Integrin activation by Fam38A uses a novel mechanism of R-Ras targeting to the endoplasmic reticulum.

Abstract: The integrin family of heterodimeric cell-surface receptors are fundamental in cell-cell and cell-matrix adhesion.

Abstract: Changes to either integrin-ligand affinity or integrin gene expression are central to a variety of disease processes, including inflammation, cardiovascular disease and cancer.

Abstract: In screening for novel activators of integrin-ligand affinity we identified the previously uncharacterised multi-transmembrane domain protein Fam38A, located at the endoplasmic reticulum (ER).

Abstract: siRNA knockdown of Fam38A in epithelial cells inactivates endogenous beta1 integrin, reducing cell adhesion.

Abstract: Fam38A mediates integrin activation by recruiting the small GTPase R-Ras to the ER, which activates the calcium-activated protease calpain by increasing Ca(2+) release from cytoplasmic stores.

Abstract: Fam38A-induced integrin activation is blocked by inhibition of either R-Ras or calpain activity, or by siRNA knockdown of talin, a well-described calpain substrate.

Abstract: This highlights a novel mechanism for integrin activation by Fam38A, utilising calpain and R-Ras signalling from the ER.

Abstract: These data represent the first description of a novel spatial regulator of R-Ras, of an alternative integrin activation-suppression pathway based on direct relocalisation of R-Ras to the ER, and of a mechanism linking R-Ras and calpain signalling from the ER with modulation of integrin-ligand affinity.


Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors

Abstract: PEROXISOMES are cytoplasmic organelles which are important in mammals in modulation of lipid homeostasis, including the metabolism of long-chain fatty acids and conversion of cholesterol to bile salts (reviewed in refs 1 and 2).

Abstract: Amphipathic carboxylates such as clofibric acid have been used in man as hypolipidaemic agents and in rodents they stimulate the proliferation of peroxisomes.

Abstract: These agents, termed peroxisome proliferators, and all-trans retinoic acid activate genes involved in peroxisomal-mediated β-oxidation of fatty acids1–4.

Abstract: Here we show that the receptor activated by peroxisome proliferators5 and the retinoid X receptor-α (ref.

Abstract: 6) form a heterodimer that activates acyl-CoA oxidase gene expression in response to either clofibric acid or the retinoid X receptor-α ligand, 9-cis retinoic acid, an all-trans retinoic acid metabolite7,8; simultaneous exposure to both activators results in a synergistic induction of gene expression.

Abstract: These data demonstrate the coupling of the peroxisome proliferator and retinoid signalling pathways and provide evidence for a physiological role for 9-cis retinoic acid in modulating lipid metabolism.


The Utilization of Extracellular Proteins as Nutrients Is Suppressed by mTORC1

Abstract: Despite being surrounded by diverse nutrients, mammalian cells preferentially metabolize glucose and free amino acids.

Abstract: Recently, Ras-induced macropinocytosis of extracellular proteins was shown to reduce a transformed cell's dependence on extracellular glutamine.

Abstract: Here, we demonstrate that protein macropinocytosis can also serve as an essential amino acid source.

Abstract: Lysosomal degradation of extracellular proteins can sustain cell survival and induce activation of mTORC1 but fails to elicit significant cell accumulation.

Abstract: Unlike its growth-promoting activity under amino-acid-replete conditions, we discovered that mTORC1 activation suppresses proliferation when cells rely on extracellular proteins as an amino acid source.

Abstract: Inhibiting mTORC1 results in increased catabolism of endocytosed proteins and enhances cell proliferation during nutrient-depleted conditions in vitro and within vascularly compromised tumors in vivo.

Abstract: Thus, by preventing nutritional consumption of extracellular proteins, mTORC1 couples growth to availability of free amino acids.

Abstract: These results may have important implications for the use of mTOR inhibitors as therapeutics.


A general model to explore complex dominance patterns in plant sporophytic self-incompatibility systems.

Abstract: We developed a general model of sporophytic self-incompatibility under negative frequency-dependent selection allowing complex patterns of dominance among alleles.

Abstract: We used this model deterministically to investigate the effects on equilibrium allelic frequencies of the number of dominance classes, the number of alleles per dominance class, the asymmetry in dominance expression between pollen and pistil, and whether selection acts on male fitness only or both on male and on female fitnesses.

Abstract: We show that the so-called "recessive effect" occurs under a wide variety of situations.

Abstract: We found emerging properties of finite population models with several alleles per dominance class such as that higher numbers of alleles are maintained in more dominant classes and that the number of dominance classes can evolve.

Abstract: We also investigated the occurrence of homozygous genotypes and found that substantial proportions of those can occur for the most recessive alleles.

Abstract: We used the model for two species with complex dominance patterns to test whether allelic frequencies in natural populations are in agreement with the distribution predicted by our model.

Abstract: We suggest that the model can be used to test explicitly for additional, allele-specific, selective forces.


Metabolic Reprograming in Macrophage Polarization

Abstract: Studying the metabolism of immune cells in recent years has emphasized the tight link existing between the metabolic state and the phenotype of these cells.

Abstract: Macrophages in particular are a good example of this phenomenon.

Abstract: Whether the macrophage obtains its energy through glycolysis or through oxidative metabolism can give rise to different phenotypes.

Abstract: Classically activated or M1 macrophages are key players of the first line of defense against bacterial infections and are known to obtain energy through glycolysis.

Abstract: Alternatively activated or M2 macrophages on the other hand are involved in tissue repair and wound healing and use oxidative metabolism to fuel their longer-term functions.

Abstract: Metabolic intermediates, however, are not just a source of energy but can be directly implicated in a particular macrophage phenotype.

Abstract: In M1 macrophages, the Krebs cycle intermediate succinate regulates HIF1α, which is responsible for driving the sustained production of the pro-inflammatory cytokine IL1β.

Abstract: In M2 macrophages, the sedoheptulose kinase carbohydrate kinase-like protein is critical for regulating the pentose phosphate pathway.

Abstract: The potential to target these events and impact on disease is an exciting prospect.


Characterization of constitutive CTCF/cohesin loci: a possible role in establishing topological domains in mammalian genomes

Abstract: BACKGROUND Recent studies suggested that human/mammalian genomes are divided into large, discrete domains that are units of chromosome organization.

Abstract: CTCF, a CCCTC binding factor, has a diverse role in genome regulation including transcriptional regulation, chromosome-boundary insulation, DNA replication, and chromatin packaging.

Abstract: It remains unclear whether a subset of CTCF binding sites plays a functional role in establishing/maintaining chromatin topological domains.

Abstract: RESULTS We systematically analysed the genomic, transcriptomic and epigenetic profiles of the CTCF binding sites in 56 human cell lines from ENCODE.

Abstract: We identified ~24,000 CTCF sites (referred to as constitutive sites) that were bound in more than 90% of the cell lines.

Abstract: Our analysis revealed: 1) constitutive CTCF loci were located in constitutive open chromatin and often co-localized with constitutive cohesin loci; 2) most constitutive CTCF loci were distant from transcription start sites and lacked CpG islands but were enriched with the full-spectrum CTCF motifs: a recently reported 33/34-mer and two other potentially novel (22/26-mer); 3) more importantly, most constitutive CTCF loci were present in CTCF-mediated chromatin interactions detected by ChIA-PET and these pair-wise interactions occurred predominantly within, but not between, topological domains identified by Hi-C.   CONCLUSIONS Our results suggest that the constitutive CTCF sites may play a role in organizing/maintaining the recently identified topological domains that are common across most human cells.


Regulation of Bcl-2 expression by HuR in HL60 leukemia cells and A431 carcinoma cells.

Abstract: Overexpression of the proto-oncogene bcl-2 promotes abnormal cell survival by inhibiting apoptosis.

Abstract: Expression of bcl-2 is determined, in part, by regulatory mechanisms that control the stability of bcl-2 mRNA.

Abstract: Elements in the 3'-untranslated region of bcl-2 mRNA have been shown to play a role in regulating the stability of the message.

Abstract: Previously, it was found that the RNA binding proteins nucleolin and Ebp1 have a role in stabilizing bcl-2 mRNA in HL60 cells.

Abstract: Here, we have identified HuR as a component of bcl-2 messenger ribonucleoprotein (mRNP) complexes.

Abstract: RNA coimmunoprecipitation assays showed that HuR binds to bcl-2 mRNA in vivo.

Abstract: We also observed an RNA-dependent coprecipitation of HuR and nucleolin, suggesting that the two proteins are present in common mRNP complexes.

Abstract: Moreover, nucleolin and HuR bind concurrently to bcl-2 AU-rich element (ARE) RNA in vitro, suggesting separate binding sites for these proteins on bcl-2 mRNA.

Abstract: Knockdown of HuR in A431 cells leads to down-regulation of bcl-2 mRNA and protein levels.

Abstract: Observation of a decreased ratio of bcl-2 mRNA to heterogeneous nuclear RNA in HuR knockdown cells confirmed a positive role for HuR in regulating bcl-2 stability.

Abstract: Recombinant HuR retards exosome-mediated decay of bcl-2 ARE RNA in extracts of HL60 cells.

Abstract: This supports a role for HuR in the regulation of bcl-2 mRNA stability in HL60 cells, as well as in A431 cells.

Abstract: Addition of nucleolin and HuR to HL60 cell extracts produced a synergistic protective effect on decay of bcl-2 ARE RNA.

Abstract: HuR knockdown also leads to redistribution of bcl-2 mRNA from polysomes to monosomes.

Abstract: Thus, HuR seems to play a positive role in both regulation of bcl-2 mRNA translation and mRNA stability.


The Worldwide Variation in Avian Clutch Size across Species and Space

Abstract: Traits such as clutch size vary markedly across species and environmental gradients but have usually been investigated from either a comparative or a geographic perspective, respectively.

Abstract: We analyzed the global variation in clutch size across 5,290 bird species, excluding brood parasites and pelagic species.

Abstract: We integrated intrinsic (morphological, behavioural), extrinsic (environmental), and phylogenetic effects in a combined model that predicts up to 68% of the interspecific variation in clutch size.

Abstract: We then applied the same species-level model to predict mean clutch size across 2,521 assemblages worldwide and found that it explains the observed eco-geographic pattern very well.

Abstract: Clutches are consistently largest in cavity nesters and in species occupying seasonal environments, highlighting the importance of offspring and adult mortality that is jointly expressed in intrinsic and extrinsic correlates.

Abstract: The findings offer a conceptual bridge between macroecology and comparative biology and provide a global and integrative understanding of the eco-geographic and cross-species variation in a core life-history trait.


Diastolic heart failure--abnormalities in active relaxation and passive stiffness of the left ventricle.

Abstract: BACKGROUND Patients with signs and symptoms of heart failure and a normal left ventricular ejection fraction are said to have diastolic heart failure.

Abstract: It has traditionally been thought that the pathophysiological cause of heart failure in these patients is an abnormality in the diastolic properties of the left ventricle; however, this hypothesis remains largely unproven.

Abstract: METHODS We prospectively identified 47 patients who met the diagnostic criteria for definite diastolic heart failure; all the patients had signs and symptoms of heart failure, a normal ejection fraction, and an increased left ventricular end-diastolic pressure.

Abstract: Ten patients who had no evidence of cardiovascular disease served as controls.

Abstract: Left ventricular diastolic function was assessed by means of cardiac catheterization and echocardiography.

Abstract: RESULTS The patients with diastolic heart failure had abnormal left ventricular relaxation and increased left ventricular chamber stiffness.

Abstract: The mean (+/-SD) time constant for the isovolumic-pressure decline (tau) was longer in the group with diastolic heart failure than in the control group (59+/-14 msec vs. 35+/-10 msec, P=0.01).

Abstract: The diastolic pressure-volume relation was shifted up and to the left in the patients with diastolic heart failure as compared with the controls.

Abstract: The corrected left ventricular passive-stiffness constant was significantly higher in the group with diastolic heart failure than in the control group (0.03+/-0.01 vs. 0.01+/-0.01, P<0.001).

Abstract: CONCLUSIONS Patients with heart failure and a normal ejection fraction have significant abnormalities in active relaxation and passive stiffness.

Abstract: In these patients, the pathophysiological cause of elevated diastolic pressures and heart failure is abnormal diastolic function.


The lncRNAs PCGEM1 and PRNCR1 are not implicated in castration resistant prostate cancer

Abstract: Long noncoding RNAs (IncRNAs) are increasingly implicated in cancer biology, contributing to essential cancer cell functions such as proliferation, invasion, and metastasis.

Abstract: In prostate cancer, several lncRNAs have been nominated as critical actors in disease pathogenesis.

Abstract: Among these, expression of PCGEM1 and PRNCR1 has been identified as a possible component in disease progression through the coordination of androgen receptor (AR) signaling (Yang et al., Nature 2013, see ref.

Abstract: However, concerns regarding the robustness of these findings have been suggested.

Abstract: Here, we sought to evaluate whether PCGEM1 and PRNCR1 are associated with prostate cancer.

Abstract: Through a comprehensive analysis of RNA-sequencing data (RNA-seq), we find evidence that PCGEM1 but not PRNCR1 is associated with prostate cancer.

Abstract: We employ a large cohort of >230 high-risk prostate cancer patients with long-term outcomes data to show that, in contrast to prior reports, neither gene is associated with poor patient outcomes.

Abstract: We further observe no evidence that PCGEM1 nor PRNCR1 interact with AR, and neither gene is a component of AR signaling.

Abstract: Thus, we conclusively demonstrate that PCGEM1 and PRNCR1 are not prognostic lncRNAs in prostate cancer and we refute suggestions that these lncRNAs interact in AR signaling.


p38MAPK controls expression of multiple cell cycle inhibitors and islet proliferation with advancing age.

Abstract: Aging is a complex organismal process that is controlled by genetic, environmental, and behavioral factors.

Abstract: Accumulating evidence supports a role for different cell cycle inhibitors in mammalian aging.

Abstract: Little is known, however, about the upstream signals that induce their expression.

Abstract: Here, we explore the role of p38MAPK by generating a dominant-negative allele (p38(AF)) in which activating phosphorylation sites Thr180 and Tyr182 are mutated.

Abstract: Heterozygous p38(AF) mice show a marked attenuation of p38-dependent signaling and age-induced expression of multiple cell cycle inhibitors in different organs, including pancreatic islets.

Abstract: As a result, aged p38(AF/+) mice show enhanced proliferation and regeneration of islets when compared to wild-type littermates.

Abstract: We further find an age-related reduction in expression of the p38-specific phosphatase Wip1.

Abstract: Wip1-deficient mice demonstrate decreased islet proliferation, while Wip1 overexpression rescues aging-related decline in proliferation and regenerative capacity.

Abstract: We propose that modulation of p38MAPK activity may provide new avenues for treating certain age-related degenerative diseases.


ACTA PSYCHIATRICA

Abstract: OBJECTIVE We explored the subjective effects associated with olanzapine, risperidone and older antipsychotics.

Abstract: METHOD We conducted a content analysis of an Internet database of comments about prescribed medications.

Abstract: RESULTS We analysed 223 comments on risperidone, 170 on olanzapine and 46 relating to three older antipsychotics.

Abstract: The predominant subjective effects produced by all drugs consisted of sedation, cognitive impairment and emotional flattening or indifference.

Abstract: Connections appeared between these effects and Parkinsonian-like symptoms with the older drugs, sexual impairment with risperidone and metabolic effects with olanzapine.

Abstract: The experience of akathisia was frequently linked to suicidal thoughts.

Abstract: Some respondents described how the drugs' subjective effects helped to reduce symptoms of mania, psychosis and anxiety.

Abstract: CONCLUSION The generalisability of Internet data is uncertain.

Abstract: However, the data suggest that adverse subjective effects play a central role in the experience of taking antipsychotic drugs and may be related to the drugs' desired benefits.


White matter hyperintensities are a core feature of Alzheimer's disease: Evidence from the dominantly inherited Alzheimer network.

Abstract: OBJECTIVE White matter hyperintensities (WMHs) are areas of increased signal on T2-weighted magnetic resonance imaging (MRI) scans that most commonly reflect small vessel cerebrovascular disease.

Abstract: Increased WMH volume is associated with risk and progression of Alzheimer's disease (AD).

Abstract: These observations are typically interpreted as evidence that vascular abnormalities play an additive, independent role contributing to symptom presentation, but not core features of AD.

Abstract: We examined the severity and distribution of WMH in presymptomatic PSEN1, PSEN2, and APP mutation carriers to determine the extent to which WMH manifest in individuals genetically determined to develop AD.

Abstract: METHODS The study comprised participants (n = 299; age = 39.03 ± 10.13) from the Dominantly Inherited Alzheimer Network, including 184 (61.5%) with a mutation that results in AD and 115 (38.5%) first-degree relatives who were noncarrier controls.

Abstract: We calculated the estimated years from expected symptom onset (EYO) by subtracting the affected parent's symptom onset age from the participant's age.

Abstract: Baseline MRI data were analyzed for total and regional WMH.

Abstract: Mixed-effects piece-wise linear regression was used to examine WMH differences between carriers and noncarriers with respect to EYO.

Abstract: RESULTS Mutation carriers had greater total WMH volumes, which appeared to increase approximately 6 years before expected symptom onset.

Abstract: Effects were most prominent for the parietal and occipital lobe, which showed divergent effects as early as 22 years before estimated onset.

Abstract: INTERPRETATION Autosomal-dominant AD is associated with increased WMH well before expected symptom onset.

Abstract: The findings suggest the possibility that WMHs are a core feature of AD, a potential therapeutic target, and a factor that should be integrated into pathogenic models of the disease.

Abstract: Ann Neurol 2016;79:929-939.


Maternal and child undernutrition: consequences for adult health and human capital

Abstract: In this paper we review the associations between maternal and child undernutrition with human capital and risk of adult diseases in low-income and middle-income countries.

Abstract: We analysed data from five long-standing prospective cohort studies from Brazil, Guatemala, India, the Philippines, and South Africa and noted that indices of maternal and child undernutrition (maternal height, birthweight, intrauterine growth restriction, and weight, height, and body-mass index at 2 years according to the new WHO growth standards) were related to adult outcomes (height, schooling, income or assets, offspring birthweight, body-mass index, glucose concentrations, blood pressure).

Abstract: We undertook systematic reviews of studies from low-income and middle-income countries for these outcomes and for indicators related to blood lipids, cardiovascular disease, lung and immune function, cancers, osteoporosis, and mental illness.

Abstract: Undernutrition was strongly associated, both in the review of published work and in new analyses, with shorter adult height, less schooling, reduced economic productivity, and--for women--lower offspring birthweight.

Abstract: Associations with adult disease indicators were not so clear-cut.

Abstract: Increased size at birth and in childhood were positively associated with adult body-mass index and to a lesser extent with blood pressure values, but not with blood glucose concentrations.

Abstract: In our new analyses and in published work, lower birthweight and undernutrition in childhood were risk factors for high glucose concentrations, blood pressure, and harmful lipid profiles once adult body-mass index and height were adjusted for, suggesting that rapid postnatal weight gain--especially after infancy--is linked to these conditions.

Abstract: The review of published works indicates that there is insufficient information about long-term changes in immune function, blood lipids, or osteoporosis indicators.

Abstract: Birthweight is positively associated with lung function and with the incidence of some cancers, and undernutrition could be associated with mental illness.

Abstract: We noted that height-for-age at 2 years was the best predictor of human capital and that undernutrition is associated with lower human capital.

Abstract: We conclude that damage suffered in early life leads to permanent impairment, and might also affect future generations.

Abstract: Its prevention will probably bring about important health, educational, and economic benefits.

Abstract: Chronic diseases are especially common in undernourished children who experience rapid weight gain after infancy.


Ubiquitin-dependent intramembrane rhomboid protease promotes ERAD of membrane proteins.

Abstract: The ER-associated degradation (ERAD) pathway serves as an important cellular safeguard by directing incorrectly folded and unassembled proteins from the ER to the proteasome.

Abstract: Still, however, little is known about the components mediating ERAD of membrane proteins.

Abstract: Here we show that the evolutionary conserved rhomboid family protein RHBDL4 is a ubiquitin-dependent ER-resident intramembrane protease that is upregulated upon ER stress.

Abstract: RHBDL4 cleaves single-spanning and polytopic membrane proteins with unstable transmembrane helices, leading to their degradation by the canonical ERAD machinery.

Abstract: RHBDL4 specifically binds the AAA+-ATPase p97, suggesting that proteolytic processing and dislocation into the cytosol are functionally linked.

Abstract: The phylogenetic relationship between rhomboids and the ERAD factor derlin suggests that substrates for intramembrane proteolysis and protein dislocation are recruited by a shared mechanism.


Detection and function of nitric oxide during the hypersensitive response in Arabidopsis thaliana: where there's a will there's a way.

Abstract: Nitric oxide (NO) was identified as a key player in plant defence responses approximately 20 years ago and a large body of evidence has accumulated since then supporting its role as a signalling molecule.

Abstract: However, there are many discrepancies in current NO detection assays and the enzymatic pathways responsible for its synthesis have yet to be determined.

Abstract: This has provoked strong debates concerning the function of NO in plants, even questioning its existence in planta.

Abstract: Here we gather data obtained using the model pathosystem Arabidopsis/Pseudomonas, which confirms the production of NO during the hypersensitive response and supports is role as a trigger of hypersensitive cell death and a mediator of defence gene expression.

Abstract: Finally, we discuss potential sources of NO synthesis, focusing on the role of nitrite as major substrate for NO production during incompatible interactions.


The Cytosolic Chaperonin CCT/TRiC and Cancer Cell Proliferation

Abstract: The molecular chaperone CCT/TRiC plays a central role in maintaining cellular proteostasis as it mediates the folding of the major cytoskeletal proteins tubulins and actins.

Abstract: CCT/TRiC is also involved in the oncoprotein cyclin E, the Von Hippel-Lindau tumour suppressor protein, cyclin B and p21(ras) folding which strongly suggests that it is involved in cell proliferation and tumor genesis.

Abstract: To assess the involvement of CCT/TRiC in tumor genesis, we quantified its expression levels and activity in 18 cancer, one non-cancer human cell lines and a non-cancer human liver.

Abstract: We show that the expression levels of CCT/TRiC in cancer cell lines are higher than that in normal cells.

Abstract: However, CCT/TRiC activity does not always correlate with its expression levels.

Abstract: We therefore documented the expression levels of CCT/TRiC modulators and partners PhLP3, Hop/P60, prefoldin and Hsc/Hsp70.

Abstract: Our analysis reveals a functional interplay between molecular chaperones that might account for a precise modulation of CCT/TRiC activity in cell proliferation through changes in the cellular levels of prefoldin and/or Hsc/p70 and CCT/TRiC client protein availability.

Abstract: Our observation and approaches bring novel insights in the role of CCT/TRiC-mediated protein folding machinery in cancer cell development.


RBP2 Belongs to a Family of Demethylases, Specific for Tri-and Dimethylated Lysine 4 on Histone 3

Abstract: Methylation of histones has been regarded as a stable modification defining the epigenetic program of the cell, which regulates chromatin structure and transcription.

Abstract: However, the recent discovery of histone demethylases has challenged the stable nature of histone methylation.

Abstract: Here we demonstrate that the JARID1 proteins RBP2, PLU1, and SMCX are histone demethylases specific for di- and trimethylated histone 3 lysine 4 (H3K4).

Abstract: Consistent with a role for the JARID1 Drosophila homolog Lid in regulating expression of homeotic genes during development, we show that RBP2 is displaced from Hox genes during embryonic stem (ES) cell differentiation correlating with an increase of their H3K4me3 levels and expression.

Abstract: Furthermore, we show that mutation or RNAi depletion of the C. elegans JARID1 homolog rbr-2 leads to increased levels of H3K4me3 during larval development and defects in vulva formation.

Abstract: Taken together, these results suggest that H3K4me3/me2 demethylation regulated by the JARID1 family plays an important role during development.


Mitochondria: Dynamic Organelles in Disease, Aging, and Development

Abstract: Mitochondria are the primary energy-generating system in most eukaryotic cells.

Abstract: Additionally, they participate in intermediary metabolism, calcium signaling, and apoptosis.

Abstract: Given these well-established functions, it might be expected that mitochondrial dysfunction would give rise to a simple and predictable set of defects in all tissues.

Abstract: However, mitochondrial dysfunction has pleiotropic effects in multicellular organisms.

Abstract: Clearly, much about the basic biology of mitochondria remains to be understood.

Abstract: Here we discuss recent work that suggests that the dynamics (fusion and fission) of these organelles is important in development and disease.


Persistence of HIV-1 Receptor-Positive Cells after HSV-2 Reactivation: A Potential Mechanism for Increased HIV-1 Acquisition

Abstract: To explore the mechanism by which herpes simplex virus (HSV)-2 infection is related to HIV-1 acquisition, we conducted in situ analysis of the cellular infiltrate from sequential biopsies of HSV-2 lesions from patients on and off antiviral therapy.

Abstract: CD4(+) and CD8(+) T cells and a mixed population of plasmacytoid and myeloid dendritic cells (DCs), including cells expressing the C-type lectin receptor DC-SIGN, persisted at sites of HSV-2 reactivation for months after healing, even with daily antiviral therapy.

Abstract: The CD4(+) T cells that persisted reacted to HSV-2 antigen, were enriched for expression of the chemokine receptor CCR5, and were contiguous to DCs expressing the interleukin-3 receptor CD123 or DC-SIGN.

Abstract: Ex vivo infection with a CCR5-tropic strain of HIV-1 revealed greater concentrations of integrated HIV-1 DNA in cells derived from healed genital lesion biopsies than in cells from control skin biopsies.

Abstract: The persistence and enrichment of HIV receptor-positive inflammatory cells in the genitalia help explain the inability of anti-HSV-2 therapy to reduce HIV acquisition.


Chronic daily headache in Taipei, Taiwan: prevalence, follow-up and outcome predictors.

Abstract: We conducted a two-stage population-based headache survey among subjects aged > or = 15 in Taipei, Taiwan.

Abstract: Subjects with chronic daily headache (CDH) in the past year were identified, interviewed and followed-up.

Abstract: CDH was defined as a headache frequency > 15 days/month, with a duration > 4 h/day.

Abstract: Of the 3377 participants, 108 (3.2%) fulfilled the criteria for CDH, with a higher prevalence in women (4.3%) than men (1.9%).

Abstract: TM was the most common subtype (55%), followed by CTTH (44%).

Abstract: Thirty-four per cent of the CDH subjects overused analgesics.

Abstract: At the 2-year follow-up, 35% of the CDH subjects still had CDH.

Abstract: The significant predictors for persistent CDH at follow-up included: older age ( > or = 40 years) (RR = 2.4), CDH onset after 32 years (RR = 1.8), CDH duration > or = 6 years (RR = 2.0), medication overuse (RR = 1.8), and "daily" headache (RR = 2.1).

Abstract: We found that CDH is not uncommon in the community and its prevalence is similar among different populations.

Abstract: Older subjects and those with medication overuse may have a more protracted course of illness.


In vivo microtubules are copolymers of available beta-tubulin isotypes: localization of each of six vertebrate beta-tubulin isotypes using polyclonal antibodies elicited by synthetic peptide antigens

Abstract: beta-Tubulin is encoded in the genomes of higher animals by a small multigene family comprising approximately seven functional genes.

Abstract: These genes produce a family of closely related, but distinct polypeptide isotypes that are distinguished principally by sequences within the approximately 15 carboxy-terminal amino acid residues.

Abstract: By immunizing rabbits with chemically synthesized peptides corresponding to these variable domain sequences, we have now prepared polyclonal antibodies specific for each of six distinct isotypes.

Abstract: Specificity of each antiserum has been demonstrated unambiguously by antibody binding to bacterially produced, cloned proteins representing each isotype and by the inhibition of such binding by preincubation of each antiserum only with the immunizing peptide and not with heterologous peptides.

Abstract: Protein blotting of known amounts of cloned, isotypically pure polypeptides has permitted accurate quantitative measurement of the amount of each beta-tubulin isotype present in the soluble and polymer forms in various cells, but has not revealed a bias for preferential assembly of any isotype.

Abstract: Localization of each isotype in three different cell types using indirect immunofluorescence has demonstrated that in vivo each class of microtubules distinguishable by light microscopy is assembled as copolymers of all isotypes expressed in a single cell.


Topiramate for smoking cessation: a randomized, placebo-controlled pilot study.

Abstract: INTRODUCTION Topiramate (TOP) blocks glutamate receptors and facilitates GABA (γ-aminobutyric acid) neurotransmission, effects that may facilitate smoking cessation.

Abstract: We compared the effects of behavioral counseling combined with (a) TOP, (b) TOP/nicotine patch (TOP/NIC), or (c) placebo (PLC) for smoking cessation.

Abstract: METHODS We conducted a 10-week randomized trial in which subjects and research personnel were blinded to TOP versus PLC but not to the TOP/NIC patch condition.

Abstract: In groups receiving TOP, the medication dosage was titrated gradually up to 200 mg/day.

Abstract: The smoking quit date (QD) was scheduled after 2 weeks of medication treatment.

Abstract: NIC (21 mg) was started on the QD in subjects randomized to the TOP/NIC condition.

Abstract: The main outcome measure was the end-of-treatment, 4-week continuous abstinence rate (CAR; biochemically confirmed).

Abstract: RESULTS Fifty-seven subjects were randomized to treatment.

Abstract: The 4-week CAR was 1 of 19 (5%) in the PLC group, 5 of 19 (26%) in the TOP group, and 7 of 19 (37%) in the TOP/NIC group (p = .056).

Abstract: Pairwise comparisons showed a difference between TOP/NIC and PLC (p = .042) and a nonsignificant difference between TOP and PLC (p = .18).

Abstract: The PLC group gained 0.37 lb/week, the TOP group lost 0.41 lb/week, and the TOP/NIC group lost 0.07 lb/week (p = .004).

Abstract: Pairwise comparisons showed a difference between TOP and PLC (p < .001) and between TOP/NIC and PLC groups (p = .035).

Abstract: Paresthesia was more frequent in subjects on TOP than PLC (p = .011).

Abstract: CONCLUSIONS TOP, alone or in combination with the NIC, resulted in a numerically higher quit rate than PLC and decreased weight.

Abstract: A larger, PLC-controlled trial is needed to confirm these findings.


Break-induced DNA replication.

Abstract: Recombination-dependent DNA replication, often called break-induced replication (BIR), was initially invoked to explain recombination events in bacteriophage but it has recently been recognized as a fundamentally important mechanism to repair double-strand chromosome breaks in eukaryotes.

Abstract: This mechanism appears to be critically important in the restarting of stalled and broken replication forks and in maintaining the integrity of eroded telomeres.

Abstract: Although BIR helps preserve genome integrity during replication, it also promotes genome instability by the production of loss of heterozygosity and the formation of nonreciprocal translocations, as well as in the generation of complex chromosomal rearrangements.


The state of US health, 1990-2010: burden of diseases, injuries, and risk factors.

Abstract: IMPORTANCE Understanding the major health problems in the United States and how they are changing over time is critical for informing national health policy.

Abstract: OBJECTIVES To measure the burden of diseases, injuries, and leading risk factors in the United States from 1990 to 2010 and to compare these measurements with those of the 34 countries in the Organisation for Economic Co-operation and Development (OECD) countries.

Abstract: DESIGN We used the systematic analysis of descriptive epidemiology of 291 diseases and injuries, 1160 sequelae of these diseases and injuries, and 67 risk factors or clusters of risk factors from 1990 to 2010 for 187 countries developed for the Global Burden of Disease 2010 Study to describe the health status of the United States and to compare US health outcomes with those of 34 OECD countries.

Abstract: Years of life lost due to premature mortality (YLLs) were computed by multiplying the number of deaths at each age by a reference life expectancy at that age.

Abstract: Years lived with disability (YLDs) were calculated by multiplying prevalence (based on systematic reviews) by the disability weight (based on population-based surveys) for each sequela; disability in this study refers to any short- or long-term loss of health.

Abstract: Disability-adjusted life-years (DALYs) were estimated as the sum of YLDs and YLLs.

Abstract: Deaths and DALYs related to risk factors were based on systematic reviews and meta-analyses of exposure data and relative risks for risk-outcome pairs.

Abstract: Healthy life expectancy (HALE) was used to summarize overall population health, accounting for both length of life and levels of ill health experienced at different ages.

Abstract: RESULTS US life expectancy for both sexes combined increased from 75.2 years in 1990 to 78.2 years in 2010; during the same period, HALE increased from 65.8 years to 68.1 years.

Abstract: The diseases and injuries with the largest number of YLLs in 2010 were ischemic heart disease, lung cancer, stroke, chronic obstructive pulmonary disease, and road injury.

Abstract: Age-standardized YLL rates increased for Alzheimer disease, drug use disorders, chronic kidney disease, kidney cancer, and falls.

Abstract: The diseases with the largest number of YLDs in 2010 were low back pain, major depressive disorder, other musculoskeletal disorders, neck pain, and anxiety disorders.

Abstract: As the US population has aged, YLDs have comprised a larger share of DALYs than have YLLs.

Abstract: The leading risk factors related to DALYs were dietary risks, tobacco smoking, high body mass index, high blood pressure, high fasting plasma glucose, physical inactivity, and alcohol use.

Abstract: Among 34 OECD countries between 1990 and 2010, the US rank for the age-standardized death rate changed from 18th to 27th, for the age-standardized YLL rate from 23rd to 28th, for the age-standardized YLD rate from 5th to 6th, for life expectancy at birth from 20th to 27th, and for HALE from 14th to 26th.

Abstract: CONCLUSIONS AND RELEVANCE From 1990 to 2010, the United States made substantial progress in improving health.

Abstract: Life expectancy at birth and HALE increased, all-cause death rates at all ages decreased, and age-specific rates of years lived with disability remained stable.

Abstract: However, morbidity and chronic disability now account for nearly half of the US health burden, and improvements in population health in the United States have not kept pace with advances in population health in other wealthy nations.


Malaria risk perception, knowledge and prophylaxis practices among travellers of African ethnicity living in Paris and visiting their country of origin in sub-Saharan Africa.

Abstract: An observational prospective cohort study assessed malaria risk perception, knowledge and prophylaxis practices among individuals of African ethnicity living in Paris and travelling to their country of origin to visit friends or relatives (VFR).

Abstract: The study compared two groups of VFR who had visited a travel clinic (TC; n=122) or a travel agency (TA; n=69) before departure.

Abstract: Of the 47% of VFR citing malaria as a health concern, 75% knew that malaria is mosquito-borne and that bed nets are an effective preventive measure.

Abstract: Perception of high malaria risk was greater in the TA group (33%) than in the TC group (7%).

Abstract: The availability of a malaria vaccine was mentioned by 35% of VFR, with frequent confusion between yellow fever vaccine and malaria prevention.

Abstract: Twenty-nine percent took adequate chemoprophylaxis with complete adherence, which was higher among the TC group (41%) than the TA group (12%).

Abstract: Effective antivector protection measures used were bed nets (16%), wearing long clothes at night (14%) and air conditioning (8%), with no differences between the study groups except in the use of impregnated bed nets (11% of the TC group and none of the TA group).

Abstract: Media coverage, malaria chemoprophylaxis repayment and cultural adaptation of preventive messages should be improved to reduce the high rate of inadequate malaria prophylaxis in VFR.


Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials

Abstract: BACKGROUND The MTHFR 677C→T polymorphism has been associated with raised homocysteine concentration and increased risk of stroke.

Abstract: A previous overview showed that the effects were greatest in regions with low dietary folate consumption, but differentiation between the effect of folate and small-study bias was difficult.

Abstract: A meta-analysis of randomised trials of homocysteine-lowering interventions showed no reduction in coronary heart disease events or stroke, but the trials were generally set in populations with high folate consumption.

Abstract: We aimed to reduce the effect of small-study bias and investigate whether folate status modifies the association between MTHFR 677C→T and stroke in a genetic analysis and meta-analysis of randomised controlled trials.

Abstract: METHODS We established a collaboration of genetic studies consisting of 237 datasets including 59,995 individuals with data for homocysteine and 20,885 stroke events.

Abstract: We compared the genetic findings with a meta-analysis of 13 randomised trials of homocysteine-lowering treatments and stroke risk (45,549 individuals, 2314 stroke events, 269 transient ischaemic attacks).

Abstract: FINDINGS The effect of the MTHFR 677C→T variant on homocysteine concentration was larger in low folate regions (Asia; difference between individuals with TT versus CC genotype, 3·12 μmol/L, 95% CI 2·23 to 4·01) than in areas with folate fortification (America, Australia, and New Zealand, high; 0·13 μmol/L, -0·85 to 1·11).

Abstract: The odds ratio (OR) for stroke was also higher in Asia (1·68, 95% CI 1·44 to 1·97) than in America, Australia, and New Zealand, high (1·03, 0·84 to 1·25).

Abstract: Most randomised trials took place in regions with high or increasing population folate concentrations.

Abstract: The summary relative risk (RR) of stroke in trials of homocysteine-lowering interventions (0·94, 95% CI 0·85 to 1·04) was similar to that predicted for the same extent of homocysteine reduction in large genetic studies in populations with similar folate status (predicted RR 1·00, 95% CI 0·90 to 1·11).

Abstract: Although the predicted effect of homocysteine reduction from large genetic studies in low folate regions (Asia) was larger (RR 0·78, 95% CI 0·68 to 0·90), no trial has evaluated the effect of lowering of homocysteine on stroke risk exclusively in a low folate region.

Abstract: INTERPRETATION In regions with increasing levels or established policies of population folate supplementation, evidence from genetic studies and randomised trials is concordant in suggesting an absence of benefit from lowering of homocysteine for prevention of stroke.

Abstract: Further large-scale genetic studies of the association between MTHFR 677C→T and stroke in low folate settings are needed to distinguish effect modification by folate from small-study bias.

Abstract: If future randomised trials of homocysteine-lowering interventions for stroke prevention are undertaken, they should take place in regions with low folate consumption.

Abstract: FUNDING Full funding sources listed at end of paper (see Acknowledgments).


Porcine circovirus type 2 DNA influences cytoskeleton rearrangements in plasmacytoid and monocyte-derived dendritic cells.

Abstract: Functional disruption of dendritic cells (DC) is an important strategy for viral pathogens to evade host defences.

Abstract: In this context, porcine circovirus type 2 (PCV2), a single-stranded DNA virus, impairs plasmacytoid DC (pDC) and conventional DC activation by certain viruses or Toll-like receptor (TLR) ligands.

Abstract: This inhibitory capacity is associated with the viral DNA, but the impairment does not affect all signalling cascades; TLR7 ligation by small chemical molecules will still induce interleukin-6 (IL-6) and tumour necrosis factor-α secretion, but not interferon-α or IL-12.

Abstract: In this study, the molecular mechanisms by which silencing occurs were investigated.

Abstract: PP2, a potent inhibitor of the Lyn and Hck kinases, produced a similar profile to the PCV2 DNA interference with cytokine secretion by pDC, efficiently inhibiting cell activation induced through TLR9, but not TLR7, ligation.

Abstract: Confocal microscopy and cytometry analysis strongly suggested that PCV2 DNA impairs actin polymerization and endocytosis in pDC and monocyte-derived DC, respectively.

Abstract: Altogether, this study delineates for the first time particular molecular mechanisms involved in PCV2 interference with DC danger recognition, which may be responsible for the virus-induced immunosuppression observed in infected pigs.


Sympathetic neural and cardiovascular responses during static handgrip exercise in women with a history of hypertensive pregnancy

Abstract: Women with a history of hypertensive pregnancy are at greater risk for future cardiovascular events; however, the mechanisms for this increased risk are unknown.

Abstract: Evidence suggests that an exercise stimulus unmasks latent hypertensive tendencies, identifying individuals at the greatest risk for developing cardiovascular disease.

Abstract: The current study examined the hypothesis that women with a hypertensive pregnancy history exhibit an augmented exercise pressor response.

Abstract: Normotensive women with a history of healthy pregnancy (CON; n = 9) and hypertensive pregnancy (HP+; n = 12) were studied during the mid-luteal phase of the menstrual cycle.

Abstract: Heart rate (HR), systolic and diastolic blood pressure (SBP, DBP), and muscle sympathetic nerve activity (MSNA) were measured during a cold pressor test (CPT), and, following a sufficient period of recovery, during static handgrip to fatigue (SHG) and post-exercise circulatory arrest (PECA).

Abstract: The BP, HR, and MSNA responses to the CPT were similar between groups.

Abstract: The SBP response to SHG and PECA was similar between groups, but DBP and HR were significantly greater in HP+ women (both p < 0.05).

Abstract: MSNA burst frequency, but not burst incidence or total activity, tended to be elevated in HP+ women during the stressor (peak Δ from baseline 31 ± 13 vs. 23 ± 13 bursts/min; p for group = 0.06).

Abstract: Despite no clinical signs of cardiovascular disease or hypertension, women with a history of hypertensive pregnancy display an enhanced cardiovascular reactivity to an exercise stimulus compared to women with a healthy pregnancy history.

Abstract: This response may be indicative of impaired cardiovascular control that precedes the clinical manifestation of hypertension or cardiovascular events.


Exercise and the immune system: regulation, integration, and adaptation.

Abstract: Stress-induced immunological reactions to exercise have stimulated much research into stress immunology and neuroimmunology.

Abstract: It is suggested that exercise can be employed as a model of temporary immunosuppression that occurs after severe physical stress.

Abstract: The exercise-stress model can be easily manipulated experimentally and allows for the study of interactions between the nervous, the endocrine, and the immune systems.

Abstract: This review focuses on mechanisms underlying exercise-induced immune changes such as neuroendocrinological factors including catecholamines, growth hormone, cortisol, beta-endorphin, and sex steroids.

Abstract: The contribution of a metabolic link between skeletal muscles and the lymphoid system is also reviewed.

Abstract: The mechanisms of exercise-associated muscle damage and the initiation of the inflammatory cytokine cascade are discussed.

Abstract: Given that exercise modulates the immune system in healthy individuals, considerations of the clinical ramifications of exercise in the prevention of diseases for which the immune system has a role is of importance.

Abstract: Accordingly, drawing on the experimental, clinical, and epidemiological literature, we address the interactions between exercise and infectious diseases as well as exercise and neoplasia within the context of both aging and nutrition.


Positive feedback between PU.1 and the cell cycle controls myeloid differentiation.

Abstract: Regulatory gene circuits with positive-feedback loops control stem cell differentiation, but several mechanisms can contribute to positive feedback.

Abstract: Here, we dissect feedback mechanisms through which the transcription factor PU.1 controls lymphoid and myeloid differentiation.

Abstract: Quantitative live-cell imaging revealed that developing B cells decrease PU.1 levels by reducing PU.1 transcription, whereas developing macrophages increase PU.1 levels by lengthening their cell cycles, which causes stable PU.1 accumulation.

Abstract: Exogenous PU.1 expression in progenitors increases endogenous PU.1 levels by inducing cell cycle lengthening, implying positive feedback between a regulatory factor and the cell cycle.

Abstract: Mathematical modeling showed that this cell cycle-coupled feedback architecture effectively stabilizes a slow-dividing differentiated state.

Abstract: These results show that cell cycle duration functions as an integral part of a positive autoregulatory circuit to control cell fate.


Peripheral B cell subsets.

Abstract: Our understanding of the origins and the biological functions of different peripheral B cell subsets continues to evolve.

Abstract: Some understanding has been obtained regarding the synergy between BCR-derived signals and other receptors and signaling pathways that drive the development of follicular, marginal zone, and B-1 B cells, but this remains a complex and poorly understood issue.

Abstract: More recent information regarding the origins of B-1 and B-2 B cells, the ability of follicular B cells to mature both in the bone marrow and the spleen, the existence of a definable precursor for MZ B cells, and the ability of follicular B cells to occupy two distinct niches are all highlighted in this review.


Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production.

Abstract: IL-10 gene transcription and IL-10 protein production was assessed in both type 1 (Th1) and type 2 (Th2) CD4+ human T cell clones by polymerase chain reaction and ELISA, respectively.

Abstract: Although Th2 clones apparently showed higher IL-10 mRNA levels, IL-10 mRNA expression was consistently found in Th1 clones, as well.

Abstract: Likewise, measurable IL-10 levels were found in the supernatants of both Th1 and Th2 clones.

Abstract: The effect of human IL-10 (h-IL-10) and viral IL-10 (v-IL-10) on the proliferative response and cytokine production by Th1 and Th2 human clones was also investigated.

Abstract: Addition in culture of h-IL-10 and v-IL-10 significantly reduced the proliferation of both Th1 and Th2 clones in response to the specific Ag and to PHA, but it had no inhibitory effect on the proliferative response of Th1 and Th2 clones to IL-2.

Abstract: h-IL-10 and v-IL-10 also inhibited the Ag-induced production of gamma-interferon (IFN-gamma) by Th1 clones and the production of IL-4 and IL-5 by Th2 clones, whereas they had no effect on the cytokine synthesis by the same clones stimulated with PMA plus anti-CD3 antibody.

Abstract: Preincubation of APC, but not of clonal T blasts, with h-IL-10 resulted in the inhibition of Ag-induced proliferation of both Th1 and Th2 clones, supporting the view that h-IL-10 primarily affects APC.

Abstract: These data demonstrate that, unlike the murine system where IL-10 is a product of Th2 (but not Th1) cells and seems to mainly down-regulate the Th1 response, in the human system, IL-10 is produced by, and down-regulates the function of, both Th1 and Th2 cells.


Evaluating strategies for improving ovarian response of the poor responder undergoing assisted reproductive techniques.

Abstract: OBJECTIVE To assess the efficacy of various controlled ovarian hyperstimulation (COH) regimens in the prior poor-responder patient preparing for assisted reproductive techniques.

Abstract: DESIGN English-language literature review.

Abstract: PATIENT(S) Candidates for assisted reproductive techniques who had been defined as having a prior suboptimal response to standard COH regimens.

Abstract: INTERVENTION(S) A variety of regimes are reviewed, including increased gonadotropin doses, change of gonadotropins, adjunctive growth hormone (GH), luteal phase (long) GnRH agonist (GnRH-a) initiation, early follicular phase (flare) GnRH-a initiation, low-dose luteal phase (ultrashort) GnRH-a initiation, progestin pretreatment, and microdose flare GnRH-a initiation.

Abstract: MAIN OUTCOME MEASURE(S)

Abstract: Maximal serum E(2) levels, follicular development, dose, and duration of gonadotropin therapy, cycle cancellation rates, oocytes retrieved, embryos transferred, and clinical and ongoing pregnancy rates.

Abstract: RESULT(S) A lack of uniformity in definition of the poor responder and of prospective randomized trials make data interpretation somewhat difficult.

Abstract: Of the varied strategies proposed, those that seem to be more uniformly beneficial are microdose GnRH-a flare and late luteal phase initiation of a short course of low-dose GnRH-a discontinued before COH.

Abstract: CONCLUSION(S) No single regimen will benefit all poor responders.

Abstract: General acceptance of uniform definitions and performance of large-scale prospective randomized trials are critical.

Abstract: Development of a reliable precycle screen will allow effective differentiation among normal responders, poor responders, and those who will not conceive with their own oocytes.


Identification and Functional Characterization of N-Terminally Acetylated Proteins in Drosophila melanogaster

Abstract: Protein modifications play a major role for most biological processes in living organisms.

Abstract: Amino-terminal acetylation of proteins is a common modification found throughout the tree of life: the N-terminus of a nascent polypeptide chain becomes co-translationally acetylated, often after the removal of the initiating methionine residue.

Abstract: While the enzymes and protein complexes involved in these processes have been extensively studied, only little is known about the biological function of such N-terminal modification events.

Abstract: To identify common principles of N-terminal acetylation, we analyzed the amino-terminal peptides from proteins extracted from Drosophila Kc167 cells.

Abstract: We detected more than 1,200 mature protein N-termini and could show that N-terminal acetylation occurs in insects with a similar frequency as in humans.

Abstract: As the sole true determinant for N-terminal acetylation we could extract the (X)PX rule that indicates the prevention of acetylation under all circumstances.

Abstract: We could show that this rule can be used to genetically engineer a protein to study the biological relevance of the presence or absence of an acetyl group, thereby generating a generic assay to probe the functional importance of N-terminal acetylation.

Abstract: We applied the assay by expressing mutated proteins as transgenes in cell lines and in flies.

Abstract: Here, we present a straightforward strategy to systematically study the functional relevance of N-terminal acetylations in cells and whole organisms.

Abstract: Since the (X)PX rule seems to be of general validity in lower as well as higher eukaryotes, we propose that it can be used to study the function of N-terminal acetylation in all species.


Bax translocation and mitochondrial fragmentation induced by Helicobacter pylori.

Abstract: BACKGROUND AND AIMS Previous in vitro and in vivo studies have revealed an association between Helicobacter pylori infection and apoptosis in gastric epithelial cells.

Abstract: Although involvement of the Bcl-2 family of proteins as well as cytochrome c release has been demonstrated in H pylori induced cell death, the exact role of the mitochondria during this type of programmed cell death has not been fully elucidated.

Abstract: Therefore, we sought to determine whether or not Bax translocation and mitochondrial fragmentation occur on exposure of gastric epithelial cells to H pylori, resulting in cell death.

Abstract: METHODS Experiments were performed with human gastric adenocarcinoma (AGS) cells, AGS cells transfected with the HPV-E6 gene (which inactivates p53 function), AGS-neo cells (transfected with the backbone construct), mouse embryonic fibroblasts (MEFs), and p19(ARF) null (ARF(-/-)) MEFs.

Abstract: Cells were incubated with a cag positive H pylori strain for up to 24 hours, lysed, and cytoplasmic and mitochondrial membrane fractions were analysed by western blot for Bax translocation.

Abstract: RESULTS Bax translocation was detected in AGS, AGS-neo, and normal MEF cells after exposure to H pylori for three hours, but not in ARF(-/-) MEFs cells.

Abstract: Translocation of Bax after H pylori incubation was also detected in AGS-E6 cells (inactive p53 gene) but to a lesser degree than in AGS-neo cells.

Abstract: In parallel studies, the mitochondrial morphology of living cells infected with H pylori was assessed by confocal microscopy.

Abstract: Mitochondrial fragmentation was detectable after 10 hours of H pylori incubation with AGS cells and after seven hours with MEF cells.

Abstract: In wild-type MEFs, mitochondrial fragmentation was significantly increased in comparison with ARF null MEFs (43% v 10.4%, respectively).

Abstract: Furthermore, mitochondrial depolarisation and caspase-3 activity were initiated within four hours in cells incubated with H pylori, and these events were inhibited by forced expression of Bcl-2.

Abstract: CONCLUSIONS These data suggest that during H pylori induced apoptosis, Bax translocates to the mitochondria which subsequently undergo depolarisation and profound fragmentation.

Abstract: Functional ARF and p53 proteins may play an important role in H pylori induced mitochondrial modification.


Cancer chemoprevention: a rapidly evolving field

Abstract: Cancer chemoprevention involves the chronic administration of a synthetic, natural or biological agent to reduce or delay the occurrence of malignancy.

Abstract: The potential value of this approach has been demonstrated with trials in breast, prostate and colon cancer.

Abstract: The paradigm for developing new chemopreventive agents has changed markedly in the last decade and now involves extensive preclinical mechanistic evaluation of agents before clinical trials are instituted and a focus on defining biomarkers of activity that can be used as early predictors of efficacy.

Abstract: This review will summarise the current status of the field of chemoprevention and highlight potential new developments.


Dengue is still an imported disease in China: a case study in Guangzhou.

Abstract: Dengue virus and its four serotypes (DENV 1-4) infect approximately 390 million people worldwide each year, with most cases in tropical and subtropical regions.

Abstract: Because of repeated introduction of DENV from epidemic regions and suitable weather conditions, many regions have shifted from hypo-endemicity to hyper-endemicity over recent decades.

Abstract: Since the first dengue outbreak in 1978, it is crucial to understand the current situation in China over nearly 40 years.

Abstract: The purpose of the study was to examine whether dengue in China was endemic or not, which is essential for relevant dengue control and prevention strategy implementation in China.

Abstract: The study, combining epidemiological characteristics of dengue from the disease notification system, phylogenetic and phylogeographic analyses, showed that all four serotypes had been detected in Guangzhou, China, which was dominated by DENV 1-2.

Abstract: The Maximum Likelihood tree analytic results showed that the virus detected in Guangzhou localized in different clades, except of virus of 2002 and 2003 clustered together.

Abstract: There existed the mutual introductions between Guangzhou and Southeast Asia.

Abstract: Most of the viruses were imported from Southeast Asia and the sources of outbreaks in Guangzhou mainly originated from Thailand, Indonesia, and the Philippines.

Abstract: The study indicates that dengue in China still remains as an imported disease, with the possibility of localization.


The UNAIDS Estimation and Projection Package: a software package to estimate and project national HIV epidemics.

Abstract: This paper describes the Estimation and Projection Package (EPP) for estimating and projecting HIV prevalence levels in countries with generalised epidemics.

Abstract: The paper gives an overall summary of the software and interface.

Abstract: It describes the process of defining and modelling a national epidemic in terms of locally relevant sub-epidemics and the four epidemiological parameters used to fit a curve to produce the prevalence trends in the epidemic.

Abstract: It also provides an example of using the EPP in a country with a generalised epidemic.

Abstract: The paper discusses the strengths and weaknesses of the software and its envisaged future developments.


Oncolytic adenovirus armed with IL-24 Inhibits the growth of breast cancer in vitro and in vivo

Abstract: BACKGROUND Interleukin-24 (IL-24) is a cytokine that belongs to the IL-10 family.

Abstract: It can selectively induce cancer cell apoptosis which has been utilized as a cancer gene therapy strategy.

Abstract: METHODS A recombinant type five adenovirus containing IL-24 gene (designated CNHK600-IL24) was constructed, whose replication is activated only in tumor cells.

Abstract: The replication of CNHK600-IL24 in breast tumor cells and fibroblasts were assessed by TCID50 and MTT assay; the secretion of IL-24 was measured by ELISA and western blotting.

Abstract: The in vivo anti-tumor effect of CNHK600-IL24 was investigated in nude mice carrying orthotopic or metastatic breast tumor.

Abstract: RESULTS We observed that CNHK600-IL24 could replicate efficiently and resulted in high level IL-24 expression and massive cell death in human breast cancer cell MDA-MB-231 but not in normal fibroblast cell MRC-5.

Abstract: In addition, orthotopic breast tumor growth in the nude mice model was significantly suppressed when CNHK600-IL24 was administered.

Abstract: In the metastatic model generated by tail vein injection, CNHK600-IL24 virotherapy significantly improved survival compared with the same virus expressing EGFP (median survival CNHK600-IL24, 55 days vs. CNHK600-EGFP, 41 day, p < 0.05 Mantal-Cox test).

Abstract: A similar phenomenon was observed in the metastatic model achieved by left ventricular injection as suggested by in vivo luminescence imaging of tumor growth.

Abstract: CONCLUSION The oncolytic adenovirus armed with IL-24, which exhibited enhanced anti-tumor activity and improved survival, is a promising candidate for virotherapy of breast cancer.


Brain stem and cerebellar hyperintense lesions in migraine.

Abstract: BACKGROUND AND PURPOSE Migraineurs are at increased risk of cerebellar infarcts and supratentorial white matter lesions.

Abstract: The prevalence, frequency, and distribution of infratentorial hyperintense lesions in migraine are unknown.

Abstract: METHODS Migraineurs with aura (n=161), without aura (n=134), and controls (n=140) from a population-based sample of adults (30 to 60 years of age) were evaluated with MRI.

Abstract: RESULTS Infratentorial hyperintensities were identified in 13 of 295 (4.4%) migraineurs and in 1 of 140 (0.7%) controls (P=0.04).

Abstract: Twelve cases had hyperintensities, mostly bilaterally, in the dorsal basis pontis.

Abstract: Those with infratentorial hyperintensities also had supratentorial white matter lesions more often.

Abstract: CONCLUSIONS We found an increased prevalence of infratentorial (mostly pontine) hyperintensities in migraineurs from the general population.

Abstract: This extends the knowledge about vulnerable brain regions and type of lesions in migraine brains.

Abstract: A hemodynamic ischemic pathogenesis is likely, but further research is needed.


NDRG1 promotes growth of hepatocellular carcinoma cells by directly interacting with GSK-3β and Nur77 to prevent β-catenin degradation

Abstract: The N-myc downstream regulated gene 1 (NDRG1) is significantly associated with advanced tumor stages and poor survival of hepatocellular carcinoma (HCC), thereby implicating it as a potential target for HCC treatment.

Abstract: We aim to further understand its biological roles in hepatocarcinogenesis, as a means to exploit it for therapeutic purposes.

Abstract: By screening using the ProtoArray® Human Protein Microarrays, we identified glycogen synthase kinase 3β (GSK-3β) and the orphan nuclear receptor (Nur77) as potential interaction partners of NDRG1.

Abstract: These interactions were confirmed in HCC cell lines in vitro by co-immunoprecipitation; and co-localizations of NDRG1 with GSK-3β and Nur77 were observed by immunofluorescence staining.

Abstract: Additionally, high levels of NDRG1 competitively bind to GSK-3β and Nur77 to allow β-catenin to escape degradation, with consequent elevated levels of downstream oncogenic genes.

Abstract: In vivo, we consistently observed that NDRG1 suppression in HCC xenografts decreased β-catenin levels and its downstream target Cyclin D1, with concomitant tumor growth inhibition.

Abstract: Clinically, the over-expression of NDRG1 in HCC patient samples is positively correlated with GSK-3β-9ser (| R | = 0.28, p = 0.01), Nur77 (| R | = 0.42, p < 0.001), and β-catenin (| R |= 0.32, p = 0.003) expressions.

Abstract: In conclusion, we identified GSK-3β and Nur77 as novel interaction partners of NDRG1.

Abstract: These protein-protein interactions regulate the turnover of β-catenin and subsequent downstream signaling mediated by β-catenin in HCC cells, and provides potential targets for future therapeutic interventions.


A tutorial on statistical methods for population association studies

Abstract: Although genetic association studies have been with us for many years, even for the simplest analyses there is little consensus on the most appropriate statistical procedures.

Abstract: Here I give an overview of statistical approaches to population association studies, including preliminary analyses (Hardy–Weinberg equilibrium testing, inference of phase and missing data, and SNP tagging), and single-SNP and multipoint tests for association.

Abstract: My goal is to outline the key methods with a brief discussion of problems (population structure and multiple testing), avenues for solutions and some ongoing developments.


Identification and Characterization of Multiple TRIM Proteins That Inhibit Hepatitis B Virus Transcription

Abstract: Tripartite motif (TRIM) proteins constitute a family of over 100 members that share conserved tripartite motifs and exhibit diverse biological functions.

Abstract: Several TRIM proteins have been shown to restrict viral infections and regulate host cellular innate immune responses.

Abstract: In order to identify TRIM proteins that modulate the infection of hepatitis B virus (HBV), we tested 38 human TRIMs for their effects on HBV gene expression, capsid assembly and DNA synthesis in human hepatoma cells (HepG2).

Abstract: The study revealed that ectopic expression of 8 TRIM proteins in HepG2 cells potently reduced the amounts of secreted HBV surface and e antigens as well as intracellular capsid and capsid DNA.

Abstract: Mechanistic analyses further demonstrated that the 8 TRIMs not only reduced the expression of HBV mRNAs, but also inhibited HBV enhancer I and enhancer II activities.

Abstract: Studies focused on TRIM41 revealed that a HBV DNA segment spanning nucleotide 1638 to nucleotide 1763 was essential for TRIM41-mediated inhibition of HBV enhancer II activity and the inhibitory effect depended on the E3 ubiquitin ligase activity of TRIM41 as well as the integrity of TRIM41 C-terminal domain.

Abstract: Moreover, knockdown of endogenous TRIM41 in a HepG2-derived stable cell line significantly increased the level of HBV preC/C RNA, leading to an increase in viral core protein, capsid and capsid DNA.

Abstract: Our studies have thus identified eight TRIM proteins that are able to inhibit HBV transcription and provided strong evidences suggesting the endogenous role of TRIM41 in regulating HBV transcription in human hepatoma cells.


A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome

Abstract: Rett syndrome (RTT) is an inherited neurodevelopmental disorder of females that occurs once in 10,000–15,000 births.

Abstract: Affected females develop normally for 6–18 months, but then lose voluntary movements, including speech and hand skills.

Abstract: Most RTT patients are heterozygous for mutations in the X-linked gene MECP2 (refs.

Abstract: 3–12), encoding a protein that binds to methylated sites in genomic DNA and facilitates gene silencing.

Abstract: Previous work with Mecp2-null embryonic stem cells indicated that MeCP2 is essential for mouse embryogenesis.

Abstract: Here we generate mice lacking Mecp2 using Cre-loxP technology.

Abstract: Both Mecp2-null mice and mice in which Mecp2 was deleted in brain showed severe neurological symptoms at approximately six weeks of age.

Abstract: Compensation for absence of MeCP2 in other tissues by MeCP1 (refs.

Abstract: 19,20) was not apparent in genetic or biochemical tests.

Abstract: After several months, heterozygous female mice also showed behavioral symptoms.

Abstract: The overlapping delay before symptom onset in humans and mice, despite their profoundly different rates of development, raises the possibility that stability of brain function, not brain development per se, is compromised by the absence of MeCP2.


The p38/MK2-Driven Exchange between Tristetraprolin and HuR Regulates AU–Rich Element–Dependent Translation

Abstract: TNF expression of macrophages is under stringent translational control that depends on the p38 MAPK/MK2 pathway and the AU-rich element (ARE) in the TNF mRNA.

Abstract: Here, we elucidate the molecular mechanism of phosphorylation-regulated translation of TNF.

Abstract: We demonstrate that translation of the TNF-precursor at the ER requires expression of the ARE-binding and -stabilizing factor human antigen R (HuR) together with either activity of the p38 MAPK/MK2 pathway or the absence of the ARE-binding and -destabilizing factor tristetraprolin (TTP).

Abstract: We show that phosphorylation of TTP by MK2 decreases its affinity to the ARE, inhibits its ability to replace HuR, and permits HuR-mediated initiation of translation of TNF mRNA.

Abstract: Since translation of TTP's own mRNA is also regulated by this mechanism, an intrinsic feedback control of the inflammatory response is ensured.

Abstract: The phosphorylation-regulated TTP/HuR exchange at target mRNAs provides a reversible switch between unstable/non-translatable and stable/efficiently translated mRNAs.


miR-205 hinders the malignant interplay between prostate cancer cells and associated fibroblasts.

Abstract: AIMS Tumor microenvironment is a strong determinant for the acquisition of metastatic potential of cancer cells.

Abstract: We have recently demonstrated that cancer-associated fibroblasts (CAFs) elicit a redox-dependent epithelial-mesenchymal transition (EMT) in prostate cancer (PCa) cells, driven by cycloxygenase-2/hypoxia-inducible factor-1 (HIF-1)/nuclear factor-κB pathway and enhancing tumor aggressiveness.

Abstract: Here, we investigated the involvement of microRNAs (miRNAs) in tumor-stroma interplay to identify possible tools to counteract oxidative stress and metastasis dissemination.

Abstract: RESULTS We found that miR-205 is the most downmodulated miRNA in PCa cells upon CAF stimulation, due to direct transcriptional repression by HIF-1, a known redox-sensitive transcription factor.

Abstract: Rescue experiments demonstrated that ectopic miR-205 overexpression in PCa cells counteracts CAF-induced EMT, thus impairing enhancement of cell invasion, acquisition of stem cell traits, tumorigenicity, and metastatic dissemination.

Abstract: In addition, miR-205 blocks tumor-driven activation of surrounding fibroblasts by reducing pro-inflammatory cytokine secretion.

Abstract: INNOVATION Overall, such findings suggest miR-205 as a brake against PCa metastasis by blocking both the afferent and efferent arms of the circuit between tumor cells and associated fibroblasts, thus interrupting the pro-oxidant and pro-inflammatory circuitries engaged by reactive stroma.

Abstract: CONCLUSION The evidence that miR-205 replacement in PCa cells is able not only to prevent but also to revert the oxidative/pro-inflammatory axis leading to EMT induced by CAFs sets the rationale for developing miRNA-based approaches to prevent and treat metastatic disease.


The prevention of type 2 diabetes

Abstract: Type 2 diabetes mellitus (T2DM) affects more than 7% of adults in the US and leads to substantial personal and economic burden.

Abstract: In prediabetic states insulin secretion and action—potential targets of preventive interventions—are impaired.

Abstract: In trials lifestyle modification (i.e. weight loss and exercise) has proven effective in preventing incident T2DM in high-risk groups, although weight loss has the greatest effect.

Abstract: Various medications (e.g. metformin, thiazolidinediones and acarbose) can also prevent or delay T2DM.

Abstract: Whether diabetes-prevention strategies also ultimately prevent the development of diabetic vascular complications is unknown, but cardiovascular risk factors are favorably affected.

Abstract: Preventive strategies that can be implemented in routine clinical settings have been developed and evaluated.

Abstract: Widespread application has, however, been limited by local financial considerations, even though cost-effectiveness might be achieved at the population level.


The transcriptional landscape of the mammalian genome.

Abstract: This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome.

Abstract: We identify the 5' and 3' boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation.

Abstract: There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins.

Abstract: Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed.

Abstract: The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.


The Protein Data Bank

Abstract: The Protein Data Bank [PDB; Berman, Westbrook et al. (2000), Nucleic Acids Res. 28, 235-242; http://www.pdb.org/] is the single worldwide archive of primary structural data of biological macromolecules.

Abstract: Many secondary sources of information are derived from PDB data.

Abstract: It is the starting point for studies in structural bioinformatics.

Abstract: This article describes the goals of the PDB, the systems in place for data deposition and access, how to obtain further information and plans for the future development of the resource.

Abstract: The reader should come away with an understanding of the scope of the PDB and what is provided by the resource.


Cell-State-Specific Metabolic Dependency in Hematopoiesis and Leukemogenesis

Abstract: The balance between oxidative and nonoxidative glucose metabolism is essential for a number of pathophysiological processes.

Abstract: By deleting enzymes that affect aerobic glycolysis with different potencies, we examine how modulating glucose metabolism specifically affects hematopoietic and leukemic cell populations.

Abstract: We find that a deficiency in the M2 pyruvate kinase isoform (PKM2) reduces the levels of metabolic intermediates important for biosynthesis and impairs progenitor function without perturbing hematopoietic stem cells (HSCs), whereas lactate dehydrogenase A (LDHA) deletion significantly inhibits the function of both HSCs and progenitors during hematopoiesis.

Abstract: In contrast, leukemia initiation by transforming alleles putatively affecting either HSCs or progenitors is inhibited in the absence of either PKM2 or LDHA, indicating that the cell-state-specific responses to metabolic manipulation in hematopoiesis do not apply to the setting of leukemia.

Abstract: This finding suggests that fine-tuning the level of glycolysis may be explored therapeutically for treating leukemia while preserving HSC function.


A transition in brain state during propofol-induced unconsciousness.

Abstract: Rhythmic oscillations shape cortical dynamics during active behavior, sleep, and general anesthesia.

Abstract: Cross-frequency phase-amplitude coupling is a prominent feature of cortical oscillations, but its role in organizing conscious and unconscious brain states is poorly understood.

Abstract: Using high-density EEG and intracranial electrocorticography during gradual induction of propofol general anesthesia in humans, we discovered a rapid drug-induced transition between distinct states with opposite phase-amplitude coupling and different cortical source distributions.

Abstract: One state occurs during unconsciousness and may be similar to sleep slow oscillations.

Abstract: A second state occurs at the loss or recovery of consciousness and resembles an enhanced slow cortical potential.

Abstract: These results provide objective electrophysiological landmarks of distinct unconscious brain states, and could be used to help improve EEG-based monitoring for general anesthesia.


Cohesins and condensins orchestrate the 4D dynamics of yeast chromosomes during the cell cycle

Abstract: Duplication and segregation of chromosomes involves dynamic reorganization of their internal structure by conserved architectural proteins, including the structural maintenance of chromosomes (SMC) complexes cohesin and condensin.

Abstract: Despite active investigation of the roles of these factors, a genome-wide view of dynamic chromosome architecture at both small and large scale during cell division is still missing.

Abstract: Here, we report the first comprehensive 4D analysis of the higher-order organization of the Saccharomyces cerevisiae genome throughout the cell cycle and investigate the roles of SMC complexes in controlling structural transitions.

Abstract: During replication, cohesion establishment promotes numerous long-range intra-chromosomal contacts and correlates with the individualization of chromosomes, which culminates at metaphase.

Abstract: In anaphase, mitotic chromosomes are abruptly reorganized depending on mechanical forces exerted by the mitotic spindle.

Abstract: Formation of a condensin-dependent loop bridging the centromere cluster with the rDNA loci suggests that condensin-mediated forces may also directly facilitate segregation.

Abstract: This work therefore comprehensively recapitulates cell cycle-dependent chromosome dynamics in a unicellular eukaryote, but also unveils new features of chromosome structural reorganization during highly conserved stages of cell division.


Genome-wide patterns of divergence and gene flow across a butterfly radiation.

Abstract: The Heliconius butterflies are a diverse recent radiation comprising multiple levels of divergence with ongoing gene flow between species.

Abstract: The recently sequenced genome of Heliconius melpomene allowed us to investigate the genomic evolution of this group using dense RAD marker sequencing.

Abstract: Phylogenetic analysis of 54 individuals robustly supported reciprocal monophyly of H. melpomene and Heliconius cydno and refuted previous phylogenetic hypotheses that H. melpomene may be paraphylectic with respect to H. cydno.

Abstract: Heliconius timareta also formed a monophyletic clade closely related but distinct from H. cydno with Heliconius heurippa falling within this clade.

Abstract: We find evidence for genetic admixture between sympatric populations of the sister clades H. melpomene and H. cydno/timareta, particularly between H. cydno and H. melpomene from Central America and between H. timareta and H. melpomene from the eastern slopes of the Andes.

Abstract: Between races, divergence is primarily explained by isolation by distance and there is no detectable genetic population structure between parapatric races, suggesting that hybrid zones between races are not zones of secondary contact.

Abstract: Our results also support previous findings that colour pattern loci are shared between populations and species with similar colour pattern elements.

Abstract: Furthermore, this pattern is almost unique to these genomic regions, with only a very small number of other loci showing significant similarity between populations and species with similar colour patterns.


Randomized, double-blind study of the safety, tolerability, and efficacy of tafenoquine versus mefloquine for malaria prophylaxis in nonimmune subjects.

Abstract: This study represents the first phase III trial of the safety, tolerability, and effectiveness of tafenoquine for malaria prophylaxis.

Abstract: In a randomized (3:1), double-blinded study, Australian soldiers received weekly malaria prophylaxis with 200 mg tafenoquine (492 subjects) or 250 mg mefloquine (162 subjects) for 6 months on a peacekeeping deployment to East Timor.

Abstract: After returning to Australia, tafenoquine-receiving subjects received a placebo and mefloquine-receiving subjects received 30 mg primaquine daily for 14 days.

Abstract: There were no clinically significant differences between hematological and biochemical parameters of the treatment groups.

Abstract: Treatment-related adverse events for the two groups were similar (tafenoquine, 13.4%; mefloquine, 11.7%).

Abstract: Three subjects on tafenoquine (0.6%) and none on mefloquine discontinued prophylaxis because of possible drug-related adverse events.

Abstract: No diagnoses of malaria occurred for either group during deployment, but 4 cases (0.9%) and 1 case (0.7%) of Plasmodium vivax infection occurred among the tafenoquine and mefloquine groups, respectively, up to 20 weeks after discontinuation of medication.

Abstract: In a subset of subjects recruited for detailed safety assessments, treatment-related mild vortex keratopathy was detected in 93% (69 of 74) of tafenoquine subjects but none of the 21 mefloquine subjects.

Abstract: The vortex keratopathy was not associated with any effect on visual acuity and was fully resolved in all subjects by 1 year.

Abstract: Tafenoquine appears to be safe and well tolerated as malaria prophylaxis.

Abstract: Although the volunteers' precise exposure to malaria could not be proven in this study, tafenoquine appears to be a highly efficacious drug for malaria prophylaxis.


Domain-wide regulation of DNA replication timing during mammalian development

Abstract: Studies of replication timing provide a handle into previously impenetrable higher-order levels of chromosome organization and their plasticity during development.

Abstract: Although mechanisms regulating replication timing are not clear, novel genome-wide studies provide a thorough survey of the extent to which replication timing is regulated during most of the early cell fate transitions in mammals, revealing coordinated changes of a defined set of 400–800 kb chromosomal segments that involve at least half the genome.

Abstract: Furthermore, changes in replication time are linked to changes in sub-nuclear organization and domain-wide transcriptional potential, and tissue-specific replication timing profiles are conserved from mouse to human, suggesting that the program has developmental significance.

Abstract: Hence, these studies have provided a solid foundation for linking megabase level chromosome structure to function, and suggest a central role for replication in domain-level genome organization.


PU.1-mediated upregulation of CSF1R is crucial for leukemia stem cell potential induced by MOZ-TIF2

Abstract: Leukemias and other cancers possess self-renewing stem cells that help to maintain the cancer.

Abstract: Cancer stem cell eradication is thought to be crucial for successful anticancer therapy.

Abstract: Using an acute myeloid leukemia (AML) model induced by the leukemia-associated monocytic leukemia zinc finger (MOZ)-TIF2 fusion protein, we show here that AML can be cured by the ablation of leukemia stem cells.

Abstract: The MOZ fusion proteins MOZ-TIF2 and MOZ-CBP interacted with the transcription factor PU.1 to stimulate the expression of macrophage colony–stimulating factor receptor (CSF1R, also known as M-CSFR, c-FMS or CD115).

Abstract: Studies using PU.1-deficient mice showed that PU.1 is essential for the ability of MOZ-TIF2 to establish and maintain AML stem cells.

Abstract: Cells expressing high amounts of CSF1R (CSF1Rhigh cells), but not those expressing low amounts of CSF1R (CSF1Rlow cells), showed potent leukemia-initiating activity.

Abstract: Using transgenic mice expressing a drug-inducible suicide gene controlled by the CSF1R promoter, we cured AML by ablation of CSF1Rhigh cells.

Abstract: Moreover, induction of AML was suppressed in CSF1R-deficient mice and CSF1R inhibitors slowed the progression of MOZ-TIF2–induced leukemia.

Abstract: Thus, in this subtype of AML, leukemia stem cells are contained within the CSF1Rhigh cell population, and we suggest that targeting of PU.1-mediated upregulation of CSF1R expression might be a useful therapeutic approach.


Pharmacological blockage of fibro/adipogenic progenitor expansion and suppression of regenerative fibrogenesis is associated with impaired skeletal muscle regeneration.

Abstract: Acute skeletal muscle injury triggers an expansion of fibro/adipogenic progenitors (FAPs) and a transient stage of fibrogenesis characterized by extracellular matrix deposition.

Abstract: While the perpetuation of such phase can lead to permanent tissue scarring, the consequences of its suppression remain to be studied.

Abstract: Using a model of acute muscle damage we were able to determine that pharmacological inhibition of FAP expansion by Nilotinib, a tyrosine kinase inhibitor with potent antifibrotic activity, exerts a detrimental effect on myogenesis during regeneration.

Abstract: We found that Nilotinib inhibits the damage-induced expansion of satellite cells in vivo, but it does not affect in vitro proliferation, suggesting a non cell-autonomous effect.

Abstract: Nilotinib impairs regenerative fibrogenesis by preventing the injury-triggered expansion and differentiation of resident CD45(-):CD31(-):α7integrin(-):Sca1(+) mesenchymal FAPs.

Abstract: Our data support the notion that the expansion of FAPs and transient fibrogenesis observed during regeneration play an important trophic role toward tissue-specific stem cells.


Deregulation of Scribble Promotes Mammary Tumorigenesis and Reveals a Role for Cell Polarity in Carcinoma

Abstract: Loss of cell polarity proteins such as Scribble induces neoplasia in Drosophila by promoting uncontrolled proliferation.

Abstract: In mammals, the role that polarity proteins play during tumorigenesis is not well understood.

Abstract: Here, we demonstrate that depletion of Scribble in mammary epithelia disrupts cell polarity, blocks three-dimensional morphogenesis, inhibits apoptosis, and induces dysplasia in vivo that progress to tumors after long latency.

Abstract: Loss of Scribble cooperates with oncogenes such as c-myc to transform epithelial cells and induce tumors in vivo by blocking activation of an apoptosis pathway.

Abstract: Like depletion, mislocalization of Scribble from cell-cell junction was sufficient to promote cell transformation.

Abstract: Interestingly, spontaneous mammary tumors in mice and humans possess both downregulated and mislocalized Scribble.

Abstract: Thus, we demonstrate that scribble inhibits breast cancer formation and that deregulation of polarity pathways promotes dysplastic and neoplastic growth in mammals by disrupting morphogenesis and inhibiting cell death.


The Polymeal: a more natural, safer, and probably tastier (than the Polypill) strategy to reduce cardiovascular disease by more than 75%.

Abstract: OBJECTIVE Although the Polypill concept (proposed in 2003) is promising in terms of benefits for cardiovascular risk management, the potential costs and adverse effects are its main pitfalls.

Abstract: The objective of this study was to identify a tastier and safer alternative to the Polypill: the Polymeal.

Abstract: METHODS Data on the ingredients of the Polymeal were taken from the literature.

Abstract: The evidence based recipe included wine, fish, dark chocolate, fruits, vegetables, garlic, and almonds.

Abstract: Data from the Framingham heart study and the Framingham offspring study were used to build life tables to model the benefits of the Polymeal in the general population from age 50, assuming multiplicative correlations.

Abstract: RESULTS Combining the ingredients of the Polymeal would reduce cardiovascular disease events by 76%.

Abstract: For men, taking the Polymeal daily represented an increase in total life expectancy of 6.6 years, an increase in life expectancy free from cardiovascular disease of 9.0 years, and a decrease in life expectancy with cardiovascular disease of 2.4 years.

Abstract: The corresponding differences for women were 4.8, 8.1, and 3.3 years.

Abstract: CONCLUSION The Polymeal promises to be an effective, non-pharmacological, safe, cheap, and tasty alternative to reduce cardiovascular morbidity and increase life expectancy in the general population.


Islet-Like Clusters Derived from Mesenchymal Stem Cells in Wharton's Jelly of the Human Umbilical Cord for Transplantation to Control Type 1 Diabetes

Abstract: BACKGROUND There is a widespread interest in developing renewable sources of islet-replacement tissue for type I diabetes mellitus.

Abstract: Human mesenchymal cells isolated from the Wharton's jelly of the umbilical cord (HUMSCs), which can be easily obtained and processed compared with embryonic and bone marrow stem cells, possess stem cell properties.

Abstract: HUMSCs may be a valuable source for the generation of islets.

Abstract: METHODOLOGY AND PRINCIPAL FINDINGS HUMSCs were induced to transform into islet-like cell clusters in vitro through stepwise culturing in neuron-conditioned medium.

Abstract: To assess the functional stability of the islet-like cell clusters in vivo, these cell clusters were transplanted into the liver of streptozotocin-induced diabetic rats via laparotomy.

Abstract: Glucose tolerance was measured on week 12 after transplantation accompanied with immunohistochemistry and electron microscopy analysis.

Abstract: These islet-like cell clusters were shown to contain human C-peptide and release human insulin in response to physiological glucose levels.

Abstract: Real-time RT-PCR detected the expressions of insulin and other pancreatic beta-cell-related genes (Pdx1, Hlxb9, Nkx2.2, Nkx6.1, and Glut-2) in these islet-like cell clusters.

Abstract: The hyperglycemia and glucose intolerance in streptozotocin-induced diabetic rats was significantly alleviated after xenotransplantation of islet-like cell clusters, without the use of immunosuppressants.

Abstract: In addition to the existence of islet-like cell clusters in the liver, some special fused liver cells were also found, which characterized by human insulin and nuclei-positive staining and possessing secretory granules.

Abstract: CONCLUSIONS AND SIGNIFICANCE In this study, we successfully differentiate HUMSCs into mature islet-like cell clusters, and these islet-like cell clusters possess insulin-producing ability in vitro and in vivo.

Abstract: HUMSCs in Wharton's Jelly of the umbilical cord seem to be the preferential source of stem cells to convert into insulin-producing cells, because of the large potential donor pool, its rapid availability, no risk of discomfort for the donor, and low risk of rejection.


Use of perioperative hydroxyethyl starch 6% and albumin 5% in elective joint arthroplasty and association with adverse outcomes: a retrospective population based analysis

Abstract: OBJECTIVE To determine whether the perioperative use of hydroxyethyl starch 6% and albumin 5% in elective joint arthroplasties are associated with an increased risk for perioperative complications.

Abstract: DESIGN Retrospective cohort study of population based data between 2006 and 2013.

Abstract: SETTING Data from 510 different hospitals across the United States participating in the Premier Perspective database.

Abstract: PARTICIPANTS 1,051,441 patients undergoing elective total hip and knee arthroplasties.

Abstract: EXPOSURES Perioperative fluid resuscitation with hydroxyethyl starch 6% or albumin 5%, or neither.

Abstract: MAIN OUTCOME MEASURES Acute renal failure and thromboembolic, cardiac, and pulmonary complications.

Abstract: RESULTS Compared with patients who received neither colloid, perioperative fluid resuscitation with hydroxyethyl starch 6% or albumin 5% was associated with an increased risk of acute renal failure (odds ratios 1.23 (95% confidence interval 1.13 to 1.34) and 1.56 (1.36 to 1.78), respectively) and most other complications.

Abstract: A recent decrease in hydroxyethyl starch 6% use was noted, whereas that of albumin 5% increased.

Abstract: CONCLUSIONS Similar to studies in critically ill patients, we showed that use of hydroxyethyl starch 6% was associated with an increased risk of acute renal failure and other complications in the elective perioperative orthopedic setting.

Abstract: This increased risk also applied to albumin 5%.

Abstract: These findings raise questions regarding the widespread use of these colloids in elective joint arthroplasty procedures.


BMAL1 and CLOCK, Two Essential Components of the Circadian Clock, Are Involved in Glucose Homeostasis

Abstract: Circadian timing is generated through a unique series of autoregulatory interactions termed the molecular clock.

Abstract: Behavioral rhythms subject to the molecular clock are well characterized.

Abstract: We demonstrate a role for Bmal1 and Clock in the regulation of glucose homeostasis.

Abstract: Inactivation of the known clock components Bmal1 (Mop3) and Clock suppress the diurnal variation in glucose and triglycerides.

Abstract: Gluconeogenesis is abolished by deletion of Bmal1 and is depressed in Clock mutants, but the counterregulatory response of corticosterone and glucagon to insulin-induced hypoglycaemia is retained.

Abstract: Furthermore, a high-fat diet modulates carbohydrate metabolism by amplifying circadian variation in glucose tolerance and insulin sensitivity, and mutation of Clock restores the chow-fed phenotype.

Abstract: Bmal1 and Clock, genes that function in the core molecular clock, exert profound control over recovery from insulin-induced hypoglycaemia.

Abstract: Furthermore, asynchronous dietary cues may modify glucose homeostasis via their interactions with peripheral molecular clocks.


Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes.

Abstract: The incidence of chronic kidney diseases is increasing worldwide, and these conditions are emerging as a major public health problem.

Abstract: While genetic factors contribute to susceptibility and progression of renal disease, proteinuria has been claimed as an independent predictor of outcome.

Abstract: Reduction of urinary protein levels by various medications and a low-protein diet limits renal function decline in individuals with nondiabetic and diabetic nephropathies to the point that remission of the disease and regression of renal lesions have been observed in experimental animals and even in humans.

Abstract: In animal models, regression of glomerular structural changes is associated with remodeling of the glomerular architecture.

Abstract: Instrumental to this discovery were 3D reconstruction studies of the glomerular capillary tuft, which allowed the quantification of sclerosis volume reduction and capillary regeneration upon treatment.

Abstract: Regeneration of capillary segments might result from the contribution of resident cells, but progenitor cells of renal or extrarenal origin may also have a role.

Abstract: This review describes recent advances in our understanding of the mechanisms and mediators underlying renal tissue repair ultimately responsible for regression of renal injury.