed effects on their proliferation. However, chronic TNF-α treatment, mimicking Parkinson's disease associated neuroinflammation, shows detrimental effects on neural progenitor cell activity. Inversely, pharmacological inhibition of neuroinflammation in a 6-hydroxydopamine mouse model led to increased neural progenitor cell proliferation in the subventricular zone and neuroblast migration into the lesioned striatum. Four months after surgery, we measured improved Parkinson's disease-associated behavior, which was correlated with long-term anti-inflammatory treatment. But surprisingly, instead of newly generated striatal neurons, oligodendrogenesis in the striatum of treated mice was enhanced.

Conclusions

We conclude that anti-inflammatory treatment, in a 6-hydroxydopamine mouse model for Parkinson's disease, leads to activation of adult neural stem cells. These adult neural stem cells generate striatal oligodendrocytes. The higher numbers of newborn oligodendrocytes possibly contribute to axonal stability and function in this mouse model of Parkinson's disease and thereby attenuate dysfunctions of basalganglian motor-control.
Myeloid-derived suppressor cells from tumor-bearing mice impair TGF-β-induced differentiation of CD4+CD25+FoxP3+ Tregs from CD4+CD25−FoxP3− T cells
Authors: Centuori Sara M , Trad Malika , LaCasse Collin J , Alizadeh Darya , Larmonier Claire B , Hanke Neale T , Kartchner Jessica , Janikashvili Nona , Bonnotte Bernard , Larmonier Nicolas , Katsanis Emmanuel
Published: August 2012

Granulocytic myeloid-derived suppressor cells from tumorbearing mice inhibit the differentiation of iTreg.

MDSCs and Tregs play an essential role in the immunosuppressive networks that contribute to tumor-immune evasion. The mechanisms by which tumors promote the expansion and/or function of these suppressive cells and the cross-talk between MDSC and Treg remain incompletely defined. Previous reports have suggested that MDSC may contribute to Treg induction in cancer. Herein, we provide evidence that tumor-induced gr-MDSCs, endowed with the potential of suppressing conventional T Lc, surprisingly impair TGF-β1-mediated generation of CD4+CD25+FoxP3+ iTregs. Furthermore, gr-MDSCs impede the proliferation of nTregs without, however, affecting FoxP3 expression. Suppression of iTreg differentiation from naïve CD4+ cells by gr-MDSC occurs early in the polarization process, requires inhibition of early T cell activation, and depends on ROS and IDO but does not require arginase 1, iNOS, NO, cystine/cysteine depletion, PD-1 and PD-L1 signaling, or COX-2. These findings thus indicate that gr-MDSCs from TB hosts have the unanticipated ability to restrict immunosuppressive Tregs.
Serum Lactate Dehydrogenase Predicts for Overall Survival Benefit in Patients With Metastatic Renal Cell Carcinoma Treated With Inhibition of Mammalian Target of Rapamycin
Authors: Armstrong Andrew J. , George Daniel J. , Halabi Susan
Published: August 2012

Purpose

Lactate dehydrogenase (LDH) is an enzyme involved in anaerobic glycolysis and regulated by the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR)–containing complex 1 (PI3K/Akt/TORC1) pathway as well as tumor hypoxia/necrosis. High serum LDH levels are associated with poor prognosis in patients with cancer, including renal cell carcinoma (RCC). We tested whether serum LDH is prognostic and has predictive value in patients with metastatic RCC receiving an mTOR inhibitor.

Patients and Methods

We evaluated pretreatment and post-treatment serum LDH in 404 poor-risk patients with RCC treated with the TORC1 inhibitor temsirolimus or interferon alfa in an international phase III randomized trial. The proportional hazards model was used to test for the prognostic and predictive association of LDH in predicting overall survival (OS).

Results

Mean baseline serum normalized LDH was 1.23 times the upper limit of normal (ULN; range, 0.05 to 28.5 × ULN). The multivariable hazard ratio for death was 2.81 (95% CI, 2.01 to 3.94; P < .001) for patients with LDH more than 1 × ULN versus patients with LDH ≤ 1 × ULN. The LDH-treatment interaction term was statistically significant for OS (P = .016). Among 140 patients with LDH above the ULN, OS was significantly improved with temsirolimus (6.9 v 4.2 months; P < .002). Among 264 patients with normal LDH, OS was not significantly improved with temsirolimus as compared with interferon therapy (11.7 v 10.4 months; P = .514).

Conclusion

Serum LDH is a prognostic and a predictive biomarker for the survival benefit conferred by TORC1 inhibition in poor-risk RCC. Further investigation of the predictive role of LDH as a measure of benefit with PI3K/TORC1 pathway inhibition in other RCC risk groups and other tumor types is warranted.
The Maximalist Novel
Authors: Ercolino Stefano
Published: August 2012

This article seeks to define a new genre of the contemporary novel: the maximalist novel. It is an aesthetically hybrid genre that developed in the United States in the early 1970s and then spread to Europe at the beginning of the twenty-first century. The aim of this article is to stake out a new conceptual territory that will contribute to a re-shaping of both the traditional view of the literary postmodern and the understanding of the development of the novel in the second half of the twentieth century. The maximalist novel has a strong symbolic and morphological identity, with ten elements that define and structure it as a highly complex literary form: length, encyclopedic mode, dissonant chorality, diegetic exuberance, completeness, narrratorial omniscience, paranoid imagination, inter-semiocity, ethical commitment, and hybrid realism. These ten categories are common to the seven novels discussed in this essay: Gravity's Rainbow by Thomas Pynchon, Infinite Jest by David Foster Wallace, Underworld by Don DeLillo, White Teeth by Zadie Smith, The Corrections by Jonathan Franzen, 2666 by Roberto Bolaño, and 2005 dopo Cristo by the Babette Factory.

Although these ten features are not all present in the same form or intensity in each of these texts, they are decisive in defining them as maximalist novels, insofar as they are systematically co-present. These elements can individually be found in modernist and postmodern novels that are not maximalist; however, it is their co-presence and their reciprocal articulation that make them fundamental in demarcating the maximalist novel as a genre. The essay shows both the peculiar significance these elements have and the function some of the categories play within the internal dialectic of the genre. It discusses chaos-function and cosmos-function and argues that categories such as “length,” “encyclopedic mode,” “dissonant chorality,” and “diegetic exuberance,” beyond their strong specificity and irreducibility to one another, play a common role against categories such as “completeness,” “narratorial omniscience,” and “paranoia,” thus creating a centrifugal/centripetal dialectic within the representation. The remaining three categories—“inter-semiocity,” “ethical commitment,” and “hybrid realism”—do not play a specific role within the internal dialectic of the genre, but are crucial—to the same extent as the other seven—to understanding the ethical and aesthetical project of the maximalist novel, which strives to relate the complexity of the world we live in and to give a synthetic and totalizing representation of it.
Rethinking Sexual Difference and Kinship in Juliet Mitchell’s Psychoanalysis and Feminism
Authors: Butler Judith
Published: August 2012

Returning to Juliet Mitchell’s own rereading of her account of sexual difference, this article takes up the question of how structures of kinship—along with the laws of sexual difference that constitute them—are transmitted. According to Mitchell, the construction of sexual difference is characterized by a certain degree of conservatism in that, despite efforts to effect social change, certain normative ways of organizing sexuality manage to persist and to be conveyed across generations. She stresses that this transmission, if it is in fact one, is not necessarily a conscious operation. As such, it is difficult to locate within a precise topography and may require us to rethink the conditions of address and reception at work in the notions of “acquisition” or “transmission.” This essay analyzes two of the examples that Mitchell offers for understanding the historical acquisition of unconscious ideas related to sexual difference, namely, the case of transgenerational guilt and that of the child who emerges into heterosexuality despite being raised by two parents of the same sex. Acknowledging Mitchell’s suggestion that sexual difference is marked by recalcitrance, but refusing the way in which she binds sexual difference to the semantic opposition between masculine and feminine, this essay offers an understanding of kinship that, first, recognizes the inadequacy of mimetic accounts of sexuality that treat parents as “models” for the formation of sexual desire and, second, argues that “invariant” laws of sexual difference, which are not merely reproduced from one generation to the next, do not persist without alteration. The trajectory of psychic contents is not unwavering, and what is relayed into the present is only communicated with translations, transpositions, and deviations that leave what is passed on changed and never fully predictable.
Freud’s Australia
Authors: Frederickson Kathleen
Published: August 2012

While the nineteenth-century consolidation of the anthropological culture concept shifted ethnological interests away from the figure of the solitary “savage” to wider structures of communal governance, it nonetheless accommodated the eighteenth-century caricatures of instinctive and passionate “savages” by redeploying the terrain of the instinctive onto collective forms of social organization. At the same time, European instincts were believed to achieve greater independence from the material stuff of daily life, being increasingly figured as outside of either social or material influence. The split appears in Freud’s analogy of “savage” sociality and the European psyche in Totem and Taboo as a hesitation about whether law and custom are external to the “savage” psyche or constituent parts of it. Freud’s chief ethnological sources for Totem and Taboo—Lorimer Fison and A. W. Howitt’s Kamilaroi and Kûrnai (1880) and Baldwin Spencer and Frank Gillen’s Native Tribes of Central Australia (1899)—do not mention instinct, but their analyses of savage sociality nonetheless become the basis for Freud’s early instinct theory. Freud sometimes presents himself as partial to the idea that instinct obviates institutional reinforcement when he needs to make the case that social structures are not transparent reflections of human wishes. This article argues that the ambivalence that appears so frequently in Freud’s analysis of instinct highlights the fact that institutions cannot be thought solely to regulate the undesirable components of instinct.
Dirty Commerce: Art Work and Sex Work Since the 1970s
Authors: Bryan-Wilson Julia
Published: August 2012

From 1974 to 1976, artists in a range of contexts produced works that drew connections between performance and prostitution. This article examines how these projects, by artists such as Carlos Ginzburg and Suzanne Lacy, speak to the wider political discourses and feminist attitudes toward prostitution in the 1970s, as well as to the economic shifts that saw the growth of service-oriented and intimate labor. In the 1970s, female performance artists and female critics who wrote for money were both likened to hookers. This article takes this analogy seriously to consider how two seemingly divergent populations—art workers and sex workers—emerged at this time. What does the conjoining of these two identifications tell us about the valuation of labor, especially when affective exchanges are involved? What were the gendered consequences of the professionalization of art, and of sex work, at this moment? Concluding with contemporary examples from the 1990s and 2000s, the author investigates ongoing questions of privilege, power, and social worth in artistic projects regarding sex work.
Still Turning: Language, “Theory,” And History’s Fascination with the New
Authors: Schafer Sylvia
Published: August 2012

This article reflects on the relief with which mainstream historical scholarship has distanced itself in the last decade or so from serious engagements with the so-called linguistic turn of the later twentieth century. This twenty-first-century repudiation of theory continually declares the importance of seeking “the next thing” in both subject matter and approach while simultaneously posting and reposting the death notice of historical writing informed by poststructuralism. Reflecting on her own intellectual trajectory and the evolution of her efforts to write genealogical histories of language and governance in modern France, the author considers the value—and costs—of persisting in such “outmoded” practices. This brief essay thus ruminates on what might be at stake for historians who continue to attend to the play of language in the texts we read—or who persist in mobilizing certain “outmoded” feminist theoretical questions for the power of the productive disturbances they can create in the interpretation of sources—in a field that takes the past as its subject but has come, increasingly, to denigrate the past of its own conceptual possibilities in its present-day celebration of the new. The repeated pronouncement of the death of history nourished by poststructuralist theory, along with a concurrent embrace of scientific imperatives of innovation, the author suggests, operate as an attempt to settle disciplinary unease with undecidability while at the same time distancing history from the possibilities opened in its own past by the practice of historical reading and writing as critique.