The polycomb group protein Suz12 is required for embryonic stem cell differentiation.

Abstract: Polycomb group (PcG) proteins form multiprotein complexes, called Polycomb repressive complexes (PRCs).

Abstract: PRC2 contains the PcG proteins EZH2, SUZ12, and EED and represses transcription through methylation of lysine (K) 27 of histone H3 (H3).

Abstract: Suz12 is essential for PRC2 activity and its inactivation results in early lethality of mouse embryos.

Abstract: Here, we demonstrate that Suz12(-/-) mouse embryonic stem (ES) cells can be established and expanded in tissue culture.

Abstract: The Suz12(-/-) ES cells are characterized by global loss of H3K27 trimethylation (H3K27me3) and higher expression levels of differentiation-specific genes.

Abstract: Moreover, Suz12(-/-) ES cells are impaired in proper differentiation, resulting in a lack of repression of ES cell markers as well as activation of differentiation-specific genes.

Abstract: Finally, we demonstrate that the PcGs are actively recruited to several genes during ES cell differentiation, which despite an increase in H3K27me3 levels is not always sufficient to prevent transcriptional activation.

Abstract: In summary, we demonstrate that Suz12 is required for the establishment of specific expression programs required for ES cell differentiation.

Abstract: Furthermore, we provide evidence that PcGs have different mechanisms to regulate transcription during cellular differentiation.


The 1.9 A structure of a proteasome-11S activator complex and implications for proteasome-PAN/PA700 interactions.

Abstract: Proteasomes are cylindrical structures that function in multiple cellular processes by degrading a wide variety of cytosolic and nuclear proteins.

Abstract: Substrate access and product release from the enclosed catalytic chamber occurs through axial pores that are opened by activator complexes.

Abstract: Here, we report high-resolution structures of wild-type and mutant archaeal proteasomes bound to the activator PA26.

Abstract: These structures support the proposal that an ordered open conformation is required for proteolysis and that its formation can be triggered by outward displacement of surrounding residues.

Abstract: The structures and associated biochemical assays reveal the mechanism of binding, which involves an interaction between the PA26 C terminus and a conserved lysine.

Abstract: Surprisingly, biochemical observations implicate an equivalent interaction for the unrelated ATP-dependent activators PAN and PA700.


Innate Immune and Chemically Triggered Oxidative Stress Modifies Translational Fidelity

Abstract: Translational fidelity, essential for protein and cell function, requires accurate transfer RNA (tRNA) aminoacylation.

Abstract: Purified aminoacyl-tRNA synthetases exhibit a fidelity of one error per 10,000 to 100,000 couplings.

Abstract: The accuracy of tRNA aminoacylation in vivo is uncertain, however, and might be considerably lower.

Abstract: Here we show that in mammalian cells, approximately 1% of methionine (Met) residues used in protein synthesis are aminoacylated to non-methionyl-tRNAs.

Abstract: Remarkably, Met-misacylation increases up to tenfold upon exposing cells to live or non-infectious viruses, toll-like receptor ligands or chemically induced oxidative stress.

Abstract: Met is misacylated to specific non-methionyl-tRNA families, and these Met-misacylated tRNAs are used in translation.

Abstract: Met-misacylation is blocked by an inhibitor of cellular oxidases, implicating reactive oxygen species (ROS) as the misacylation trigger.

Abstract: Among six amino acids tested, tRNA misacylation occurs exclusively with Met.

Abstract: As Met residues are known to protect proteins against ROS-mediated damage, we propose that Met-misacylation functions adaptively to increase Met incorporation into proteins to protect cells against oxidative stress.

Abstract: In demonstrating an unexpected conditional aspect of decoding mRNA, our findings illustrate the importance of considering alternative iterations of the genetic code.


Yeast sirtuins and the regulation of aging.

Abstract: The sirtuins are a phylogenetically conserved family of NAD(+) -dependent protein deacetylases that consume one molecule of NAD(+) for every deacetylated lysine side chain.

Abstract: Their requirement for NAD(+) potentially makes them prone to regulation by fluctuations in NAD(+) or biosynthesis intermediates, thus linking them to cellular metabolism.

Abstract: The Sir2 protein from Saccharomyces cerevisiae is the founding sirtuin family member and has been well characterized as a histone deacetylase that functions in transcriptional silencing of heterochromatin domains and as a pro-longevity factor for replicative life span (RLS), defined as the number of times a mother cell divides (buds) before senescing.

Abstract: Deleting SIR2 shortens RLS, while increased gene dosage causes extension.

Abstract: Furthermore, Sir2 has been implicated in mediating the beneficial effects of caloric restriction (CR) on life span, not only in yeast, but also in higher eukaryotes.

Abstract: While this paradigm has had its share of disagreements and debate, it has also helped rapidly drive the aging research field forward.

Abstract: S. cerevisiae has four additional sirtuins, Hst1, Hst2, Hst3, and Hst4.

Abstract: This review discusses the function of Sir2 and the Hst homologs in replicative aging and chronological aging, and also addresses how the sirtuins are regulated in response to environmental stresses such as CR.


The effect of combination treatment with aliskiren and blockers of the renin-angiotensin system on hyperkalaemia and acute kidney injury: systematic review and meta-analysis

Abstract: OBJECTIVE To examine the safety of using aliskiren combined with agents used to block the renin-angiotensin system.

Abstract: DESIGN Systematic review and meta-analysis of randomised controlled trials.

Abstract: DATA SOURCES Medline, Embase, the Cochrane Library, and two trial registries, published up to 7 May 2011.

Abstract: STUDY SELECTION Published and unpublished randomised controlled trials that compared combined treatment using aliskiren and angiotensin converting enzyme inhibitors or angiotensin receptor blockers with monotherapy using these agents for at least four weeks and that provided numerical data on the adverse event outcomes of hyperkalaemia and acute kidney injury.

Abstract: A random effects model was used to calculate pooled risk ratios and 95% confidence intervals for these outcomes.

Abstract: RESULTS 10 randomised controlled studies (4814 participants) were included in the analysis.

Abstract: Combination therapy with aliskiren and angiotensin converting enzyme inhibitors or angiotensin receptor blockers significantly increased the risk of hyperkalaemia compared with monotherapy using angiotensin converting enzymes or angiotensin receptor blockers (relative risk 1.58, 95% confidence interval 1.24 to 2.02) or aliskiren alone (1.67, 1.01 to 2.79).

Abstract: The risk of acute kidney injury did not differ significantly between the combined therapy and monotherapy groups (1.14, 0.68 to 1.89).

Abstract: CONCLUSION Use of aliskerin in combination with angiotensin converting enzyme inhibitors or angiotensin receptor blockers is associated with an increased risk for hyperkalaemia.

Abstract: The combined use of these agents warrants careful monitoring of serum potassium levels.


The ins and outs of DNA transfer in bacteria.

Abstract: Transformation and conjugation permit the passage of DNA through the bacterial membranes and represent dominant modes for the transfer of genetic information between bacterial cells or between bacterial and eukaryotic cells.

Abstract: As such, they are responsible for the spread of fitness-enhancing traits, including antibiotic resistance.

Abstract: Both processes usually involve the recognition of double-stranded DNA, followed by the transfer of single strands.

Abstract: Elaborate molecular machines are responsible for negotiating the passage of macromolecular DNA through the layers of the cell surface.

Abstract: All or nearly all the machine components involved in transformation and conjugation have been identified, and here we present models for their roles in DNA transport.


Synaptic islands defined by the territory of a single astrocyte.

Abstract: In the mammalian brain, astrocytes modulate neuronal function, in part, by synchronizing neuronal firing and coordinating synaptic networks.

Abstract: Little, however, is known about how this is accomplished from a structural standpoint.

Abstract: To investigate the structural basis of astrocyte-mediated neuronal synchrony and synaptic coordination, the three-dimensional relationships between cortical astrocytes and neurons was investigated.

Abstract: Using a transgenic and viral approach to label astrocytes with enhanced green fluorescent protein, we performed a three-dimensional reconstruction of astrocytes from tissue sections or live animals in vivo.

Abstract: We found that cortical astrocytes occupy nonoverlapping territories similar to those described in the hippocampus.

Abstract: Using immunofluorescence labeling of neuronal somata, a single astrocyte enwraps on average four neuronal somata with an upper limit of eight.

Abstract: Single-neuron dye-fills allowed us to estimate that one astrocyte contacts 300-600 neuronal dendrites.

Abstract: Together with the recent findings showing that glial Ca2+ signaling is restricted to individual astrocytes in vivo, and that Ca2+ signaling leads to gliotransmission, we propose the concept of functional islands of synapses in which groups of synapses confined within the boundaries of an individual astrocyte are modulated by the gliotransmitter environment controlled by that astrocyte.

Abstract: Our description offers a new structurally based conceptual framework to evaluate functional data involving interactions between neurons and astrocytes in the mammalian brain.


Role of DNA Methylation and Epigenetic Silencing of HAND2 in Endometrial Cancer Development

Abstract: BACKGROUND Endometrial cancer incidence is continuing to rise in the wake of the current ageing and obesity epidemics.

Abstract: Much of the risk for endometrial cancer development is influenced by the environment and lifestyle.

Abstract: Accumulating evidence suggests that the epigenome serves as the interface between the genome and the environment and that hypermethylation of stem cell polycomb group target genes is an epigenetic hallmark of cancer.

Abstract: The objective of this study was to determine the functional role of epigenetic factors in endometrial cancer development.

Abstract: METHODS AND FINDINGS Epigenome-wide methylation analysis of >27,000 CpG sites in endometrial cancer tissue samples (n = 64) and control samples (n = 23) revealed that HAND2 (a gene encoding a transcription factor expressed in the endometrial stroma) is one of the most commonly hypermethylated and silenced genes in endometrial cancer.

Abstract: A novel integrative epigenome-transcriptome-interactome analysis further revealed that HAND2 is the hub of the most highly ranked differential methylation hotspot in endometrial cancer.

Abstract: These findings were validated using candidate gene methylation analysis in multiple clinical sample sets of tissue samples from a total of 272 additional women.

Abstract: Increased HAND2 methylation was a feature of premalignant endometrial lesions and was seen to parallel a decrease in RNA and protein levels.

Abstract: Furthermore, women with high endometrial HAND2 methylation in their premalignant lesions were less likely to respond to progesterone treatment.

Abstract: HAND2 methylation analysis of endometrial secretions collected using high vaginal swabs taken from women with postmenopausal bleeding specifically identified those patients with early stage endometrial cancer with both high sensitivity and high specificity (receiver operating characteristics area under the curve = 0.91 for stage 1A and 0.97 for higher than stage 1A).

Abstract: Finally, mice harbouring a Hand2 knock-out specifically in their endometrium were shown to develop precancerous endometrial lesions with increasing age, and these lesions also demonstrated a lack of PTEN expression.

Abstract: CONCLUSIONS HAND2 methylation is a common and crucial molecular alteration in endometrial cancer that could potentially be employed as a biomarker for early detection of endometrial cancer and as a predictor of treatment response.

Abstract: The true clinical utility of HAND2 DNA methylation, however, requires further validation in prospective studies.

Abstract: Please see later in the article for the Editors' Summary.


Socioeconomic factors, material inequalities, and perceived control in self-rated health: cross-sectional data from seven post-communist countries.

Abstract: This study examined the association between perceived control and several socioeconomic variables and self-rated health in seven post-communist countries (Russia, Estonia, Lithuania, Latvia, Hungary, Poland, Czech Republic).

Abstract: Questionnaire interviews were used to collect data on self-rated health in the last 12 months, education, marital status, perceived control based on nine questions, and material deprivation based on availability of food, clothing and heating.

Abstract: For each population, two ecological measures of material inequalities were available: an inequality score estimated from the survey data as the distance between the 90th and 10th percentiles of material deprivation, and Gini coefficient from published sources.

Abstract: Data on 5330 men and women aged 20-60 were analysed.

Abstract: Prevalence of poor health (worse than average) varied between 8% in Czechs and 19% in Hungarians.

Abstract: The age-sex-adjusted odds ratio for university vs primary education was 0.36 (0.26-0.49); odds ratios per 1 standard deviation increase in perceived control and in material deprivation were 0.58 (95% CI 0.48-0.69) and 1.51 (1.40-1.63), respectively.

Abstract: The odds ratio for an increase in inequality equivalent to the difference between the most and the least unequal populations was 1.49 (0.88-2.52) using the material inequality score and 1.41 (0.91-2.20) using the Gini coefficient.

Abstract: No indication of an effect of either inequality measure was seen after adjustment for individuals' deprivation or perceived control.

Abstract: The results suggest that, as in western populations, education and material deprivation are strongly related to self-rated health.

Abstract: Perceived control appeared statistically to mediate some of the effects of material deprivation.

Abstract: The non-significant effects of both ecological measures of inequality were eliminated by controlling for individuals' characteristics.


Integrin αvβ3/c-src “Oncogenic Unit” Promotes Anchorage-independence and Tumor Progression

Abstract: Integrins regulate adhesion-dependent growth, survival and invasion of tumor cells.

Abstract: In particular, expression of integrin alpha(v)beta(3) is associated with progression of a variety of human tumors.

Abstract: Here we reveal a previously undescribed adhesion-independent role for integrin alpha(v)beta(3) in pancreatic cancer and other carcinomas.

Abstract: Specifically, alpha(v)beta(3) expressed in carcinoma cells enhanced anchorage-independent tumor growth in vitro and increased lymph node metastases in vivo.

Abstract: These effects required recruitment of c-Src to the beta(3) integrin cytoplasmic tail, leading to c-Src activation, Crk-associated substrate (CAS) phosphorylation and tumor cell survival that, unexpectedly, was independent of cell adhesion or focal adhesion kinase (FAK) activation.

Abstract: Pharmacological blockade of c-Src kinase activity or decreased expression of endogenous alpha(v)beta(3) integrin or c-Src not only inhibited anchorage-independent growth but also suppressed metastasis in vivo, yet these manipulations did not affect tumor cell migration or invasion.

Abstract: These data define an unexpected role for an integrin as a mediator of anchorage independence, suggesting that an alpha(v)beta(3)-c-Src signaling module may account for the aggressive behavior of integrin alpha(v)beta(3)-expressing tumors in humans.


Genomewide Analysis of PRC1 and PRC2 Occupancy Identifies Two Classes of Bivalent Domains

Abstract: In embryonic stem (ES) cells, bivalent chromatin domains with overlapping repressive (H3 lysine 27 tri-methylation) and activating (H3 lysine 4 tri-methylation) histone modifications mark the promoters of more than 2,000 genes.

Abstract: To gain insight into the structure and function of bivalent domains, we mapped key histone modifications and subunits of Polycomb-repressive complexes 1 and 2 (PRC1 and PRC2) genomewide in human and mouse ES cells by chromatin immunoprecipitation, followed by ultra high-throughput sequencing.

Abstract: We find that bivalent domains can be segregated into two classes -- the first occupied by both PRC2 and PRC1 (PRC1-positive) and the second specifically bound by PRC2 (PRC2-only).

Abstract: PRC1-positive bivalent domains appear functionally distinct as they more efficiently retain lysine 27 tri-methylation upon differentiation, show stringent conservation of chromatin state, and associate with an overwhelming number of developmental regulator gene promoters.

Abstract: We also used computational genomics to search for sequence determinants of Polycomb binding.

Abstract: This analysis revealed that the genomewide locations of PRC2 and PRC1 can be largely predicted from the locations, sizes, and underlying motif contents of CpG islands.

Abstract: We propose that large CpG islands depleted of activating motifs confer epigenetic memory by recruiting the full repertoire of Polycomb complexes in pluripotent cells.


Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis.

Abstract: Epithelial-mesenchymal transition (EMT) is implicated in converting stationary epithelial tumor cells into motile mesenchymal cells during metastasis.

Abstract: However, the involvement of EMT in metastasis is still controversial, due to the lack of a mesenchymal phenotype in human carcinoma metastases.

Abstract: Using a spontaneous squamous cell carcinoma mouse model, we show that activation of the EMT-inducing transcription factor Twist1 is sufficient to promote carcinoma cells to undergo EMT and disseminate into blood circulation.

Abstract: Importantly, in distant sites, turning off Twist1 to allow reversion of EMT is essential for disseminated tumor cells to proliferate and form metastases.

Abstract: Our study demonstrates in vivo the requirement of "reversible EMT" in tumor metastasis and may resolve the controversy on the importance of EMT in carcinoma metastasis.


Control of Apoptosis by Asymmetric Cell Division

Abstract: Asymmetric cell division and apoptosis (programmed cell death) are two fundamental processes that are important for the development and function of multicellular organisms.

Abstract: We have found that the processes of asymmetric cell division and apoptosis can be functionally linked.

Abstract: Specifically, we show that asymmetric cell division in the nematode Caenorhabditis elegans is mediated by a pathway involving three genes, dnj-11 MIDA1, ces-2 HLF, and ces-1 Snail, that directly control the enzymatic machinery responsible for apoptosis.

Abstract: Interestingly, the MIDA1-like protein GlsA of the alga Volvox carteri, as well as the Snail-related proteins Snail, Escargot, and Worniu of Drosophila melanogaster, have previously been implicated in asymmetric cell division.

Abstract: Therefore, C. elegans dnj-11 MIDA1, ces-2 HLF, and ces-1 Snail may be components of a pathway involved in asymmetric cell division that is conserved throughout the plant and animal kingdoms.

Abstract: Furthermore, based on our results, we propose that this pathway directly controls the apoptotic fate in C. elegans, and possibly other animals as well.


CXCR2 mediates NADPH oxidase–independent neutrophil extracellular trap formation in cystic fibrosis airway inflammation

Abstract: Upon activation, neutrophils release DNA fibers decorated with antimicrobial proteins, forming neutrophil extracellular traps (NETs).

Abstract: Although NETs are bactericidal and contribute to innate host defense, excessive NET formation has been linked to the pathogenesis of autoinflammatory diseases.

Abstract: However, the mechanisms regulating NET formation, particularly during chronic inflammation, are poorly understood.

Abstract: Here we show that the G protein–coupled receptor (GPCR) CXCR2 mediates NET formation.

Abstract: Downstream analyses showed that CXCR2-mediated NET formation was independent of NADPH oxidase and involved Src family kinases.

Abstract: We show the pathophysiological relevance of this mechanism in cystic fibrosis lung disease, characterized by chronic neutrophilic inflammation.

Abstract: We found abundant NETs in airway fluids of individuals with cystic fibrosis and mouse cystic fibrosis lung disease, and NET amounts correlated with impaired obstructive lung function.

Abstract: Pulmonary blockade of CXCR2 by intra-airway delivery of small-molecule antagonists inhibited NET formation and improved lung function in vivo without affecting neutrophil recruitment, proteolytic activity or antibacterial host defense.

Abstract: These studies establish CXCR2 as a receptor mediating NADPH oxidase–independent NET formation and provide evidence that this GPCR pathway is operative and druggable in cystic fibrosis lung disease.


Modelling the Impact of Artemisinin Combination Therapy and Long-Acting Treatments on Malaria Transmission Intensity

Abstract: BACKGROUND Artemisinin derivatives used in recently introduced combination therapies (ACTs) for Plasmodium falciparum malaria significantly lower patient infectiousness and have the potential to reduce population-level transmission of the parasite.

Abstract: With the increased interest in malaria elimination, understanding the impact on transmission of ACT and other antimalarial drugs with different pharmacodynamics becomes a key issue.

Abstract: This study estimates the reduction in transmission that may be achieved by introducing different types of treatment for symptomatic P. falciparum malaria in endemic areas.

Abstract: METHODS AND FINDINGS We developed a mathematical model to predict the potential impact on transmission outcomes of introducing ACT as first-line treatment for uncomplicated malaria in six areas of varying transmission intensity in Tanzania.

Abstract: We also estimated the impact that could be achieved by antimalarials with different efficacy, prophylactic time, and gametocytocidal effects.

Abstract: Rates of treatment, asymptomatic infection, and symptomatic infection in the six study areas were estimated using the model together with data from a cross-sectional survey of 5,667 individuals conducted prior to policy change from sulfadoxine-pyrimethamine to ACT.

Abstract: The effects of ACT and other drug types on gametocytaemia and infectiousness to mosquitoes were independently estimated from clinical trial data.

Abstract: Predicted percentage reductions in prevalence of infection and incidence of clinical episodes achieved by ACT were highest in the areas with low initial transmission.

Abstract: A 53% reduction in prevalence of infection was seen if 100% of current treatment was switched to ACT in the area where baseline slide-prevalence of parasitaemia was lowest (3.7%), compared to an 11% reduction in the highest-transmission setting (baseline slide prevalence = 57.1%).

Abstract: Estimated percentage reductions in incidence of clinical episodes were similar.

Abstract: The absolute size of the public health impact, however, was greater in the highest-transmission area, with 54 clinical episodes per 100 persons per year averted compared to five per 100 persons per year in the lowest-transmission area.

Abstract: High coverage was important.

Abstract: Reducing presumptive treatment through improved diagnosis substantially reduced the number of treatment courses required per clinical episode averted in the lower-transmission settings although there was some loss of overall impact on transmission.

Abstract: An efficacious antimalarial regimen with no specific gametocytocidal properties but a long prophylactic time was estimated to be more effective at reducing transmission than a short-acting ACT in the highest-transmission setting.

Abstract: CONCLUSIONS Our results suggest that ACTs have the potential for transmission reductions approaching those achieved by insecticide-treated nets in lower-transmission settings.

Abstract: ACT partner drugs and nonartemisinin regimens with longer prophylactic times could result in a larger impact in higher-transmission settings, although their long term benefit must be evaluated in relation to the risk of development of parasite resistance.


Systems metabolic engineering of Escherichia coli for L-threonine production

Abstract: Amino-acid producers have traditionally been developed by repeated random mutagenesis owing to the difficulty in rationally engineering the complex and highly regulated metabolic network.

Abstract: Here, we report the development of the genetically defined L-threonine overproducing Escherichia coli strain by systems metabolic engineering.

Abstract: Feedback inhibitions of aspartokinase I and III (encoded by thrA and lysC, respectively) and transcriptional attenuation regulations (located in thrL) were removed.

Abstract: Pathways for Thr degradation were removed by deleting tdh and mutating ilvA. The metA and lysA genes were deleted to make more precursors available for Thr biosynthesis.

Abstract: Further target genes to be engineered were identified by transcriptome profiling combined with in silico flux response analysis, and their expression levels were manipulated accordingly.

Abstract: The final engineered E. coli strain was able to produce Thr with a high yield of 0.393 g per gram of glucose, and 82.4 g/l Thr by fed-batch culture.

Abstract: The systems metabolic engineering strategy reported here may be broadly employed for developing genetically defined organisms for the efficient production of various bioproducts.


Association Between ADHD and Obesity: A Systematic Review and Meta-Analysis.

Abstract: OBJECTIVE Impulsivity and inattention related to attention deficit hyperactivity disorder (ADHD) may increase food intake and, consequently, weight gain.

Abstract: However, findings on the association between obesity/overweight and ADHD are mixed.

Abstract: The authors conducted a meta-analysis to estimate this association.

Abstract: METHOD A broad range of databases was searched through Aug. 31, 2014.

Abstract: Unpublished studies were also obtained.

Abstract: Study quality was rated with the Newcastle-Ottawa Scale.

Abstract: Random-effects models were used.

Abstract: RESULTS Forty-two studies that included a total of 728,136 individuals (48,161 ADHD subjects; 679,975 comparison subjects) were retained.

Abstract: A significant association between obesity and ADHD was found for both children (odds ratio=1.20, 95% CI=1.05-1.37) and adults (odds ratio=1.55, 95% CI=1.32-1.81).

Abstract: The pooled prevalence of obesity was increased by about 70% in adults with ADHD (28.2%, 95% CI=22.8-34.4) compared with those without ADHD (16.4%, 95% CI=13.4-19.9), and by about 40% in children with ADHD (10.3%, 95% CI=7.9-13.3) compared with those without ADHD (7.4%, 95% CI=5.4-10.1).

Abstract: The significant association between ADHD and obesity remained when limited to studies 1) reporting odds ratios adjusted for possible confounding factors; 2) diagnosing ADHD by direct interview; and 3) using directly measured height and weight.

Abstract: Gender, study setting, study country, and study quality did not moderate the association between obesity and ADHD.

Abstract: ADHD was also significantly associated with overweight.

Abstract: Individuals medicated for ADHD were not at higher risk of obesity.

Abstract: CONCLUSIONS This study provides meta-analytic evidence for a significant association between ADHD and obesity/overweight.

Abstract: Further research should address possible underlying mechanisms and the long-term effects of ADHD treatments on weight in individuals with both ADHD and obesity.


Amyloid-DNA Composites of Bacterial Biofilms Stimulate Autoimmunity.

Abstract: Research on the human microbiome has established that commensal and pathogenic bacteria can influence obesity, cancer, and autoimmunity through mechanisms mostly unknown.

Abstract: We found that a component of bacterial biofilms, the amyloid protein curli, irreversibly formed fibers with bacterial DNA during biofilm formation.

Abstract: This interaction accelerated amyloid polymerization and created potent immunogenic complexes that activated immune cells, including dendritic cells, to produce cytokines such as type I interferons, which are pathogenic in systemic lupus erythematosus (SLE).

Abstract: When given systemically, curli-DNA composites triggered immune activation and production of autoantibodies in lupus-prone and wild-type mice.

Abstract: We also found that the infection of lupus-prone mice with curli-producing bacteria triggered higher autoantibody titers compared to curli-deficient bacteria.

Abstract: These data provide a mechanism by which the microbiome and biofilm-producing enteric infections may contribute to the progression of SLE and point to a potential molecular target for treatment of autoimmunity.


Comprehensive genomic characterization defines human glioblastoma genes and core pathways

Abstract: Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation.

Abstract: The Cancer Genome Atlas ( TCGA) pilot project aims to assess the value of large- scale multi- dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community.

Abstract: Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas - the most common type of primary adult brain cancer - and nucleotide sequence aberrations in 91 of the 206 glioblastomas.

Abstract: This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol- 3- OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma.

Abstract: Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications.

Abstract: Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.


LY2405319, an Engineered FGF21 Variant, Improves the Metabolic Status of Diabetic Monkeys

Abstract: Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator that represents a promising target for the treatment of several metabolic diseases.

Abstract: Administration of recombinant wild type FGF21 to diabetic animals leads to a dramatic improvement in glycaemia and ameliorates other systemic measures of metabolic health.

Abstract: Here we report the pharmacologic outcomes observed in non-human primates upon administration of a recently described FGF21 analogue, LY2405319 (LY).

Abstract: Diabetic rhesus monkeys were treated subcutaneously with LY once daily for a period of seven weeks.

Abstract: The doses of LY used were 3, 9 and 50 mg/kg each delivered in an escalating fashion with washout measurements taken at 2, 4, 6 and 8 weeks following the final LY dose.

Abstract: LY therapy led to a dramatic and rapid lowering of several important metabolic parameters including glucose, body weight, insulin, cholesterol and triglyceride levels at all doses tested.

Abstract: In addition, we observed favorable changes in circulating profiles of adipokines, with increased adiponectin and reduced leptin indicative of direct FGF21 action on adipose tissue.

Abstract: Importantly, and for the first time we show that FGF21 based therapy has metabolic efficacy in an animal with late stage diabetes.

Abstract: While the glycemic efficacy of LY in this animal was partially attenuated its lipid lowering effect was fully preserved suggesting that FGF21 may be a viable treatment option even in patients with advanced disease progression.

Abstract: These findings support continued exploration of the FGF21 pathway for the treatment of metabolic disease.


Epigenetic Control of Stem Cell Potential during Homeostasis, Aging, and Disease.

Abstract: Stem cell decline is an important cellular driver of aging-associated pathophysiology in multiple tissues.

Abstract: Epigenetic regulation is central to establishing and maintaining stem cell function, and emerging evidence indicates that epigenetic dysregulation contributes to the altered potential of stem cells during aging.

Abstract: Unlike terminally differentiated cells, the impact of epigenetic dysregulation in stem cells is propagated beyond self; alterations can be heritably transmitted to differentiated progeny, in addition to being perpetuated and amplified within the stem cell pool through self-renewal divisions.

Abstract: This Review focuses on recent studies examining epigenetic regulation of tissue-specific stem cells in homeostasis, aging, and aging-related disease.


Host–Parasite Interactions and the Evolution of Gene Expression

Abstract: Interactions between hosts and parasites provide an ongoing source of selection that promotes the evolution of a variety of features in the interacting species.

Abstract: Here, we use a genetically explicit mathematical model to explore how patterns of gene expression evolve at genetic loci responsible for host resistance and parasite infection.

Abstract: Our results reveal the striking yet intuitive conclusion that gene expression should evolve along very different trajectories in the two interacting species.

Abstract: Specifically, host resistance loci should frequently evolve to co-express alleles, whereas parasite infection loci should evolve to express only a single allele.

Abstract: This result arises because hosts that co-express resistance alleles are able to recognize and clear a greater diversity of parasite genotypes.

Abstract: By the same token, parasites that co-express antigen or elicitor alleles are more likely to be recognized and cleared by the host, and this favours the expression of only a single allele.

Abstract: Our model provides testable predictions that can help interpret accumulating data on expression levels for genes relevant to host−parasite interactions.


A crucial role for interleukin (IL)-1 in the induction of IL-17–producing T cells that mediate autoimmune encephalomyelitis

Abstract: It was recently demonstrated that interleukin (IL)-23–driven IL-17–producing (ThIL-17) T cells mediate inflammatory pathology in certain autoimmune diseases.

Abstract: We show that the induction of antigen-specific ThIL-17 cells, but not T helper (Th)1 or Th2 cells, by immunization with antigens and adjuvants is abrogated in IL-1 receptor type I–deficient (IL-1RI−/−) mice.

Abstract: Furthermore, the incidence of experimental autoimmune encephalomyelitis (EAE) was significantly lower in IL-1RI−/− compared with wild-type mice, and this correlated with a failure to induce autoantigen-specific ThIL-17 cells, whereas induction of Th1 and Th2 responses was not substantially different.

Abstract: However, EAE was induced in IL-1RI−/− mice by adoptive transfer of autoantigen-specific cells from wild-type mice with EAE.

Abstract: IL-23 alone did not induce IL-17 production by T cells from IL-1RI−/− mice, and IL-23–induced IL-17 production was substantially enhanced by IL-1α or IL-1β, even in the absence of T cell receptor stimulation.

Abstract: We demonstrate essential roles for phosphatidylinositol 3-kinase, nuclear factor κB, and novel protein kinase C isoforms in IL-1– and IL-23–mediated IL-17 production.

Abstract: Tumor necrosis factor α also synergized with IL-23 to enhance IL-17 production, and this was IL-1 dependent.

Abstract: Our findings demonstrate that IL-1 functions upstream of IL-17 to promote pathogenic ThIL-17 cells in EAE.


Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers

Abstract: Basal-like breast cancers arising in women carrying mutations in the BRCA1 gene, encoding the tumor suppressor protein BRCA1, are thought to develop from the mammary stem cell.

Abstract: To explore early cellular changes that occur in BRCA1 mutation carriers, we have prospectively isolated distinct epithelial subpopulations from normal mammary tissue and preneoplastic specimens from individuals heterozygous for a BRCA1 mutation.

Abstract: We describe three epithelial subsets including basal stem/progenitor, luminal progenitor and mature luminal cells.

Abstract: Unexpectedly, we found that breast tissue from BRCA1 mutation carriers harbors an expanded luminal progenitor population that shows factor-independent growth in vitro.

Abstract: Moreover, gene expression profiling revealed that breast tissue heterozygous for a BRCA1 mutation and basal breast tumors were more similar to normal luminal progenitor cells than any other subset, including the stem cell–enriched population.

Abstract: The c-KIT tyrosine kinase receptor (encoded by KIT) emerged as a key marker of luminal progenitor cells and was more highly expressed in BRCA1-associated preneoplastic tissue and tumors.

Abstract: Our findings suggest that an aberrant luminal progenitor population is a target for transformation in BRCA1-associated basal tumors .


Getting to the site of inflammation: the leukocyte adhesion cascade updated

Abstract: Neutrophil recruitment, lymphocyte recirculation and monocyte trafficking all require adhesion and transmigration through blood-vessel walls.

Abstract: The traditional three steps of rolling, activation and firm adhesion have recently been augmented and refined.

Abstract: Slow rolling, adhesion strengthening, intraluminal crawling and paracellular and transcellular migration are now recognized as separate, additional steps.

Abstract: In neutrophils, a second activation pathway has been discovered that does not require signalling through G-protein-coupled receptors and the signalling steps leading to integrin activation are beginning to emerge.

Abstract: This Review focuses on new aspects of one of the central paradigms of inflammation and immunity — the leukocyte adhesion cascade.


Genome-wide loss of 5-hmC is a novel epigenetic feature of Huntington's disease.

Abstract: 5-Hydroxymethylcytosine (5-hmC) may represent a new epigenetic modification of cytosine.

Abstract: While the dynamics of 5-hmC during neurodevelopment have recently been reported, little is known about its genomic distribution and function(s) in neurodegenerative diseases such as Huntington's disease (HD).

Abstract: We here observed a marked reduction of the 5-hmC signal in YAC128 (yeast artificial chromosome transgene with 128 CAG repeats) HD mouse brain tissues when compared with age-matched wild-type (WT) mice, suggesting a deficiency of 5-hmC reconstruction in HD brains during postnatal development.

Abstract: Genome-wide distribution analysis of 5-hmC further confirmed the diminishment of the 5-hmC signal in striatum and cortex in YAC128 HD mice.

Abstract: General genomic features of 5-hmC are highly conserved, not being affected by either disease or brain regions.

Abstract: Intriguingly, we have identiﬁed disease-specific (YAC128 versus WT) differentially hydroxymethylated regions (DhMRs), and found that acquisition of DhmRs in gene body is a positive epigenetic regulator for gene expression.

Abstract: Ingenuity pathway analysis (IPA) of genotype-specific DhMR-annotated genes revealed that alternation of a number of canonical pathways involving neuronal development/differentiation (Wnt/β-catenin/Sox pathway, axonal guidance signaling pathway) and neuronal function/survival (glutamate receptor/calcium/CREB, GABA receptor signaling, dopamine-DARPP32 feedback pathway, etc.) could be important for the onset of HD.

Abstract: Our results indicate that loss of the 5-hmC marker is a novel epigenetic feature in HD, and that this aberrant epigenetic regulation may impair the neurogenesis, neuronal function and survival in HD brain.

Abstract: Our study also opens a new avenue for HD treatment; re-establishing the native 5-hmC landscape may have the potential to slow/halt the progression of HD.


Planning for Postdisaster Resiliency

Abstract: The focus of this article is planning for resiliency in the aftermath of a catastrophe.

Abstract: First, the authors offer their conception of planning for resiliency as a goal for recovering communities, and the benefits of planning in efforts to create more resilient places.

Abstract: Next, they discuss major issues associated with planning for postdisaster recovery, including barriers posed by federal and state governments to planning for resiliency, the promise and risks of compact urban form models for guiding rebuilding, and the failure to involve citizens in planning for disasters.

Abstract: Finally, they discuss lessons from prior research that address these issues and policy recommendations that foster predisaster recovery planning for resilient communities.


Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress.

Abstract: OBJECTIVE The authors sought to determine innate immune system activation following psychosocial stress in patients with major depression and increased early life stress.

Abstract: METHOD Plasma interleukin (IL)-6, lymphocyte subsets, and DNA binding of nuclear factor (NF)-kB in peripheral blood mononuclear cells were compared in medically healthy male subjects with current major depression and increased early life stress (N=14) versus nondepressed male comparison subjects (N=14) before and after completion of the Trier Social Stress Test.

Abstract: RESULTS Trier Social Stress Test-induced increases in IL-6 and NF-kappaB DNA-binding were greater in major depression patients with increased early life stress and independently correlated with depression severity, but not early life stress.

Abstract: Natural killer (NK) cell percentages also increased following stress.

Abstract: However, there were no differences between groups and no correlation between NK cell percentage and stress-induced NF-kappaB DNA-binding or IL-6.

Abstract: CONCLUSIONS Male major depression patients with increased early life stress exhibit enhanced inflammatory responsiveness to psychosocial stress, providing preliminary indication of a link between major depression, early life stress and adverse health outcomes in diseases associated with inflammation.


KIF3A/B: a heterodimeric kinesin superfamily protein that works as a microtubule plus end-directed motor for membrane organelle transport

Abstract: We cloned a new member of the murine brain kinesin superfamily, KIF3B, and found that its amino acid sequence is highly homologous but not identical to KIF3A, which we previously cloned and named KIF3 (47% identical).

Abstract: KIF3B is localized in various organ tissues and developing neurons of mice and accumulates with anterogradely moving membranous organelles after ligation of nerve axons.

Abstract: Immunoprecipitation assay of the brain revealed that KIF3B forms a complex with KIF3A and three other high molecular weight (approximately 100 kD)-associated polypeptides, called the kinesin superfamily-associated protein 3 (KAP3).

Abstract: In vitro reconstruction using baculovirus expression systems showed that KIF3A and KIF3B directly bind with each other in the absence of KAP3.

Abstract: The recombinant KIF3A/B complex (approximately 50-nm rod with two globular heads and a single globular tail) demonstrated plus end-directed microtubule sliding activity in vitro.

Abstract: In addition, we showed that KIF3B itself has motor activity in vitro, by making a complex of wild-type KIF3B and a chimeric motor protein (KIF3B head and KIF3A rod tail).

Abstract: Subcellular fractionation of mouse brain homogenates showed a considerable amount of the native KIF3 complex to be associated with membrane fractions other than synaptic vesicles.

Abstract: Immunoprecipitation by anti-KIF3B antibody-conjugated beads and its electron microscopic study also revealed that KIF3 is associated with membranous organelles.

Abstract: Moreover, we found that the composition of KAP3 is different in the brain and testis.

Abstract: Our findings suggest that KIF3B forms a heterodimer with KIF3A and functions as a new microtubule-based anterograde translocator for membranous organelles, and that KAP3 may determine functional diversity of the KIF3 complex in various kinds of cells in vivo.


A genetic screen identifies an LKB1–MARK signalling axis controlling the Hippo–YAP pathway

Abstract: The Hippo–YAP pathway is an emerging signalling cascade involved in the regulation of stem cell activity and organ size.

Abstract: To identify components of this pathway, we performed an RNAi-based kinome screen in human cells.

Abstract: Our screen identified several kinases not previously associated with Hippo signalling that control multiple cellular processes.

Abstract: One of the hits, LKB1, is a common tumour suppressor whose mechanism of action is only partially understood.

Abstract: We demonstrate that LKB1 acts through its substrates of the microtubule affinity-regulating kinase family to regulate the localization of the polarity determinant Scribble and the activity of the core Hippo kinases.

Abstract: Our data also indicate that YAP is functionally important for the tumour suppressive effects of LKB1.

Abstract: Our results identify a signalling axis that links YAP activation with LKB1 mutations, and have implications for the treatment of LKB1-mutant human malignancies.

Abstract: In addition, our findings provide insight into upstream signals of the Hippo–YAP signalling cascade.


Beyond melanoma: inhibiting the PD-1/PD-L1 pathway in solid tumors.

Abstract: Immune checkpoint inhibitors have been identified as breakthrough treatment in melanoma given its dramatic response to PD-1/PD-L1 blockade.

Abstract: This is likely to extend to many other cancers as hundreds of clinical trials are being conducted or proposed using this exciting modality of therapy in a variety of malignancies.

Abstract: While immune checkpoint inhibitors have been extensively studied in melanoma and more recently in lung cancer, little is known regarding immune checkpoint blockade in other cancers.

Abstract: This review will focus on the tumor immune microenvironment, the expression of PD-1/PD-L1 and the effect of immune modulation using PD-1 or PD-L1 inhibitors in patients with head and neck, prostate, urothelial, renal, breast, gastrointestinal and lung cancers.


Partitioning the symptoms of hypoglycaemia using multi-sample confirmatory factor analysis

Abstract: The allocation of hypoglycaemic symptoms to autonomie or neuroglycopenic groups tends to occur on an a priori basis.

Abstract: In view of the practical need for clear symptom markers of hypoglycaemia more scientific approaches must be pursued.

Abstract: Substantial evidence is presented from two large scale studies we performed which support a three factor model of hypoglycaemic symptomatology, based on the statistical associations discovered among symptoms reported by diabetic patients.

Abstract: Study 1 involved 295 insulin-treated outpatients and found that 11 key hypoglycaemic symptoms segregated into three clear factors: autonomie (sweating, palpitation, shaking and hunger) neuroglycopenic (confusion, drowsiness, odd behaviour, speech difficulty and incoordination), and malaise (nausea and headache).

Abstract: The three factors were validated on a separate group of 303 insulin-treated diabetic out-patients.

Abstract: Confirmatory factor analyses showed that the three factor model was the optimal model for explaining symptom covariance in each group.

Abstract: A multi-sample confirmatory factor analysis tested the rigorous assumptions that the relative loadings of symptoms on factors across groups were equal, and that the residual variance for each symptom was identical across groups.

Abstract: These assumptions were successful, indicating that the three factor model was replicated in detail across these two large samples.

Abstract: It is suggested that the results indicate valid groupings of symptoms that may be used in future research and in clinical practice.


Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction.

Abstract: AIMS Recent evidence suggests that cardiac progenitor cells (CPCs) may improve cardiac function after injury.

Abstract: The underlying mechanisms are indirect, but their mediators remain unidentified.

Abstract: Exosomes and other secreted membrane vesicles, hereafter collectively referred to as extracellular vesicles (EVs), act as paracrine signalling mediators.

Abstract: Here, we report that EVs secreted by human CPCs are crucial cardioprotective agents.

Abstract: METHODS AND RESULTS CPCs were derived from atrial appendage explants from patients who underwent heart valve surgery.

Abstract: CPC-conditioned medium (CM) inhibited apoptosis in mouse HL-1 cardiomyocytic cells, while enhancing tube formation in human umbilical vein endothelial cells.

Abstract: These effects were abrogated by depleting CM of EVs.

Abstract: They were reproduced by EVs secreted by CPCs, but not by those secreted by human dermal fibroblasts.

Abstract: Transmission electron microscopy and nanoparticle tracking analysis showed most EVs to be 30-90 nm in diameter, the size of exosomes, although smaller and larger vesicles were also present.

Abstract: MicroRNAs most highly enriched in EVs secreted by CPCs compared with fibroblasts included miR-210, miR-132, and miR-146a-3p.

Abstract: miR-210 down-regulated its known targets, ephrin A3 and PTP1b, inhibiting apoptosis in cardiomyocytic cells.

Abstract: miR-132 down-regulated its target, RasGAP-p120, enhancing tube formation in endothelial cells.

Abstract: Infarcted hearts injected with EVs from CPCs, but not from fibroblasts, exhibited less cardiomyocyte apoptosis, enhanced angiogenesis, and improved LV ejection fraction (0.8 ± 6.8 vs. -21.3 ± 4.5%; P < 0.05) compared with those injected with control medium.

Abstract: CONCLUSION EVs are the active component of the paracrine secretion by human CPCs.

Abstract: As a cell-free approach, EVs could circumvent many of the limitations of cell transplantation.


Increased Adipocyte O2 Consumption Triggers HIF-1α, Causing Inflammation and Insulin Resistance in Obesity

Abstract: Adipose tissue hypoxia and inflammation have been causally implicated in obesity-induced insulin resistance.

Abstract: Here, we report that, early in the course of high-fat diet (HFD) feeding and obesity, adipocyte respiration becomes uncoupled, leading to increased oxygen consumption and a state of relative adipocyte hypoxia.

Abstract: These events are sufficient to trigger HIF-1α induction, setting off the chronic adipose tissue inflammatory response characteristic of obesity.

Abstract: At the molecular level, these events involve saturated fatty acid stimulation of the adenine nucleotide translocase 2 (ANT2), an inner mitochondrial membrane protein, which leads to the uncoupled respiratory state.

Abstract: Genetic or pharmacologic inhibition of either ANT2 or HIF-1α can prevent or reverse these pathophysiologic events, restoring a state of insulin sensitivity and glucose tolerance.

Abstract: These results reveal the sequential series of events in obesity-induced inflammation and insulin resistance.


Lpcat3-dependent production of arachidonoyl phospholipids is a key determinant of triglyceride secretion

Abstract: The role of specific phospholipids (PLs) in lipid transport has been difficult to assess due to an inability to selectively manipulate membrane composition in vivo.

Abstract: Here we show that the phospholipid remodeling enzyme lysophosphatidylcholine acyltransferase 3 (Lpcat3) is a critical determinant of triglyceride (TG) secretion due to its unique ability to catalyze the incorporation of arachidonate into membranes.

Abstract: Mice lacking Lpcat3 in the intestine fail to thrive during weaning and exhibit enterocyte lipid accumulation and reduced plasma TGs.

Abstract: Mice lacking Lpcat3 in the liver show reduced plasma TGs, hepatosteatosis, and secrete lipid-poor very low-density lipoprotein (VLDL) lacking arachidonoyl PLs.

Abstract: Mechanistic studies indicate that Lpcat3 activity impacts membrane lipid mobility in living cells, suggesting a biophysical basis for the requirement of arachidonoyl PLs in lipidating lipoprotein particles.

Abstract: These data identify Lpcat3 as a key factor in lipoprotein production and illustrate how manipulation of membrane composition can be used as a regulatory mechanism to control metabolic pathways.


Characterization of a single-stranded DNA-binding protein from Pseudomonas aeruginosa PAO1.

Abstract: Single-stranded DNA-binding protein (SSB) plays an important role in DNA metabolism, such as in DNA replication, repair, and recombination, and is essential for cell survival.

Abstract: We characterized the single-stranded DNA (ssDNA)-binding properties of Pseudomonas aeruginosa PAO1 SSB (PaSSB) by using fluorescence quenching measurements and electrophoretic mobility shift analysis (EMSA).

Abstract: Analysis of purified PaSSB by gel filtration chromatography revealed a stable tetramer in solution.

Abstract: In fluorescence titrations, PaSSB bound 22-32 nucleotides (nt) per tetramer depending on salt concentration.

Abstract: Using EMSA, we characterized the stoichiometry of PaSSB complexed with a series of ssDNA homopolymers, and the size of the binding site was determined to be 29 ± 1 nt.

Abstract: Furthermore, EMSA results indicated that the dissociation constants of PaSSB for the first tetramer were less than those for the second tetramer.

Abstract: On the basis of these biophysical analyses, the ssDNA binding mode of PaSSB is expected to be noncooperative.


Primary cilia and coordination of receptor tyrosine kinase (RTK) signalling.

Abstract: Primary cilia are microtubule-based sensory organelles that coordinate signalling pathways in cell-cycle control, migration, differentiation and other cellular processes critical during development and for tissue homeostasis.

Abstract: Accordingly, defects in assembly or function of primary cilia lead to a plethora of developmental disorders and pathological conditions now known as ciliopathies.

Abstract: In this review, we summarize the current status of the role of primary cilia in coordinating receptor tyrosine kinase (RTK) signalling pathways.

Abstract: Further, we present potential mechanisms of signalling crosstalk and networking in the primary cilium and discuss how defects in ciliary RTK signalling are linked to human diseases and disorders.


Detecting and targeting tumor relapse by its resistance to innate effectors at early recurrence

Abstract: Tumor recurrence represents a major clinical challenge.

Abstract: Our data show that emergent recurrent tumors acquire a phenotype radically different from that of their originating primary tumors.

Abstract: This phenotype allows them to evade a host-derived innate immune response elicited by the progression from minimal residual disease (MRD) to actively growing recurrence.

Abstract: Screening for this innate response predicted accurately in which mice recurrence would occur.

Abstract: Premature induction of recurrence resensitized MRD to the primary therapy, suggesting a possible paradigm shift for clinical treatment of dormant disease in which the current expectant approach is replaced with active attempts to uncover MRD before evolution of the escape phenotype is complete.

Abstract: By combining screening with second-line treatments targeting innate insensitivity, up to 100% of mice that would have otherwise relapsed were cured.

Abstract: These data may open new avenues for early detection and appropriately timed, highly targeted treatment of tumor recurrence irrespective of tumor type or frontline treatment.


Forces in Tissue Morphogenesis and Patterning

Abstract: During development, mechanical forces cause changes in size, shape, number, position, and gene expression of cells.

Abstract: They are therefore integral to any morphogenetic processes.

Abstract: Force generation by actin-myosin networks and force transmission through adhesive complexes are two self-organizing phenomena driving tissue morphogenesis.

Abstract: Coordination and integration of forces by long-range force transmission and mechanosensing of cells within tissues produce large-scale tissue shape changes.

Abstract: Extrinsic mechanical forces also control tissue patterning by modulating cell fate specification and differentiation.

Abstract: Thus, the interplay between tissue mechanics and biochemical signaling orchestrates tissue morphogenesis and patterning in development.


CD169+ MACROPHAGES PRESENT LIPID ANTIGENS TO MEDIATE EARLY ACTIVATION OF INVARIANT NKT CELLS IN LYMPH NODES

Abstract: Invariant natural killer T cells (iNKT cells) are involved in the host defense against microbial infection.

Abstract: Although it is known that iNKT cells recognize glycolipids presented by CD1d, how and where they encounter antigen in vivo remains unclear.

Abstract: Here we used multiphoton microscopy to visualize the dynamics and activation of iNKT cells in lymph nodes.

Abstract: After antigen administration, iNKT cells became confined in a CD1d-dependent manner in close proximity to subcapsular sinus CD169(+) macrophages.

Abstract: These macrophages retained, internalized and presented lipid antigen and were required for iNKT cell activation, cytokine production and population expansion.

Abstract: Thus, CD169(+) macrophages can act as true antigen-presenting cells controlling early iNKT cell activation and favoring the fast initiation of immune responses.


Oxygen Metabolism Causes Chromosome Breaks and Is Associated with the Neuronal Apoptosis Observed in DNA Double-Strand Break Repair Mutants

Abstract: Cells deficient in a major DNA double-strand break repair pathway (nonhomologous DNA end joining [NHEJ]) have increased spontaneous chromosome breaks; however, the source of these chromosome breaks has remained undefined.

Abstract: Here, we show that the observed spontaneous chromosome breaks are partially suppressed by reducing the cellular oxygen tension.

Abstract: Conversely, elevating the level of reactive oxygen species by overexpressing the antioxidant enzyme superoxide dismutase 1 (SOD1), in a transgenic mouse, increases chromosome breakage.

Abstract: The effect of SOD1 can also be modulated by cellular oxygen tension.

Abstract: The elevated chromosome breakage correlates histologically with a significant increase in the amount of neuronal cell death in Ku86(-/-) SOD1 transgenic embryos over that seen in Ku86(-/-) embryos.

Abstract: Therefore, oxygen metabolism is a major source of the genomic instability observed in NHEJ-deficient cells and, presumably, in all cells.


Insertional mutagenesis in gene therapy and stem cell biology.

Abstract: PURPOSE OF REVIEW Recent preclinical and clinical studies revealed that the semirandom insertion of transgenes into chromosomal DNA of hematopoietic cells may induce clonal competition, which potentially may even trigger leukemia or sarcoma.

Abstract: Insertional mutagenesis caused by gene vectors has thus led to major uncertainty among those developing advanced hematopoietic cell therapies.

Abstract: This review summarizes novel studies of underlying mechanisms; these studies have demonstrated the possibility of improved gene vector biosafety and generated new insights into stem cell biology.

Abstract: RECENT FINDINGS The characteristic insertion pattern of various retroviral gene vector systems may be explained by properties of the viral integrase and associated cellular cofactors.

Abstract: Cell culture assays and animal models, including disease-specific and cancer-prone mouse models, are emerging that reveal the contributions of vector features and systemic factors to induction of clonal imbalance.

Abstract: Databases summarizing vector insertion sites in dominant hematopoietic clones are evolving as new tools to identify genes that regulate clonal homeostasis.

Abstract: SUMMARY Mechanistic studies of insertional mutagenesis by random gene vector insertion will lead to improved tools for advanced hematopoietic cell therapy.

Abstract: Simultaneously, fascinating insights into gene networks that regulate cell fitness will be generated, with important consequences for the fields of hematology, oncology and regenerative medicine.


Markets, voucher subsidies and free nets combine to achieve high bed net coverage in rural Tanzania

Abstract: BACKGROUND Tanzania has a well-developed network of commercial ITN retailers.

Abstract: In 2004, the government introduced a voucher subsidy for pregnant women and, in mid 2005, helped distribute free nets to under-fives in small number of districts, including Rufiji on the southern coast, during a child health campaign.

Abstract: Contributions of these multiple insecticide-treated net delivery strategies existing at the same time and place to coverage in a poor rural community were assessed.

Abstract: METHODS Cross-sectional household survey in 6,331 members of randomly selected 1,752 households of 31 rural villages of Demographic Surveillance System in Rufiji district, Southern Tanzania was conducted in 2006.

Abstract: A questionnaire was administered to every consenting respondent about net use, treatment status and delivery mechanism.

Abstract: FINDINGS Net use was 62.7% overall, 87.2% amongst infants (0 to 1 year), 81.8% amongst young children (>1 to 5 years), 54.5% amongst older children (6 to 15 years) and 59.6% amongst adults (>15 years).

Abstract: 30.2% of all nets had been treated six months prior to interview.

Abstract: The biggest source of nets used by infants was purchase from the private sector with a voucher subsidy (41.8%).

Abstract: Half of nets used by young children (50.0%) and over a third of those used by older children (37.2%) were obtained free of charge through the vaccination campaign.

Abstract: The largest source of nets amongst the population overall was commercial purchase (45.1% use) and was the primary means for protecting adults (60.2% use).

Abstract: All delivery mechanisms, especially sale of nets at full market price, under-served the poorest but no difference in equity was observed between voucher-subsidized and freely distributed nets.

Abstract: CONCLUSION All three delivery strategies enabled a poor rural community to achieve net coverage high enough to yield both personal and community level protection for the entire population.

Abstract: Each of them reached their relevant target group and free nets only temporarily suppressed the net market, illustrating that in this setting that these are complementary rather than mutually exclusive approaches.


Human chorionic gonadotropin levels in maternal blood in late pregnancy: relation to birthweight, sex and condition of the infant at birth.

Abstract: A total of 527 blood samples was obtained from an unselected population of women between 36 and 40 weeks gestation.

Abstract: Serum human chorionic gonadotropin (hCG) levels were measured using a specific radioimmunoassay for the beta 1-subunit of hCG.

Abstract: Serum hCG levels were higher in primigravidae and in women carrying female fetuses.

Abstract: They were also related to the birthweight of the child and to the occurrence of fetal distress.


Brain-Specific Phosphorylation of MeCP2 Regulates Activity-Dependent Bdnf Transcription, Dendritic Growth, and Spine Maturation

Abstract: Mutations or duplications in MECP2 cause Rett and Rett-like syndromes, neurodevelopmental disorders characterized by mental retardation, motor dysfunction, and autistic behaviors.

Abstract: MeCP2 is expressed in many mammalian tissues and functions as a global repressor of transcription; however, the molecular mechanisms by which MeCP2 dysfunction leads to the neural-specific phenotypes of RTT remain poorly understood.

Abstract: Here, we show that neuronal activity and subsequent calcium influx trigger the de novo phosphorylation of MeCP2 at serine 421 (S421) by a CaMKII-dependent mechanism.

Abstract: MeCP2 S421 phosphorylation is induced selectively in the brain in response to physiological stimuli.

Abstract: Significantly, we find that S421 phosphorylation controls the ability of MeCP2 to regulate dendritic patterning, spine morphogenesis, and the activity-dependent induction of Bdnf transcription.

Abstract: These findings suggest that, by triggering MeCP2 phosphorylation, neuronal activity regulates a program of gene expression that mediates nervous system maturation and that disruption of this process in individuals with mutations in MeCP2 may underlie the neural-specific pathology of RTT.


Abstract: Correction for:    Kurreeman FAS, Padyukov L, Marques RB, Schrodi SJ, Seddighzadeh M, et al. (2007)

Abstract: A Candidate Gene Approach Identifies the TRAF1/C5 Region as a Risk Factor for Rheumatoid Arthritis.

Abstract: PLoS Med 4(9): e278.

Abstract: doi:10.1371/journal.pmed.0040278    In Table 1, the allele ratio in column eight (Allele Ratiosb: Cases, Controls) refers to allele A: allele B and not allele1:allele2 as described in footnote b, with Allele A being the Susceptibility Allele as denoted in column seven.

Abstract: The footnote should read:    bNumber of alleles were compared in cases versus controls: allele A: allele B cases, allele A: allele B controls.

Abstract: Allele A refers to the susceptibility alleles as given in column seven.


Potential use of γ-secretase modulators in the treatment of Alzheimer disease.

Abstract: Although significant progress has occurred in the past 20 years regarding our understanding of Alzheimer disease pathogenesis, we have yet to identify disease-modifying therapeutics capable of substantially altering the clinical course of this prevalent neurodegenerative disease.

Abstract: In this short review, we discuss 2 approaches that are currently being tested clinically (γ-secretase inhibition and γ-secretase modulation) and emphasize the significant differences between these 2 therapeutic approaches.

Abstract: We also discuss certain genetic- and biomarker-based translational and clinical trial paradigms that may assist in developing a useful therapeutic agent.


Rational design of a flavivirus vaccine by abolishing viral RNA 2'-O methylation.

Abstract: Viruses that replicate in the cytoplasm cannot access the host nuclear capping machinery.

Abstract: These viruses have evolved viral methyltransferase(s) to methylate N-7 and 2'-O cap of their RNA; alternatively, they "snatch" host mRNA cap to form the 5' end of viral RNA.

Abstract: The function of 2'-O methylation of viral RNA cap is to mimic cellular mRNA and to evade host innate immune restriction.

Abstract: A cytoplasmic virus defective in 2'-O methylation is replicative, but its viral RNA lacks 2'-O methylation and is recognized and eliminated by the host immune response.

Abstract: Such a mutant virus could be rationally designed as a live attenuated vaccine.

Abstract: Here, we use Japanese encephalitis virus (JEV), an important mosquito-borne flavivirus, to prove this novel vaccine concept.

Abstract: We show that JEV methyltransferase is responsible for both N-7 and 2'-O cap methylations as well as evasion of host innate immune response.

Abstract: Recombinant virus completely defective in 2'-O methylation was stable in cell culture after being passaged for >30 days.

Abstract: The mutant virus was attenuated in mice, elicited robust humoral and cellular immune responses, and retained the engineered mutation in vivo.

Abstract: A single dose of immunization induced full protection against lethal challenge with JEV strains in mice.

Abstract: Mechanistically, the attenuation phenotype was attributed to the enhanced sensitivity of the mutant virus to the antiviral effects of interferon and IFIT proteins.

Abstract: Collectively, the results demonstrate the feasibility of using 2'-O methylation-defective virus as a vaccine approach; this vaccine approach should be applicable to other flaviviruses and nonflaviviruses that encode their own viral 2'-O methyltransferases.


Fruit consumption and risk of type 2 diabetes: results from three prospective longitudinal cohort studies

Abstract: OBJECTIVE To determine whether individual fruits are differentially associated with risk of type 2 diabetes.

Abstract: DESIGN Prospective longitudinal cohort study.

Abstract: SETTING Health professionals in the United States.

Abstract: PARTICIPANTS 66,105 women from the Nurses' Health Study (1984-2008), 85,104 women from the Nurses' Health Study II (1991-2009), and 36,173 men from the Health Professionals Follow-up Study (1986-2008) who were free of major chronic diseases at baseline in these studies.

Abstract: MAIN OUTCOME MEASURE Incident cases of type 2 diabetes, identified through self report and confirmed by supplementary questionnaires.

Abstract: RESULTS During 3,464,641 person years of follow-up, 12,198 participants developed type 2 diabetes.

Abstract: After adjustment for personal, lifestyle, and dietary risk factors of diabetes, the pooled hazard ratio of type 2 diabetes for every three servings/week of total whole fruit consumption was 0.98 (95% confidence interval 0.97 [corrected] to 0.99).

Abstract: With mutual adjustment of individual fruits, the pooled hazard ratios of type 2 diabetes for every three servings/week were 0.74 (0.66 to 0.83) for blueberries, 0.88 (0.83 to 0.93) for grapes and raisins, 0.89 (0.79 to 1.01) for prunes, 0.93 (0.90 to 0.96) for apples and pears, 0.95 (0.91 to 0.98) for bananas, 0.95 (0.91 to 0.99) for grapefruit, 0.97 (0.92 to 1.02) for peaches, plums, and apricots, 0.99 (0.95 to 1.03) for oranges, 1.03 (0.96 to 1.10) for strawberries, and 1.10 (1.02 to 1.18) for cantaloupe.

Abstract: The pooled hazard ratio for the same increment in fruit juice consumption was 1.08 (1.05 to 1.11).

Abstract: The associations with risk of type 2 diabetes differed significantly among individual fruits (P<0.001 in all cohorts).

Abstract: CONCLUSION Our findings suggest the presence of heterogeneity in the associations between individual fruit consumption and risk of type 2 diabetes.

Abstract: Greater consumption of specific whole fruits, particularly blueberries, grapes, and apples, is significantly associated with a lower risk of type 2 diabetes, whereas greater consumption of fruit juice is associated with a higher risk.


OncomiR-196 promotes an invasive phenotype in oral cancer through the NME4-JNK-TIMP1-MMP signaling pathway

Abstract: BACKGROUND MicroRNA-196 (miR-196), which is highly up-regulated in oral cancer cells, has been reported to be aberrantly expressed in several cancers; however, the significance of miR-196 in oral cancer has not yet been addressed.

Abstract: METHODS Cellular functions in response to miR-196 modulation were examined, including cell growth, migration, invasion and radio/chemosensitivity.

Abstract: Algorithm-based studies were used to identify the regulatory target of miR-196.

Abstract: The miR-196 target gene and downstream molecular mechanisms were confirmed by RT-qPCR, western blot, luciferase reporter and confocal microscopy analyses.

Abstract: miR-196 expression was determined in paired cancer and adjacent normal tissues from oral cancer patients.

Abstract: RESULTS Both miR-196a and miR-196b were highly over-expressed in the cancer tissue and correlated with lymph node metastasis (P = 0.001 and P = 0.006, respectively).

Abstract: Functionally, miR-196 actively promoted cell migration and invasion without affecting cell growth.

Abstract: Mechanistically, miR-196 performed it's their function by inhibiting NME4 expression and further activating p-JNK, suppressing TIMP1, and augmenting MMP1/9.

Abstract: CONCLUSION miR-196 contributes to oral cancer by promoting cell migration and invasion.

Abstract: Clinically, miR-196a/b was significantly over-expressed in the cancer tissues and correlated with lymph node metastasis.

Abstract: Thus, our findings provide new knowledge of the underlying mechanism of cancer metastasis.

Abstract: miR-196 may serve as a promising marker for better oral cancer management.


Reverse engineering of TLX oncogenic transcriptional networks identifies RUNX1 as tumor suppressor in T-ALL

Abstract: The TLX1 and TLX3 transcription factor oncogenes have a key role in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL).

Abstract: Here we used reverse engineering of global transcriptional networks to decipher the oncogenic regulatory circuit controlled by TLX1 and TLX3.

Abstract: This systems biology analysis defined T cell leukemia homeobox 1 (TLX1) and TLX3 as master regulators of an oncogenic transcriptional circuit governing T-ALL.

Abstract: Notably, a network structure analysis of this hierarchical network identified RUNX1 as a key mediator of the T-ALL induced by TLX1 and TLX3 and predicted a tumor-suppressor role for RUNX1 in T cell transformation.

Abstract: Consistent with these results, we identified recurrent somatic loss-of-function mutations in RUNX1 in human T-ALL.

Abstract: Overall, these results place TLX1 and TLX3 at the top of an oncogenic transcriptional network controlling leukemia development, show the power of network analyses to identify key elements in the regulatory circuits governing human cancer and identify RUNX1 as a tumor-suppressor gene in T-ALL.


The Impact of the New WHO Antiretroviral Treatment Guidelines on HIV Epidemic Dynamics and Cost in South Africa

Abstract: BACKGROUND Since November 2009, WHO recommends that adults infected with HIV should initiate antiretroviral therapy (ART) at CD4+ cell counts of ≤350 cells/µl rather than ≤200 cells/µl.

Abstract: South Africa decided to adopt this strategy for pregnant and TB co-infected patients only.

Abstract: We estimated the impact of fully adopting the new WHO guidelines on HIV epidemic dynamics and associated costs.

Abstract: METHODS AND FINDING We used an established model of the transmission and control of HIV in specified sexual networks and healthcare settings.

Abstract: We quantified the model to represent Hlabisa subdistrict, KwaZulu-Natal, South Africa.

Abstract: We predicted the HIV epidemic dynamics, number on ART and program costs under the new guidelines relative to treating patients at ≤200 cells/µl for the next 30 years.

Abstract: During the first five years, the new WHO treatment guidelines require about 7% extra annual investments, whereas 28% more patients receive treatment.

Abstract: Furthermore, there will be a more profound impact on HIV incidence, leading to relatively less annual costs after seven years.

Abstract: The resulting cumulative net costs reach a break-even point after on average 16 years.

Abstract: CONCLUSIONS Our study strengthens the WHO recommendation of starting ART at ≤350 cells/µl for all HIV-infected patients.

Abstract: Apart from the benefits associated with many life-years saved, a modest frontloading appears to lead to net savings within a limited time-horizon.

Abstract: This finding is robust to alternative assumptions and foreseeable changes in ART prices and effectiveness.

Abstract: Therefore, South Africa should aim at rapidly expanding its healthcare infrastructure to fully embrace the new WHO guidelines.


ER-associated mitochondrial division links the distribution of mitochondria and mitochondrial DNA in yeast

Abstract: Mitochondrial division is important for mitochondrial distribution and function.

Abstract: Recent data have demonstrated that ER-mitochondria contacts mark mitochondrial division sites, but the molecular basis and functions of these contacts are not understood.

Abstract: Here we show that in yeast, the ER-mitochondria tethering complex, ERMES, and the highly conserved Miro GTPase, Gem1, are spatially and functionally linked to ER-associated mitochondrial division.

Abstract: Gem1 acts as a negative regulator of ER-mitochondria contacts, an activity required for the spatial resolution and distribution of newly generated mitochondrial tips following division.

Abstract: Previous data have demonstrated that ERMES localizes with a subset of actively replicating mitochondrial nucleoids.

Abstract: We show that mitochondrial division is spatially linked to nucleoids and that a majority of these nucleoids segregate prior to division, resulting in their distribution into newly generated tips in the mitochondrial network.

Abstract: Thus, we postulate that ER-associated division serves to link the distribution of mitochondria and mitochondrial nucleoids in cells.


BMI-1 Autoantibody as a New Potential Biomarker for Cervical Carcinoma

Abstract: BMI-1 is overexpressed in a variety of cancers, which can elicit an immune response leading to the induction of autoantibodies.

Abstract: However, BMI-1 autoantibody as a biomarker has seldom been studied with the exception of nasopharyngeal carcinoma.

Abstract: Whether BMI-1 autoantibodies can be used as a biomarker for cervical carcinoma is unclear.

Abstract: In this study,BMI-1 proteins were isolated by screening of a T7 phage cDNA library from mixed cervical carcinoma tissues.

Abstract: We analyzed BMI-1 autoantibody levels in serum samples from 67 patients with cervical carcinoma and 65 controls using ELISA and immunoblot.

Abstract: BMI-1 mRNA or protein levels were over-expressed in cervical carcinoma cell lines.

Abstract: Immunoblot results exhibited increased BMI-1 autoantibody levels in patient sera compared to normal sera.

Abstract: Additionally, the results for antibody affinity assay showed that there was no difference between cervical polyps and normal sera of BMI-1 autoantibody levels, but it was significantly greater in patient sera than that in normal controls (patient 0.827±0.043 and normal 0.445±0.023; P<0.001).

Abstract: What's more, the levels of BMI-1 autoantibody increased significantly at stage I (0.672±0.019) compared to normal sera (P<0.001), and levels of BMI-1 autoantibodies were increased gradually during the tumor progression (stage I 0.672±0.019; stage II 0.775 ±0.019; stage III 0.890 ±0.027; stage IV 1.043±0.041), which were significantly correlated with disease progression of cervical cancer (P<0.001).

Abstract: Statistical analyses using logistic regression and receiver operating characteristics (ROC) curves indicated that the BMI-1 autoantibody level can be used as a biomarker for cervical carcinoma (sensitivity 0.78 and specificity 0.76; AUC = 0.922).

Abstract: In conclusion, measuring BMI-1 autoantibody levels of patients with cervical cancer could have clinical prognostic value as well as a non-tissue specific biomarker for neoplasms expressing BMI-1.


MicroRNAs can generate thresholds in target gene expression

Abstract: MicroRNAs (miRNAs) are short, highly conserved noncoding RNA molecules that repress gene expression in a sequence-dependent manner.

Abstract: We performed single-cell measurements using quantitative fluorescence microscopy and flow cytometry to monitor a target gene's protein expression in the presence and absence of regulation by miRNA.

Abstract: We find that although the average level of repression is modest, in agreement with previous population-based measurements, the repression among individual cells varies dramatically.

Abstract: In particular, we show that regulation by miRNAs establishes a threshold level of target mRNA below which protein production is highly repressed.

Abstract: Near this threshold, protein expression responds sensitively to target mRNA input, consistent with a mathematical model of molecular titration.

Abstract: These results show that miRNAs can act both as a switch and as a fine-tuner of gene expression.


Oncogenic mTOR signaling recruits myeloid-derived suppressor cells to promote tumor initiation

Abstract: Myeloid-derived suppressor cells (MDSCs) play critical roles in primary and metastatic cancer progression.

Abstract: MDSC regulation is widely variable even among patients harbouring the same type of malignancy, and the mechanisms governing such heterogeneity are largely unknown.

Abstract: Here, integrating human tumour genomics and syngeneic mammary tumour models, we demonstrate that mTOR signalling in cancer cells dictates a mammary tumour's ability to stimulate MDSC accumulation through regulating G-CSF.

Abstract: Inhibiting this pathway or its activators (for example, FGFR) impairs tumour progression, which is partially rescued by restoring MDSCs or G-CSF.

Abstract: Tumour-initiating cells (TICs) exhibit elevated G-CSF.

Abstract: MDSCs reciprocally increase TIC frequency through activating Notch in tumour cells, forming a feedforward loop.

Abstract: Analyses of primary breast cancers and patient-derived xenografts corroborate these mechanisms in patients.

Abstract: These findings establish a non-canonical oncogenic role of mTOR signalling in recruiting pro-tumorigenic MDSCs and show how defined cancer subsets may evolve to promote and depend on a distinct immune microenvironment.


Management of women who have a genetic predisposition for breast cancer.

Abstract: The management of women who have a genetic predisposition for breast cancer requires careful planning.

Abstract: Women who have BRCA 1 and BRCA 2 mutations are at increased risk for breast cancer and for other cancers as well, particularly ovarian cancer.

Abstract: Screening, prophlyactic surgery, and chemoprevention are commonly utilized strategies in the management of these patients, and women may choose more than one of these strategies.

Abstract: No randomized prospective trials have assessed the impact of these strategies specifically in mutation carriers.

Abstract: All patients should be informed that screening, prophylactic surgery, and chemoprevention have the potential for harm as well as benefit.


Astrocytes from Familial and Sporadic ALS Patients are Toxic to Motor Neurons

Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease, with astrocytes implicated as contributing substantially to motor neuron death in familial (F)ALS.

Abstract: However, the proposed role of astrocytes in the pathology of ALS derives in part from rodent models of FALS based upon dominant mutations within the superoxide dismutase 1 (SOD1) gene, which account for <2% of all ALS cases.

Abstract: Their role in sporadic (S)ALS, which affects >90% of ALS patients, remains to be established.

Abstract: Using astrocytes generated from postmortem tissue from both FALS and SALS patients, we show that astrocytes derived from both patient groups are similarly toxic to motor neurons.

Abstract: We also demonstrate that SOD1 is a viable target for SALS, as its knockdown significantly attenuates astrocyte-mediated toxicity toward motor neurons.

Abstract: Our data highlight astrocytes as a non-cell autonomous component in SALS and provide an in vitro model system to investigate common disease mechanisms and evaluate potential therapies for SALS and FALS.


High-intensity functional exercise program and protein-enriched energy supplement for older persons dependent in activities of daily living: a randomised controlled trial.

Abstract: The aims of this randomised controlled trial were to determine if a high-intensity functional exercise program improves balance, gait ability, and lower-limb strength in older persons dependent in activities of daily living and if an intake of protein-enriched energy supplement immediately after the exercises increases the effects of the training.

Abstract: One hundred and ninety-one older persons dependent in activities of daily living, living in residential care facilities, and with a Mini-Mental State Examination (MMSE) score of ?

Abstract: 10 participated.

Abstract: They were randomised to a high-intensity functional exercise program or a control activity, which included 29 sessions over 3 months, as well as to protein-enriched energy supplement or placebo.

Abstract: Berg Balance Scale, self-paced and maximum gait speed, and one-repetition maximum in lower-limb strength were followed-up at three and six months and analysed by 2 x 2 factorial ANCOVA, using the intention-to-treat principle.

Abstract: At three months, the exercise group had improved significantly in self-paced gait speed compared with the control group (mean difference 0.04 m/s, p = 0.02).

Abstract: At six months, there were significant improvements favouring the exercise group for Berg Balance Scale (1.9 points, p = 0.05), self-paced gait speed (0.05 m/s, p = 0.009), and lower-limb strength (10.8 kg, p = 0.03).

Abstract: No interaction effects were seen between the exercise and nutrition interventions.

Abstract: In conclusion, a high-intensity functional exercise program has positive long-term effects in balance, gait ability, and lower-limb strength for older persons dependent in activities of daily living.

Abstract: An intake of protein-enriched energy supplement immediately after the exercises does not appear to increase the effects of the training.


Inhibition of fatty acid oxidation modulates immunosuppressive functions of myeloid-derived suppressor cells and enhances cancer therapies

Abstract: Myeloid-derived suppressor cells (MDSC) promote tumor growth by inhibiting T-cell immunity and promoting malignant cell proliferation and migration.

Abstract: The therapeutic potential of blocking MDSC in tumors has been limited by their heterogeneity, plasticity, and resistance to various chemotherapy agents.

Abstract: Recent studies have highlighted the role of energy metabolic pathways in the differentiation and function of immune cells; however, the metabolic characteristics regulating MDSC remain unclear.

Abstract: We aimed to determine the energy metabolic pathway(s) used by MDSC, establish its impact on their immunosuppressive function, and test whether its inhibition blocks MDSC and enhances antitumor therapies.

Abstract: Using several murine tumor models, we found that tumor-infiltrating MDSC (T-MDSC) increased fatty acid uptake and activated fatty acid oxidation (FAO).

Abstract: This was accompanied by an increased mitochondrial mass, upregulation of key FAO enzymes, and increased oxygen consumption rate.

Abstract: Pharmacologic inhibition of FAO blocked immune inhibitory pathways and functions in T-MDSC and decreased their production of inhibitory cytokines.

Abstract: FAO inhibition alone significantly delayed tumor growth in a T-cell-dependent manner and enhanced the antitumor effect of adoptive T-cell therapy.

Abstract: Furthermore, FAO inhibition combined with low-dose chemotherapy completely inhibited T-MDSC immunosuppressive effects and induced a significant antitumor effect.

Abstract: Interestingly, a similar increase in fatty acid uptake and expression of FAO-related enzymes was found in human MDSC in peripheral blood and tumors.

Abstract: These results support the possibility of testing FAO inhibition as a novel approach to block MDSC and enhance various cancer therapies.


Predicting mortality of patients hospitalized for acutely exacerbated chronic obstructive pulmonary disease.

Abstract: PURPOSE To identify factors affecting the short-term prognosis of patients with acutely exacerbated chronic obstructive pulmonary disease (COPD).

Abstract: PATIENTS AND METHODS The 590 patients having COPD as primary disease who were hospitalized in the pneumology unit of a university hospital from 1981 to 1990 were studied.

Abstract: A standardized protocol for the treatment of acutely exacerbated COPD was adopted for all the patients.

Abstract: The patient records were retrospectively analyzed by two observers, and 23 clinical and laboratory variables defining the patient status on admission were collected.

Abstract: Age and arterial gas data were also taken into account, and the outcome mortality was recorded.

Abstract: Interobserver reproducibility was tested by computing the kappa coefficient and Spearman's rho for dichotomous and continuous variables, respectively.

Abstract: The relationship of clinical and laboratory factors to the outcome was assessed first by univariate analysis and then by a logistic regression analysis assessing the independent predictive role of variables previously shown to be univariately correlated with mortality.

Abstract: RESULTS The mortality rate was 14.4%.

Abstract: The logistic regression analysis identified four independent predictors of death: age (odds ratio [OR] 1.07; 95% confidence interval [CI] 1.04 to 1.11), alveolar-arterial oxygen gradient greater than 41 mm Hg (OR 2.33; 95% CI 1.39 to 3.90), ventricular arrhythmias (OR 1.91; 95% CI 1.10 to 3.31), and atrial fibrillation (OR 2.27; 95% CI 1.14 to 4.51).

Abstract: CONCLUSIONS Patients with acutely exacerbated COPD having a high risk of death can be identified at the time of admission.

Abstract: Variables reflecting heart dysfunction are important determinants of this risk.

Abstract: Among pulmonary function data, only alveolar-arterial oxygen gradient contributes to the predictive model.


Clathrin is required for the function of the mitotic spindle

Abstract: Clathrin has an established function in the generation of vesicles that transfer membrane and proteins around the cell.

Abstract: The formation of clathrin-coated vesicles occurs continuously in non-dividing cells, but is shut down during mitosis, when clathrin concentrates at the spindle apparatus.

Abstract: Here, we show that clathrin stabilizes fibres of the mitotic spindle to aid congression of chromosomes.

Abstract: Clathrin bound to the spindle directly by the amino-terminal domain of clathrin heavy chain.

Abstract: Depletion of clathrin heavy chain using RNA interference prolonged mitosis; kinetochore fibres were destabilized, leading to defective congression of chromosomes to the metaphase plate and persistent activation of the spindle checkpoint.

Abstract: Normal mitosis was rescued by clathrin triskelia but not the N-terminal domain of clathrin heavy chain, indicating that stabilization of kinetochore fibres was dependent on the unique structure of clathrin.

Abstract: The importance of clathrin for normal mitosis may be relevant to understanding human cancers that involve gene fusions of clathrin heavy chain.


The origin and neuronal function of in vivo nonsynaptic glutamate.

Abstract: Basal extracellular glutamate sampled in vivo is present in micromolar concentrations in the extracellular space outside the synaptic cleft, and neither the origin nor the function of this glutamate is known.

Abstract: This report reveals that blockade of glutamate release from the cystine-glutamate antiporter produced a significant decrease (60%) in extrasynaptic glutamate levels in the rat striatum, whereas blockade of voltage-dependent Na+ and Ca2+ channels produced relatively minimal changes (0-30%).

Abstract: This indicates that the primary origin of in vivo extrasynaptic glutamate in the striatum arises from nonvesicular glutamate release by the cystine-glutamate antiporter.

Abstract: By measuring [35S]cystine uptake, it was shown that similar to vesicular release, the activity of the cystine-glutamate antiporter is negatively regulated by group II metabotropic glutamate receptors (mGluR2/3) via a cAMP-dependent protein kinase mechanism.

Abstract: Extracellular glutamate derived from the antiporter was shown to regulate extracellular levels of glutamate and dopamine.

Abstract: Infusion of the mGluR2/3 antagonist (RS)-1-amino-5-phosphonoindan-1-carboxylic acid (APICA) increased extracellular glutamate levels, and previous blockade of the antiporter prevented the APICA-induced rise in extracellular glutamate.

Abstract: This suggests that glutamate released from the antiporter is a source of endogenous tone on mGluR2/3.

Abstract: Blockade of the antiporter also produced an increase in extracellular dopamine that was reversed by infusing the mGluR2/3 agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxlylate, indicating that antiporter-derived glutamate can modulate dopamine transmission via mGluR2/3 heteroreceptors.

Abstract: These results suggest that nonvesicular release from the cystine-glutamate antiporter is the primary source of in vivo extracellular glutamate and that this glutamate can modulate both glutamate and dopamine transmission.


Disease-associated functions of IL-33: the new kid in the IL-1 family

Abstract: Interleukin-33 (IL-33), a newly described member of the IL-1 family, is expressed by many cell types following pro-inflammatory stimulation and is thought to be released on cell lysis.

Abstract: The IL-33 receptor, consisting of ST2 and IL-1 receptor accessory protein, is also widely expressed, particularly by T helper 2 (TH2) cells and mast cells.

Abstract: IL-33 is host-protective against helminth infection and reduces atherosclerosis by promoting TH2-type immune responses.

Abstract: However, IL-33 can also promote the pathogenesis of asthma by expanding TH2 cells and mediate joint inflammation, atopic dermatitis and anaphylaxis by mast cell activation.

Abstract: Thus IL-33 could be a new target for therapeutic intervention across a range of diseases.


Interferon alpha therapy for hepatitis C: treatment completion and response rates among patients with substance use disorders

Abstract: BackgroundIndividuals with substance use disorders (SUDs) are at increased risk for hepatitis C viral infection (HCV), and few studies have explored their treatment responses empirically.

Abstract: The objective of this study was to assess interferon alpha therapy (IFN) completion and response rates among patients with HCV who had a history of comorbid SUDs.

Abstract: More data is needed to inform treatment strategies and guidelines for these patients.

Abstract: Using a medical record database, information was retrospectively collected on 307,437 veterans seen in the Veterans Integrated Service Network 20 (VISN 20) of the Veterans Healthcare Administration (VHA) between 1998 and 2003.

Abstract: For patients treated with any type of IFN (including regular or pegylated IFN) or combination therapy (IFN and ribavirin) who had a known HCV genotype, IFN completion and response rates were compared among patients with a history of SUD (SUD+ Group) and patients without a history of SUD (SUD- Group).ResultsOdds ratio analyses revealed that compared with the SUD- Group, the SUD+ Group was equally likely to complete IFN therapy if they had genotypes 2 and 3 (73.1% vs. 68.0%), and if they had genotypes 1 and 4 (39.5% vs. 39.9%).

Abstract: Within the sample of all patients who began IFN therapy, the SUD- and SUD+ groups were similarly likely to achieve an end of treatment response (genotypes 2 and 3, 52.8% vs. 54.3%; genotypes 1 and 4, 24.5% vs. 24.8%) and a sustained viral response (genotypes 2 and 3, 42.6% vs. 41.1%; genotypes 1 and 4: 16.0% vs. 22.3%).ConclusionIndividuals with and without a history of SUD responded to antiviral therapy for HCV at similar rates.

Abstract: Collectively, these findings suggest that patients who have co-morbid SUD and HCV diagnoses can successfully complete a course of antiviral therapy.


Association between infection with Helicobacter pylori and risk of gastric cancer: evidence from a prospective investigation.

Abstract: OBJECTIVE To investigate the association between gastric cancer and prior infection with Helicobacter pylori.

Abstract: DESIGN Case-control comparison of prevalence of IgG antibodies to H pylori in blood samples collected prospectively, before diagnosis of gastric cancer in the cases.

Abstract: Presence of H pylori antibody (greater than 10 micrograms IgG/ml) determined by enzyme linked immunosorbent assay (ELISA).

Abstract: SUBJECTS 29 men with a subsequent diagnosis of gastric cancer and 116 aged matched controls selected from over 22,000 middle aged men participating in two ongoing cohort studies (the British United Provident Association study and the Caerphilly collaborative heart disease study), who had provided blood samples during 1975-1982.

Abstract: RESULTS 20 of the 29 cases (69%) and 54 of the 116 controls (47%) were positive for H pylori specific antibody.

Abstract: The median specific IgG concentration was significantly higher in the cases than controls (90 micrograms/ml v 3.6 micrograms/ml, p less than 0.01).

Abstract: The estimated odds ratio for the risk of gastric cancer in those with a history of infection with H pylori was 2.77 (95% confidence interval 1.04 to 7.97, 2p = 0.039).

Abstract: CONCLUSIONS H pylori infection may be an important cause of gastric cancer; between 35% and 55% of all cases may be associated with such an infection.