Contemporary type 1 diabetes pregnancy outcomes: impact of obesity and glycaemic control.

Abstract: OBJECTIVE To compare contemporary pregnancy outcomes in women with and without type 1 diabetes, and to examine the effects of obesity and glycaemic control on these outcomes.

Abstract: DESIGN AND SETTING Historical cohort study in a specialist diabetes and maternity network in Victoria.

Abstract: PARTICIPANTS All singleton births (at least 20 weeks' gestation), 2010-2013, were analysed: 107 pregnancies to women with type 1 diabetes and 27 075 pregnancies to women without diabetes.

Abstract: Women with type 2 diabetes or gestational diabetes were excluded.

Abstract: METHODS Data were extracted from the Birthing Outcomes System database; associations between type 1 diabetes and pregnancy outcomes were analysed by multivariable regression.

Abstract: MAIN OUTCOME MEASURES Mode of birth; maternal and neonatal outcomes.

Abstract: RESULTS The mean body mass index was higher for women with type 1 diabetes than for women without diabetes (mean, 27.3 kg/m(2) [SD, 5.0] v 25.7 kg/m(2) [SD, 5.9]; P = 0.01); the median gestation period for their babies was shorter (median, 37.3 weeks [IQR, 34.6-38.1] v 39.4 weeks [IQR, 38.4-40.4]; P < 0.001) and they were more likely to be large for gestational age (LGA) (adjusted odds ratio [aOR], 7.9; 95% CI, 5.3-11.8).

Abstract: Women with type 1 diabetes were more likely to have had labour induced (aOR, 3.0; 95% CI, 2.0-4.5), a caesarean delivery (aOR, 4.6; 95% CI, 3.1-7.0), or a pre-term birth (aOR, 6.7; 95% CI, 4.5-10.0); their babies were more likely to have shoulder dystocia (aOR, 8.2; 95% CI, 3.6-18.7), hypoglycaemia (aOR, 10.3; 95% CI, 6.8-15.6), jaundice (aOR, 5.1; 95% CI, 3.3-7.7), respiratory distress (aOR, 2.5; 95% CI, 1.4-4.4) or to suffer perinatal death (aOR, 4.3; 95% CI, 1.9-9.9).

Abstract: In women with type 1 diabetes, greater obesity was associated with increased odds for an LGA baby or congenital malformation, and increased HbA1c levels were associated with pre-term birth and perinatal death.

Abstract: CONCLUSION Women with type 1 diabetes, even when managed in a specialist setting, still experience adverse obstetric and neonatal outcomes.

Abstract: Poor glycaemic control is not wholly responsible for adverse outcomes, reinforcing the importance of other risk factors, such as obesity and weight gain.


Molecular Mechanisms of Vitamin D Action

Abstract: The hormonal metabolite of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25D), initiates biological responses via binding to the vitamin D receptor (VDR).

Abstract: When occupied by 1,25D, VDR interacts with the retinoid X receptor (RXR) to form a heterodimer that binds to vitamin D responsive elements in the region of genes directly controlled by 1,25D.

Abstract: By recruiting complexes of either coactivators or corepressors, ligand-activated VDR-RXR modulates the transcription of genes encoding proteins that promulgate the traditional functions of vitamin D, including signaling intestinal calcium and phosphate absorption to effect skeletal and calcium homeostasis.

Abstract: Thus, vitamin D action in a particular cell depends upon the metabolic production or delivery of sufficient concentrations of the 1,25D ligand, expression of adequate VDR and RXR coreceptor proteins, and cell-specific programming of transcriptional responses to regulate select genes that encode proteins that function in mediating the effects of vitamin D. For example, 1,25D induces RANKL, SPP1 (osteopontin), and BGP (osteocalcin) to govern bone mineral remodeling; TRPV6, CaBP9k, and claudin 2 to promote intestinal calcium absorption; and TRPV5, klotho, and Npt2c to regulate renal calcium and phosphate reabsorption.

Abstract: VDR appears to function unliganded by 1,25D in keratinocytes to drive mammalian hair cycling via regulation of genes such as CASP14, S100A8, SOSTDC1, and others affecting Wnt signaling.

Abstract: Finally, alternative, low-affinity, non-vitamin D VDR ligands, e.g., lithocholic acid, docosahexaenoic acid, and curcumin, have been reported.

Abstract: Combined alternative VDR ligand(s) and 1,25D/VDR control of gene expression may delay chronic disorders of aging such as osteoporosis, type 2 diabetes, cardiovascular disease, and cancer.


Quantitative Temporal Viromics: An Approach to Investigate Host-Pathogen Interaction

Abstract: A systematic quantitative analysis of temporal changes in host and viral proteins throughout the course of a productive infection could provide dynamic insights into virus-host interaction.

Abstract: We developed a proteomic technique called "quantitative temporal viromics" (QTV), which employs multiplexed tandem-mass-tag-based mass spectrometry.

Abstract: Human cytomegalovirus (HCMV) is not only an important pathogen but a paradigm of viral immune evasion.

Abstract: QTV detailed how HCMV orchestrates the expression of >8,000 cellular proteins, including 1,200 cell-surface proteins to manipulate signaling pathways and counterintrinsic, innate, and adaptive immune defenses.

Abstract: QTV predicted natural killer and T cell ligands, as well as 29 viral proteins present at the cell surface, potential therapeutic targets.

Abstract: Temporal profiles of >80% of HCMV canonical genes and 14 noncanonical HCMV open reading frames were defined.

Abstract: QTV is a powerful method that can yield important insights into viral infection and is applicable to any virus with a robust in vitro model.


Interactions between sleep, circadian function, and glucose metabolism: implications for risk and severity of diabetes.

Abstract: Sleep disturbances, including sleep insufficiency and sleep fragmentation, have been linked to abnormal glucose metabolism and increased diabetes risk.

Abstract: Well-controlled laboratory studies have provided insights regarding the underlying mechanisms.

Abstract: Several large prospective studies suggest that these sleep disturbances are associated with an increased risk of incident diabetes.

Abstract: Obstructive sleep apnea, which combines sleep fragmentation and hypoxemia, is a major risk factor for insulin resistance and possibly diabetes.

Abstract: Whether glycemic control in type 2 diabetes patients can be improved by treating sleep apnea remains controversial.

Abstract: Recently, sleep disturbances during pregnancy and their relationship to gestational diabetes and hyperglycemia have received considerable attention owing to potential adverse effects on maternal and fetal health.

Abstract: Additionally, evidence from animal models has identified disruption of the circadian system as a putative risk factor for adverse metabolic outcomes.

Abstract: The purpose of this review is to provide an update on the current state of knowledge linking sleep disturbances, circadian dysfunction, and glucose metabolism.

Abstract: Experimental, prospective, and interventional studies are discussed.


Antibody-Based HIV-1 Vaccines: Recent Developments and Future Directions

Abstract: The Global HIV Vaccine Enterprise convened a two-day workshop in May of 2007 to discuss humoral immune responses to HIV and approaches to design vaccines that induce viral neutralizing and other potentially protective antibody responses.

Abstract: The goals of this workshop were to identify key scientific issues, gaps, and opportunities that have emerged since the Enterprise Strategic Plan was first published in 2005 [1], and to make recommendations that Enterprise stakeholders can use to plan new activities.

Abstract: Most effective viral vaccines work, at least in part, by generating antibodies that inactivate or neutralize the invading virus, and the existing data strongly suggest that an optimally effective HIV-1 vaccine should elicit potent antiviral neutralizing antibodies.

Abstract: However, unlike acute viral pathogens, HIV-1 chronically replicates in the host and evades the antibody response.

Abstract: This immune evasion, along with the large genetic variation among HIV-1 strains worldwide, has posed major obstacles to vaccine development.

Abstract: Current HIV vaccine candidates do not elicit neutralizing antibodies against most circulating virus strains, and thus the induction of a protective antibody response remains a major priority for HIV-1 vaccine development.

Abstract: For an antibody-based HIV-1 vaccine, progress in vaccine design is generally gauged by in vitro assays that measure the ability of vaccine-induced antibodies to neutralize a broad spectrum of viral isolates representing the major genetic subtypes (clades) of HIV-1 [2].

Abstract: Although it is not known what magnitude and breadth of neutralization will predict protection in vaccine recipients, it is clear that current vaccine immunogens elicit antibodies that neutralize only a minority of circulating isolates.

Abstract: Thus, much progress needs to be made in this area.

Abstract: Also, though virus neutralization is considered a critical benchmark for a vaccine, this may not be the only benchmark for predicting success with antibody-based HIV-1 vaccine immunogens.

Abstract: The main targets for neutralizing antibodies to HIV-1 are the surface gp120 and trans-membrane gp41 envelope glycoproteins (Env) that mediate receptor and coreceptor binding and the subsequent membrane fusion events that allow the virus to gain entry into cells [3].

Abstract: Antibodies neutralize the virus by binding these viral spikes and blocking virus entry into susceptible cells, such as CD4+ T cells [4,5].

Abstract: In order to chronically replicate in the host, the virus exploits several mechanisms to shield itself against antibody recognition, including a dense outer coating of sugar molecules (N-linked glycans) and the strategic positioning of cysteine–cysteine loop structures on the gp120 molecule [6–8].

Abstract: These shielding mechanisms, although highly effective, have vulnerabilities imposed by fitness constraints.

Abstract: Information on the precise location and molecular structure of these vulnerable regions could be valuable for the rational design of improved vaccine immunogens.

Abstract: Participants in the workshop identified four areas that, if given proper attention, could provide key information that would bring the field closer to an effective antibody-based HIV-1 vaccine: (1) structure-assisted immunogen design, (2) role of Fc receptors and complement, (3) assay standardization and validation, and (4) immunoregulation of B cell responses.


Targeted therapy for cancer stem cells: the patched pathway and ABC transporters

Abstract: Data from certain leukemias as well as brain and breast cancer indicate that there is a small population of tumor cells with ‘stem cell’ characteristics and the capacity for self-renewal.

Abstract: The self-renewing cells have many of the properties of normal stem cells and have been termed ‘cancer stem cells’.

Abstract: These cancer stem cells make up as few as 1% of the cells in a tumor, making them difficult to detect and study.

Abstract: Like normal stem cells, cancer stem cells have a number of properties permitting them to survive traditional cancer chemotherapy and radiation therapy.

Abstract: These cells express high levels of ATP-binding cassette (ABC) drug transporters, providing for a level of resistance; are relatively quiescent; have higher levels of DNA repair and a lowered ability to enter apoptosis.

Abstract: Combined cancer therapy approaches targeting the cancer stem cells and the non-stem cells may be developed with increased efficacy.

Abstract: Efforts to target the Hedgehog/Patched pathway, critical to embryonic growth and differentiation, and the ABCG2 drug efflux transporter will be presented.


Increased in vivo amyloid-β42 production, exchange, and loss in presenilin mutation carriers.

Abstract: Alzheimer's disease (AD) is hypothesized to be caused by an overproduction or reduced clearance of amyloid-β (Aβ) peptide.

Abstract: Autosomal dominant AD (ADAD) caused by mutations in the presenilin (PSEN) gene have been postulated to result from increased production of Aβ42 compared to Aβ40 in the central nervous system (CNS).

Abstract: This has been demonstrated in rodent models of ADAD but not in human mutation carriers.

Abstract: We used compartmental modeling of stable isotope labeling kinetic (SILK) studies in human carriers of PSEN mutations and related noncarriers to evaluate the pathophysiological effects of PSEN1 and PSEN2 mutations on the production and turnover of Aβ isoforms.

Abstract: We compared these findings by mutation status and amount of fibrillar amyloid deposition as measured by positron emission tomography (PET) using the amyloid tracer Pittsburgh compound B (PIB).

Abstract: CNS Aβ42 to Aβ40 production rates were 24% higher in mutation carriers compared to noncarriers, and this was independent of fibrillar amyloid deposits quantified by PET PIB imaging.

Abstract: The fractional turnover rate of soluble Aβ42 relative to Aβ40 was 65% faster in mutation carriers and correlated with amyloid deposition, consistent with increased deposition of Aβ42 into plaques, leading to reduced recovery of Aβ42 in cerebrospinal fluid (CSF).

Abstract: Reversible exchange of Aβ42 peptides with preexisting unlabeled peptide was observed in the presence of plaques.

Abstract: These findings support the hypothesis that Aβ42 is overproduced in the CNS of humans with PSEN mutations that cause AD, and demonstrate that soluble Aβ42 turnover and exchange processes are altered in the presence of amyloid plaques, causing a reduction in Aβ42 concentrations in the CSF.


Basic residues in the T-cell receptor ζ cytoplasmic domain mediate membrane association and modulate signaling.

Abstract: The T-cell receptor (TCR) consists of a TCRαβ heterodimer, a TCRζ homodimer, and CD3γε and CD3δε heterodimers.

Abstract: The precise mechanism of T-cell triggering following TCR ligand engagement remains elusive.

Abstract: Previous studies reported that the cytoplasmic tail of CD3ε binds to the plasma membrane through a basic residue-rich stretch (BRS) and proposed that dissociation from the membrane is required for phosphorylation thereof.

Abstract: In this report we show that BRS motifs within the cytoplasmic tail of TCRζ mediate association with the plasma membrane and that TCR engagement results in TCRζ dissociation from the membrane.

Abstract: This dissociation requires phosphorylation of the TCRζ immunoreceptor tyrosine-based activation motifs by lymphocyte cell-specificprotein tyrosine kinase (Lck) but not ζ-chain-associated protein kinase 70 binding.

Abstract: Mutations of the TCRζ BRS motifs that disrupt this membrane association attenuate proximal and distal responses induced by TCR engagement.

Abstract: These mutations appear to alter the localization of TCRζ with respect to Lck as well as the mobility of the TCR complex.

Abstract: This study reveals that tyrosine phosphorylation of the TCRζ cytoplasmic domain regulates its association with the plasma membrane and highlights the functional importance of TCRζ BRS motifs.


Policies for alcohol restriction and their association with interpersonal violence: a time-series analysis of homicides in Cali, Colombia.

Abstract: BACKGROUND Cali, Colombia, has a high incidence of interpersonal violence deaths.

Abstract: Various alcohol control policies have been implemented to reduce alcohol-related problems.

Abstract: The objective of this study was to determine whether different alcohol control policies were associated with changes in the incidence rate of homicides.

Abstract: METHODS Ecologic study conducted during 2004-08 using a time-series design.

Abstract: Policies were implemented with variations in hours of restriction of sales and consumption of alcohol.

Abstract: Most restrictive policies prohibited alcohol between 2 a.m. and 10 a.m. for 446 non-consecutive days.

Abstract: Moderately restrictive policies prohibited alcohol between 3 a.m. and 10 a.m. for 1277 non-consecutive days.

Abstract: Lax policies prohibited alcohol between 4 a.m. and 10 a.m. for 104 non-consecutive days.

Abstract: In conditional autoregressive negative binomial regressions, rates of homicides and unintentional injury deaths (excluding traffic events) were compared between different periods of days when different policies were in effect.

Abstract: RESULTS There was an increased risk of homicides in periods when the moderately restrictive policies were in effect compared with periods when the most restrictive policies were in effect [incidence rate ratio (IRR) 1.15, 90% confidence interval (CI) 1.05-1.26, P = 0.012], and there was an even higher risk of homicides in periods when the lax policies were in effect compared with periods when the most restrictive policies were in effect (IRR 1.42, 90% CI 1.26-1.61, P < 0.001).

Abstract: Less restrictive policies were not associated with increased risk of unintentional injury deaths.

Abstract: CONCLUSION Extended hours of sales and consumption of alcohol were associated with increased risk of homicides.

Abstract: Strong restrictions on alcohol availability could reduce the incidence of interpersonal violence events in communities where homicides are high.


Effects of SNF1 on Maltose Metabolism and Leavening Ability of Baker's Yeast in Lean Dough.

Abstract: Maltose metabolism of baker's yeast (Saccharomyces cerevisiae) in lean dough is negatively influenced by glucose repression, thereby delaying the dough fermentation.

Abstract: To improve maltose metabolism and leavening ability, it is necessary to alleviate glucose repression.

Abstract: The Snf1 protein kinase is well known to be essential for the response to glucose repression and required for transcription of glucose-repressed genes including the maltose-utilization genes (MAL).

Abstract: In this study, the SNF1 overexpression and deletion industrial baker's yeast strains were constructed and characterized in terms of maltose utilization, growth and fermentation characteristics, mRNA levels of MAL genes (MAL62 encoding the maltase and MAL61 encoding the maltose permease) and maltase and maltose permease activities.

Abstract: Our results suggest that overexpression of SNF1 was effective to glucose derepression for enhancing MAL expression levels and enzymes (maltase and maltose permease) activities.

Abstract: These enhancements could result in an 18% increase in maltose metabolism of industrial baker's yeast in LSMLD medium (the low sugar model liquid dough fermentation medium) containing glucose and maltose and a 15% increase in leavening ability in lean dough.

Abstract: These findings provide a valuable insight of breeding industrial baker's yeast for rapid fermentation.


Review article

Abstract: Ribosomopathies compose a collection of disorders in which genetic abnormalities cause impaired ribosome biogenesis and function, resulting in specific clinical phenotypes.

Abstract: Congenital mutations in RPS19 and other genes encoding ribosomal proteins cause Diamond-Blackfan anemia, a disorder characterized by hypoplastic, macrocytic anemia.

Abstract: Mutations in other genes required for normal ribosome biogenesis have been implicated in other rare congenital syndromes, Schwachman-Diamond syndrome, dyskeratosis congenita, cartilage hair hypoplasia, and Treacher Collins syndrome.

Abstract: In addition, the 5q- syndrome, a subtype of myelodysplastic syndrome, is caused by a somatically acquired deletion of chromosome 5q, which leads to haploinsufficiency of the ribosomal protein RPS14 and an erythroid phenotype highly similar to Diamond-Blackfan anemia.

Abstract: Acquired abnormalities in ribosome function have been implicated more broadly in human malignancies.

Abstract: The p53 pathway provides a surveillance mechanism for protein translation as well as genome integrity and is activated by defects in ribosome biogenesis; this pathway appears to be a critical mediator of many of the clinical features of ribosomopathies.

Abstract: Elucidation of the mechanisms whereby selective abnormalities in ribosome biogenesis cause specific clinical syndromes will hopefully lead to novel therapeutic strategies for these diseases.


PD-L1 expression in human cancers and its association with clinical outcomes

Abstract: PD-L1 is an immunoinhibitory molecule that suppresses the activation of T cells, leading to the progression of tumors.

Abstract: Overexpression of PD-L1 in cancers such as gastric cancer, hepatocellular carcinoma, renal cell carcinoma, esophageal cancer, pancreatic cancer, ovarian cancer, and bladder cancer is associated with poor clinical outcomes.

Abstract: In contrast, PD-L1 expression correlates with better clinical outcomes in breast cancer and merkel cell carcinoma.

Abstract: The prognostic value of PD-L1 expression in lung cancer, colorectal cancer, and melanoma is controversial.

Abstract: Blocking antibodies that target PD-1 and PD-L1 have achieved remarkable response rates in cancer patients who have PD-L1-overexpressing tumors.

Abstract: However, using PD-L1 as an exclusive predictive biomarker for cancer immunotherapy is questionable due to the low accuracy of PD-L1 immunohistochemistry staining.

Abstract: Factors that affect the accuracy of PD-L1 immunohistochemistry staining are as follows.

Abstract: First, antibodies used in different studies have different sensitivity.

Abstract: Second, in different studies, the cut-off value of PD-L1 staining positivity is different.

Abstract: Third, PD-L1 expression in tumors is not uniform, and sampling time and location may affect the results of PD-L1 staining.

Abstract: Therefore, better understanding of tumor microenvironment and use of other biomarkers such as gene marker and combined index are necessary to better identify patients who will benefit from PD-1/PD-L1 checkpoint blockade therapy.


Primate cytomegaloviruses encode and express an IL-10-like protein.

Abstract: An open reading frame (ORF) with homology to interleukin-10 (IL-10) has been identified in rhesus cytomegalovirus (RhCMV).

Abstract: The IL-10-like protein is generated from a multispliced, polyadenylated early gene transcript encompassing part of the corresponding UL111A ORF of human CMV (HCMV).

Abstract: Immunological analyses confirm expression of the IL-10-like protein both in tissue culture and in RhCMV-infected rhesus macaques.

Abstract: Conserved ORFs were subsequently identified in human, baboon, and African green monkey CMV, and a fully processed transcript has been mapped in fibroblasts infected with the Towne strain of HCMV.

Abstract: The conservation of this previously unrecognized ORF suggests that the protein may play an essential role in primate CMV persistence and pathogenesis.


Genome Sequencing and Analysis of the Tasmanian Devil and Its Transmissible Cancer

Abstract: The Tasmanian devil (Sarcophilus harrisii), the largest marsupial carnivore, is endangered due to a transmissible facial cancer spread by direct transfer of living cancer cells through biting.

Abstract: Here we describe the sequencing, assembly, and annotation of the Tasmanian devil genome and whole-genome sequences for two geographically distant subclones of the cancer.

Abstract: Genomic analysis suggests that the cancer first arose from a female Tasmanian devil and that the clone has subsequently genetically diverged during its spread across Tasmania.

Abstract: The devil cancer genome contains more than 17,000 somatic base substitution mutations and bears the imprint of a distinct mutational process.

Abstract: Genotyping of somatic mutations in 104 geographically and temporally distributed Tasmanian devil tumors reveals the pattern of evolution and spread of this parasitic clonal lineage, with evidence of a selective sweep in one geographical area and persistence of parallel lineages in other populations.


A Temporarily Distinct Subpopulation of Slow-Cycling Melanoma Cells Is Required for Continuous Tumor Growth

Abstract: Melanomas are highly heterogeneous tumors, but the biological significance of their different subpopulations is not clear.

Abstract: Using the H3K4 demethylase JARID1B (KDM5B/PLU-1/RBP2-H1) as a biomarker, we have characterized a small subpopulation of slow-cycling melanoma cells that cycle with doubling times of >4 weeks within the rapidly proliferating main population.

Abstract: Isolated JARID1B-positive melanoma cells give rise to a highly proliferative progeny.

Abstract: Knockdown of JARID1B leads to an initial acceleration of tumor growth followed by exhaustion which suggests that the JARID1B-positive subpopulation is essential for continuous tumor growth.

Abstract: Expression of JARID1B is dynamically regulated and does not follow a hierarchical cancer stem cell model because JARID1B-negative cells can become positive and even single melanoma cells irrespective of selection are tumorigenic.

Abstract: These results suggest a new understanding of melanoma heterogeneity with tumor maintenance as a dynamic process mediated by a temporarily distinct subpopulation.


A map of human circular RNAs in clinically relevant tissues

Abstract: Cellular circular RNAs (circRNAs) are generated by head-to-tail splicing and are present in all multicellular organisms studied so far.

Abstract: Recently, circRNAs have emerged as a large class of RNA which can function as post-transcriptional regulators.

Abstract: It has also been shown that many circRNAs are tissue- and stage-specifically expressed.

Abstract: Moreover, the unusual stability and expression specificity make circRNAs important candidates for clinical biomarker research.

Abstract: Here, we present a circRNA expression resource of 20 human tissues highly relevant to disease-related research: vascular smooth muscle cells (VSMCs), human umbilical vein cells (HUVECs), artery endothelial cells (HUAECs), atrium, vena cava, neutrophils, platelets, cerebral cortex, placenta, and samples from mesenchymal stem cell differentiation.

Abstract: In eight different samples from a single donor, we found highly tissue-specific circRNA expression.

Abstract: Circular-to-linear RNA ratios revealed that many circRNAs were expressed higher than their linear host transcripts.

Abstract: Among the 71 validated circRNAs, we noticed potential biomarkers.

Abstract: In adenosine deaminase-deficient, severe combined immunodeficiency (ADA-SCID) patients and in Wiskott-Aldrich-Syndrome (WAS) patients' samples, we found evidence for differential circRNA expression of genes that are involved in the molecular pathogenesis of both phenotypes.

Abstract: Our findings underscore the need to assess circRNAs in mechanisms of human disease.

Abstract: KEY MESSAGES: circRNA resource catalog of 20 clinically relevant tissues.

Abstract: circRNA expression is highly tissue-specific.

Abstract: circRNA transcripts are often more abundant than their linear host RNAs.

Abstract: circRNAs can be differentially expressed in disease-associated genes.


Arp2/3 complex inhibition radically alters lamellipodial actin architecture, suspended cell shape, and the cell spreading process

Abstract: Recent studies have investigated the dendritic actin cytoskeleton of the cell edge's lamellipodial (LP) region by experimentally decreasing the activity of the actin filament nucleator and branch former, the Arp2/3 complex.

Abstract: Here we extend these studies via pharmacological inhibition of the Arp2/3 complex in sea urchin coelomocytes, cells that possess an unusually broad LP region and display correspondingly exaggerated centripetal flow.

Abstract: Using light and electron microscopy, we demonstrate that Arp2/3 complex inhibition via the drug CK666 dramatically altered LP actin architecture, slowed centripetal flow, drove a lamellipodial-to-filopodial shape change in suspended cells, and induced a novel actin structural organization during cell spreading.

Abstract: A general feature of the CK666 phenotype in coelomocytes was transverse actin arcs, and arc generation was arrested by a formin inhibitor.

Abstract: We also demonstrate that CK666 treatment produces actin arcs in other cells with broad LP regions, namely fish keratocytes and Drosophila S2 cells.

Abstract: We hypothesize that the actin arcs made visible by Arp2/3 complex inhibition in coelomocytes may represent an exaggerated manifestation of the elongate mother filaments that could possibly serve as the scaffold for the production of the dendritic actin network.


Synergistic Activation of HIV-1 Expression by Deacetylase Inhibitors and Prostratin: Implications for Treatment of Latent Infection

Abstract: The persistence of transcriptionally silent but replication-competent HIV-1 reservoirs in Highly Active Anti-Retroviral Therapy (HAART)-treated infected individuals, represents a major hurdle to virus eradication.

Abstract: Activation of HIV-1 gene expression in these cells together with an efficient HAART has been proposed as an adjuvant therapy aimed at decreasing the pool of latent viral reservoirs.

Abstract: Using the latently-infected U1 monocytic cell line and latently-infected J-Lat T-cell clones, we here demonstrated a strong synergistic activation of HIV-1 production by clinically used histone deacetylase inhibitors (HDACIs) combined with prostratin, a non-tumor-promoting nuclear factor (NF)- kappaB inducer.

Abstract: In J-Lat cells, we showed that this synergism was due, at least partially, to the synergistic recruitment of unresponsive cells into the expressing cell population.

Abstract: A combination of prostratin+HDACI synergistically activated the 5' Long Terminal Repeat (5'LTR) from HIV-1 Major group subtypes representing the most prevalent viral genetic forms, as shown by transient transfection reporter assays.

Abstract: Mechanistically, HDACIs increased prostratin-induced DNA-binding activity of nuclear NF-kappaB and degradation of cytoplasmic NF-kappaB inhibitor, IkappaBalpha .

Abstract: Moreover, the combined treatment prostratin+HDACI caused a more pronounced nucleosomal remodeling in the U1 viral promoter region than the treatments with the compounds alone.

Abstract: This more pronounced remodeling correlated with a synergistic reactivation of HIV-1 transcription following the combined treatment prostratin+HDACI, as demonstrated by measuring recruitment of RNA polymerase II to the 5'LTR and both initiated and elongated transcripts.

Abstract: The physiological relevance of the prostratin+HDACI synergism was shown in CD8(+)-depleted peripheral blood mononuclear cells from HAART-treated patients with undetectable viral load.

Abstract: Moreover, this combined treatment reactivated viral replication in resting CD4(+) T cells isolated from similar patients.

Abstract: Our results suggest that combinations of different kinds of proviral activators may have important implications for reducing the size of latent HIV-1 reservoirs in HAART-treated patients.


Centrosome aberrations: cause or consequence of cancer progression?

Abstract: Many human tumours show centrosome aberrations, indicating an underlying deregulation of centrosome structure, duplication or segregation.

Abstract: Centrosomes organize microtubule arrays throughout the cell cycle, thereby influencing both tissue architecture and the accuracy of chromosome segregation.

Abstract: But what are the origins of centrosomal abnormalities in tumours, and what impact do they have on the generation of invasive, genetically unbalanced cells during cancer progression?


Autonomic neuropathy, QT interval lengthening, and unexpected deaths in male diabetic patients

Abstract: QT intervals were measured over RR intervals ranging from 500 ms to 1000 ms in 13 normal male subjects, 13 male diabetic subjects without and 13 with autonomic neuropathy.

Abstract: There was a close linear relationship between QT and RR in all subjects.

Abstract: The slope of the regression line was significantly greater in the autonomic neuropathy group than the normal group.

Abstract: Thirty-two male diabetic subjects with varying degrees of autonomic dysfunction had repeat QT measurements 3 (range 2–6) years later.

Abstract: QT and QTC lengthened significantly at the second visit, unrelated to age or time between recordings, but which corresponded with changes in autonomic function.

Abstract: Of 71 male diabetic subjects under 60 years followed for 3 years, 13 had died, 8 unexpectedly.

Abstract: Of those with autonomic neuropathy, QT and QTC were significantly longer in those who subsequently died, despite similar ages and duration of diabetes.

Abstract: We conclude that QT/RR interval relationships are altered in diabetic autonomic neuropathy, and that changes in QT length with time parallel changese in autonomic function.

Abstract: There may be an association between QT interval prolongation and the risk of dying unexpectedly in diabetic autonomic neuropathy.


Incidence of cancer after immunosuppressive treatment for heart transplantation.

Abstract: Prolonged or intensive immunosuppressive therapy used after organ transplantation is complicated by an increased incidence of cancer.

Abstract: Striking differences in incidence are observed in heart and heart-lung transplant recipients when compared with renal transplant patients.

Abstract: The most significant increase was in the incidence of lymphomas in cardiac versus renal patients.

Abstract: Moreover, a two-fold greater increase of all neoplasms was found in cardiac recipients, with nearly a six-fold increase in visceral tumors.

Abstract: Several factors may account for these differences.

Abstract: In cardiac allograft recipients, intensive immunosuppression is frequently used to reverse acute rejection and the highest number of cardiac transplants was performed in the era of polypharmacy, usually consisting of triple therapy.


Nucleating actin for invasion

Abstract: The invasion of cancer cells into the surrounding tissue is a prerequisite and initial step in metastasis, which is the leading cause of death from cancer.

Abstract: Invasive cell migration requires the formation of various structures, such as invadopodia and pseudopodia, which require actin assembly that is regulated by specialized actin nucleation factors.

Abstract: There is a large variety of different actin nucleators in human cells, such as formins, spire and Arp2/3-regulating proteins, and the list is likely to grow.

Abstract: Studies of the mechanisms of various actin nucleation factors that are involved in cancer cell function may ultimately provide new treatments for invasive and metastatic disease.


GFI1 and GFI1B control the loss of endothelial identity of hemogenic endothelium during hematopoietic commitment.

Abstract: Recent studies have established that during embryonic development, hematopoietic progenitors and stem cells are generated from hemogenic endothelium precursors through a process termed endothelial to hematopoietic transition (EHT).

Abstract: The transcription factor RUNX1 is essential for this process, but its main downstream effectors remain largely unknown.

Abstract: Here, we report the identification of Gfi1 and Gfi1b as direct targets of RUNX1 and critical regulators of EHT.

Abstract: GFI1 and GFI1B are able to trigger, in the absence of RUNX1, the down-regulation of endothelial markers and the formation of round cells, a morphologic change characteristic of EHT.

Abstract: Conversely, blood progenitors in Gfi1- and Gfi1b-deficient embryos maintain the expression of endothelial genes.

Abstract: Moreover, those cells are not released from the yolk sac and disseminated into embryonic tissues.

Abstract: Taken together, our findings demonstrate a critical and specific role of the GFI1 transcription factors in the first steps of the process leading to the generation of hematopoietic progenitors from hemogenic endothelium.


An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells.

Abstract: In a diverse group of organisms that includes Caenorhabditis elegans, Drosophila, planaria, hydra, trypanosomes, fungi and plants, the introduction of double-stranded RNAs inhibits gene expression in a sequence-specific manner.

Abstract: These responses, called RNA interference or post-transcriptional gene silencing, may provide anti-viral defence, modulate transposition or regulate gene expression.

Abstract: We have taken a biochemical approach towards elucidating the mechanisms underlying this genetic phenomenon.

Abstract: Here we show that 'loss-of-function' phenotypes can be created in cultured Drosophila cells by transfection with specific double-stranded RNAs.

Abstract: This coincides with a marked reduction in the level of cognate cellular messenger RNAs.

Abstract: Extracts of transfected cells contain a nuclease activity that specifically degrades exogenous transcripts homologous to transfected double-stranded RNA.

Abstract: This enzyme contains an essential RNA component.

Abstract: After partial purification, the sequence-specific nuclease co-fractionates with a discrete, approximately 25-nucleotide RNA species which may confer specificity to the enzyme through homology to the substrate mRNAs.


Expression of basal cell keratin 15 and keratin 19 in oral squamous neoplasms represents diverse pathophysiologies.

Abstract: Human epithelium contains keratin, which is expressed during differentiation.

Abstract: Depending on the target cell type, different types of keratin are expressed, and their alterations seem to represent changes in cell properties.

Abstract: The basal cells of oral epithelium express keratin 5 (K5), K14, K15 and K19, but their alterations in tumors are unclear.

Abstract: To address this issue and to seek possible diagnostic application, we examined the expression of these keratins in oral squamous cell carcinoma (OSCC) and squamous intraepithelial neoplasm (SIN).

Abstract: cDNA microarray analysis of 43 OSCC revealed slight upregulation of KRT14, downregulation of KRT15 and KRT19, and unaltered KRT5 expression.

Abstract: There were great variations in KRT15 and KRT19 expression across each cancer.

Abstract: Well-differentiated OSCC tended to express more KRT15 and less KRT19 compared to moderately- or poorly-differentiated OSCC.

Abstract: KRT15 was positively correlated with differentiation-related keratin, KRT13.

Abstract: These observations were further investigated by immunohistochemical examination.

Abstract: K5 and K14 were ubiquitously expressed in all 50 OSCC and 50 SIN examined.

Abstract: K15 and K19 were generally downregulated, but were considerably retained in about half of the cases and showed diverse expression patterns.

Abstract: K15-positive cancers tended to show a well-differentiated phenotype, and K19-positive cancers tended to show more invasive tumor fronts.

Abstract: Most K19-positive cancers appeared to develop with little associating SIN.

Abstract: K19 was consistently downregulated in SIN, while K15 was downregulated mainly in high grade SIN.

Abstract: In summary, K15 and K19, unlike K5 or K14, are expressed variably in both SIN and OSCC, which reflects the differences in their pathogenesis and biological behaviors, suggesting their prospective applications as markers for subclassifying OSCC and SIN.


Exosomes in Plasma of Patients with Ovarian Carcinoma: Potential Biomarkers of Tumor Progression and Response to Therapy.

Abstract: BACKGROUND In patients with Ovarian Cancer (OvCa) exosomes released by tumor cells are present in the plasma and could be involved in tumor progression.

Abstract: This study examines the association between the exosome presence/protein content in plasma of OvCa patients and disease outcome, response to standard therapy and/or tumorresistance to therapies in patients studied at diagnosis and also serially during and after therapy.

Abstract: DESIGN AND METHODS Exosomes were purified from OvCa patients' plasma (n=22), patients with benign tumors (n=10) or (n=10) healthy controls (NC) using ultracentrifugation.

Abstract: Exosomes were visualized by scanning electron microscopy.

Abstract: Their protein content was measured.

Abstract: The presence of MAGE 3/6 and TGF-β1 in exosomes was evaluated in Western blots.

Abstract: RESULTS The OvCa patients' plasma contained higher levels of exosomal proteins (p<0.05) compared to those isolated from plasma of patients with benign tumors or NC.

Abstract: Exosomes isolated from OvCa patients's plasma carried TGF-β1 and MAGE3/6, which distinguished OvCa patients from those with benign tumors and NC.

Abstract: High protein levels of exosomes were seen in newly diagnosed patients; however in advanced stages of OvCa patients the protein content of isolated exosomes was significantly higher than that of early stages.

Abstract: The exosome levels variably changed during/after chemotherapy, and correlations between the changes in exosomal protein levels and clinical data suggested that the protein content of exosomes might be useful in predicting responses to therapy and prognosis in OvCa patients.

Abstract: CONCLUSION Analysis of plasma exosomes levels offers a novel approach to diagnosis and monitoring response to therapies in OvCa patients.


Insecticide impregnated curtains to control domestic transmission of cutaneous leishmaniasis in Venezuela: cluster randomised trial.

Abstract: OBJECTIVE To measure the impact on transmission of leishmaniasis of curtains impregnated with insecticide.

Abstract: DESIGN Cluster randomised controlled trial: household interview survey, observational study of people's behaviour, entomological study with light trap captures of sandflies inside houses.

Abstract: SETTING 14 urban sectors in Trujillo, Venezuela.

Abstract: PARTICIPANTS 2913 inhabitants of 569 houses.

Abstract: INTERVENTION Sectors were paired according to their 12 month cumulative incidence of cutaneous leishmaniasis, one sector in each pair was randomly allocated to receive polyester curtains impregnated with lambdacyhalothrin (intervention group) while the other sector received curtains without insecticide or no curtains (control groups).

Abstract: After 12 months a follow up household survey was conducted.

Abstract: MAIN OUTCOME MEASURES Reduction in abundance of sandflies indoors and 12 month incidence of clinical cases of cutaneous leishmaniasis.

Abstract: RESULTS Transmission of cutaneous leishmaniasis occurred mainly in the domestic setting, with the incidence over 12 months of 4%.

Abstract: The mean number of sandflies per trap per night was 16.

Abstract: After follow up the 12 month incidence of cutaneous leishmaniasis was 0% in the intervention group and 8% in the six pairs in the control group that received unimpregnated curtains (mean difference 8, 95% confidence interval 4.22 to 11.78; P=0.001).

Abstract: There were significantly fewer sandflies in the intervention group (2 v 15, mean difference 13 sandflies per trap; 9 to 17; P<0.001).

Abstract: CONCLUSION Curtains impregnated with insecticide provide a high degree of protection against indoor transmission of cutaneous leishmaniasis.


Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice.

Abstract: Pancreatic ductal adenocarcinoma (PDA), one of the deadliest human cancers, often involves somatic activation of K-Ras oncogenes.

Abstract: We report that selective expression of an endogenous K-Ras(G12V) oncogene in embryonic cells of acinar/centroacinar lineage results in pancreatic intraepithelial neoplasias (PanINs) and invasive PDA, suggesting that PDA originates by differentiation of acinar/centroacinar cells or their precursors into ductal-like cells.

Abstract: Surprisingly, adult mice become refractory to K-Ras(G12V)-induced PanINs and PDA.

Abstract: However, if these mice are challenged with a mild form of chronic pancreatitis, they develop the full spectrum of PanINs and invasive PDA.

Abstract: These observations suggest that, during adulthood, PDA stems from a combination of genetic (e.g., somatic K-Ras mutations) and nongenetic (e.g., tissue damage) events.


Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cells transplanted into infarcted mice.

Abstract: RATIONALE Multiple biological mechanisms contribute to the efficacy of cardiac cell therapy.

Abstract: Most prominent among these are direct heart muscle and blood vessel regeneration from transplanted cells, as opposed to paracrine enhancement of tissue preservation and/or recruitment of endogenous repair.

Abstract: OBJECTIVE Human cardiac progenitor cells, cultured as cardiospheres (CSps) or as CSp-derived cells (CDCs), have been shown to be capable of direct cardiac regeneration in vivo.

Abstract: Here we characterized paracrine effects in CDC transplantation and investigated their relative importance versus direct differentiation of surviving transplanted cells.

Abstract: METHODS AND RESULTS In vitro, many growth factors were found in media conditioned by human adult CSps and CDCs; CDC-conditioned media exerted antiapoptotic effects on neonatal rat ventricular myocytes, and proangiogenic effects on human umbilical vein endothelial cells.

Abstract: In vivo, human CDCs secreted vascular endothelial growth factor, hepatocyte growth factor, and insulin-like growth factor 1 when transplanted into the same SCID mouse model of acute myocardial infarction where they were previously shown to improve function and to produce tissue regeneration.

Abstract: Injection of CDCs in the peri-infarct zone increased the expression of Akt, decreased apoptotic rate and caspase 3 level, and increased capillary density, indicating overall higher tissue resilience.

Abstract: Based on the number of human-specific cells relative to overall increases in capillary density and myocardial viability, direct differentiation quantitatively accounted for 20% to 50% of the observed effects.

Abstract: CONCLUSIONS Together with their spontaneous commitment to cardiac and angiogenic differentiation, transplanted CDCs serve as "role models," recruiting endogenous regeneration and improving tissue resistance to ischemic stress.

Abstract: The contribution of the role model effect rivals or exceeds that of direct regeneration.


The IC(50) of anti-Pfs25 antibody in membrane-feeding assay varies among species.

Abstract: Plasmodium falciparum surface protein 25 (Pfs25) is a candidate for transmission-blocking vaccines (TBVs).

Abstract: Anti-Pfs25 antibodies block the development of oocysts in membrane-feeding assays and we have shown the activity correlates with antibody titer.

Abstract: In this study, we purified Pfs25-specific IgGs to convert antibody titer to microg/mL and determined the amount of antibody required to inhibit 50% of oocyst development (IC(50)).

Abstract: The IC(50) were, 15.9, 4.2, 41.2, and 85.6microg/mL for mouse, rabbit, monkey and human, respectively, and the differences among species were significant.

Abstract: Anti-Pfs25 sera from rabbit, monkey and human showed different patterns of competition against 6 mouse monoclonal antibodies, and the avidity of antibodies among four species were also different.

Abstract: These data suggests that information obtained from animal studies which assess efficacy of TBV candidates may be difficult to translate to human immunization.


Single-Cell RNA-Seq Reveals Dynamic, Random Monoallelic Gene Expression in Mammalian Cells

Abstract: Expression from both alleles is generally observed in analyses of diploid cell populations, but studies addressing allelic expression patterns genome-wide in single cells are lacking.

Abstract: Here, we present global analyses of allelic expression across individual cells of mouse preimplantation embryos of mixed background (CAST/EiJ × C57BL/6J).

Abstract: We discovered abundant (12 to 24%) monoallelic expression of autosomal genes and that expression of the two alleles occurs independently.

Abstract: The monoallelic expression appeared random and dynamic because there was considerable variation among closely related embryonic cells.

Abstract: Similar patterns of monoallelic expression were observed in mature cells.

Abstract: Our allelic expression analysis also demonstrates the de novo inactivation of the paternal X chromosome.

Abstract: We conclude that independent and stochastic allelic transcription generates abundant random monoallelic expression in the mammalian cell.


Lipopolysaccharide-dependent prostaglandin E(2) production is regulated by the glutathione-dependent prostaglandin E(2) synthase gene induced by the Toll-like receptor 4/MyD88/NF-IL6 pathway.

Abstract: Macrophages produce a large amount of PGE(2) during inflammation.

Abstract: This lipid mediator modulates various immune responses.

Abstract: PGE(2) acts on macrophages and inhibits production of cytokines such as TNF-alpha and IL-12.

Abstract: Membrane-bound glutathione-dependent PGE(2) synthase (mPGES) has been shown to be a terminal enzyme of the cyclooxygenase-2-mediated PGE(2) biosynthesis.

Abstract: Here we identified mPGES as a molecule that is induced by LPS in macrophages.

Abstract: The expression of mPGES was not induced by LPS in mice lacking Toll-like receptor 4 or MyD88.

Abstract: Furthermore, mice deficient in NF-IL6 showed neither induction of mPGES nor biosynthesis of PGE(2) in response to LPS, indicating that mPGES expression in response to LPS is regulated by a Toll-like receptor 4/MyD88/NF-IL6-dependent signaling pathway.

Abstract: We generated mPGES-deficient mice and investigated the role of mPGES in vivo.

Abstract: The mice showed no augmentation of the PGE(2) production in response to LPS.

Abstract: However, they were not impaired in the LPS-induced production of inflammatory cytokines and showed normal response to the LPS-induced shock.

Abstract: Thus, mPGES is critically involved in the biosynthesis of PGE(2) induced by LPS, but is dispensable for the modulation of inflammatory responses.


A microRNA feedback loop regulates global microRNA abundance during aging.

Abstract: Expression levels of many microRNAs (miRNAs) change during aging, notably declining globally in a number of organisms and tissues across taxa.

Abstract: However, little is known about the mechanisms or the biological relevance for this change.

Abstract: We investigated the network of genes that controls miRNA transcription and processing during C. elegans aging.

Abstract: We found that miRNA biogenesis genes are highly networked with transcription factors and aging-associated miRNAs.

Abstract: In particular, miR-71, known to influence life span and itself up-regulated during aging, represses alg-1/Argonaute expression post-transcriptionally during aging.

Abstract: Increased ALG-1 abundance in mir-71 loss-of-function mutants led to globally increased miRNA expression.

Abstract: Interestingly, these mutants demonstrated widespread mRNA expression dysregulation and diminished levels of variability both in gene expression and in overall life span.

Abstract: Thus, the progressive molecular decline often thought to be the result of accumulated damage over an organism's life may be partially explained by a miRNA-directed mechanism of age-associated decline.


Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice

Abstract: Interleukin 7 (IL-7) stimulates the proliferation of B cell progenitors, thymocytes, and mature T cells through an interaction with a high affinity receptor (IL-7R) belonging to the hematopoietin receptor superfamily.

Abstract: We have further addressed the role of IL-7 and its receptor during B and T cell development by generating mice genetically deficient in IL-7R.

Abstract: Mutant mice display a profound reduction in thymic and peripheral lymphoid cellularity.

Abstract: Analyses of lymphoid progenitor populations in IL-7R-deficient mice define precisely those developmental stages affected by the mutation and reveal a critical role for IL-7R during early lymphoid development.

Abstract: Significantly, these studies indicate that the phase of thymocyte expansion occurring before the onset of T cell receptor gene rearrangement is critically dependent upon, and mediated by the high affinity receptor for IL-7.


Immune Activation with HIV Vaccines

Abstract: The development of a safe and effective HIV vaccine is perhaps the most important and challenging goal remaining in HIV-AIDS research.

Abstract: Recent progress using a poxvirus vector prime and envelope protein boost strategy demonstrated a modest but statistically significant level of efficacy and established the concept that a vaccine could prevent HIV infection (1), and approaches to boost durability and efficacy are currently in the planning stages (2).

Abstract: But the results of two vaccine concepts based on recombinant adenovirus serotype-5 (rAd5) (3–5) pointed to a potential major problem—that such vaccines might increase susceptibility to HIV infection.

Abstract: This also raised the question of whether the problem extends to some or all of the other recombinant adenovirus vectors currently in development or to other vector-based vaccines.


Distribution of dystrophin- and utrophin-associated protein complexes during activation of human neutrophils.

Abstract: OBJECTIVE Dystrophins, utrophins, and their associated proteins are involved in structural and signaling roles in nonmuscle tissues; however, description of these proteins in neutrophils remained unexplored.

Abstract: Therefore we characterize the pattern expression, and the cellular distribution of dystrophin and utrophin gene products and dystrophin-associated proteins (i.e., beta-dystroglycan, alpha-syntrophin, and alpha-dystrobrevins) in relation to actin filaments in resting and activated with formyl-methionyl-leucyl-phenylalanine human neutrophils.

Abstract: MATERIALS AND METHODS Resting and fMLP-activated human neutrophils were analyzed by immunoblot and by confocal microscopy analysis.

Abstract: Immunoprecipitation assays were performed to corroborate the presence of protein complexes.

Abstract: RESULTS Immunoprecipitation assays and confocal analysis demonstrated the presence of two dystrophin-associated protein complexes in resting and activated neutrophils: the former formed by Dp71d/Dp71Delta(110)(m) and dystrophin-associated proteins (beta-dystroglycan, alpha-syntrophin, alpha-dystrobrevin-1, and -2), while the latter contains Up400, instead of Dp71d/Dp71Delta(110)(m), as a central component of the dystrophin-associated protein complexes (DAPC).

Abstract: Confocal analysis also showed the subcellular redistribution of Dp71d/Dp71Delta(110)(m) approximately DAPC and Up400 approximately DAPC in F-actin-based structures displayed during activation process with fMLP.

Abstract: CONCLUSIONS Our study showed the existence of two protein complexes formed by Dp71d/Dp71Delta(110)(m) or Up400 associated with DAPs in resting and fMLP-treated human polymorphonuclears.

Abstract: The interaction of these complexes with the actin cytoskeleton is indicative of their dynamic participation in the chemotaxis process.


Global and regional burden of hospital admissions for severe acute lower respiratory infections in young children in 2010: a systematic analysis

Abstract: BACKGROUND The annual number of hospital admissions and in-hospital deaths due to severe acute lower respiratory infections (ALRI) in young children worldwide is unknown.

Abstract: We aimed to estimate the incidence of admissions and deaths for such infections in children younger than 5 years in 2010.

Abstract: METHODS We estimated the incidence of admissions for severe and very severe ALRI in children younger than 5 years, stratified by age and region, with data from a systematic review of studies published between Jan 1, 1990, and March 31, 2012, and from 28 unpublished population-based studies.

Abstract: We applied these incidence estimates to population estimates for 2010, to calculate the global and regional burden in children admitted with severe ALRI in that year.

Abstract: We estimated in-hospital mortality due to severe and very severe ALRI by combining incidence estimates with case fatality ratios from hospital-based studies.

Abstract: FINDINGS We identified 89 eligible studies and estimated that in 2010, 11·9 million (95% CI 10·3-13·9 million) episodes of severe and 3·0 million (2·1-4·2 million) episodes of very severe ALRI resulted in hospital admissions in young children worldwide.

Abstract: Incidence was higher in boys than in girls, the sex disparity being greatest in South Asian studies.

Abstract: On the basis of data from 37 hospital studies reporting case fatality ratios for severe ALRI, we estimated that roughly 265,000 (95% CI 160,000-450,000) in-hospital deaths took place in young children, with 99% of these deaths in developing countries.

Abstract: Therefore, the data suggest that although 62% of children with severe ALRI are treated in hospitals, 81% of deaths happen outside hospitals.

Abstract: INTERPRETATION Severe ALRI is a substantial burden on health services worldwide and a major cause of hospital referral and admission in young children.

Abstract: Improved hospital access and reduced inequities, such as those related to sex and rural status, could substantially decrease mortality related to such infection.

Abstract: Community-based management of severe disease could be an important complementary strategy to reduce pneumonia mortality and health inequities.

Abstract: FUNDING WHO.


Identification of a novel p53 functional domain that is necessary for mediating apoptosis.

Abstract: The ability of p53 to induce apoptosis requires its sequence-specific DNA binding activity; however, the transactivation-deficient p53(Gln22-Ser23) can still induce apoptosis.

Abstract: Previously, we have shown that the region between residues 23 and 97 in p53 is necessary for such activity.

Abstract: In an effort to more precisely map a domain necessary for apoptosis within the N terminus, we found that deletion of the N-terminal 23 amino acids compromises, but does not abolish, p53 induction of apoptosis.

Abstract: Surprisingly, p53(Delta1-42), which lacks the N-terminal 42 amino acids and the previously defined activation domain, retains the ability to induce apoptosis to an even higher level than wild-type p53.

Abstract: A more extensive deletion, which eliminates the N-terminal 63 amino acids, renders p53 completely inert in mediating apoptosis.

Abstract: In addition, we found that both p53(Delta1-42) and p53(Gln22-Ser23) can activate a subset of cellular p53 targets.

Abstract: Furthermore, we showed that residues 53 and 54 are critical for the apoptotic and transcriptional activities of both p53(Delta1-42) and p53(Gln22-Ser23).

Abstract: Taken together, these data suggest that within residues 43-63 lie an apoptotic domain as well as another transcriptional activation domain.

Abstract: We therefore postulate that the apoptotic activity in p53(Gln22-Ser23) and p53(Delta1-42) is still transcription-dependent.


Risk of breast cancer in relation to blood lipids: a prospective study of 31,209 Norwegian women

Abstract: In this prospective study, the relationship between blood lipids and breast cancer risk was examined.

Abstract: Between 1977 and 1983, 31,209 Norwegian women, 20 to 54 years of age, attended a health screening carried out by the Norwegian National Health Screening Services.

Abstract: The screening consisted of a questionnaire, anthropometric measurements, and nonfasting blood drawn for analysis of total serum cholesterol (TC), triglyceride (TG), and high density lipoprotein (HDL) cholesterol.

Abstract: Low density lipoprotein (LDL) cholesterol was calculated by the Friedewald's formula.

Abstract: During the seven to 13 years of follow-up, 302 breast cancer cases were identified by linkage to the Norwegian Cancer Registry.

Abstract: After adjustment for some of the known risk factors of breast cancer, the relative risk of women in the highest quartile of TC compared with women in the lowest quartile was 0.87 (95 percent confidence interval [CI]=0.61–1.23).

Abstract: The corresponding relative risks and CIs were 0.82 (CI=0.58–1.16) for TG, 1.02 (CI=0.73–1.42) for HDL, and 0.93 (CI=0.67–1.29) for LDL.

Abstract: No association between breast cancer risk and blood lipids was found in the total population, nor when the data were divided into those diagnosed before or after the age of 50 as a dividing line between pre- and postmenopausal diagnosis.


Involvement of lysosomal dysfunction in autophagosome accumulation and early pathologies in adipose tissue of obese mice

Abstract: Whether obesity accelerates or suppresses autophagy in adipose tissue is still debatable.

Abstract: To clarify dysregulation of autophagy and its role in pathologies of obese adipose tissue, we focused on lysosomal function, protease maturation and activity, both in vivo and in vitro.

Abstract: First, we showed that autophagosome formation was accelerated, but autophagic clearance was impaired in obese adipose tissue.

Abstract: We also found protein and activity levels of CTSL (cathepsin L) were suppressed in obese adipose tissue, while the activity of CTSB (cathepsin B) was significantly enhanced.

Abstract: Moreover, cellular senescence and inflammasomes were activated in obese adipose tissue.

Abstract: In 3T3L1 adipocytes, downregulation of CTSL deteriorated autophagic clearance, upregulated expression of CTSB, promoted cellular senescence and activated inflammasomes.

Abstract: Upregulation of CTSB promoted additional activation of inflammasomes.

Abstract: Therefore, we suggest lysosomal dysfunction observed in obese adipose tissue leads to lower autophagic clearance, resulting in autophagosome accumulation.

Abstract: Simultaneously, lysosomal abnormalities, including deteriorated CTSL function and compensatory activation of CTSB, caused cellular senescence and inflammasome activation.

Abstract: Our findings strongly suggest lysosomal dysfunction is involved in early pathologies of obese adipose tissue.


ARNO regulates VEGF-dependent tissue responses by stabilizing endothelial VEGFR-2 surface expression.

Abstract: AIMS The vascular endothelial growth factor (VEGF) stimulates angiogenesis by induction of vessel permeability, proliferation, and migration of endothelial cells, an important process in ischaemic diseases.

Abstract: ADP-ribosylation factor (ARF) nucleotide-binding site opener (ARNO) (cytohesin-2) is a guanine exchange factor important for cellular signalling through ARF GTPases.

Abstract: However, a role for ARNO in VEGF-dependent endothelial processes has so far not been documented.

Abstract: Therefore, we investigated whether ARNO has a role in VEGF-dependent activation of endothelial cells and thus vessel permeability.

Abstract: METHODS AND RESULTS ARNO expression was observed in endothelial cells in vitro by RT-PCR, western blotting, and immunofluorescence as well as ex vivo by immunohistochemical staining of mouse aorta.

Abstract: Treatment with the cytohesin inhibitor SecinH3 or with an ARNO siRNA prevented VEGF-dependent Akt activation, assessed by detection of phosphorylated Akt, and proliferation of endothelial cells in vitro, measured by methylthiazoletetrazolium (MTT) reduction.

Abstract: In addition, ARNO suppression reduced VEGF-induced permeability in vessels of the mouse (C57BL/6) cremaster muscle in vivo, as measured by extravasation of fluorescein isothiocyanate (FITC)-dextran.

Abstract: Moreover, ARNO knock-down accelerated ligand-induced reduction in vascular endothelial growth factor receptor-2 (VEGFR-2) surface expression, internalization, and degradation, as assessed by flow cytometry and western blotting, respectively.

Abstract: CONCLUSION Our findings indicate an important and novel role for endothelial ARNO in VEGF-dependent initiation of angiogenesis by regulation of VEGFR-2 internalization in endothelial cells, resulting in the activation of the Akt pathway, vessel permeability, and ultimately endothelial proliferation.

Abstract: Thus, ARNO may be a new essential player in endothelial signalling and angiogenesis.


Effects of Hypoxia and Oxidative Stress on Expression of Neprilysin in Human Neuroblastoma Cells and Rat Cortical Neurones and Astrocytes

Abstract: Pathogenesis of Alzheimer’s disease (AD), which is characterised by accumulation of extracellular deposits of β-amyloid peptide (Aβ) in the brain, has recently been linked to vascular disorders such as ischemia and stroke.

Abstract: Aβ is constantly produced in the brain from amyloid precursor protein (APP) through its cleavage by β- and γ-secretases and certain Aβ species are toxic for neurones.

Abstract: The brain has an endogenous mechanism of Aβ removal via proteolytic degradation and the zinc metalloproteinase neprilysin (NEP) is a critical regulator of Aβ concentration.

Abstract: Down-regulation of NEP could predispose to AD.

Abstract: By comparing the effects of hypoxia and oxidative stress on expression and activity of the Aβ-degrading enzyme NEP in human neuroblastoma NB7 cells and rat primary cortical neurones we have demonstrated that hypoxia reduced NEP expression at the protein and mRNA levels as well as its activity.

Abstract: On contrary in astrocytes hypoxia increased NEP mRNA expression.


Genetics and Beyond – The Transcriptome of Human Monocytes and Disease Susceptibility

Abstract: BACKGROUND Variability of gene expression in human may link gene sequence variability and phenotypes; however, non-genetic variations, alone or in combination with genetics, may also influence expression traits and have a critical role in physiological and disease processes.

Abstract: METHODOLOGY/PRINCIPAL FINDINGS To get better insight into the overall variability of gene expression, we assessed the transcriptome of circulating monocytes, a key cell involved in immunity-related diseases and atherosclerosis, in 1,490 unrelated individuals and investigated its association with >675,000 SNPs and 10 common cardiovascular risk factors.

Abstract: Out of 12,808 expressed genes, 2,745 expression quantitative trait loci were detected (P<5.78x10(-12)), most of them (90%) being cis-modulated.

Abstract: Extensive analyses showed that associations identified by genome-wide association studies of lipids, body mass index or blood pressure were rarely compatible with a mediation by monocyte expression level at the locus.

Abstract: At a study-wide level (P<3.9x10(-7)), 1,662 expression traits (13.0%) were significantly associated with at least one risk factor.

Abstract: Genome-wide interaction analyses suggested that genetic variability and risk factors mostly acted additively on gene expression.

Abstract: Because of the structure of correlation among expression traits, the variability of risk factors could be characterized by a limited set of independent gene expressions which may have biological and clinical relevance.

Abstract: For example expression traits associated with cigarette smoking were more strongly associated with carotid atherosclerosis than smoking itself.

Abstract: CONCLUSIONS/SIGNIFICANCE This study demonstrates that the monocyte transcriptome is a potent integrator of genetic and non-genetic influences of relevance for disease pathophysiology and risk assessment.


Molecular mechanisms of (-)-epicatechin and chlorogenic acid on the regulation of the apoptotic and survival/proliferation pathways in a human hepatoma cell line.

Abstract: Dietary polyphenols have been associated with reduced risk of chronic diseases, but the precise molecular mechanisms of protection remain unclear.

Abstract: This work was aimed at studying the effect of (-)-epicatechin (EC) and chlorogenic acid (CGA) on the regulation of apoptotic and survival/proliferation pathways in a human hepatoma cell line (HepG2).

Abstract: EC or CGA treatment for 18 h had a slight effect on cell viability and decreased reactive oxygen species formation, and EC alone promoted cell proliferation, whereas CGA increased glutathione levels.

Abstract: Phenols neither induced the caspase cascade for apoptosis nor affected expression levels of Bcl-xL or Bax.

Abstract: A sustained activation of the major survival signals AKT/PI-3-kinase and ERK was shown in EC-treated cells, rather than in CGA-exposed cells.

Abstract: These data suggest that EC and CGA have no effect on apoptosis and enhance the intrinsic cellular tolerance against oxidative insults either by activating survival/proliferation pathways or by increasing antioxidant potential in HepG2.


Wnt5a mediates nerve growth factor-dependent axonal branching and growth in developing sympathetic neurons.

Abstract: Nerve growth factor (NGF) is a potent survival and axon growth factor for neuronal populations in the peripheral nervous system.

Abstract: Although the mechanisms by which target-derived NGF influences survival of innervating neurons have been extensively investigated, its regulation of axonal growth and target innervation are just being elucidated.

Abstract: Here, we identify Wnt5a, a member of the Wnt family of secreted growth factors, as a key downstream effector of NGF in mediating axonal branching and growth in developing sympathetic neurons.

Abstract: Wnt5a is robustly expressed in sympathetic neurons when their axons are innervating NGF-expressing targets.

Abstract: NGF:TrkA signaling enhances neuronal expression of Wnt5a.

Abstract: Wnt5a rapidly induces axon branching while it has a long-term effect on promoting axon extension.

Abstract: Loss of Wnt5a function revealed that it is necessary for NGF-dependent axonal branching and growth, but not survival, in vitro.

Abstract: Furthermore, Wnt5a(-/-) mice display reduced innervation of NGF-expressing target tissues, and a subsequent increase in neuronal apoptosis, in vivo.

Abstract: Wnt5a functions in developing sympathetic neurons by locally activating protein kinase C in axons.

Abstract: Together, our findings define a novel regulatory pathway in which Wnt5a, expressed in sympathetic neurons in response to target-derived NGF, regulates innervation of peripheral targets.


The Snf1 kinase controls glucose repression in yeast by modulating interactions between the Mig1 repressor and the Cyc8-Tup1 co-repressor.

Abstract: Among lower eukaryotes, glucose repression is a conserved, widely spread mechanism regulating carbon catabolism.

Abstract: The yeast Snf1 kinase, the Mig1 DNA-binding repressor and the Mig1-interacting co-repressor complex Cyc8(Ssn6)-Tup1 are central components of this pathway.

Abstract: Previous experiments suggested that cytoplasmic translocation of Mig1, upon its phosphorylation by Snf1 in the nucleus, is the key regulatory step for releasing glucose repression.

Abstract: In this report we re-evaluate this model.

Abstract: We establish the coordinated repressive action of Mig1 and Cyc8-Tup1 on GAL1 transcription, but we find that Cyc8-Tup1 is not tethered by Mig1 to the promoter DNA.

Abstract: We demonstrate that both negative regulators occupy GAL1 continuously under either repression or activation conditions, although the majority of the Mig1 is redistributed to the cytoplasm upon activation.

Abstract: We show that Snf1-dependent phosphorylation of Mig1 abolishes interaction with Cyc8-Tup1, and we propose that regulation of this interaction, not the Mig1 cytoplasmic localization, is the molecular switch that controls transcriptional repression/de-repression.


ARID1A mutations in endometriosis-associated ovarian carcinomas.

Abstract: BACKGROUND Ovarian clear-cell and endometrioid carcinomas may arise from endometriosis, but the molecular events involved in this transformation have not been described.

Abstract: METHODS We sequenced the whole transcriptomes of 18 ovarian clear-cell carcinomas and 1 ovarian clear-cell carcinoma cell line and found somatic mutations in ARID1A (the AT-rich interactive domain 1A [SWI-like] gene) in 6 of the samples.

Abstract: ARID1A encodes BAF250a, a key component of the SWI–SNF chromatin remodeling complex.

Abstract: We sequenced ARID1A in an additional 210 ovarian carcinomas and a second ovarian clear-cell carcinoma cell line and measured BAF250a expression by means of immunohistochemical analysis in an additional 455 ovarian carcinomas.

Abstract: RESULTS ARID1A mutations were seen in 55 of 119 ovarian clear-cell carcinomas (46%), 10 of 33 endometrioid carcinomas (30%), and none of the 76 high-grade serous ovarian carcinomas.

Abstract: Seventeen carcinomas had two somatic mutations each.

Abstract: Loss of the BAF250a protein correlated strongly with the ovarian clear-cell carcinoma and endometrioid carcinoma subtypes and the presence of ARID1A mutations.

Abstract: In two patients, ARID1A mutations and loss of BAF250a expression were evident in the tumor and contiguous atypical endometriosis but not in distant endometriotic lesions.

Abstract: CONCLUSIONS These data implicate ARID1A as a tumor-suppressor gene frequently disrupted in ovarian clear-cell and endometrioid carcinomas.

Abstract: Since ARID1A mutation and loss of BAF250a can be seen in the preneoplastic lesions, we speculate that this is an early event in the transformation of endometriosis into cancer.

Abstract: (Funded by the British Columbia Cancer Foundation and the Vancouver General Hospital–University of British Columbia Hospital Foundation.).


The ALS-associated proteins FUS and TDP-43 function together to affect Drosophila locomotion and life span.

Abstract: The fatal adult motor neuron disease amyotrophic lateral sclerosis (ALS) shares some clinical and pathological overlap with frontotemporal dementia (FTD), an early-onset neurodegenerative disorder.

Abstract: The RNA/DNA-binding proteins fused in sarcoma (FUS; also known as TLS) and TAR DNA binding protein-43 (TDP-43) have recently been shown to be genetically and pathologically associated with familial forms of ALS and FTD.

Abstract: It is currently unknown whether perturbation of these proteins results in disease through mechanisms that are independent of normal protein function or via the pathophysiological disruption of molecular processes in which they are both critical.

Abstract: Here, we report that Drosophila mutants in which the homolog of FUS is disrupted exhibit decreased adult viability, diminished locomotor speed, and reduced life span compared with controls.

Abstract: These phenotypes were fully rescued by wild-type human FUS, but not ALS-associated mutant FUS proteins.

Abstract: A mutant of the Drosophila homolog of TDP-43 had similar, but more severe, deficits.

Abstract: Through cross-rescue analysis, we demonstrated that FUS acted together with and downstream of TDP-43 in a common genetic pathway in neurons.

Abstract: Furthermore, we found that these proteins associated with each other in an RNA-dependent complex.

Abstract: Our results establish that FUS and TDP-43 function together in vivo and suggest that molecular pathways requiring the combined activities of both of these proteins may be disrupted in ALS and FTD.


Non-canonical PI3K-Cdc42-Pak-Mek-Erk Signaling Promotes Immune-Complex-Induced Apoptosis in Human Neutrophils

Abstract: Neutrophils are peripheral blood leukocytes that represent the first line of immune cell defense against bacterial and fungal infections but are also crucial players in the generation of the inflammatory response.

Abstract: Many neutrophil cell surface receptors regulate important cellular processes via activation of agonist-activated PI3Ks.

Abstract: We show here that activation of human neutrophils with insoluble immune complexes drives a previously uncharacterized, PI3K-dependent, non-canonical, pro-apoptotic signaling pathway, FcγR-PI3Kβ/δ-Cdc42-Pak-Mek-Erk.

Abstract: This is a rare demonstration of Ras/Raf-independent activation of Erk and of PI3K-mediated activation of Cdc42.

Abstract: In addition, comparative analysis of immune-complex- and fMLF-induced signaling uncovers key differences in pathways used by human and murine neutrophils.

Abstract: The non-canonical pathway we identify in this study may be important for the resolution of inflammation in chronic inflammatory diseases that rely on immune-complex-driven neutrophil activation.


Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4.

Abstract: Chronic inflammation is a known risk factor for tumorigenesis, yet the precise mechanism of this association is currently unknown.

Abstract: The inflammasome, a multiprotein complex formed by NOD-like receptor (NLR) family members, has recently been shown to orchestrate multiple innate and adaptive immune responses, yet its potential role in inflammation-induced cancer has been little studied.

Abstract: Using the azoxymethane and dextran sodium sulfate colitis-associated colorectal cancer model, we show that caspase-1-deficient (Casp1(-/-)) mice have enhanced tumor formation.

Abstract: Surprisingly, the role of caspase-1 in tumorigenesis was not through regulation of colonic inflammation, but rather through regulation of colonic epithelial cell proliferation and apoptosis.

Abstract: Consequently, caspase-1-deficient mice demonstrate increased colonic epithelial cell proliferation in early stages of injury-induced tumor formation and reduced apoptosis in advanced tumors.

Abstract: We suggest a model in which the NLRC4 inflammasome is central to colonic inflammation-induced tumor formation through regulation of epithelial cell response to injury.


The nuclear receptors SF1 and LRH1 are expressed in endometrial cancer cells and regulate steroidogenic gene transcription by cooperating with AP-1 factors.

Abstract: Excessive exposure to estradiol represents the main risk factor for endometrial cancer.

Abstract: The abnormally high estradiol levels in the endometrium of women with endometrial cancer are most likely due to overproduction by the tumour itself.

Abstract: Endometrial cancer cells express the genes encoding the steroidogenic enzymes involved in estradiol synthesis.

Abstract: Here we used RT-PCR and Western blot to show that the nuclear receptors SF1 and LRH1, two well-known regulators of steroidogenic gene expression in gonadal and adrenal cells, are also expressed in endometrial cancer cell lines.

Abstract: By transient transfections, we found that SF1 and LRH1, but not the related nuclear receptor NUR77, can activate the promoters of three human steroidogenic genes: STAR, HSD3B2, and CYP19A1 PII.

Abstract: Similarly, forskolin but not PMA, could activate all three promoters.

Abstract: In addition, we found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters.

Abstract: All together, our data provide novel insights into the mechanisms of steroidogenic gene expression in endometrial cancer cells and thus in the regulation of estradiol biosynthesis by tumour cells.


Dietary factors in chronic inflammation: food tolerances and intolerances of a New Zealand Caucasian Crohn's disease population.

Abstract: Diet is known to play a major role in the symptoms of the inflammatory bowel disease, Crohn's disease (CD).

Abstract: Although no single diet is appropriate to all individuals, most CD patients are aware of foods that provide adverse or beneficial effects.

Abstract: This study seeks to categorise foods in relation to their effects on symptoms of CD, in a New Zealand Caucasian population.

Abstract: Four hundred and forty-six subjects from two different centres in New Zealand were recruited into the study.

Abstract: An extensive dietary questionnaire (257 food items in 15 groups) recorded self-reported dietary tolerances and intolerances.

Abstract: Across each of the food groups, there were statistically significant differences among responses to foods.

Abstract: A two-dimensional graphical summary enabled stratification of foods according to the probability that they will be either beneficial or detrimental.

Abstract: A small number of foods are frequently considered to be beneficial, including white fish, salmon and tuna, gluten-free products, oatmeal, bananas, boiled potatoes, sweet potatoes (kumara), pumpkin, soya milk, goat's milk and yoghurt.

Abstract: Foods that are typically considered detrimental include grapefruit, chilli or chilli sauce, corn and corn products, peanuts, cream, salami, curried foods, cola drinks, high energy drinks, beer, and red wine.

Abstract: For a number of the food items, the same item that was beneficial for one group of subjects was detrimental to others; in particular soya milk, goat's milk, yoghurt, oatmeal, kiwifruit, prunes, apple, broccoli, cauliflower, linseed, pumpkin seed, sunflower seed, ginger and ginger products, beef, lamb, liver, and oily fish.

Abstract: It was not possible to identify a specific group of food items that should be avoided by all CD patients.

Abstract: The wide range of detrimental items suggests that dietary maintenance of remission is likely to be difficult, and to exclude a substantial number of foods.

Abstract: Personalised diets may be especially important to these individuals.


Age as a risk factor for thrombocytopenia and anaemia in children treated for acute uncomplicated falciparum malaria.

Abstract: BACKGROUND & OBJECTIVES Anaemia is commonly observed in children with malaria, but reports on leucocyte and platelet count abnormalities associated with malaria are inconsistent.

Abstract: This study examined the effect of age, gender, parasite density and temperature on haematological parameters in children with acute uncomplicated malaria.

Abstract: METHODS Haematological parameters were determined in children with acute uncomplicated malaria, and these were correlated with age, sex, temperature and parasite density.

Abstract: Statistical analysis was done using SAS 9.1.

Abstract: RESULTS Six hundred and ninety five children with acute uncomplicated malaria participated in the study.

Abstract: The mean age was 51.7 months +/-

Abstract: At presentation, anaemia occurred in 43.8% of the patients and children <5 yr had a significantly lower haematocrit (28.4% +/- 4.8) than that of older children (32.8% +/-

Abstract: 4.8) (p <0.001), but the haematocrit was not significantly different by days 14 and 28.

Abstract: There was no difference between both sexes.

Abstract: Leucocytosis was more frequently seen than leucopenia (9.5% vs 3%).

Abstract: Thrombocytopenia was found in 59.3% of enrolled patients.

Abstract: More than half of the patients with thrombocytopenia had recovered by Day 28.

Abstract: Baseline platelet count was related to Day 14 (r = 0.6, p < 0.0001) and Day 28 (r = 0.2, p = 0.0015) and the haematocrit on Day 28 (r = 0.12, p = 0.00197).

Abstract: Platelet count showed no correlation with temperature, parasite density and leucocyte count.

Abstract: Haematocrit correlated with age (r = 0.4, p < 0.0001); but not with parasite density or temperature.

Abstract: Leucocyte count showed no correlation with age or parasite density.

Abstract: CONCLUSION While thrombocytopenia was the most common haematological finding and may be of diagnostic importance, anaemia and leucocytosis were more common in the under fives.


Discovery of endogenous catecholamines in lymphocytes and evidence for catecholamine regulation of lymphocyte function via an autocrine loop.

Abstract: Evidence has been obtained that catecholamines and their metabolites are present in single lymphocytes and extracts of T- and B-cell clones by use of capillary electrophoresis with electrochemical detection.

Abstract: Pharmacological inhibition of tyrosine hydroxylase reduces observed catecholamine levels, suggesting catecholamine synthesis by lymphocytes.

Abstract: Intracellular dopamine levels are shown to be increased by extra-cellular dopamine, suggesting a cellular-uptake mechanism.

Abstract: Furthermore, incubation with either dopamine or L-dihydroxyphenylalanine, a precursor of dopamine, results in a dose-dependent inhibition of lymphocyte proliferation and differentiation.

Abstract: Together, these results suggest the presence of an autocrine loop whereby lymphocytes down-regulate their own activity.


Structure-based drug design identifies polythiophenes as antiprion compounds

Abstract: Prions cause transmissible spongiform encephalopathies for which no treatment exists.

Abstract: Prions consist of PrPSc, a misfolded and aggregated form of the cellular prion protein (PrPC).

Abstract: We explore the antiprion properties of luminescent conjugated polythiophenes (LCPs) that bind and stabilize ordered protein aggregates.

Abstract: By administering a library of structurally diverse LCPs to the brains of prion-infected mice via osmotic minipumps, we found that antiprion activity required a minimum of five thiophene rings bearing regularly spaced carboxyl side groups.

Abstract: Solid-state nuclear magnetic resonance analyses and molecular dynamics simulations revealed that anionic side chains interacted with complementary, regularly spaced cationic amyloid residues of model prions.

Abstract: These findings allowed us to extract structural rules governing the interaction between LCPs and protein aggregates, which we then used to design a new set of LCPs with optimized binding.

Abstract: The new set of LCPs showed robust prophylactic and therapeutic potency in prion-infected mice, with the lead compound extending survival by >80% and showing activity against both mouse and hamster prions as well as efficacy upon intraperitoneal administration into mice.

Abstract: These results demonstrate the feasibility of targeted chemical design of compounds that may be useful for treating diseases of aberrant protein aggregation such as prion disease.


Comparisons of patient and physician expectations for cancer survivorship care.

Abstract: PURPOSE To compare expectations for cancer survivorship care between patients and their physicians and between primary care providers (PCPs) and oncologists.

Abstract: METHODS Survivors and their physicians were surveyed to evaluate for expectations regarding physician participation in primary cancer follow-up, screening for other cancers, general preventive health, and management of comorbidities.

Abstract: RESULTS Of 992 eligible survivors and 607 physicians surveyed, 535 (54%) and 378 (62%) were assessable, respectively.

Abstract: Among physician respondents, 255 (67%) were PCPs and 123 (33%) were oncologists.

Abstract: Comparing patients with their oncologists, expectations were highly discrepant for screening for cancers other than the index one (agreement rate, 29%), with patients anticipating significantly more oncologist involvement.

Abstract: Between patients and their PCPs, expectations were most incongruent for primary cancer follow-up (agreement rate, 35%), with PCPs indicating they should contribute a much greater part to this aspect of care.

Abstract: Expectations between patients and their PCPs were generally more concordant than between patients and their oncologists.

Abstract: PCPs and oncologists showed high discordances in perceptions of their own roles for primary cancer follow-up, cancer screening, and general preventive health (agreement rates of 3%, 44%, and 51%, respectively).

Abstract: In the case of primary cancer follow-up, both PCPs and oncologists indicated they should carry substantial responsibility for this task.

Abstract: CONCLUSION Patients and physicians have discordant expectations with respect to the roles of PCPs and oncologists in cancer survivorship care.

Abstract: Uncertainties around physician roles and responsibilities can lead to deficiencies in care, supporting the need to make survivorship care planning a standard component in cancer management.


MHC class I antigen presentation: learning from viral evasion strategies

Abstract: The cell surface display of peptides by MHC class I molecules to lymphocytes provides the host with an important surveillance mechanism to protect against invading pathogens.

Abstract: However, in turn, viruses have evolved elegant strategies to inhibit various stages of the MHC class I antigen presentation pathway and prevent the display of viral peptides.

Abstract: This Review highlights how the elucidation of mechanisms of viral immune evasion is important for advancing our understanding of virus–host interactions and can further our knowledge of the MHC class I presentation pathway as well as other cellular pathways.


T cell receptor-proximal signals are sustained in peripheral microclusters and terminated in the central supramolecular activation cluster.

Abstract: T cell receptor (TCR) signaling is initiated and sustained in microclusters; however, it's not known whether signaling also occurs in the TCR-rich central supramolecular activation cluster (cSMAC).

Abstract: We showed that the cSMAC formed by fusion of microclusters contained more CD45 than microclusters and is a site enriched in lysobisphosphatidic acid, a lipid involved in sorting ubiquitinated membrane proteins for degradation.

Abstract: Calcium signaling via TCR was blocked within 2 min by anti-MHCp treatment and 1 min by latrunculin-A treatment.

Abstract: TCR-MHCp interactions in the cSMAC survived these perturbations for 10 min and hence were not sufficient to sustain signaling.

Abstract: TCR microclusters were also resistant to disruption by anti-MHCp and latrunculin-A treatments.

Abstract: We propose that TCR signaling is sustained by stabilized microclusters and is terminated in the cSMAC, a structure from which TCR are sorted for degradation.

Abstract: Our studies reveal a role for F-actin in TCR signaling beyond microcluster formation.


The role of red cell distribution width in the prognosis of patients with gastric cancer.

Abstract: BACKGROUND Although the red cell distribution width (RDW) has been reported as a reliable predictor of prognosis in several types of cancer, to our knowledge the prognostic value of RDW in gastric carcinoma has not been studied, so far.

Abstract: OBJECTIVE We aimed to investigate the role of red cell distribution width (RDW) in predicting prognosis in gastric cancer patients.

Abstract: METHODS All gastric cancer patients who underwent curative surgery (n= 172, 110M/62F) over a five-year study period were evaluated.

Abstract: Data on demographics, preoperative RDW levels, tumor characteristics (early stage: I and II, advanced stage: IIIA-B-C), disease-free (DFS) and overall survival (OS) were retrospectively reviewed.

Abstract: Patients were classified as high RDW group (RDW ≥ 16, n= 62) or low RDW group (RDW < 16, n= 110).

Abstract: RESULTS Overall mortality and postoperative 60-day mortality in both groups were 55% and 14%, respectively.

Abstract: A borderline significant association between RDW (0.063) and mortality was noted.

Abstract: Preoperative RDW levels were significantly higher in patients with short-term mortality (17.9 ± 4.3 vs. 16 ± 3.2, p= 0.015).

Abstract: In high RDW group, the incidence of advanced gastric cancer was significantly higher (75 vs. 51%, p= 0.002), whereas DFS (0.035) and OS (p= 0.04) were lower.

Abstract: CONCLUSION The frequency of advanced cancer was high in patients with high RDWvalues.

Abstract: High RDW values were strongly associated with short-term mortality although only a borderline relationship with overall survival was observed.


Vascular responsiveness in isolated perfused kidneys of diabetic hypertensive rats.

Abstract: OBJECTIVE The aim of this study was to investigate whether diabetes and hypertension cause additive effects in the responses to various vasoconstrictor and vasodilator agents, in isolated perfused kidneys obtained from streptozotocin (STZ)-diabetic Wistar-Kyoto (WKY) rats and from diabetic spontaneously hypertensive rats (SHR).

Abstract: METHODS SHR and WKY rats were administered STZ 55 mg/kg by intravenous injection into a lateral tail vein at age 12 weeks.

Abstract: Eight weeks later the kidneys were isolated and perfused via the left renal artery with a physiological salt solution.

Abstract: Renal perfusion pressure was measured continuously.

Abstract: Concentration response curves were plotted for various vasoconstrictor and vasodilator agents.

Abstract: RESULTS Both the diabetic and the hypertensive state were associated with an increased wet kidney weight.

Abstract: The contractile responses of the renal arterial system to phenylephrine (PhE), serotonin (5-HT) and angiotensin II (Ang II) in terms both of the maximal rise in perfusion pressure (mmHg) and of the sensitivity (log EC50) were the same in preparations from diabetic WKY rats and in those from normoglycaemic WKY rats.

Abstract: The maximal contractile responses both to PhE and to Ang II were enhanced in kidneys from SHR compared with those in kidneys from their normotensive controls, whereas simultaneously occurring diabetes impaired this sensitization.

Abstract: After precontraction with 3 x 10(-6) mol/l PhE both endothelium-dependent (methacholine) and endothelium-independent (sodium nitroprusside) vasodilator drugs caused the same vasodilator response in the preparations taken from the four groups of animals.

Abstract: CONCLUSION In isolated perfused kidneys obtained from STZ-diabetic WKY rats and SHR, the isolated diabetic state did not influence the vasoconstriction caused by various agonists.

Abstract: However, the enhanced vascular reactivity in the hypertensive state was blunted by simultaneously occurring diabetes mellitus.

Abstract: Endothelium-dependent and -independent vasorelaxation in this model was not affected neither by the hypertensive nor by the diabetic state.


DNA replication is required To elicit cellular responses to psoralen-induced DNA interstrand cross-links.

Abstract: Following introduction of DNA interstrand cross-links (ICLs), mammalian cells display chromosome breakage or cell cycle delay with a 4N DNA content.

Abstract: To further understand the nature of the delay, previously described as a G(2)/M arrest, we developed a protocol to generate ICLs during specific intervals of the cell cycle.

Abstract: Synchronous populations of G(1), S, and G(2) cells were treated with photoactivated 4'-hydroxymethyl-4,5',8-trimethylpsoralen (HMT) and scored for normal passage into mitosis.

Abstract: In contrast to what was found for ionizing radiation, ICLs introduced during G(2) did not result in a G(2)/M arrest, mitotic arrest, or chromosome breakage.

Abstract: Rather, subsequent passage through S phase was required to trigger both chromosome breakage and arrest in the next cell cycle.

Abstract: Similarly, ICLs introduced during G(1) did not cause a G(1)/S arrest.

Abstract: We conclude that DNA replication is required to elicit the cellular responses of cell cycle arrest and genomic instability after psoralen-induced ICLs.

Abstract: In primary human fibroblasts, the 4N DNA content cell cycle arrest triggered by ICLs was long lasting but reversible.

Abstract: Kinetic analysis suggested that these cells could remove up to approximately 2,500 ICLs/genome at an average rate of 11 ICLs/genome/h.


DNA methylation and healthy human aging

Abstract: The process of aging results in a host of changes at the cellular and molecular levels, which include senescence, telomere shortening, and changes in gene expression.

Abstract: Epigenetic patterns also change over the lifespan, suggesting that epigenetic changes may constitute an important component of the aging process.

Abstract: The epigenetic mark that has been most highly studied is DNA methylation, the presence of methyl groups at CpG dinucleotides.

Abstract: These dinucleotides are often located near gene promoters and associate with gene expression levels.

Abstract: Early studies indicated that global levels of DNA methylation increase over the first few years of life and then decrease beginning in late adulthood.

Abstract: Recently, with the advent of microarray and next-generation sequencing technologies, increases in variability of DNA methylation with age have been observed, and a number of site-specific patterns have been identified.

Abstract: It has also been shown that certain CpG sites are highly associated with age, to the extent that prediction models using a small number of these sites can accurately predict the chronological age of the donor.

Abstract: Together, these observations point to the existence of two phenomena that both contribute to age-related DNA methylation changes: epigenetic drift and the epigenetic clock.

Abstract: In this review, we focus on healthy human aging throughout the lifetime and discuss the dynamics of DNA methylation as well as how interactions between the genome, environment, and the epigenome influence aging rates.

Abstract: We also discuss the impact of determining 'epigenetic age' for human health and outline some important caveats to existing and future studies.


Parathyroid hormone-induced E4BP4/NFIL3 down-regulates transcription in osteoblasts.

Abstract: Parathyroid hormone (PTH), a major regulator of bone metabolism, activates the PTHR1 receptor on the osteoblast plasma membrane to initiate signaling and induce transcription of primary response genes.

Abstract: Subsequently, primary genes with transcriptional activity regulate expression of downstream PTH targets.

Abstract: We have identified the adenovirus E4 promoter-binding protein/nuclear factor regulated by IL-3 (E4bp4) as a PTH-induced primary gene in osteoblasts.

Abstract: E4BP4 is a basic leucine zipper (bZIP) transcription factor that represses or activates transcription in non-osteoblastic cells.

Abstract: We report here that PTH rapidly and transiently induced E4bp4 mRNA in osteoblastic cells and that this induction did not require protein synthesis.

Abstract: PTH also induced E4BP4 protein synthesis and E4BP4 binding to a consensus but not to a mutant E4BP4 response element (EBPRE).

Abstract: E4BP4 overexpression inhibited an EBPRE-containing promoter-reporter construct, whereas PTH treatment attenuated activity of the same construct in primary mouse osteoblasts.

Abstract: Finally, E4BP4 overexpression inhibited PTH-induced activity of a cyclooxygenase-2 promoter-reporter construct.

Abstract: Our data suggest a role for E4BP4 in attenuation of PTH target gene transcription in osteoblasts.