Low drug levels and thrombotic complications in high‐risk atrial fibrillation patients treated with direct oral anticoagulants

Abstract: Essentials Direct oral anticoagulants (DOACs) do not require laboratory monitoring currently.

Abstract: DOAC specific measurements were performed at trough in patients with atrial fibrillation.

Abstract: Patients who developed thromboembolic events showed lower DOAC plasma levels.

Abstract: This study supports the concept of measuring DOAC levels at steady state.

Abstract: SUMMARY Background Direct oral anticoagulants (DOACs) are administered at fixed doses without the need for dose adjustment according to laboratory testing.

Abstract: High interindividual variability in drug blood levels has been shown with all DOACs.

Abstract: To evaluate a possible relationship between DOAC C-trough anticoagulant levels and thromboembolic events, 565 consecutive naive patients with atrial fibrillation (AF) were enrolled in this study performed within the START Laboratory Registry.

Abstract: Methods DOAC-specific measurements (diluted thrombin time or anti-activated factor II calibrated for dabigatran; anti-activated FX calibrated for rivaroxaban or apixaban) at C-trough were performed locally at steady state within 15-25 days after the start of treatment.

Abstract: For each DOAC, the interval of C-trough levels, from the limit of quantification to the highest value, was subdivided into four equal classes, and results were attributed to these classes; the median values of results were also calculated.

Abstract: Thromboembolic complications occurring during 1 year of follow-up were recorded.

Abstract: Results Thromboembolic events (1.8%) occurred in 10 patients who had baseline C-trough levels in the lowest class of drug levels.

Abstract: The incidence of thromboembolic events among patients with DOAC C-trough levels in the lowest level class was 2.4%, and that in the remaining groups was 0%.

Abstract: The patients with thrombotic complications also had a higher mean CHA2 DS2 -VASc score than that of the total patient population: 5.3 (95% confidence interval [CI] 4.3-6.3 versus 3.0 (95% CI 2.9-3.1).

Abstract: Conclusion In this study cohort, thrombotic complications occurred only in DOAC-treated AF patients who had very low C-trough levels, with a relatively high CHA2 DS2 -VASc score.

Abstract: Larger studies are warranted to confirm these preliminary observations.


Consensus guidelines for the detection of immunogenic cell death.

Abstract: Apoptotic cells have long been considered as intrinsically tolerogenic or unable to elicit immune responses specific for dead cell-associated antigens.

Abstract: However, multiple stimuli can trigger a functionally peculiar type of apoptotic demise that does not go unnoticed by the adaptive arm of the immune system, which we named "immunogenic cell death" (ICD).

Abstract: ICD is preceded or accompanied by the emission of a series of immunostimulatory damage-associated molecular patterns (DAMPs) in a precise spatiotemporal configuration.

Abstract: Several anticancer agents that have been successfully employed in the clinic for decades, including various chemotherapeutics and radiotherapy, can elicit ICD.

Abstract: Moreover, defects in the components that underlie the capacity of the immune system to perceive cell death as immunogenic negatively influence disease outcome among cancer patients treated with ICD inducers.

Abstract: Thus, ICD has profound clinical and therapeutic implications.

Abstract: Unfortunately, the gold-standard approach to detect ICD relies on vaccination experiments involving immunocompetent murine models and syngeneic cancer cells, an approach that is incompatible with large screening campaigns.

Abstract: Here, we outline strategies conceived to detect surrogate markers of ICD in vitro and to screen large chemical libraries for putative ICD inducers, based on a high-content, high-throughput platform that we recently developed.

Abstract: Such a platform allows for the detection of multiple DAMPs, like cell surface-exposed calreticulin, extracellular ATP and high mobility group box 1 (HMGB1), and/or the processes that underlie their emission, such as endoplasmic reticulum stress, autophagy and necrotic plasma membrane permeabilization.

Abstract: We surmise that this technology will facilitate the development of next-generation anticancer regimens, which kill malignant cells and simultaneously convert them into a cancer-specific therapeutic vaccine.


Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression.

Abstract: Induction of compensatory mechanisms and ERK reactivation has limited the effectiveness of Raf and MEK inhibitors in RAS-mutant cancers.

Abstract: We determined that direct pharmacologic inhibition of ERK suppressed the growth of a subset of KRAS-mutant pancreatic cancer cell lines and that concurrent phosphatidylinositol 3-kinase (PI3K) inhibition caused synergistic cell death.

Abstract: Additional combinations that enhanced ERK inhibitor action were also identified.

Abstract: Unexpectedly, long-term treatment of sensitive cell lines caused senescence, mediated in part by MYC degradation and p16 reactivation.

Abstract: Enhanced basal PI3K-AKT-mTOR signaling was associated with de novo resistance to ERK inhibitor, as were other protein kinases identified by kinome-wide siRNA screening and a genetic gain-of-function screen.

Abstract: Our findings reveal distinct consequences of inhibiting this kinase cascade at the level of ERK.


TRF2 Recruits RTEL1 to Telomeres in S Phase to Promote T-Loop Unwinding

Abstract: The helicase RTEL1 promotes t-loop unwinding and suppresses telomere fragility to maintain the integrity of vertebrate telomeres.

Abstract: An interaction between RTEL1 and PCNA is important to prevent telomere fragility, but how RTEL1 engages with the telomere to promote t-loop unwinding is unclear.

Abstract: Here, we establish that the shelterin protein TRF2 recruits RTEL1 to telomeres in S phase, which is required to prevent catastrophic t-loop processing by structure-specific nucleases.

Abstract: We show that the TRF2-RTEL1 interaction is mediated by a metal-coordinating C4C4 motif in RTEL1, which is compromised by the Hoyeraal-Hreidarsson syndrome (HHS) mutation, RTEL1(R1264H).

Abstract: Conversely, we define a TRF2(I124D) substitution mutation within the TRFH domain of TRF2, which eliminates RTEL1 binding and phenocopies the RTEL1(R1264H) mutation, giving rise to aberrant t-loop excision, telomere length heterogeneity, and loss of the telomere as a circle.

Abstract: These results implicate TRF2 in the recruitment of RTEL1 to facilitate t-loop disassembly at telomeres in S phase.


Macrophages Facilitate Electrical Conduction in the Heart

Abstract: Organ-specific functions of tissue-resident macrophages in the steady-state heart are unknown.

Abstract: Here, we show that cardiac macrophages facilitate electrical conduction through the distal atrioventricular node, where conducting cells densely intersperse with elongated macrophages expressing connexin 43.

Abstract: When coupled to spontaneously beating cardiomyocytes via connexin-43-containing gap junctions, cardiac macrophages have a negative resting membrane potential and depolarize in synchrony with cardiomyocytes.

Abstract: Conversely, macrophages render the resting membrane potential of cardiomyocytes more positive and, according to computational modeling, accelerate their repolarization.

Abstract: Photostimulation of channelrhodopsin-2-expressing macrophages improves atrioventricular conduction, whereas conditional deletion of connexin 43 in macrophages and congenital lack of macrophages delay atrioventricular conduction.

Abstract: In the Cd11bDTR mouse, macrophage ablation induces progressive atrioventricular block.

Abstract: These observations implicate macrophages in normal and aberrant cardiac conduction.


A Tunable Diffusion‐Consumption Mechanism of Cytokine Propagation Enables Plasticity in Cell‐to‐Cell Communication in the Immune System

Abstract: &NA; Immune cells communicate by exchanging cytokines to achieve a context‐appropriate response, but the distances over which such communication happens are not known.

Abstract: Here, we used theoretical considerations and experimental models of immune responses in vitro and in vivo to quantify the spatial extent of cytokine communications in dense tissues.

Abstract: We established that competition between cytokine diffusion and consumption generated spatial niches of high cytokine concentrations with sharp boundaries.

Abstract: The size of these self‐assembled niches scaled with the density of cytokine‐consuming cells, a parameter that gets tuned during immune responses.

Abstract: In vivo, we measured interactions on length scales of 80–120 &mgr;m, which resulted in a high degree of cell‐to‐cell variance in cytokine exposure.

Abstract: Such heterogeneous distributions of cytokines were a source of non‐genetic cell‐to‐cell variability that is often overlooked in single‐cell studies.

Abstract: Our findings thus provide a basis for understanding variability in the patterning of immune responses by diffusible factors.

Abstract: Graphical Abstract Figure.

Abstract: No caption available.

Abstract: HighlightsCytokine penetration in tissues is governed by a diffusion‐consumption mechanismSpherical cytokine niches are generated around cytokine‐producing cellsThe characteristic niche size depends on the density of cytokine consumersCytokine niches are a source of variability in otherwise identical cells &NA; Cytokine‐mediated communication allows immune cells to achieve a context‐appropriate response, but the distance over which this communication happens is unclear.

Abstract: Oyler‐Yaniv et al. (2017) show that a simple diffusion‐consumption mechanism quantitatively describes the spatial spread of cytokines in vivo and results in localized niches of high cytokine concentrations that contribute to cell‐to‐cell variability.


Cardiac neural crest contributes to cardiomyogenesis in zebrafish.

Abstract: In birds and mammals, cardiac neural crest is essential for heart development and contributes to conotruncal cushion formation and outflow tract septation.

Abstract: The zebrafish prototypical heart lacks outflow tract septation, raising the question of whether cardiac neural crest exists in zebrafish.

Abstract: Here, results from three distinct lineage-labeling approaches identify zebrafish cardiac neural crest cells and indicate that these cells have the ability to generate MF20-positive muscle cells in the myocardium of the major chambers during development.

Abstract: Fate-mapping demonstrates that cardiac neural crest cells originate both from neural tube regions analogous to those found in birds, as well as from a novel region rostral to the otic vesicle.

Abstract: In contrast to other vertebrates, cardiac neural crest invades the myocardium in all segments of the heart, including outflow tract, atrium, atrioventricular junction, and ventricle in zebrafish.

Abstract: Three distinct groups of premigratory neural crest along the rostrocaudal axis have different propensities to contribute to different segments in the heart and are correspondingly marked by unique combinations of gene expression patterns.

Abstract: Zebrafish will serve as a model for understanding interactions between cardiac neural crest and cardiovascular development.


Sodium Hydroxide Production from Seawater Desalination Brine: Process Design and Energy Efficiency.

Abstract: The ability to increase pH is a crucial need for desalination pretreatment (especially in reverse osmosis) and for other industries, but processes used to raise pH often incur significant emissions and nonrenewable resource use.

Abstract: Alternatively, waste brine from desalination can be used to create sodium hydroxide, via appropriate concentration and purification pretreatment steps, for input into the chlor-alkali process.

Abstract: In this work, an efficient process train (with variations) is developed and modeled for sodium hydroxide production from seawater desalination brine using membrane chlor-alkali electrolysis.

Abstract: The integrated system includes nanofiltration, concentration via evaporation or mechanical vapor compression, chemical softening, further ion-exchange softening, dechlorination, and membrane electrolysis.

Abstract: System productivity, component performance, and energy consumption of the NaOH production process are highlighted, and their dependencies on electrolyzer outlet conditions and brine recirculation are investigated.

Abstract: The analysis of the process also includes assessment of the energy efficiency of major components, estimation of system operating expense and comparison with similar processes.

Abstract: The brine-to-caustic process is shown to be technically feasible while offering several advantages, that is, the reduced environmental impact of desalination through lessened brine discharge, and the increase in the overall water recovery ratio of the reverse osmosis facility.

Abstract: Additionally, best-use conditions are given for producing caustic not only for use within the plant, but also in excess amounts for potential revenue.


High-Throughput Genetic Screens Identify a Large and Diverse Collection of New Sporulation Genes in Bacillus subtilis

Abstract: The differentiation of the bacterium Bacillus subtilis into a dormant spore is among the most well-characterized developmental pathways in biology.

Abstract: Classical genetic screens performed over the past half century identified scores of factors involved in every step of this morphological process.

Abstract: More recently, transcriptional profiling uncovered additional sporulation-induced genes required for successful spore development.

Abstract: Here, we used transposon-sequencing (Tn-seq) to assess whether there were any sporulation genes left to be discovered.

Abstract: Our screen identified 133 out of the 148 genes with known sporulation defects.

Abstract: Surprisingly, we discovered 24 additional genes that had not been previously implicated in spore formation.

Abstract: To investigate their functions, we used fluorescence microscopy to survey early, middle, and late stages of differentiation of null mutants from the B. subtilis ordered knockout collection.

Abstract: This analysis identified mutants that are delayed in the initiation of sporulation, defective in membrane remodeling, and impaired in spore maturation.

Abstract: Several mutants had novel sporulation phenotypes.

Abstract: We performed in-depth characterization of two new factors that participate in cell-cell signaling pathways during sporulation.

Abstract: One (SpoIIT) functions in the activation of σE in the mother cell; the other (SpoIIIL) is required for σG activity in the forespore.

Abstract: Our analysis also revealed that as many as 36 sporulation-induced genes with no previously reported mutant phenotypes are required for timely spore maturation.

Abstract: Finally, we discovered a large set of transposon insertions that trigger premature initiation of sporulation.

Abstract: Our results highlight the power of Tn-seq for the discovery of new genes and novel pathways in sporulation and, combined with the recently completed null mutant collection, open the door for similar screens in other, less well-characterized processes.


Psychobiological mechanisms underlying the social buffering of the hypothalamic-pituitary-adrenocortical axis: a review of animal models and human studies across development.

Abstract: Discovering the stress-buffering effects of social relationships has been one of the major findings in psychobiology in the last century.

Abstract: However, an understanding of the underlying neurobiological and psychological mechanisms of this buffering is only beginning to emerge.

Abstract: An important avenue of this research concerns the neurocircuitry that can regulate the activity of the hypothalamic-pituitary-adrenocortical (HPA) axis.

Abstract: The present review is a translational effort aimed at integrating animal models and human studies of the social regulation of the HPA axis from infancy to adulthood, specifically focusing on the process that has been named social buffering.

Abstract: This process has been noted across species and consists of a dampened HPA axis stress response to threat or challenge that occurs with the presence or assistance of a conspecific.

Abstract: We describe aspects of the relevant underlying neurobiology when enough information exists and expose major gaps in our understanding across all domains of the literatures we aimed to integrate.

Abstract: We provide a working conceptual model focused on the role of oxytocinergic systems and prefrontal neural networks as 2 of the putative biological mediators of this process, and propose that the role of early experiences is critical in shaping later social buffering effects.

Abstract: This synthesis points to both general future directions and specific experiments that need to be conducted to build a more comprehensive model of the HPA social buffering effect across the life span that incorporates multiple levels of analysis: neuroendocrine, behavioral, and social.


Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development

Abstract: Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months.

Abstract: PDAC has been linked with obesity and glucose intolerance, but whether changes in circulating metabolites are associated with early cancer progression is unknown.

Abstract: To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from individuals with pancreatic cancer (cases) and matched controls from four prospective cohort studies.

Abstract: We find that elevated plasma levels of branched-chain amino acids (BCAAs) are associated with a greater than twofold increased risk of future pancreatic cancer diagnosis.

Abstract: This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years before diagnosis, when occult disease is probably present.

Abstract: We show that plasma BCAAs are also elevated in mice with early-stage pancreatic cancers driven by mutant Kras expression but not in mice with Kras-driven tumors in other tissues, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early-stage disease.

Abstract: Together, these findings suggest that increased whole-body protein breakdown is an early event in development of PDAC.


Effective Use of PI3K and MEK Inhibitors to Treat Mutant K-Ras G12D and PIK3CA H1047R Murine Lung Cancers

Abstract: Somatic mutations that activate phosphoinositide 3-kinase (PI3K) have been identified in the p110-alpha catalytic subunit (encoded by PIK3CA).

Abstract: They are most frequently observed in two hotspots: the helical domain (E545K and E542K) and the kinase domain (H1047R).

Abstract: Although the p110-alpha mutants are transforming in vitro, their oncogenic potential has not been assessed in genetically engineered mouse models.

Abstract: Furthermore, clinical trials with PI3K inhibitors have recently been initiated, and it is unknown if their efficacy will be restricted to specific, genetically defined malignancies.

Abstract: In this study, we engineered a mouse model of lung adenocarcinomas initiated and maintained by expression of p110-alpha H1047R.

Abstract: Treatment of these tumors with NVP-BEZ235, a dual pan-PI3K and mammalian target of rapamycin (mTOR) inhibitor in clinical development, led to marked tumor regression as shown by positron emission tomography-computed tomography, magnetic resonance imaging and microscopic examination.

Abstract: In contrast, mouse lung cancers driven by mutant Kras did not substantially respond to single-agent NVP-BEZ235.

Abstract: However, when NVP-BEZ235 was combined with a mitogen-activated protein kinase kinase (MEK) inhibitor, ARRY-142886, there was marked synergy in shrinking these Kras-mutant cancers.

Abstract: These in vivo studies suggest that inhibitors of the PI3K-mTOR pathway may be active in cancers with PIK3CA mutations and, when combined with MEK inhibitors, may effectively treat KRAS mutated lung cancers.


Transdifferentiation of glioblastoma cells into vascular endothelial cells.

Abstract: Glioblastoma (GBM) is the most malignant brain tumor and is highly resistant to intensive combination therapies and anti-VEGF therapies.

Abstract: To assess the resistance mechanism to anti-VEGF therapy, we examined the vessels of GBMs in tumors that were induced by the transduction of p53(+/-) heterozygous mice with lentiviral vectors containing oncogenes and the marker GFP in the hippocampus of GFAP-Cre recombinase (Cre) mice.

Abstract: We were surprised to observe GFP(+) vascular endothelial cells (ECs).

Abstract: Transplantation of mouse GBM cells revealed that the tumor-derived endothelial cells (TDECs) originated from tumor-initiating cells and did not result from cell fusion of ECs and tumor cells.

Abstract: An in vitro differentiation assay suggested that hypoxia is an important factor in the differentiation of tumor cells to ECs and is independent of VEGF.

Abstract: TDEC formation was not only resistant to an anti-VEGF receptor inhibitor in mouse GBMs but it led to an increase in their frequency.

Abstract: A xenograft model of human GBM spheres from clinical specimens and direct clinical samples from patients with GBM also showed the presence of TDECs.

Abstract: We suggest that the TDEC is an important player in the resistance to anti-VEGF therapy, and hence a potential target for GBM therapy.


Ribosomal DNA copy loss and repeat instability in ATRX-mutated cancers

Abstract: ATRX (alpha thalassemia/mental retardation X-linked) complexes with DAXX to deposit histone variant H3.3 into repetitive heterochromatin.

Abstract: Recent genome sequencing studies in cancers have revealed mutations in ATRX and their association with ALT (alternative lengthening of telomeres) activation.

Abstract: Here we report depletion of ATRX in mouse ES cells leads to selective loss in ribosomal RNA gene (rDNA) copy number.

Abstract: Supporting this, ATRX-mutated human ALT-positive tumors also show a substantially lower rDNA copy than ALT-negative tumors.

Abstract: Further investigation shows that the rDNA copy loss and repeat instability are caused by a disruption in H3.3 deposition and thus a failure in heterochromatin formation at rDNA repeats in the absence of ATRX.

Abstract: We also find that ATRX-depleted cells are reduced in ribosomal RNA transcription output and show increased sensitivity to RNA polymerase I (Pol I) transcription inhibitor CX5461.

Abstract: In addition, human ALT-positive cancer cell lines are also more sensitive to CX5461 treatment.

Abstract: Our study provides insights into the contribution of ATRX loss of function to tumorigenesis through the loss of rDNA stability and suggests the therapeutic potential of targeting Pol I transcription in ALT cancers.


Combining indoor residual spraying and insecticide-treated nets for malaria control in Africa: a review of possible outcomes and an outline of suggestions for the future

Abstract: Insecticide-treated nets (ITNs) and indoor residual spraying (IRS) are currently the preferred methods of malaria vector control.

Abstract: In many cases, these methods are used together in the same households, especially to suppress transmission in holoendemic and hyperendemic scenarios.

Abstract: Though widespread, there has been limited evidence suggesting that such co-application confers greater protective benefits than either ITNs or IRS when used alone.

Abstract: Since both methods are insecticide-based and intradomicilliary, this article hypothesises that outcomes of their combination would depend on effects of the candidate active ingredients on mosquitoes that enter or those that attempt to enter houses.

Abstract: It is suggested here that enhanced household level protection can be achieved if the ITNs and IRS have divergent yet complementary properties, e.g. highly deterrent IRS compounds coupled with highly toxic ITNs.

Abstract: To ensure that the problem of insecticide resistance is avoided, the ITNs and IRS products should preferably be of different insecticide classes, e.g. pyrethroid-based nets combined with organophosphate or carbamate based IRS.

Abstract: The overall community benefits would however depend also on other factors such as proportion of people covered by the interventions and the behaviour of vector species.

Abstract: This article concludes by emphasizing the need for basic and operational research, including mathematical modelling to evaluate IRS/ITN combinations in comparison to IRS alone or ITNs alone.


Membrane estrogen receptor-α levels in MCF-7 breast cancer cells predict cAMP and proliferation responses

Abstract: 17β-estradiol (E2) can rapidly induce cAMP production, but the conditions under which these cAMP levels are best measured and the signaling pathways responsible for the consequent proliferative effects on breast cancer cells are not fully understood.

Abstract: To help resolve these issues, we compared cAMP mechanistic responses in MCF-7 cell lines selected for low (mERlow) and high (mERhigh) expression of the membrane form of estrogen receptor (mER)-α, and thus addressed the receptor subform involved in cAMP signaling.

Abstract: MCF-7 cells were immunopanned and subsequently separated by fluorescence activated cell sorting into mERhigh (mER-α-enriched) and mERlow (mER-α-depleted) populations.

Abstract: Unique (compared with previously reported) incubation conditions at 4°C were found to be optimal for demonstrating E2-induced cAMP production.

Abstract: Time-dependent and dose-dependent effects of E2 on cAMP production were determined for both cell subpopulations.

Abstract: The effects of forskolin, 8-CPT cAMP, protein kinase A inhibitor (H-89), and adenylyl cyclase inhibitor (SQ 22,536) on E2-induced cell proliferation were assessed using the crystal violet assay.

Abstract: We demonstrated a rapid and transient cAMP increase after 1 pmol/l E2 stimulation in mERhigh cells; at 4°C these responses were much more reliable and robust than at 37°C (the condition most often used).

Abstract: The loss of cAMP at 37°C was not due to export.

Abstract: 3-Isobutyl-1-methylxanthine (IBMX; 1 mmol/l) only partially preserved cAMP, suggesting that multiple phosphodiesterases modulate its level.

Abstract: The accumulated cAMP was consistently much higher in mERhigh cells than in mERlow cells, implicating mER-α levels in the process.

Abstract: ICI172,780 blocked the E2-induced response and 17α-estradiol did not elicit the response, also suggesting activity through an estrogen receptor.

Abstract: E2 dose-dependent cAMP production, although biphasic in both cell types, was responsive to 50-fold higher E2 concentrations in mERhigh cells.

Abstract: Proliferation of mERlow cells was stimulated over the whole range of E2concentrations, whereas the number of mERhigh cells was greatly decreased at concentrations above 1 nmol/l, suggesting that estrogen over-stimulation can lead to cell death, as has previously been reported, and that mER-α participates.

Abstract: E2-mediated activation of adenylyl cyclase and downstream participation of protein kinase A were shown to be involved in these responses.

Abstract: Rapid mER-α-mediated nongenomic signaling cascades generate cAMP and downstream signaling events, which contribute to the regulation of breast cancer cell number.


The embryonic cell lineage of the nematode Caenorhabditis elegans.

Abstract: The embryonic cell lineage of Caenorhabditis elegans has been traced from zygote to newly hatched larva, with the result that the entire cell lineage of this organism is now known.

Abstract: During embryogenesis 671 cells are generated; in the hermaphrodite 113 of these (in the male 111) undergo programmed death and the remainder either differentiate terminally or become postembryonic blast cells.

Abstract: The embryonic lineage is highly invariant, as are the fates of the cells to which it gives rise.

Abstract: In spite of the fixed relationship between cell ancestry and cell fate, the correlation between them lacks much obvious pattern.

Abstract: Thus, although most neurons arise from the embryonic ectoderm, some are produced by the mesoderm and a few are sisters to muscles; again, lineal boundaries do not necessarily coincide with functional boundaries.

Abstract: Nevertheless, cell ablation experiments (as well as previous cell isolation experiments) demonstrate substantial cell autonomy in at least some sections of embryogenesis.

Abstract: We conclude that the cell lineage itself, complex as it is, plays an important role in determining cell fate.

Abstract: We discuss the origin of the repeat units (partial segments) in the body wall, the generation of the various orders of symmetry, the analysis of the lineage in terms of sublineages, and evolutionary implications.


Self-Reactive B Cells in the Germinal Center Reaction.

Abstract: Maintenance of immunological self-tolerance requires lymphocytes carrying self-reactive antigen receptors to be selectively prevented from mounting destructive or inflammatory effector responses.

Abstract: Classically, self-tolerance is viewed in terms of the removal, editing, or silencing of B and T cells that have formed self-reactive antigen receptors during their early development.

Abstract: However, B cells activated by foreign antigen can enter germinal centers (GCs), where they further modify their antigen receptor by somatic hypermutation (SHM) of their immunoglobulin genes.

Abstract: The inevitable emergence of activated, self-reactive GC B cells presents a unique challenge to the maintenance of self-tolerance that must be rapidly countered to avoid autoantibody production.

Abstract: Here we discuss current knowledge of the mechanisms that enforce B cell self-tolerance, with particular focus on the control of self-reactive GC B cells.

Abstract: We also consider how self-reactive GC B cells can escape self-tolerance to initiate autoantibody production or instead be redeemed via SHM and used in productive antibody responses.


Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases.

Abstract: Human aging is characterized by a chronic, low-grade inflammation, and this phenomenon has been termed as "inflammaging.

Abstract: Inflammaging is a highly significant risk factor for both morbidity and mortality in the elderly people, as most if not all age-related diseases share an inflammatory pathogenesis.

Abstract: Nevertheless, the precise etiology of inflammaging and its potential causal role in contributing to adverse health outcomes remain largely unknown.

Abstract: The identification of pathways that control age-related inflammation across multiple systems is therefore important in order to understand whether treatments that modulate inflammaging may be beneficial in old people.

Abstract: The session on inflammation of the Advances in Gerosciences meeting held at the National Institutes of Health/National Institute on Aging in Bethesda on October 30 and 31, 2013 was aimed at defining these important unanswered questions about inflammaging.

Abstract: This article reports the main outcomes of this session.


Cryptochromes Enabling Plants and Animals to Determine Circadian Time

Abstract: Cryptochromes are flavin-containing blue light photoreceptors related to photolyases-they are found in both plants and animals and have recently been described for bacteria.

Abstract: In plants, cryptochromes perform a variety of functions including the entrainment of circadian rhythms.

Abstract: They serve a similar role in Drosophila and mammals, where the cryptochromes also perform an additional function as an essential component of the circadian clock.


Neural crest-derived stem cells migrate and differentiate into cardiomyocytes after myocardial infarction.

Abstract: OBJECTIVE We recently demonstrated that primitive neural crest-derived (NC) cells migrate from the cardiac neural crest during embryonic development and remain in the heart as dormant stem cells, with the capacity to differentiate into various cell types, including cardiomyocytes.

Abstract: Here, we examined the migration and differentiation potential of these cells on myocardial infarction (MI).

Abstract: METHODS AND RESULTS We obtained double-transgenic mice by crossing protein-0 promoter-Cre mice with Floxed-enhanced green fluorescent protein mice, in which the NC cells express enhanced green fluorescent protein.

Abstract: In the neonatal heart, NC stem cells (NCSCs) were localized predominantly in the outflow tract, but they were also distributed in a gradient from base to apex throughout the ventricular myocardium.

Abstract: Time-lapse video analysis revealed that the NCSCs were migratory.

Abstract: Some NCSCs persisted in the adult heart.

Abstract: On MI, NCSCs accumulated at the ischemic border zone area (BZA), which expresses monocyte chemoattractant protein-1 (MCP-1).

Abstract: Ex vivo cell migration assays demonstrated that MCP-1 induced NCSC migration and that this chemotactic effect was significantly depressed by an anti-MCP-1 antibody.

Abstract: Small NC cardiomyocytes first appeared in the BZA 2 weeks post-MI and gradually increased in number thereafter.

Abstract: CONCLUSIONS These results suggested that NCSCs migrate into the BZA via MCP-1/CCR2 signaling and contribute to the provision of cardiomyocytes for cardiac regeneration after MI.


Mitochondria as sensors and regulators of calcium signalling

Abstract: During the past two decades calcium (Ca2+) accumulation in energized mitochondria has emerged as a biological process of utmost physiological relevance.

Abstract: Mitochondrial Ca2+ uptake was shown to control intracellular Ca2+ signalling, cell metabolism, cell survival and other cell-type specific functions by buffering cytosolic Ca2+ levels and regulating mitochondrial effectors.

Abstract: Recently, the identity of mitochondrial Ca2+ transporters has been revealed, opening new perspectives for investigation and molecular intervention.


Caspase-11 promotes the fusion of phagosomes harboring pathogenic bacteria with lysosomes by modulating actin polymerization.

Abstract: Inflammasomes are multiprotein complexes that include members of the NLR (nucleotide-binding domain leucine-rich repeat containing) family and caspase-1.

Abstract: Once bacterial molecules are sensed within the macrophage, the inflammasome is assembled, mediating the activation of caspase-1.

Abstract: Caspase-11 mediates caspase-1 activation in response to lipopolysaccharide and bacterial toxins, and yet its role during bacterial infection is unknown.

Abstract: Here, we demonstrated that caspase-11 was dispensable for caspase-1 activation in response to Legionella, Salmonella, Francisella, and Listeria.

Abstract: We also determined that active mouse caspase-11 was required for restriction of L. pneumophila infection.

Abstract: Similarly, human caspase-4 and caspase-5, homologs of mouse caspase-11, cooperated to restrict L. pneumophila infection in human macrophages.

Abstract: Caspase-11 promoted the fusion of the L. pneumophila vacuole with lysosomes by modulating actin polymerization through cofilin.

Abstract: However, caspase-11 was dispensable for the fusion of lysosomes with phagosomes containing nonpathogenic bacteria, uncovering a fundamental difference in the trafficking of phagosomes according to their cargo.


Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling.

Abstract: Chronic inflammation constitutes an important link between obesity and its pathophysiological sequelae.

Abstract: In contrast to the belief that inflammatory signals exert a fundamentally negative impact on metabolism, we show that proinflammatory signaling in the adipocyte is in fact required for proper adipose tissue remodeling and expansion.

Abstract: Three mouse models with an adipose tissue-specific reduction in proinflammatory potential were generated that display a reduced capacity for adipogenesis in vivo, while the differentiation potential is unaltered in vitro.

Abstract: Upon high-fat-diet exposure, the expansion of visceral adipose tissue is prominently affected.

Abstract: This is associated with decreased intestinal barrier function, increased hepatic steatosis, and metabolic dysfunction.

Abstract: An impaired local proinflammatory response in the adipocyte leads to increased ectopic lipid accumulation, glucose intolerance, and systemic inflammation.

Abstract: Adipose tissue inflammation is therefore an adaptive response that enables safe storage of excess nutrients and contributes to a visceral depot barrier that effectively filters gut-derived endotoxin.


Chronic variable stress activates hematopoietic stem cells

Abstract: Exposure to psychosocial stress is a risk factor for many diseases, including atherosclerosis.

Abstract: Although incompletely understood, interaction between the psyche and the immune system provides one potential mechanism linking stress and disease inception and progression.

Abstract: Known cross-talk between the brain and immune system includes the hypothalamic-pituitary-adrenal axis, which centrally drives glucocorticoid production in the adrenal cortex, and the sympathetic-adrenal-medullary axis, which controls stress-induced catecholamine release in support of the fight-or-flight reflex.

Abstract: It remains unknown, however, whether chronic stress changes hematopoietic stem cell activity.

Abstract: Here we show that stress increases proliferation of these most primitive hematopoietic progenitors, giving rise to higher levels of disease-promoting inflammatory leukocytes.

Abstract: We found that chronic stress induced monocytosis and neutrophilia in humans.

Abstract: While investigating the source of leukocytosis in mice, we discovered that stress activates upstream hematopoietic stem cells.

Abstract: Under conditions of chronic variable stress in mice, sympathetic nerve fibers released surplus noradrenaline, which signaled bone marrow niche cells to decrease CXCL12 levels through the β3-adrenergic receptor.

Abstract: Consequently, hematopoietic stem cell proliferation was elevated, leading to an increased output of neutrophils and inflammatory monocytes.

Abstract: When atherosclerosis-prone Apoe(-/-) mice were subjected to chronic stress, accelerated hematopoiesis promoted plaque features associated with vulnerable lesions that cause myocardial infarction and stroke in humans.


CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK

Abstract: Ciliary neurotrophic factor (CNTF) induces weight loss and improves glucose tolerance in humans and rodents.

Abstract: CNTF is thought to act centrally by inducing hypothalamic neurogenesis to modulate food intake and peripherally by altering hepatic gene expression, in a manner similar to that of leptin.

Abstract: Here, we show that CNTF signals through the CNTFRα–IL-6R–gp130β receptor complex to increase fatty-acid oxidation and reduce insulin resistance in skeletal muscle by activating AMP-activated protein kinase (AMPK), independent of signaling through the brain.

Abstract: Thus, our findings further show that the antiobesogenic effects of CNTF in the periphery result from direct effects on skeletal muscle, and that these peripheral effects are not suppressed by diet-induced or genetic models of obesity, an essential requirement for the therapeutic treatment of obesity-related diseases.


The Global Spread of Hepatitis C Virus 1a and 1b: A Phylodynamic and Phylogeographic Analysis

Abstract: BACKGROUND Hepatitis C virus (HCV) is estimated to affect 130-180 million people worldwide.

Abstract: Although its origin is unknown, patterns of viral diversity suggest that HCV genotype 1 probably originated from West Africa.

Abstract: Previous attempts to estimate the spatiotemporal parameters of the virus, both globally and regionally, have suggested that epidemic HCV transmission began in 1900 and grew steadily until the late 1980s.

Abstract: However, epidemiological data suggest that the expansion of HCV may have occurred after the Second World War.

Abstract: The aim of our study was to elucidate the timescale and route of the global spread of HCV.

Abstract: METHODS AND FINDINGS We show that the rarely sequenced HCV region (E2P7NS2) is more informative for molecular epidemiology studies than the more commonly used NS5B region.

Abstract: We applied phylodynamic methods to a substantial set of new E2P7NS2 and NS5B sequences, together with all available global HCV sequences with information in both of these genomic regions, in order to estimate the timescale and nature of the global expansion of the most prevalent HCV subtypes, 1a and 1b.

Abstract: We showed that transmission of subtypes 1a and 1b "exploded" between 1940 and 1980, with the spread of 1b preceding that of 1a by at least 16 y (95% confidence interval 15-17).

Abstract: Phylogeographic analysis of all available NS5B sequences suggests that HCV subtypes 1a and 1b disseminated from the developed world to the developing countries.

Abstract: CONCLUSIONS The evolutionary rate of HCV appears faster than previously suggested.

Abstract: The global spread of HCV coincided with the widespread use of transfused blood and blood products and with the expansion of intravenous drug use but slowed prior to the wide implementation of anti-HCV screening.

Abstract: Differences in the transmission routes associated with subtypes 1a and 1b provide an explanation of the relatively earlier expansion of 1b.

Abstract: Our data show that the most plausible route of the HCV dispersal was from developed countries to the developing world.

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


Pharmacological interventions for smoking cessation: an overview and network meta-analysis.

Abstract: BACKGROUND Smoking is the leading preventable cause of illness and premature death worldwide.

Abstract: Some medications have been proven to help people to quit, with three licensed for this purpose in Europe and the USA: nicotine replacement therapy (NRT), bupropion, and varenicline.

Abstract: Cytisine (a treatment pharmacologically similar to varenicline) is also licensed for use in Russia and some of the former socialist economy countries.

Abstract: Other therapies, including nortriptyline, have also been tested for effectiveness.

Abstract: OBJECTIVES How do NRT, bupropion and varenicline compare with placebo and with each other in achieving long-term abstinence (six months or longer)?

Abstract: How do the remaining treatments compare with placebo in achieving long-term abstinence?

Abstract: How do the risks of adverse and serious adverse events (SAEs) compare between the treatments, and are there instances where the harms may outweigh the benefits?

Abstract: METHODS The overview is restricted to Cochrane reviews, all of which include randomised trials.

Abstract: Participants are usually adult smokers, but we exclude reviews of smoking cessation for pregnant women and in particular disease groups or specific settings.

Abstract: We cover nicotine replacement therapy (NRT), antidepressants (bupropion and nortriptyline), nicotine receptor partial agonists (varenicline and cytisine), anxiolytics, selective type 1 cannabinoid receptor antagonists (rimonabant), clonidine, lobeline, dianicline, mecamylamine, Nicobrevin, opioid antagonists, nicotine vaccines, and silver acetate.

Abstract: Our outcome for benefit is continuous or prolonged abstinence at least six months from the start of treatment.

Abstract: Our outcome for harms is the incidence of serious adverse events associated with each of the treatments.

Abstract: We searched the Cochrane Database of Systematic Reviews (CDSR) in The Cochrane Library, for any reviews with 'smoking' in the title, abstract or keyword fields.

Abstract: The last search was conducted in November 2012.

Abstract: We assessed methodological quality using a revised version of the AMSTAR scale.

Abstract: For NRT, bupropion and varenicline we conducted network meta-analyses, comparing each with the others and with placebo for benefit, and varenicline and bupropion for risks of serious adverse events.

Abstract: MAIN RESULTS We identified 12 treatment-specific reviews.

Abstract: The analyses covered 267 studies, involving 101,804 participants.

Abstract: Both NRT and bupropion were superior to placebo (odds ratios (OR) 1.84; 95% credible interval (CredI) 1.71 to 1.99, and 1.82; 95% CredI 1.60 to 2.06 respectively).

Abstract: Varenicline increased the odds of quitting compared with placebo (OR 2.88; 95% CredI 2.40 to 3.47).

Abstract: Head-to-head comparisons between bupropion and NRT showed equal efficacy (OR 0.99; 95% CredI 0.86 to 1.13).

Abstract: Varenicline was superior to single forms of NRT (OR 1.57; 95% CredI 1.29 to 1.91), and to bupropion (OR 1.59; 95% CredI 1.29 to 1.96).

Abstract: Varenicline was more effective than nicotine patch (OR 1.51; 95% CredI 1.22 to 1.87), than nicotine gum (OR 1.72; 95% CredI 1.38 to 2.13), and than 'other' NRT (inhaler, spray, tablets, lozenges; OR 1.42; 95% CredI 1.12 to 1.79), but was not more effective than combination NRT (OR 1.06; 95% CredI 0.75 to 1.48).

Abstract: Combination NRT also outperformed single formulations.

Abstract: The four categories of NRT performed similarly against each other, apart from 'other' NRT, which was marginally more effective than NRT gum (OR 1.21; 95% CredI 1.01 to 1.46).

Abstract: Cytisine (a nicotine receptor partial agonist) returned positive findings (risk ratio (RR) 3.98; 95% CI 2.01 to 7.87), without significant adverse events or SAEs.

Abstract: Across the 82 included and excluded bupropion trials, our estimate of six seizures in the bupropion arms versus none in the placebo arms was lower than the expected rate (1:1000), at about 1:1500.

Abstract: SAE meta-analysis of the bupropion studies demonstrated no excess of neuropsychiatric (RR 0.88; 95% CI 0.31 to 2.50) or cardiovascular events (RR 0.77; 95% CI 0.37 to 1.59).

Abstract: SAE meta-analysis of 14 varenicline trials found no difference between the varenicline and placebo arms (RR 1.06; 95% CI 0.72 to 1.55), and subgroup analyses detected no significant excess of neuropsychiatric events (RR 0.53; 95% CI 0.17 to 1.67), or of cardiac events (RR 1.26; 95% CI 0.62 to 2.56).

Abstract: Nortriptyline increased the chances of quitting (RR 2.03; 95% CI 1.48 to 2.78).

Abstract: Neither nortriptyline nor bupropion were shown to enhance the effect of NRT compared with NRT alone.

Abstract: Clonidine increased the chances of quitting (RR 1.63; 95% CI 1.22 to 2.18), but this was offset by a dose-dependent rise in adverse events.

Abstract: Mecamylamine in combination with NRT may increase the chances of quitting, but the current evidence is inconclusive.

Abstract: Other treatments failed to demonstrate a benefit compared with placebo.

Abstract: Nicotine vaccines are not yet licensed for use as an aid to smoking cessation or relapse prevention.

Abstract: Nicobrevin's UK license is now revoked, and the manufacturers of rimonabant, taranabant and dianicline are no longer supporting the development or testing of these treatments.

Abstract: AUTHORS' CONCLUSIONS NRT, bupropion, varenicline and cytisine have been shown to improve the chances of quitting.

Abstract: Combination NRT and varenicline are equally effective as quitting aids.

Abstract: Nortriptyline also improves the chances of quitting.

Abstract: On current evidence, none of the treatments appear to have an incidence of adverse events that would mitigate their use.

Abstract: Further research is warranted into the safety of varenicline and into cytisine's potential as an effective and affordable treatment, but not into the efficacy and safety of NRT.


A library of yeast transcription factor motifs reveals a widespread function for Rsc3 in targeting nucleosome exclusion at promoters.

Abstract: The sequence specificity of DNA-binding proteins is the primary mechanism by which the cell recognizes genomic features.

Abstract: Here, we describe systematic determination of yeast transcription factor DNA-binding specificities.

Abstract: We obtained binding specificities for 112 DNA-binding proteins representing 19 distinct structural classes.

Abstract: One-third of the binding specificities have not been previously reported.

Abstract: Several binding sequences have striking genomic distributions relative to transcription start sites, supporting their biological relevance and suggesting a role in promoter architecture.

Abstract: Among these are Rsc3 binding sequences, containing the core CGCG, which are found preferentially approximately 100 bp upstream of transcription start sites.

Abstract: Mutation of RSC3 results in a dramatic increase in nucleosome occupancy in hundreds of proximal promoters containing a Rsc3 binding element, but has little impact on promoters lacking Rsc3 binding sequences, indicating that Rsc3 plays a broad role in targeting nucleosome exclusion at yeast promoters.


EphA3 maintains tumorigenicity and is a therapeutic target in glioblastoma multiforme.

Abstract: Significant endeavor has been applied to identify functional therapeutic targets in glioblastoma (GBM) to halt the growth of this aggressive cancer.

Abstract: We show that the receptor tyrosine kinase EphA3 is frequently overexpressed in GBM and, in particular, in the most aggressive mesenchymal subtype.

Abstract: Importantly, EphA3 is highly expressed on the tumor-initiating cell population in glioma and appears critically involved in maintaining tumor cells in a less differentiated state by modulating mitogen-activated protein kinase signaling.

Abstract: EphA3 knockdown or depletion of EphA3-positive tumor cells reduced tumorigenic potential to a degree comparable to treatment with a therapeutic radiolabelled EphA3-specific monoclonal antibody.

Abstract: These results identify EphA3 as a functional, targetable receptor in GBM.


Chimeric antigen receptor-modified T cells for acute lymphoid leukemia.

Abstract: Chimeric antigen receptor-modified T cells with specificity for CD19 have shown promise in the treatment of chronic lymphocytic leukemia (CLL).

Abstract: It remains to be established whether chimeric antigen receptor T cells have clinical activity in acute lymphoblastic leukemia (ALL).

Abstract: Two children with relapsed and refractory pre-B-cell ALL received infusions of T cells transduced with anti-CD19 antibody and a T-cell signaling molecule (CTL019 chimeric antigen receptor T cells), at a dose of 1.4×10(6) to 1.2×10(7) CTL019 cells per kilogram of body weight.

Abstract: In both patients, CTL019 T cells expanded to a level that was more than 1000 times as high as the initial engraftment level, and the cells were identified in bone marrow.

Abstract: In addition, the chimeric antigen receptor T cells were observed in the cerebrospinal fluid (CSF), where they persisted at high levels for at least 6 months.

Abstract: Eight grade 3 or 4 adverse events were noted.

Abstract: The cytokine-release syndrome and B-cell aplasia developed in both patients.

Abstract: In one child, the cytokine-release syndrome was severe; cytokine blockade with etanercept and tocilizumab was effective in reversing the syndrome and did not prevent expansion of chimeric antigen receptor T cells or reduce antileukemic efficacy.

Abstract: Complete remission was observed in both patients and is ongoing in one patient at 11 months after treatment.

Abstract: The other patient had a relapse, with blast cells that no longer expressed CD19, approximately 2 months after treatment.

Abstract: Chimeric antigen receptor-modified T cells are capable of killing even aggressive, treatment-refractory acute leukemia cells in vivo.

Abstract: The emergence of tumor cells that no longer express the target indicates a need to target other molecules in addition to CD19 in some patients with ALL.


Extended-connectivity fingerprints.

Abstract: Extended-connectivity fingerprints (ECFPs) are a novel class of topological fingerprints for molecular characterization.

Abstract: Historically, topological fingerprints were developed for substructure and similarity searching.

Abstract: ECFPs were developed specifically for structure-activity modeling.

Abstract: ECFPs are circular fingerprints with a number of useful qualities: they can be very rapidly calculated; they are not predefined and can represent an essentially infinite number of different molecular features (including stereochemical information); their features represent the presence of particular substructures, allowing easier interpretation of analysis results; and the ECFP algorithm can be tailored to generate different types of circular fingerprints, optimized for different uses.

Abstract: While the use of ECFPs has been widely adopted and validated, a description of their implementation has not previously been presented in the literature.


Suppressor of cytokine signaling 3 inhibits antiviral IFN-beta signaling to enhance HIV-1 replication in macrophages.

Abstract: HIV-1 replication within macrophages of the CNS often results in cognitive and motor impairment, which is known as HIV-associated dementia (HAD) in its most severe form.

Abstract: IFN-beta suppresses viral replication within these cells during early CNS infection, but the effect is transient.

Abstract: HIV-1 eventually overcomes this protective innate immune response to resume replication through an unknown mechanism, initiating the progression toward HAD.

Abstract: In this article, we show that Suppressor of Cytokine Signaling (SOCS)3, a molecular inhibitor of IFN signaling, may allow HIV-1 to evade innate immunity within the CNS.

Abstract: We found that SOCS3 is elevated in an in vivo SIV/macaque model of HAD and that the pattern of expression correlates with recurrence of viral replication and onset of CNS disease.

Abstract: In vitro, the HIV-1 regulatory protein transactivator of transcription induces SOCS3 in human and murine macrophages in a NF-kappaB-dependent manner.

Abstract: SOCS3 expression attenuates the response of macrophages to IFN-beta at proximal levels of pathway activation and downstream antiviral gene expression and consequently overcomes the inhibitory effect of IFN-beta on HIV-1 replication.

Abstract: These studies indicate that SOCS3 expression, induced by stimuli present in the HIV-1-infected brain, such as transactivator of transcription, inhibits antiviral IFN-beta signaling to enhance HIV-1 replication in macrophages.

Abstract: This consequence of SOCS3 expression in vitro, supported by a correlation with increased viral load and onset of CNS disease in vivo, suggests that SOCS3 may allow HIV-1 to evade the protective innate immune response within the CNS, allowing the recurrence of viral replication and, ultimately, promoting progression toward HAD.


Molecular model of the human 26S proteasome.

Abstract: The 26S proteasome plays a fundamental role in eukaryotic homeostasis by undertaking the highly controlled degradation of a wide range of proteins, including key cellular regulators such as those controlling cell-cycle progression and apoptosis.

Abstract: Here we report the structure of the human 26S proteasome determined by cryo-electron microscopy and single-particle analysis, with secondary structure elements identified both in the 20S proteolytic core region and in the 19S regulatory particle.

Abstract: We have used this information together with crystal structures, homology models, and other biochemical information to construct a molecular model of the complete 26S proteasome.

Abstract: This model allows for a detailed description of the 20S core within the 26S proteasome and redefines the overall assignment of subunits within the 19S regulatory particle.

Abstract: The information presented here provides a strong basis for a mechanistic understanding of the 26S proteasome.


Urinary bisphenol A concentrations and early reproductive health outcomes among women undergoing IVF.

Abstract: STUDY QUESTION In women undergoing IVF, are urinary bisphenol A (BPA) concentrations associated with ovarian response and early reproductive outcomes, including oocyte maturation and fertilization, Day 3 embryo quality and blastocyst formation?

Abstract: SUMMARY ANSWER Higher urinary BPA concentrations were found to be associated with decreased ovarian response, number of fertilized oocytes and decreased blastocyst formation.

Abstract: WHAT IS KNOWN ALREADY Experimental animal and in vitro studies have reported associations between BPA exposure and adverse reproductive outcomes.

Abstract: We previously reported an association between urinary BPA and decreased ovarian response [peak serum estradiol (E(2)) and oocyte count at the time of retrieval] in women undergoing IVF; however, there are limited human data on reproductive health outcomes, such as fertilization and embryo development.

Abstract: STUDY DESIGN, SIZE AND DURATION Prospective preconception cohort study.

Abstract: One hundred and seventy-four women aged 18-45 years and undergoing 237 IVF cycles were recruited at the Massachusetts General Hospital Fertility Center, Boston, MA, USA, between November 2004 and August 2010.

Abstract: These women were followed until they either had a live birth or discontinued treatment.

Abstract: Cryothaw and donor egg cycles were not included in the analysis.

Abstract: PARTICIPANTS/MATERIALS, SETTING AND METHODS Urinary BPA concentrations were measured by online solid-phase extraction-high-performance liquid chromatography-isotope dilution-tandem mass spectrometry.

Abstract: Mixed effect models, poisson regression and multivariate logistic regression models were used wherever appropriate to evaluate the association between cycle-specific urinary BPA concentrations and measures of ovarian response, oocyte maturation (metaphase II), fertilization, embryo quality and cleavage rate.

Abstract: We accounted for correlation among multiple IVF cycles in the same woman using generalized estimating equations.

Abstract: MAIN RESULTS AND THE ROLE OF CHANCE The geometric mean (SD) for urinary BPA concentrations was 1.50 (2.22) µg/l.

Abstract: After adjustment for age and other potential confounders (Day 3 serum FSH, smoking, BMI), there was a significant linear dose-response association between increased urinary BPA concentrations and decreased number of oocytes (overall and mature), decreased number of normally fertilized oocytes and decreased E(2) levels (mean decreases of 40, 253 and 471 pg/ml for urinary BPA quartiles 2, 3 and 4, when compared with the lowest quartile, respectively; P-value for trend = 0.001).

Abstract: The mean number of oocytes and normally fertilized oocytes decreased by 24 and 27%, respectively, for the highest versus the lowest quartile of urinary BPA (trend test P < 0.001 and 0.002, respectively).

Abstract: Women with urinary BPA above the lowest quartile had decreased blastocyst formation (trend test P-value = 0.08).

Abstract: LIMITATIONS AND REASONS FOR CAUTION Potential limitations include exposure misclassification due to the very short half-life of BPA and its high variability over time; uncertainty about the generalizability of the results to the general population of women conceiving naturally and limited sample.

Abstract: WIDER IMPLICATIONS OF THE FINDINGS The results from this extended study, using IVF as a model to study early reproductive health outcomes in humans, indicate a negative dose-response association between urinary BPA concentrations and serum peak E(2) and oocyte yield, confirming our previous findings.

Abstract: In addition, we found significantly decreased metaphase II oocyte count and number of normally fertilizing oocytes and a suggestive association between BPA urinary concentrations and decreased blastocyst formation, thus indicating that BPA may alter reproductive function in susceptible women undergoing IVF.

Abstract: STUDY FUNDING/COMPETING INTEREST(S) This work was supported by grants ES009718 and ES000002 from the National Institute of Environmental Health Sciences and grant OH008578 from the National Institute for Occupational Safety and Health.

Abstract: None of the authors has actual or potential competing financial interests.

Abstract: DISCLAIMER The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.


Cost-effectiveness of options for the diagnosis of high blood pressure in primary care: a modelling study.

Abstract: BACKGROUND The diagnosis of hypertension has traditionally been based on blood-pressure measurements in the clinic, but home and ambulatory measurements better correlate with cardiovascular outcome, and ambulatory monitoring is more accurate than both clinic and home monitoring in diagnosing hypertension.

Abstract: We aimed to compare the cost-effectiveness of different diagnostic strategies for hypertension.

Abstract: METHODS We did a Markov model-based probabilistic cost-effectiveness analysis.

Abstract: We used a hypothetical primary-care population aged 40 years or older with a screening blood-pressure measurement greater than 140/90 mm Hg and risk-factor prevalence equivalent to the general population.

Abstract: We compared three diagnostic strategies-further blood pressure measurement in the clinic, at home, and with an ambulatory monitor-in terms of lifetime costs, quality-adjusted life years, and cost-effectiveness.

Abstract: FINDINGS Ambulatory monitoring was the most cost-effective strategy for the diagnosis of hypertension for men and women of all ages.

Abstract: It was cost-saving for all groups (from -£56 [95% CI -105 to -10] in men aged 75 years to -£323 [-389 to -222] in women aged 40 years) and resulted in more quality-adjusted life years for men and women older than 50 years (from 0·006 [0·000 to 0·015] for women aged 60 years to 0·022 [0·012 to 0·035] for men aged 70 years).

Abstract: This finding was robust when assessed with a wide range of deterministic sensitivity analyses around the base case, but was sensitive if home monitoring was judged to have equal test performance to ambulatory monitoring or if treatment was judged effective irrespective of whether an individual was hypertensive.

Abstract: INTERPRETATION Ambulatory monitoring as a diagnostic strategy for hypertension after an initial raised reading in the clinic would reduce misdiagnosis and save costs.

Abstract: Additional costs from ambulatory monitoring are counterbalanced by cost savings from better targeted treatment.

Abstract: Ambulatory monitoring is recommended for most patients before the start of antihypertensive drugs.

Abstract: FUNDING National Institute for Health Research and the National Institute for Health and Clinical Excellence.


Folic acid improves endothelial function in coronary artery disease via mechanisms largely independent of homocysteine lowering.

Abstract: BACKGROUND Homocysteine is a risk factor for coronary artery disease (CAD), although a causal relation remains to be proven.

Abstract: The importance of determining direct causality rests in the fact that plasma homocysteine can be safely and inexpensively reduced by 25% with folic acid.

Abstract: This reduction is maximally achieved by doses of 0.4 mg/d.

Abstract: High-dose folic acid (5 mg/d) improves endothelial function in CAD, although the mechanism is controversial.

Abstract: It has been proposed that improvement occurs through reduction in total (tHcy) or free (non-protein bound) homocysteine (fHcy).

Abstract: We investigated the effects of folic acid on endothelial function before a change in homocysteine in patients with CAD.

Abstract: METHODS AND RESULTS A randomized, placebo-controlled study of folic acid (5 mg/d) for 6 weeks was undertaken in 33 patients.

Abstract: Endothelial function, assessed by flow-mediated dilatation (FMD), was measured before, at 2 and 4 hours after the first dose of folic acid, and after 6 weeks of treatment.

Abstract: Plasma folate increased markedly by 1 hour (200 compared with 25.8 nmol/L; P<0.001).

Abstract: FMD improved at 2 hours (83 compared with 47 microm; P<0.001) and was largely complete by 4 hours (101 compared with 51 microm; P<0.001).

Abstract: tHcy did not significantly differ acutely (4-hour tHcy, 9.56 compared with 9.79 micromol/L; P=NS).

Abstract: fHcy did not differ at 3 hours but was slightly reduced at 4 hours (1.55 compared with 1.78 micromol/L; P=0.02).

Abstract: FMD improvement did not correlate with reductions in either fHcy or tHcy at any time.

Abstract: CONCLUSIONS These data suggest that folic acid improves endothelial function in CAD acutely by a mechanism largely independent of homocysteine.


Focal adhesion kinase links mechanical force to skin fibrosis via inflammatory signaling

Abstract: Exuberant fibroproliferation is a common complication after injury for reasons that are not well understood.

Abstract: One key component of wound repair that is often overlooked is mechanical force, which regulates cell-matrix interactions through intracellular focal adhesion components, including focal adhesion kinase (FAK).

Abstract: Here we report that FAK is activated after cutaneous injury and that this process is potentiated by mechanical loading.

Abstract: Fibroblast-specific FAK knockout mice have substantially less inflammation and fibrosis than control mice in a model of hypertrophic scar formation.

Abstract: We show that FAK acts through extracellular-related kinase (ERK) to mechanically trigger the secretion of monocyte chemoattractant protein-1 (MCP-1, also known as CCL2), a potent chemokine that is linked to human fibrotic disorders.

Abstract: Similarly, MCP-1 knockout mice form minimal scars, indicating that inflammatory chemokine pathways are a major mechanism by which FAK mechanotransduction induces fibrosis.

Abstract: Small-molecule inhibition of FAK blocks these effects in human cells and reduces scar formation in vivo through attenuated MCP-1 signaling and inflammatory cell recruitment.

Abstract: These findings collectively indicate that physical force regulates fibrosis through inflammatory FAK–ERK–MCP-1 pathways and that molecular strategies targeting FAK can effectively uncouple mechanical force from pathologic scar formation.


Prognostic Accuracy of the SOFA Score, SIRS Criteria, and qSOFA Score for In-Hospital Mortality Among Adults With Suspected Infection Admitted to the Intensive Care Unit

Abstract: Importance The Sepsis-3 Criteria emphasized the value of a change of 2 or more points in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score, introduced quick SOFA (qSOFA), and removed the systemic inflammatory response syndrome (SIRS) criteria from the sepsis definition.

Abstract: Objective Externally validate and assess the discriminatory capacities of an increase in SOFA score by 2 or more points, 2 or more SIRS criteria, or a qSOFA score of 2 or more points for outcomes among patients who are critically ill with suspected infection.

Abstract: Design, Setting, and Participants Retrospective cohort analysis of 184 875 patients with an infection-related primary admission diagnosis in 182 Australian and New Zealand intensive care units (ICUs) from 2000 through 2015.

Abstract: Exposures SOFA, qSOFA, and SIRS criteria applied to data collected within 24 hours of ICU admission.

Abstract: Main Outcomes and Measures The primary outcome was in-hospital mortality.

Abstract: In-hospital mortality or ICU length of stay (LOS) of 3 days or more was a composite secondary outcome.

Abstract: Discrimination was assessed using the area under the receiver operating characteristic curve (AUROC).

Abstract: Adjusted analyses were performed using a model of baseline risk determined using variables independent of the scoring systems.

Abstract: Results Among 184 875 patients (mean age, 62.9 years [SD, 17.4]; women, 82 540 [44.6%]; most common diagnosis bacterial pneumonia, 32 634 [17.7%]), a total of 34 578 patients (18.7%) died in the hospital, and 102 976 patients (55.7%) died or experienced an ICU LOS of 3 days or more.

Abstract: SOFA score increased by 2 or more points in 90.1%; 86.7% manifested 2 or more SIRS criteria, and 54.4% had a qSOFA score of 2 or more points.

Abstract: SOFA demonstrated significantly greater discrimination for in-hospital mortality (crude AUROC, 0.753 [99% CI, 0.750-0.757]) than SIRS criteria (crude AUROC, 0.589 [99% CI, 0.585-0.593]) or qSOFA (crude AUROC, 0.607 [99% CI, 0.603-0.611]).

Abstract: Incremental improvements were 0.164 (99% CI, 0.159-0.169) for SOFA vs SIRS criteria and 0.146 (99% CI, 0.142-0.151) for SOFA vs qSOFA (P <.001).

Abstract: SOFA (AUROC, 0.736 [99% CI, 0.733-0.739]) outperformed the other scores for the secondary end point (SIRS criteria: AUROC, 0.609 [99% CI, 0.606-0.612]; qSOFA: AUROC, 0.606 [99% CI, 0.602-0.609]).

Abstract: Incremental improvements were 0.127 (99% CI, 0.123-0.131) for SOFA vs SIRS criteria and 0.131 (99% CI, 0.127-0.134) for SOFA vs qSOFA (P <.001).

Abstract: Findings were consistent for both outcomes in multiple sensitivity analyses.

Abstract: Conclusions and Relevance Among adults with suspected infection admitted to an ICU, an increase in SOFA score of 2 or more had greater prognostic accuracy for in-hospital mortality than SIRS criteria or the qSOFA score.

Abstract: These findings suggest that SIRS criteria and qSOFA may have limited utility for predicting mortality in an ICU setting.


Predictors of mammographic density: insights gained from a novel regression analysis of a twin study.

Abstract: Understanding which factors influence mammographically dense and nondense areas is important because percent mammographic density adjusted for age is a strong, continuously distributed risk factor for breast cancer, especially when adjusted for weight or body mass index.

Abstract: Using computer-assisted methods, we measured mammographically dense areas for 571 monozygotic and 380 dizygotic Australian and North American twin pairs ages 40 to 70 years.

Abstract: We used a novel regression modeling approach in which each twin's measure of dense and nondense area was regressed against one or both of the twin's and co-twin's covariates.

Abstract: The nature of changes to regression estimates with the inclusion of the twin and/or co-twin's covariates can be evaluated for consistency with causal and/or other models.

Abstract: By causal, we mean that if it were possible to vary a covariate experimentally then the expected value of the outcome measure would change.

Abstract: After adjusting for the individual's weight, the co-twin associations with weight were attenuated, consistent with a causal effect of weight on mammographic measures, which in absolute log cm(2)/kg was thrice stronger for nondense than dense area.

Abstract: After adjusting for weight, later age at menarche, and greater height were associated with greater dense and lesser nondense areas in a manner inconsistent with causality.

Abstract: The associations of dense and nondense areas with parity are consistent with a causal effect and/or within-person confounding.

Abstract: The associations between mammographic density measures and height are consistent with shared early life environmental factors that predispose to both height and percent mammographic density and possibly breast cancer risk.


Shaping the landscape of the Escherichia coli chromosome: replication-transcription encounters in cells with an ectopic replication origin

Abstract: Each cell division requires the unwinding of millions of DNA base pairs to allow chromosome duplication and gene transcription.

Abstract: As DNA replication and transcription share the same template, conflicts between both processes are unavoidable and head-on collisions are thought to be particularly problematic.

Abstract: Surprisingly, a recent study reported unperturbed cell cycle progression in Escherichia coli cells with an ectopic replication origin in which highly transcribed rrn operons were forced to be replicated opposite to normal.

Abstract: In this study we have re-generated a similar strain and found the doubling time to be twice that of normal cells.

Abstract: Replication profiles of this background revealed significant deviations in comparison to wild-type profiles, particularly in highly transcribed regions and the termination area.

Abstract: These deviations were alleviated by mutations that either inactivate the termination area or destabilise RNA polymerase complexes and allow their easier displacement by replication forks.

Abstract: Our data demonstrate that head-on replication-transcription conflicts are highly problematic.

Abstract: Indeed, analysis of the replication profile of the previously published E. coli construct revealed a chromosomal rearrangement that alleviates replication-transcription conflicts in an intriguingly simple way.

Abstract: Our data support the idea that avoiding head-on collisions has significantly contributed to shaping the distinct architecture of bacterial chromosomes.


Epithelial–mesenchymal transitions in tumour progression

Abstract: Without epithelial–mesenchymal transitions, in which polarized epithelial cells are converted into motile cells, multicellular organisms would be incapable of getting past the blastula stage of embryonic development.

Abstract: However, this important developmental programme has a more sinister role in tumour progression.

Abstract: Epithelial–mesenchymal transition provides a new basis for understanding the progression of carcinoma towards dedifferentiated and more malignant states.


Platelets at the interface of thrombosis, inflammation, and cancer.

Abstract: Although once primarily recognized for its roles in hemostasis and thrombosis, the platelet has been increasingly recognized as a multipurpose cell.

Abstract: Indeed, circulating platelets have the ability to influence a wide range of seemingly unrelated pathophysiologic events.

Abstract: Here, we highlight some of the notable observations that link platelets to inflammation, reinforcing the platelet's origin from a lower vertebrate cell type with both hemostatic and immunologic roles.

Abstract: In addition, we consider the relevance of platelets in cancer biology by focusing on the hallmarks of cancer and the ways platelets can influence multistep development of tumors.

Abstract: Beyond its traditional role in hemostasis and thrombosis, the platelet's involvement in the interplay between hemostasis, thrombosis, inflammation, and cancer is likely complex, yet extremely important in each disease process.

Abstract: The existence of animal models of platelet dysfunction and currently used antiplatelet therapies provide a framework for understanding mechanistic insights into a wide range of pathophysiologic events.

Abstract: Thus, the basic scientist studying platelet function can think beyond the traditional hemostasis and thrombosis paradigms, while the practicing hematologist must appreciate platelet relevance in a wide range of disease processes.


Cellular roles of DNA topoisomerases: a molecular perspective

Abstract: DNA topoisomerases are the magicians of the DNA world — by allowing DNA strands or double helices to pass through each other, they can solve all of the topological problems of DNA in replication, transcription and other cellular transactions.

Abstract: Extensive biochemical and structural studies over the past three decades have provided molecular models of how the various subfamilies of DNA topoisomerase manipulate DNA.

Abstract: In this review, the cellular roles of these enzymes are examined from a molecular point of view.


MicroRNA sponges: progress and possibilities.

Abstract: The microRNA (miRNA) "sponge" method was introduced three years ago as a means to create continuous miRNA loss of function in cell lines and transgenic organisms.

Abstract: Sponge RNAs contain complementary binding sites to a miRNA of interest, and are produced from transgenes within cells.

Abstract: As with most miRNA target genes, a sponge's binding sites are specific to the miRNA seed region, which allows them to block a whole family of related miRNAs.

Abstract: This transgenic approach has proven to be a useful tool to probe miRNA functions in a variety of experimental systems.

Abstract: Here we will discuss the ways sponge and related constructs can be optimized and review recent applications of this method with particular emphasis on stable expression in cancer studies and in transgenic animals.


Wip1 phosphatase regulates p53-dependent apoptosis of stem cells and tumorigenesis in the mouse intestine.

Abstract: Colorectal cancer is one of the major causes of cancer-related deaths.

Abstract: To gain further insights into the mechanisms underlying its development, we investigated the role of Wip1 phosphatase, which is highly expressed in intestinal stem cells, in the mouse model of APC(Min)-driven polyposis.

Abstract: We found that Wip1 removal increased the life span of APC(Min) mice through a significant suppression of polyp formation.

Abstract: This protection was dependent on the p53 tumor suppressor, which plays a putative role in the regulation of apoptosis of intestinal stem cells.

Abstract: Activation of apoptosis in stem cells of Wip1-deficient mice, but not wild-type APC(Min) mice, increased when the Wnt pathway was constitutively activated.

Abstract: We propose, therefore, that the Wip1 phosphatase regulates homeostasis of intestinal stem cells.

Abstract: In turn, Wip1 loss suppresses APC(Min)-driven polyposis by lowering the threshold for p53-dependent apoptosis of stem cells, thus preventing their conversion into tumor-initiating stem cells.


The shunt problem: control of functional shunting in normal and tumour vasculature

Abstract: Networks of blood vessels in normal and tumour tissues have heterogeneous structures, with widely varying blood flow pathway lengths.

Abstract: To achieve efficient blood flow distribution, mechanisms for the structural adaptation of vessel diameters must be able to inhibit the formation of functional shunts (whereby short pathways become enlarged and flow bypasses long pathways).

Abstract: Such adaptation requires information about tissue metabolic status to be communicated upstream to feeding vessels, through conducted responses.

Abstract: We propose that impaired vascular communication in tumour microvascular networks, leading to functional shunting, is a primary cause of dysfunctional microcirculation and local hypoxia in cancer.

Abstract: We suggest that anti-angiogenic treatment of tumours may restore vascular communication and thereby improve or normalize flow distribution in tumour vasculature.


Pharmacological Blockade of ASCT2-dependent Glutamine Transport Leads To Anti-tumor Efficacy in Preclinical Models

Abstract: The unique metabolic demands of cancer cells underscore potentially fruitful opportunities for drug discovery in the era of precision medicine.

Abstract: However, therapeutic targeting of cancer metabolism has led to surprisingly few new drugs to date.

Abstract: The neutral amino acid glutamine serves as a key intermediate in numerous metabolic processes leveraged by cancer cells, including biosynthesis, cell signaling, and oxidative protection.

Abstract: Herein we report the preclinical development of V-9302, a competitive small molecule antagonist of transmembrane glutamine flux that selectively and potently targets the amino acid transporter ASCT2.

Abstract: Pharmacological blockade of ASCT2 with V-9302 resulted in attenuated cancer cell growth and proliferation, increased cell death, and increased oxidative stress, which collectively contributed to antitumor responses in vitro and in vivo.

Abstract: This is the first study, to our knowledge, to demonstrate the utility of a pharmacological inhibitor of glutamine transport in oncology, representing a new class of targeted therapy and laying a framework for paradigm-shifting therapies targeting cancer cell metabolism.


An Antidepressant Decreases CSF Aβ Production in Healthy Individuals and in Transgenic AD Mice

Abstract: Serotonin signaling suppresses generation of amyloid-β (Aβ) in vitro and in animal models of Alzheimer’s disease (AD).

Abstract: We show that in an aged transgenic AD mouse model (APP/PS1 plaque-bearing mice), the antidepressant citalopram, a selective serotonin reuptake inhibitor, decreased Aβ in brain interstitial fluid in a dose-dependent manner.

Abstract: Growth of individual amyloid plaques was assessed in plaque-bearing mice that were chronically administered citalopram.

Abstract: Citalopram arrested the growth of preexisting plaques and reduced the appearance of new plaques by 78%.

Abstract: In healthy human volunteers, citalopram’s effects on Aβ production and Aβ concentrations in cerebrospinal fluid (CSF) were measured prospectively using stable isotope labeling kinetics, with CSF sampling during acute dosing of citalopram.

Abstract: Aβ production in CSF was slowed by 37% in the citalopram group compared to placebo.

Abstract: This change was associated with a 38% decrease in total CSF Aβ concentrations in the drug-treated group.

Abstract: The ability to safely decrease Aβ concentrations is potentially important as a preventive strategy for AD.

Abstract: This study demonstrates key target engagement for future AD prevention trials.


Variations in the quality and sustainability of long-term glycaemic control with continuous subcutaneous insulin infusion.

Abstract: AIMS To investigate the pattern of changes in HbA1c in people with Type 1 diabetes managed by long-term Continuous subcutaneous insulin infusion.

Abstract: METHODS We studied HbA1c changes using computerized clinic records in 35 adult people with Type 1 diabetes and an elevated HbA1c (≥ 64 mmol/mol, 8.0%) on multiple daily insulin injections, who were then switched to continuous subcutaneous insulin infusion for at least 5 years.

Abstract: RESULTS We identified three subgroups with similar baseline HbA1c but different long-term responses to pump therapy: group A--those with improvement followed by deterioration (57%); group B--those with improvement that was sustained throughout the 5 years (31%); and group C-those where HbA1c did not change significantly from baseline (12%).

Abstract: The patients in group C had a higher BMI: 31.0 ± 5.2 vs. 25.9 ± 3.3 vs. 25.2 ± 3.1 kg/m² (group C vs. group A and group B; P = 0.02).

Abstract: CONCLUSIONS Improved glycaemic control with continuous subcutaneous insulin infusion was maintained over 5 years by 88% of people with Type 1 diabetes in this study, but there were variations in the long-term efficacy, with some people improving and worsening, others maintaining strict control and a few subcutaneous insulin infusion 'non-responders'.


Historical review: megakaryopoiesis and thrombopoiesis.

Abstract: The study of thrombopoiesis has evolved greatly since an era when platelets were termed "the dust of the blood," only about 100 years ago.

Abstract: During this time megakaryocytes were identified as the origin of blood platelets; marrow-derived megakaryocytic progenitor cells were functionally defined and then purified; and the primary regulator of the process, thrombopoietin, was cloned and characterized and therapeutic thrombopoietic agents developed.

Abstract: During this journey we continue to learn that the physiologic mechanisms that drive proplatelet formation can be recapitulated in cell-free systems and their biochemistry evaluated; the molecular underpinnings of endomitosis are being increasingly understood; the intracellular signals sent by engagement of a large number of megakaryocyte surface receptors have been defined; and many of the transcription factors that drive megakaryocytic fate determination have been identified and experimentally manipulated.

Abstract: While some of these biologic processes mimic those seen in other cell types, megakaryocytes and platelets possess enough unique developmental features that we are virtually assured that continued study of thrombopoiesis will yield innumerable clinical and scientific insights for many decades to come.


Obesity and Its Metabolic Complications: The Role of Adipokines and the Relationship between Obesity, Inflammation, Insulin Resistance, Dyslipidemia and Nonalcoholic Fatty Liver Disease

Abstract: Accumulating evidence indicates that obesity is closely associated with an increased risk of metabolic diseases such as insulin resistance, type 2 diabetes, dyslipidemia and nonalcoholic fatty liver disease.

Abstract: Obesity results from an imbalance between food intake and energy expenditure, which leads to an excessive accumulation of adipose tissue.

Abstract: Adipose tissue is now recognized not only as a main site of storage of excess energy derived from food intake but also as an endocrine organ.

Abstract: The expansion of adipose tissue produces a number of bioactive substances, known as adipocytokines or adipokines, which trigger chronic low-grade inflammation and interact with a range of processes in many different organs.

Abstract: Although the precise mechanisms are still unclear, dysregulated production or secretion of these adipokines caused by excess adipose tissue and adipose tissue dysfunction can contribute to the development of obesity-related metabolic diseases.

Abstract: In this review, we focus on the role of several adipokines associated with obesity and the potential impact on obesity-related metabolic diseases.

Abstract: Multiple lines evidence provides valuable insights into the roles of adipokines in the development of obesity and its metabolic complications.

Abstract: Further research is still required to fully understand the mechanisms underlying the metabolic actions of a few newly identified adipokines.


Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways

Abstract: Trastuzumab is a successful rationally designed ERBB2-targeted therapy.

Abstract: However, about half of individuals with ERBB2-overexpressing breast cancer do not respond to trastuzumab-based therapies, owing to various resistance mechanisms.

Abstract: Clinically applicable regimens for overcoming trastuzumab resistance of different mechanisms are not yet available.

Abstract: We show that the nonreceptor tyrosine kinase c-SRC (SRC) is a key modulator of trastuzumab response and a common node downstream of multiple trastuzumab resistance pathways.

Abstract: We find that SRC is activated in both acquired and de novo trastuzumab-resistant cells and uncover a novel mechanism of SRC regulation involving dephosphorylation by PTEN.

Abstract: Increased SRC activation conferred considerable trastuzumab resistance in breast cancer cells and correlated with trastuzumab resistance in patients.

Abstract: Targeting SRC in combination with trastuzumab sensitized multiple lines of trastuzumab-resistant cells to trastuzumab and eliminated trastuzumab-resistant tumors in vivo, suggesting the potential clinical application of this strategy to overcome trastuzumab resistance.


MicroRNAs: new tools for diagnosis, prognosis, and therapy in hepatocellular carcinoma?

Abstract: MicroRNAs (miRNAs) are evolutionarily conserved small noncoding RNAs involved in the regulation of gene expression and protein translation.

Abstract: Many studies have shown that they play a crucial role in driving organ and tissue differentiation during embryogenesis and in the fine-tuning of fundamental biological processes, such as proliferation and apoptosis.

Abstract: Growing evidence indicates that their deregulation plays an important role in cancer onset and progression as well, where they act as oncogenes or oncosuppressors.

Abstract: In this review, we highlight the most recent findings regarding the role of miRNAs in hepatocellular carcinoma (HCC) by analyzing the possible mechanisms by which they contribute to this neoplasm.

Abstract: Moreover, we discuss the possible role of circulating miRNAs as biomarkers, a field that needs urgent improvement in the clinical surveillance of HCC, and the fascinating possibility of using them as therapeutic targets or drugs themselves.


A vertebrate gene, ticrr, is an essential checkpoint and replication regulator.

Abstract: Eukaryotes have numerous checkpoint pathways to protect genome fidelity during normal cell division and in response to DNA damage.

Abstract: Through a screen for G2/M checkpoint regulators in zebrafish, we identified ticrr (for TopBP1-interacting, checkpoint, and replication regulator), a previously uncharacterized gene that is required to prevent mitotic entry after treatment with ionizing radiation.

Abstract: Ticrr deficiency is embryonic-lethal in the absence of exogenous DNA damage because it is essential for normal cell cycle progression.

Abstract: Specifically, the loss of ticrr impairs DNA replication and disrupts the S/M checkpoint, leading to premature mitotic entry and mitotic catastrophe.

Abstract: We show that the human TICRR ortholog associates with TopBP1, a known checkpoint protein and a core component of the DNA replication preinitiation complex (pre-IC), and that the TICRR-TopBP1 interaction is stable without chromatin and requires BRCT motifs essential for TopBP1's replication and checkpoint functions.

Abstract: Most importantly, we find that ticrr deficiency disrupts chromatin binding of pre-IC, but not prereplication complex, components.

Abstract: Taken together, our data show that TICRR acts in association with TopBP1 and plays an essential role in pre-IC formation.

Abstract: It remains to be determined whether Ticrr represents the vertebrate ortholog of the yeast pre-IC component Sld3, or a hitherto unknown metazoan replication and checkpoint regulator.


A maternally methylated CpG island in KvLQT1 is associated with an antisense paternal transcript and loss of imprinting in Beckwith-Wiedemann syndrome.

Abstract: Loss of imprinting at IGF2, generally through an H19-independent mechanism, is associated with a large percentage of patients with the overgrowth and cancer predisposition condition Beckwith-Wiedemann syndrome (BWS).

Abstract: Imprinting control elements are proposed to exist within the KvLQT1 locus, because multiple BWS-associated chromosome rearrangements disrupt this gene.

Abstract: We have identified an evolutionarily conserved, maternally methylated CpG island (KvDMR1) in an intron of the KvLQT1 gene.

Abstract: Among 12 cases of BWS with normal H19 methylation, 5 showed demethylation of KvDMR1 in fibroblast or lymphocyte DNA; whereas, in 4 cases of BWS with H19 hypermethylation, methylation at KvDMRl was normal.

Abstract: Thus, inactivation of H19 and hypomethylation at KvDMR1 (or an associated phenomenon) represent distinct epigenetic anomalies associated with biallelic expression of IGF2.

Abstract: Reverse transcription-PCR analysis of the human and syntenic mouse loci identified the presence of a KvDMR1-associated RNA transcribed exclusively from the paternal allele and in the opposite orientation with respect to the maternally expressed KvLQT1 gene.

Abstract: We propose that KvDMR1 and/or its associated antisense RNA (KvLQT1-AS) represents an additional imprinting control element or center in the human 11p15.5 and mouse distal 7 imprinted domains.


Alarming levels of drug-resistant tuberculosis in Belarus: results of a survey in Minsk

Abstract: Resistance to anti-tuberculosis (TB) medicines is a major public health threat in most countries of the former Soviet Union.

Abstract: As no representative and quality-assured information on the magnitude of this problem existed in Belarus, a survey was conducted in the capital city of Minsk.

Abstract: Between November 2009 and December 2010, 156 consecutively diagnosed new and 68 previously treated culture-positive TB patients residing in Minsk were enrolled in the survey.

Abstract: Mycobacterium tuberculosis isolates were obtained from each patient and tested for susceptibility to first- and second-line anti-TB drugs.

Abstract: Multidrug-resistant (MDR)-TB was found in 35.3% (95% CI 27.7-42.8) of new patients and 76.5% (95% CI 66.1-86.8) of those previously treated.

Abstract: Overall, nearly one in two patients enrolled had MDR-TB.

Abstract: Extensively drug-resistant TB was reported in 15 of the 107 MDR-TB patients (14.0%, 95% CI 7.3-20.7).

Abstract: Patients <35 yrs of age have shown a two times higher odds ratio of multidrug-resistant TB than those aged >35 yrs.

Abstract: The findings of this survey in Minsk city are alarming and represent the highest proportions of MDR-TB ever recorded in the world.

Abstract: This study greatly contributes to the understanding of the burden of drug-resistant TB in urban areas of Belarus.


Partitioning regulatory mechanisms of within-host malaria dynamics using the effective propagation number.

Abstract: Immune clearance and resource limitation (via red blood cell depletion) shape the peaks and troughs of malaria parasitemia, which in turn affect disease severity and transmission.

Abstract: Quantitatively partitioning the relative roles of these effects through time is challenging.

Abstract: Using data from rodent malaria, we estimated the effective propagation number, which reflects the relative importance of contrasting within-host control mechanisms through time and is sensitive to the inoculating parasite dose.

Abstract: Our analysis showed that the capacity of innate responses to restrict initial parasite growth saturates with parasite dose and that experimentally enhanced innate immunity can affect parasite density indirectly via resource depletion.

Abstract: Such a statistical approach offers a tool to improve targeting of drugs or vaccines for human therapy by revealing the dynamics and interactions of within-host regulatory mechanisms.


Life is sweet: candy consumption and longevity.

Abstract: Our attitude towards candy—“if it tastes that good, it can't be healthy”—betrays society's puritanical stance towards pleasure.

Abstract: Candy has been blamed for various ills, including hyperactivity in children; however, clinical trials have not supported this.1  Candy—sugar confectionery and chocolate—is not a recent invention: the ancient Arabs, Chinese, and Egyptians candied fruits and nuts in honey, and the Aztecs made a chocolate drink from the bean of the cacao tree.

Abstract: Today, Americans gratify themselves with, on average, 5.4 kg of sugar candy and 6.5 kg of chocolate per person annually.2  Since candy has existed for centuries, we surmised that it cannot be totally unhealthy.

Abstract: We decided to investigate whether candy consumption was associated with longevity.

Abstract: Subjects were from the Harvard alumni health study, an ongoing study of men entering Harvard University as undergraduates between 1916 and 1950.

Abstract: We included 7841 men, free of cardiovascular disease and cancer, who responded to a health survey …


Inter-individual variability and genetic influences on cytokine responses to bacteria and fungi

Abstract: Little is known about the inter-individual variation of cytokine responses to different pathogens in healthy individuals.

Abstract: To systematically describe cytokine responses elicited by distinct pathogens and to determine the effect of genetic variation on cytokine production, we profiled cytokines produced by peripheral blood mononuclear cells from 197 individuals of European origin from the 200 Functional Genomics (200FG) cohort in the Human Functional Genomics Project (http://www.humanfunctionalgenomics.org), obtained over three different years.

Abstract: We compared bacteria- and fungi-induced cytokine profiles and found that most cytokine responses were organized around a physiological response to specific pathogens, rather than around a particular immune pathway or cytokine.

Abstract: We then correlated genome-wide single-nucleotide polymorphism (SNP) genotypes with cytokine abundance and identified six cytokine quantitative trait loci (QTLs).

Abstract: Among them, a cytokine QTL at the NAA35-GOLM1 locus markedly modulated interleukin (IL)-6 production in response to multiple pathogens and was associated with susceptibility to candidemia.

Abstract: Furthermore, the cytokine QTLs that we identified were enriched among SNPs previously associated with infectious diseases and heart diseases.

Abstract: These data reveal and begin to explain the variability in cytokine production by human immune cells in response to pathogens.


Integrins promote cytokinesis through the RSK signaling axis.

Abstract: Cytokinesis is the final stage in cell division.

Abstract: Although integrins can regulate cytokinesis, the mechanisms involved are not fully understood.

Abstract: In this study, we demonstrate that integrin-regulated ERK (extracellular signal-related kinase) and RSK (p90 ribosomal S6 kinase) signaling promotes successful cytokinesis.

Abstract: Inhibiting the activation of ERK and RSK in CHO cells by a mutation in the integrin β1 cytoplasmic tail or with pharmacological inhibitors results in the accumulation of cells with midbodies and the formation of binucleated cells.

Abstract: Activation of ERK and RSK signaling by the expression of constitutively active RAF1 suppresses the mutant phenotype in a RSK-dependent manner.

Abstract: Constitutively active RSK2 also restores cytokinesis inhibited by the mutant integrin.

Abstract: Importantly, the regulatory role of the RSK pathway is not specific to CHO cells.

Abstract: MCF-10A human mammary epithelial cells and HPNE human pancreatic ductal epithelial cells exhibit a similar dependence on RSK for successful cytokinesis.

Abstract: In addition, depriving mitotic MCF10A cells of integrin-mediated adhesion by incubating them in suspension suppressed ERK and RSK activation and resulted in a failure of cytokinesis.

Abstract: Furthermore, inhibition of RSK or integrins within the 3D context of a developing salivary gland organ explant also leads to an accumulation of epithelial cells with midbodies, suggesting a similar defect in cytokinesis.

Abstract: Interestingly, neither ERK nor RSK regulates cytokinesis in human fibroblasts, suggesting cell-type specificity.

Abstract: Taken together, our results identify the integrin-RSK signaling axis as an important regulator of cytokinesis in epithelial cells.

Abstract: We propose that the proper interaction of cells with their microenvironment through integrins contributes to the maintenance of genomic stability by promoting the successful completion of cytokinesis.