US-SOMO HPLC-SAXS module: dealing with capillary fouling and extraction of pure component patterns from poorly resolved SEC-SAXS data

Abstract: Size-exclusion chromatography coupled with SAXS (small-angle X-ray scattering), often performed using a flow-through capillary, should allow direct collection of monodisperse sample data.

Abstract: However, capillary fouling issues and non-baseline-resolved peaks can hamper its efficacy.

Abstract: The UltraScan solution modeler (US-SOMO) HPLC-SAXS (high-performance liquid chromatography coupled with SAXS) module provides a comprehensive framework to analyze such data, starting with a simple linear baseline correction and symmetrical Gaussian decomposition tools [Brookes, Pérez, Cardinali, Profumo, Vachette & Rocco (2013 ▸).

Abstract: J. Appl.

Abstract: Cryst.46, 1823-1833].

Abstract: In addition to several new features, substantial improvements to both routines have now been implemented, comprising the evaluation of outcomes by advanced statistical tools.

Abstract: The novel integral baseline-correction procedure is based on the more sound assumption that the effect of capillary fouling on scattering increases monotonically with the intensity scattered by the material within the X-ray beam.

Abstract: Overlapping peaks, often skewed because of sample interaction with the column matrix, can now be accurately decomposed using non-symmetrical modified Gaussian functions.

Abstract: As an example, the case of a polydisperse solution of aldolase is analyzed: from heavily convoluted peaks, individual SAXS profiles of tetramers, octamers and dodecamers are extracted and reliably modeled.


Determination of Malaria Epidemiological Status in Iran’s Malarious Areas as Baseline Information for Implementation of Malaria Elimination Program in Iran

Abstract: BACKGROUND According to willingness of the Ministry of Health, Iran and presence of appropriate conditions for disease elimination, national malaria control program decided to conduct a research to clarify malaria status in 2007 and to provide required information to perform the elimination program.

Abstract: This review is comprised of the basis of national malaria elimination program in vision of 2025, which was started in 2010.

Abstract: METHODS In this descriptive study, data were analyzed by applications of different variables at district level.

Abstract: All districts in the three south eastern provinces, in which malaria has local transmission, were considered.

Abstract: Malaria cases has been determined and studied based on the national malaria surveillance system.

Abstract: RESULTS Since vivax malaria is predominant in Sistan & Baluchestan Province, number of vivax cases is equal to malaria positive cases approximately.

Abstract: The important point is that Nikshahr contains the maximum number of local vivax cases in this province and the maximum number of falciparum cases is reported from Sarbaz district.

Abstract: Among all districts of Hormozgan Province, no case of autochthonous falciparum was detected except in Bandar Jask and one case in Minab.

Abstract: There was no case of autochthonous falciparum in Kerman Province, except in Kahnoj and Ghale Ganj that each of them had one case in 2007.

Abstract: CONCLUSION It appears that the report of locally transmitted cases in Iran is increasing over the past few years, before starting malaria elimination plan.

Abstract: Since the Afghan refugees started to return to their own country so the main source of reporting of imported malaria cases reduced and local cases would be demonstrated more clearly.


Local neuroinflammation and the progression of Alzheimer’s disease

Abstract: Postmortem immunohistochemical studies have revealed a state of chronic inflammation limited to lesioned areas of brain in Alzheimer’s disease.

Abstract: Some key actors in this inflammation are activated microglia (brain macrophages), proteins of the classical complement cascade, the pentraxins, cytokines, and chemokines.

Abstract: The inflammation does not involve the adaptive immune system or peripheral organs, but is rather due to the phylogenetically much older innate immune system, which appears to operate in most tissues of the body.

Abstract: Chronic inflammation can damage host tissue and the brain may be particularly vulnerable because of the postmitotic nature of neurons.

Abstract: Many of the inflammatory mediators have been shown to be locally produced and selectively elevated in affected regions of Alzheimer’s brain.

Abstract: Moreover, studies of tissue in such degenerative processes as atherosclerosis and infarcted heart suggest a similar local innate immune reaction may be important in such conditions.

Abstract: Much epidemiological and limited clinical evidence suggests that nonsteroidal anti-inflammatory drugs may impede the onset and slow the progression of Alzheimer’s disease.

Abstract: But these drugs strike at the periphery of the inflammatory reaction.

Abstract: Much better results might be obtained if drugs were found that could inhibit the activation of microglia or the complement system in brain, and combinations of drugs aimed at different inflammatory targets might be much more effective than single agents.


BLAST+: architecture and applications

Abstract: BACKGROUND Sequence similarity searching is a very important bioinformatics task.

Abstract: While Basic Local Alignment Search Tool (BLAST) outperforms exact methods through its use of heuristics, the speed of the current BLAST software is suboptimal for very long queries or database sequences.

Abstract: There are also some shortcomings in the user-interface of the current command-line applications.

Abstract: RESULTS We describe features and improvements of rewritten BLAST software and introduce new command-line applications.

Abstract: Long query sequences are broken into chunks for processing, in some cases leading to dramatically shorter run times.

Abstract: For long database sequences, it is possible to retrieve only the relevant parts of the sequence, reducing CPU time and memory usage for searches of short queries against databases of contigs or chromosomes.

Abstract: The program can now retrieve masking information for database sequences from the BLAST databases.

Abstract: A new modular software library can now access subject sequence data from arbitrary data sources.

Abstract: We introduce several new features, including strategy files that allow a user to save and reuse their favorite set of options.

Abstract: The strategy files can be uploaded to and downloaded from the NCBI BLAST web site.

Abstract: CONCLUSION The new BLAST command-line applications, compared to the current BLAST tools, demonstrate substantial speed improvements for long queries as well as chromosome length database sequences.

Abstract: We have also improved the user interface of the command-line applications.


Intrauterine environments and breast cancer risk: meta-analysis and systematic review

Abstract: INTRODUCTION Various perinatal factors, including birth weight, birth order, maternal age, gestational age, twin status, and parental smoking, have been postulated to affect breast cancer risk in daughters by altering the hormonal environment of the developing fetal mammary glands.

Abstract: Despite ample biologic plausibility, epidemiologic studies to date have yielded conflicting results.

Abstract: We investigated the associations between perinatal factors and subsequent breast cancer risk through meta-analyses.

Abstract: METHODS We reviewed breast cancer studies published from January 1966 to February 2007 that included data on birth weight, birth order, maternal age, gestational age, twin status, and maternal or paternal smoking.

Abstract: Meta-analyses using random effect models were employed to summarize the results.

Abstract: RESULTS We found that heavier birth weights were associated with increased breast cancer risk, with studies involving five categories of birth weight identifying odds ratios (ORs) of 1.24 (95% confidence interval [CI] 1.04 to 1.48) for 4,000 g or more and 1.15 (95% CI 1.04 to 1.26) for 3,500 g to 3,999 g, relative to a birth weight of 2,500 to 2,599 g. These studies provided no support for a J-shaped relationship of birthweight to risk.

Abstract: Support for an association with birthweight was also derived from studies based on three birth weight categories (OR 1.15 [95% CI 1.01 to 1.31] for > or =4,000 g relative to <3,000 g) and two birth weight categories (OR 1.09 [95% CI 1.02 to 1.18] for > or =3,000 g relative to <3,000 g).

Abstract: Women born to older mothers and twins were also at some increased risk, but the results were heterogeneous across studies and publication years.

Abstract: Birth order, prematurity, and maternal smoking were unrelated to breast cancer risk.

Abstract: CONCLUSION Our findings provide some support for the hypothesis that in utero exposures reflective of higher endogenous hormone levels could affect risk for development of breast cancer in adulthood.


Epidemiologic studies on Dengue in Santiago de Cuba, 1997.

Abstract: A small, isolated outbreak of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) due to dengue virus type 2 (DEN-2) was documented in Santiago de Cuba on the island of Cuba beginning in January 1997.

Abstract: There were 205 DHF/DSS cases, all in persons older than age 15 years.

Abstract: All but three had evidence of a prior dengue infection, with the only known opportunity being the islandwide dengue virus type 1 (DEN-1) epidemic of 1977-1979.

Abstract: Virtually complete clinical and laboratory surveillance of overt disease was achieved.

Abstract: From December 1997 to January 1998, a random, age-stratified serum sample was obtained from 1,151 persons in 40 residential clusters in Santiago.

Abstract: Sera were tested for DEN-1 and DEN-2 neutralizing antibodies.

Abstract: The prevalence of DEN-2 antibodies in children age 15 years and under, born after the 1981 DEN-2 epidemic, was taken as the 1997 DEN-2 infection rate.

Abstract: This was adjusted slightly to accommodate observed cases, resulting in an estimated infection rate of 4.3%.

Abstract: Dengue fever and DHF/DSS attack rates were calculated from estimated total primary and secondary DEN-2 infections.

Abstract: Only 3% of 13,116 primary infections were overt.

Abstract: The DHF/DSS attack rate for adults of all ages was 420 per 10,000 secondary DEN-2 infections.


Prognostic and Predictive Value of KRAS Mutations in Advanced Non-Small Cell Lung Cancer

Abstract: Clinical implications of KRAS mutations in advanced non-small cell lung cancer remain unclear.

Abstract: We retrospectively evaluated the prognostic and predictive value of KRAS mutations in patients with advanced NSCLC.

Abstract: Among 484 patients with available results for both KRAS and EGFR mutations, 39 (8%) had KRAS and 182 (38%) EGFR mutations, with two cases having both mutations.

Abstract: The median overall survivals for patients with KRAS mutations, EGFR mutations, or both wild types were 7.7, 38.0, and 15.0 months, respectively (P<0.001).

Abstract: The KRAS mutation was an independent poor prognostic factor in the multivariate analysis (hazard ratio = 2.6, 95% CI: 1.8-3.7).

Abstract: Response rates and progression-free survival (PFS) for the pemetrexed-based regimen in the KRAS mutation group were 14% and 2.1 months, inferior to those (28% and 3.9 months) in the KRAS wild type group.

Abstract: KRAS mutation tended to be associated with inferior treatment outcomes after gemcitabine-based chemotherapy, while there was no difference regarding taxane-based regimen.

Abstract: Although the clinical outcomes to EGFR tyrosine kinase inhibitors (TKIs) seemed to be better in patients with KRAS wild type than those with KRAS mutations, there was no statistical difference in response rates and PFS according to KRAS mutation status when EGFR mutation status was considered.

Abstract: Two patients with both KRAS and EGFR mutations showed partial response to EGFR TKIs.

Abstract: Although G12D mutation appeared more frequently in never smokers, there was no difference in clinical outcomes according to KRAS genotypes.

Abstract: These results suggested KRAS mutations have an independent prognostic value but a limited predictive role for EGFR TKIs or cytotoxic chemotherapy in advanced NSCLC.


A Heteroskedasticity-Consistent Covariance Matrix Estimator And A Direct Test For Heteroskedasticity

Abstract: This paper presents a parameter covariance matrix estimator which is consistent even when the disturbances of a linear regression model are heteroskedastic.

Abstract: This estimator does not depend on a formal model of the structure of the heteroskedasticity.

Abstract: By comparing the elements of the new estimator to those of the usual covariance estimator, one obtains a direct test for heteroskedasticity, since in the absence of heteroskedasticity, the two estimators will be approximately equal, but will generally diverge otherwise.

Abstract: The test has an appealing least squares interpretation.


Two Subsets of Naive T Helper Cells with Distinct T Cell Receptor Excision Circle Content in Human Adult Peripheral Blood

Abstract: During ageing thymic function declines and is unable to meet the demand for peripheral T helper (Th) cell replenishment.

Abstract: Therefore, population maintenance of naive Th cells must be at least partly peripherally based.

Abstract: Such peripheral postthymic expansion of recent thymic emigrants (RTEs) during ageing consequently should lead to loss or dilution of T cell receptor excision circles (TRECs) from a subset of naive T cells.

Abstract: We have identified two subsets of naive Th cells in human adult peripheral blood characterized by a striking unequal content of TRECs, indicating different peripheral proliferative histories.

Abstract: TRECs are highly enriched in peripheral naive CD45RA+ Th cells coexpressing CD31 compared with peripheral naive CD45RA+ Th cells lacking CD31 expression, in which TRECs can hardly be detected.

Abstract: Furthermore we show that CD31−CD45RA+ Th cells account for increasing percentages of the naive peripheral Th cell pool during ageing but retain phenotypic and functional features of naive Th cells.

Abstract: As CD31 is lost upon T cell receptor (TCR) engagement in vitro, we hypothesize that TCR triggering is a prerequisite for homeostatically driven peripheral postthymic expansion of human naive RTEs.

Abstract: We describe here the identification of peripherally expanded naive Th cells in human adult blood characterized by the loss of CD31 expression and a highly reduced TREC content.


A Role for the Vacuolating Cytotoxin, VacA, in Colonization and Helicobacter pylori–Induced Metaplasia in the Stomach

Abstract: Carriage of Helicobacter pylori strains producing more active (s1/i1) forms of VacA is strongly associated with gastric adenocarcinoma.

Abstract: To our knowledge, we are the first to determine effects of different polymorphic forms of VacA on inflammation and metaplasia in the mouse stomach.

Abstract: Bacteria producing the less active s2/i2 form of VacA colonized mice more efficiently than mutants null for VacA or producing more active forms of it, providing the first evidence of a positive role for the minimally active s2/i2 toxin.

Abstract: Strains producing more active toxin forms induced more severe and extensive metaplasia and inflammation in the mouse stomach than strains producing weakly active (s2/i2) toxin.

Abstract: We also examined the association in humans, controlling for cagPAI status.

Abstract: In human gastric biopsy specimens, the vacA i1 allele was strongly associated with precancerous intestinal metaplasia, with almost complete absence of intestinal metaplasia in subjects infected with i2-type strains, even in a vacA s1, cagA(+) background.


Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer.

Abstract: OBJECTIVE To review the evidence for the use of bisphosphonates to reduce skeletal morbidity in cancer patients with bone metastases.

Abstract: DATA SOURCES Electronic databases, scanning reference lists, and consultation with experts and pharmaceutical companies.

Abstract: Foreign language papers were included.

Abstract: STUDY SELECTION Included trials were randomised controlled trials of patients with malignant disease and bone metastases who were treated with oral or intravenous bisphosphonate compared with another bisphosphonate, placebo, or standard care.

Abstract: All trials measured at least one outcome of skeletal morbidity.

Abstract: RESULTS 95 articles were identified; 30 studies fulfilled inclusion criteria.

Abstract: In studies that lasted > or = 6 months, compared with placebo bisphosphonates significantly reduced the odds ratio for fractures (vertebral 0.69, 95% confidence interval 0.57 to 0.84, P < 0.0001; non-vertebral 0.65, 0.54 to 0.79, P < 0.0001; combined 0.65, 0.55 to 0.78, P < 0.0001), radiotherapy (0.67, 0.57 to 0.79, P < 0.0001), and hypercalcaemia (0.54, 0.36 to 0.81, P = 0.003) but not for orthopaedic surgery (0.70, 0.46 to 1.05, P = 0.086) or spinal cord compression (0.71, 0.47 to 1.08, P = 0.113).

Abstract: The reduction in orthopaedic surgery was significant in studies that lasted over a year (0.59, 0.39 to 0.88, P = 0.009).

Abstract: Use of bisphosphonates significantly increased time to first skeletal related event but did not increase survival.

Abstract: Subanalyses showed that most evidence supports use of intravenous aminobisphosphonates.

Abstract: CONCLUSIONS In people with metastatic bone disease bisphosphonates significantly decrease skeletal morbidity, except for spinal cord compression and increased time to first skeletal related event.

Abstract: Treatment should start when bone metastases are diagnosed and continue until it is no longer clinically relevant.


Rodent Models of Depression: Neurotrophic and Neuroinflammatory Biomarkers

Abstract: Rodent models are an indispensable tool for studying etiology and progress of depression.

Abstract: Since interrelated systems of neurotrophic factors and cytokines comprise major regulatory mechanisms controlling normal brain plasticity, impairments of these systems form the basis for development of cerebral pathologies, including mental diseases.

Abstract: The present review focuses on the numerous experimental rodent models of depression induced by different stress factors (exteroceptive and interoceptive) during early life (including prenatal period) or adulthood, giving emphasis to the data on the changes of neurotrophic factors and neuroinflammatory indices in the brain.

Abstract: These parameters are closely related to behavioral depression-like symptoms and impairments of neuronal plasticity and are both gender- and genotype-dependent.

Abstract: Stress-related changes in expression of neurotrophins and cytokines in rodent brain are region-specific.

Abstract: Some contradictory data reported by different groups may be a consequence of differences of stress paradigms or their realization in different laboratories.

Abstract: Like all experimental models, stress-induced depression-like conditions are experimental simplification of clinical depression states; however, they are suitable for understanding the involvement of neurotrophic factors and cytokines in the pathogenesis of the disease-a goal unachievable in the clinical reality.

Abstract: These major regulatory systems may be important targets for therapeutic measures as well as for development of drugs for treatment of depression states.


The docking domain of histone H2A is required for H1 binding and RSC-mediated nucleosome remodeling

Abstract: Histone variants within the H2A family show high divergences in their C-terminal regions.

Abstract: In this work, we have studied how these divergences and in particular, how a part of the H2A COOH-terminus, the docking domain, is implicated in both structural and functional properties of the nucleosome.

Abstract: Using biochemical methods in combination with Atomic Force Microscopy and Electron Cryo-Microscopy, we show that the H2A-docking domain is a key structural feature within the nucleosome.

Abstract: Deletion of this domain or replacement with the incomplete docking domain from the variant H2A.Bbd results in significant structural alterations in the nucleosome, including an increase in overall accessibility to nucleases, un-wrapping of ∼10 bp of DNA from each end of the nucleosome and associated changes in the entry/exit angle of DNA ends.

Abstract: These structural alterations are associated with a reduced ability of the chromatin remodeler RSC to both remodel and mobilize the nucleosomes.

Abstract: Linker histone H1 binding is also abrogated in nucleosomes containing the incomplete docking domain of H2A.Bbd.

Abstract: Our data illustrate the unique role of the H2A-docking domain in coordinating the structural-functional aspects of the nucleosome properties.

Abstract: Moreover, our data suggest that incorporation of a 'defective' docking domain may be a primary structural role of H2A.Bbd in chromatin.


Regulation of poly(A) site choice of several yeast mRNAs

Abstract: Several yeast genes produce multiple transcripts with different 3'-ends.

Abstract: Of these, four genes are known to produce truncated transcripts that end within the coding sequence of longer transcripts: CBP1 , AEP2 / ATP13 , RNA14 and SIR1 .

Abstract: It has been shown that the level of the truncated CBP1 transcript increases during the switch to respiratory growth while that of the full-length transcript decreases.

Abstract: To determine whether this phenomenon is unique to CBP1 , northern analysis was used to determine whether the levels of other truncated transcripts are regulated similarly by carbon source.

Abstract: The levels of the shortest transcripts of AEP2 / ATP13 and RNA14 increased during respiration while the shortest SIR1 transcript remained constant.

Abstract: However, two longer SIR1 transcripts were regulated reciprocally by carbon source.

Abstract: Mapping the 3'-ends of each transcript by sequencing partial cDNA clones revealed multiple 3'-ends for each transcript.

Abstract: Examination of the sequences surrounding the 3'-ends of the induced transcripts failed to identify a consensus sequence but did reveal weak putative 3'-end formation signals in all of the transcripts.

Abstract: Similarly, no consensus sequence was found when the sequences surrounding the 3'-ends of the longest transcripts were compared, but again weak putative 3'-end formation signals were identified.

Abstract: These data are suggestive of carbon source regulation of alternative poly(A) site choice in yeast.


Circular RNA and miR-7 in cancer.

Abstract: MicroRNAs (miRNA) play important roles in fine-tuning gene expression and are often deregulated in cancer.

Abstract: The identification of competing endogenous RNA and circular RNA (circRNA) as important regulators of miRNA activity underscores the increasing complexity of ncRNA-mediated regulatory networks.

Abstract: Particularly, the recently identified circular RNA, ciRS-7, which acts as a designated miR-7 inhibitor/sponge, has conceptually changed the mechanistic understanding of miRNA networks.

Abstract: As miR-7 modulates the expression of several oncogenes, disclosing the regulation of miR-7 activity will likely advance the understanding of various cancer etiologies.

Abstract: Here, we review the current knowledge about the ciRS-7/miR-7 axis in cancer-related pathways and discuss possible models explaining the relevance of coexpressing miR-7 along with a circRNA inhibitor.


Angiotensin II Evokes Angiogenic Signals within Skeletal Muscle through Co-ordinated Effects on Skeletal Myocytes and Endothelial Cells

Abstract: Skeletal muscle overload induces the expression of angiogenic factors such as vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-2, leading to new capillary growth.

Abstract: We found that the overload-induced increase in angiogenesis, as well as increases in VEGF, MMP-2 and MT1-MMP transcripts were abrogated in muscle VEGF KO mice, highlighting the critical role of myocyte-derived VEGF in controlling this process.

Abstract: The upstream mediators that contribute to overload-induced expression of VEGF have yet to be ascertained.

Abstract: We found that muscle overload increased angiotensinogen expression, a precursor of angiotensin (Ang) II, and that Ang II signaling played an important role in basal VEGF production in C2C12 cells.

Abstract: Furthermore, matrix-bound VEGF released from myoblasts induced the activation of endothelial cells, as evidenced by elevated endothelial cell phospho-p38 levels.

Abstract: We also found that exogenous Ang II elevates VEGF expression, as well as MMP-2 transcript levels in C2C12 myotubes.

Abstract: Interestingly, these responses also were observed in skeletal muscle endothelial cells in response to Ang II treatment, indicating that these cells also can respond directly to the stimulus.

Abstract: The involvement of Ang II in muscle overload-induced angiogenesis was assessed.

Abstract: We found that blockade of AT1R-dependent Ang II signaling using losartan did not attenuate capillary growth.

Abstract: Surprisingly, increased levels of VEGF protein were detected in overloaded muscle from losartan-treated rats.

Abstract: Similarly, we observed elevated VEGF production in cultured endothelial cells treated with losartan alone or in combination with Ang II.

Abstract: These studies conclusively establish the requirement for muscle derived VEGF in overload-induced angiogenesis and highlight a role for Ang II in basal VEGF production in skeletal muscle.

Abstract: However, while Ang II signaling is activated following overload and plays a role in muscle VEGF production, inhibition of this pathway is not sufficient to halt overload-induced angiogenesis, indicating that AT1-independent signals maintain VEGF production in losartan-treated muscle.


A specific loop in human DNA polymerase mu allows switching between creative and DNA-instructed synthesis

Abstract: Human DNA polymerase mu (Polμ) is a family X member that has terminal transferase activity but, in spite of a non-orthodox selection of the template information, displays its maximal catalytic efficiency in DNA-templated reactions.

Abstract: As terminal deoxynucleotidyl transferase (TdT), Polμ has a specific loop (loop1) that could provide this enzyme with its terminal transferase activity.

Abstract: When loop1 was deleted, human Polμ lacked TdT activity but improved DNA-binding and DNA template-dependent polymerization.

Abstract: Interestingly, when loop1 from TdT was inserted in Polμ (substituting its cognate loop1), the resulting chimaera displayed TdT activity, preferentially inserting dGTP residues, but had a strongly reduced template-dependent polymerization activity.

Abstract: Therefore, a specialized loop in Polμ, that could adopt alternative conformations, appears to provide this enzyme with a dual capacity: (i) template independency to create new DNA information, in which loop1 would have an active role by acting as a ‘pseudotemplate’; (ii) template-dependent polymerization, in which loop1 must allow binding of the template strand.

Abstract: Recent in vivo and in vitro data suggest that such a dual capacity could be advantageous to resolve microhomology-mediated end-joining reactions.


Dnmt1-Independent CG Methylation Contributes to Nucleosome Positioning in Diverse Eukaryotes

Abstract: Dnmt1 epigenetically propagates symmetrical CG methylation in many eukaryotes.

Abstract: Their genomes are typically depleted of CG dinucleotides because of imperfect repair of deaminated methylcytosines.

Abstract: Here, we extensively survey diverse species lacking Dnmt1 and show that, surprisingly, symmetrical CG methylation is nonetheless frequently present and catalyzed by a different DNA methyltransferase family, Dnmt5.

Abstract: Numerous Dnmt5-containing organisms that diverged more than a billion years ago exhibit clustered methylation, specifically in nucleosome linkers.

Abstract: Clustered methylation occurs at unprecedented densities and directly disfavors nucleosomes, contributing to nucleosome positioning between clusters.

Abstract: Dense methylation is enabled by a regime of genomic sequence evolution that enriches CG dinucleotides and drives the highest CG frequencies known.

Abstract: Species with linker methylation have small, transcriptionally active nuclei that approach the physical limits of chromatin compaction.

Abstract: These features constitute a previously unappreciated genome architecture, in which dense methylation influences nucleosome positions, likely facilitating nuclear processes under extreme spatial constraints.


The Immunogenicity and Safety of the Live-attenuated SA 14-14-2 Japanese Encephalitis Vaccine Given with a Two-dose Primary Schedule in Children

Abstract: Effective and tolerable vaccination is an essential strategy to prevent Japanese encephalitis (JE) in endemic areas.

Abstract: Although the live attenuated SA 14-14-2 JE vaccine (LAJEV) has been widely used since its introduction, the systemic data of LAJEV was very rarely available in Korea.

Abstract: We conducted the open-label, prospective cohort study to assess the immunogenicity and safety of this vaccine.

Abstract: Ninety subjects were enrolled, and LAJEV in a 2-dose primary series was given with a 12-month interval.

Abstract: Neutralizing antibody titers were measured before and after each vaccination, and active monitoring for adverse events was performed.

Abstract: After the first dose, 91.1% of subjects had seroprotection with a geometric mean titer (GMT) of 40.9.

Abstract: Seroprotection rate after the second dose was 97%, and GMT showed an increase of 6.5-fold.

Abstract: Most adverse events following immunization were self-limited, and no serious adverse events were reported until 42 days after each dose.

Abstract: The 2-dose administration of LAJEV in the primary immunization schedule appeared to be highly immunogenic and safe.


Centrosome-dependent asymmetric inheritance of the midbody ring in Drosophila germline stem cell division

Abstract: Many stem cells, including Drosophila germline stem cells (GSCs), divide asymmetrically, producing one stem cell and one differentiating daughter.

Abstract: Cytokinesis is often asymmetric, in that only one daughter cell inherits the midbody ring (MR) upon completion of abscission even in apparently symmetrically dividing cells.

Abstract: However, whether the asymmetry in cytokinesis correlates with cell fate or has functional relevance has been poorly explored.

Abstract: Here we show that the MR is asymmetrically segregated during GSC divisions in a centrosome age-dependent manner: male GSCs, which inherit the mother centrosome, exclude the MR, whereas female GSCs, which we here show inherit the daughter centrosome, inherit the MR.

Abstract: We further show that stem cell identity correlates with the mode of MR inheritance.

Abstract: Together our data suggest that the MR does not inherently dictate stem cell identity, although its stereotypical inheritance is under the control of stemness and potentially provides a platform for asymmetric segregation of certain factors.


Penile Curvature Incidence in Hypospadias: Can It Be Determined?

Abstract: The aim was to retrospectively determine the real incidence of congenital penile curvature in various forms of hypospadias, in order to indicate intraoperative assessment and correction of curvature.

Abstract: We analyzed 842 patients with hypospadias who underwent surgery from 2003 to 2010, classified into two groups.

Abstract: First group was intraoperatively checked for curvature as a routine procedure, while a curvature in the second group was assessed mostly in severe hypospadias.

Abstract: Results are analyzed using Fisher's and chi-square tests.

Abstract: In total, 238 cases (28.3%) of associated curvature were confirmed.

Abstract: Curvature was significantly more frequent in the first group, regarding hypospadias in general (P < 0.01), as well as distal (P < 0.05) and midshaft forms (P < 0.01).

Abstract: Penile curvature is common figure in hypospadias, including distal types.

Abstract: Intraoperative testing for associated curvature should be considered as a routine procedure in hypospadias repair.


Home birth and barriers to referring women with obstetric complications to hospitals: a mixed-methods study in Zahedan, southeastern Iran

Abstract: BACKGROUND One factor that contributes to high maternal mortality in developing countries is the delayed use of Emergency Obstetric-Care (EmOC) facilities.

Abstract: The objective of this study was to determine the factors that hinder midwives and parturient women from using hospitals when complications occur during home birth in Sistan and Baluchestan province, Iran, where 23% of all deliveries take place in non- hospital settings.

Abstract: METHODS In the study and data management, a mixed-methods approach was used.

Abstract: In the quantitative phase, we compared the existing health-sector data with World Health Organization (WHO) standards for the availability and use of EmOC services.

Abstract: The qualitative phase included collection and analysis of interviews with midwives and traditional birth attendants and twenty-one in-depth interviews with mothers.

Abstract: The data collected in this phase were managed according to the principles of qualitative data analysis.

Abstract: RESULTS The findings demonstrate that three distinct factors lead to indecisiveness and delay in the use of EmOC by the midwives and mothers studied.

Abstract: Socio-cultural and familial reasons compel some women to choose to give birth at home and to hesitate seeking professional emergency care for delivery complications.

Abstract: Apprehension about being insulted by physicians, the necessity of protecting their professional integrity in front of patients and an inability to persuade their patients lead to an over-insistence by midwives on completing deliveries at the mothers' homes and a reluctance to refer their patients to hospitals.

Abstract: The low quality and expense of EmOC and the mothers' lack of health insurance also contribute to delays in referral.

Abstract: CONCLUSIONS Women who choose to give birth at home accept the risk that complications may arise.

Abstract: Training midwives and persuading mothers and significant others who make decisions about the value of referring women to hospitals at the onset of life-threatening complications are central factors to increasing the use of available hospitals.

Abstract: The hospitals must be safe, comfortable and attractive environments for parturition and should give appropriate consideration to the ethical and cultural concerns of the women.

Abstract: Appropriate management of financial and insurance-related issues can help midwives and mothers make a rational decision when complications arise.


ATPase-Dependent Control of the Mms21 SUMO Ligase during DNA Repair

Abstract: Modification of proteins by SUMO is essential for the maintenance of genome integrity.

Abstract: During DNA replication, the Mms21-branch of the SUMO pathway counteracts recombination intermediates at damaged replication forks, thus facilitating sister chromatid disjunction.

Abstract: The Mms21 SUMO ligase docks to the arm region of the Smc5 protein in the Smc5/6 complex; together, they cooperate during recombinational DNA repair.

Abstract: Yet how the activity of the SUMO ligase is controlled remains unknown.

Abstract: Here we show that the SUMO ligase and the chromosome disjunction functions of Mms21 depend on its docking to an intact and active Smc5/6 complex, indicating that the Smc5/6-Mms21 complex operates as a large SUMO ligase in vivo.

Abstract: In spite of the physical distance separating the E3 and the nucleotide-binding domains in Smc5/6, Mms21-dependent sumoylation requires binding of ATP to Smc5, a step that is part of the ligase mechanism that assists Ubc9 function.

Abstract: The communication is enabled by the presence of a conserved disruption in the coiled coil domain of Smc5, pointing to potential conformational changes for SUMO ligase activation.

Abstract: In accordance, scanning force microscopy of the Smc5-Mms21 heterodimer shows that the molecule is physically remodeled in an ATP-dependent manner.

Abstract: Our results demonstrate that the ATP-binding activity of the Smc5/6 complex is coordinated with its SUMO ligase, through the coiled coil domain of Smc5 and the physical remodeling of the molecule, to promote sumoylation and chromosome disjunction during DNA repair.


Cadherins in brain morphogenesis and wiring.

Abstract: Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis.

Abstract: Various cadherin-related molecules have also been identified, which show diverse functions, not only for the regulation of cell adhesion but also for that of cell proliferation and planar cell polarity.

Abstract: During the past decade, understanding of the roles of these molecules in the nervous system has significantly progressed.

Abstract: They are important not only for the development of the nervous system but also for its functions and, in turn, for neural disorders.

Abstract: In this review, we discuss the roles of cadherins and related molecules in neural development and function in the vertebrate brain.


Autocrine WNT signaling contributes to breast cancer cell proliferation via the canonical WNT pathway and EGFR transactivation

Abstract: De-regulation of the wingless and integration site growth factor (WNT) signaling pathway via mutations in APC and Axin, proteins that target β-catenin for destruction, have been linked to various types of human cancer.

Abstract: These genetic alterations rarely, if ever, are observed in breast tumors.

Abstract: However, various lines of evidence suggest that WNT signaling may also be de-regulated in breast cancer.

Abstract: Most breast tumors show hypermethylation of the promoter region of secreted Frizzled-related protein 1 (sFRP1), a negative WNT pathway regulator, leading to downregulation of its expression.

Abstract: As a consequence, WNT signaling is enhanced and may contribute to proliferation of human breast tumor cells.

Abstract: We previously demonstrated that, in addition to the canonical WNT/β-catenin pathway, WNT signaling activates the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway in mouse mammary epithelial cells via epidermal growth factor receptor (EGFR) transactivation.

Abstract: Using the WNT modulator sFRP1 and short interfering RNA-mediated Dishevelled (DVL) knockdown, we interfered with autocrine WNT signaling at the ligand-receptor level.

Abstract: The impact on proliferation was measured by cell counting, YOPRO, and the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) assay; β-catenin, EGFR, ERK1/2 activation, and PARP (poly [ADP-ribose]polymerase) cleavages were assessed by Western blotting after treatment of human breast cancer cell lines with conditioned media, purified proteins, small-molecule inhibitors, or blocking antibodies.

Abstract: Phospho-DVL and stabilized β-catenin are present in many breast tumor cell lines, indicating autocrine WNT signaling activity.

Abstract: Interfering with this loop decreases active β-catenin levels, lowers ERK1/2 activity, blocks proliferation, and induces apoptosis in MDA-MB-231, BT474, SkBr3, JIMT-1, and MCF-7 cells.

Abstract: The effects of WNT signaling are mediated partly by EGFR transactivation in human breast cancer cells in a metalloprotease- and Src-dependent manner.

Abstract: Furthermore, Wnt1 rescues estrogen receptor-positive (ER+) breast cancer cells from the anti-proliferative effects of 4-hydroxytamoxifen (4-HT) and this activity can be blocked by an EGFR tyrosine kinase inhibitor.

Abstract: Our data show that interference with autocrine WNT signaling in human breast cancer reduces proliferation and survival of human breast cancer cells and rescues ER+ tumor cells from 4-HT by activation of the canonical WNT pathway and EGFR transactivation.

Abstract: These findings suggest that interference with WNT signaling at the ligand-receptor level in combination with other targeted therapies may improve the efficiency of breast cancer treatments.


Alternative Markers of Hyperglycemia and Risk of Diabetes

Abstract: OBJECTIVE Fructosamine, glycated albumin, and 1,5-anhydroglucitol (1,5-AG) are of interest for monitoring short-term glycemic control in patients with diabetes; however, their associations with diabetes risk are uncharacterized.

Abstract: RESEARCH DESIGN AND METHODS

Abstract: We used Cox proportional hazards models to examine the associations of fructosamine, glycated albumin, and 1,5-AG with incident diabetes in 1,299 participants, from the Atherosclerosis Risk in Communities (ARIC) Study (2005-2006), who had no history of diagnosed diabetes at baseline.

Abstract: Incident diabetes was self-reported during annual telephone calls.

Abstract: RESULTS There were 119 new cases of diabetes during a median follow-up of 3.3 years.

Abstract: When compared with the lowest quartile, the fourth quartiles of fructosamine and glycated albumin were significantly associated with diabetes risk (hazard ratio [HR] 3.99 [95% CI 1.93-8.28] and 5.22 [2.49-10.94], respectively).

Abstract: The fourth quartile of 1,5-AG was associated with a significantly lower diabetes risk (0.27 [0.14-0.55]).

Abstract: Associations were attenuated but still significant after adjustment for hemoglobin A(1c) (A1C) or fasting glucose.

Abstract: CONCLUSIONS Fructosamine, glycated albumin, and 1,5-AG were associated with the subsequent development of diabetes independently of baseline A1C and fasting glucose.

Abstract: Our results suggest these alternative biomarkers may be useful in identifying persons at risk for diabetes.


ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer

Abstract: The androgen receptor (AR) is overexpressed and hyperactivated in human castration-resistant prostate cancer (CRPC).

Abstract: However, the determinants of AR overexpression in CRPC are poorly defined.

Abstract: Here we show that retinoic acid receptor-related orphan receptor γ (ROR-γ) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-γ drives AR expression in the tumors.

Abstract: ROR-γ recruits nuclear receptor coactivator 1 and 3 (NCOA1 and NCOA3, also known as SRC-1 and SRC-3) to an AR-ROR response element (RORE) to stimulate AR gene transcription.

Abstract: ROR-γ antagonists suppress the expression of both AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors.

Abstract: ROR-γ antagonists also markedly diminish genome-wide AR binding, H3K27ac abundance and expression of the AR target gene network.

Abstract: Finally, ROR-γ antagonists suppressed tumor growth in multiple AR-expressing, but not AR-negative, xenograft PCa models, and they effectively sensitized CRPC tumors to enzalutamide, without overt toxicity, in mice.

Abstract: Taken together, these results establish ROR-γ as a key player in CRPC by acting upstream of AR and as a potential therapeutic target for advanced PCa.


affy--analysis of Affymetrix GeneChip data at the probe level.

Abstract: MOTIVATION The processing of the Affymetrix GeneChip data has been a recent focus for data analysts.

Abstract: Alternatives to the original procedure have been proposed and some of these new methods are widely used.

Abstract: RESULTS The affy package is an R package of functions and classes for the analysis of oligonucleotide arrays manufactured by Affymetrix.

Abstract: The package is currently in its second release, affy provides the user with extreme flexibility when carrying out an analysis and make it possible to access and manipulate probe intensity data.

Abstract: In this paper, we present the main classes and functions in the package and demonstrate how they can be used to process probe-level data.

Abstract: We also demonstrate the importance of probe-level analysis when using the Affymetrix GeneChip platform.


Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation.

Abstract: To test the feasibility of a single T-cell manipulation to eliminate alloreactivity while sparing antiviral and antitumor T cells, we infused 12 haploidentical hematopoietic stem cell transplant patients with increasing numbers of alloreplete haploidentical T cells expressing the inducible caspase 9 suicide gene (iC9-T cells).

Abstract: We determined whether the iC9-T cells produced immune reconstitution and if any resultant graft-versus-host disease (GVHD) could be controlled by administration of a chemical inducer of dimerization (CID; AP1903/Rimiducid).

Abstract: All patients receiving >10(4) alloreplete iC9-T lymphocytes per kilogram achieved rapid reconstitution of immune responses toward 5 major pathogenic viruses and concomitant control of active infections.

Abstract: Four patients received a single AP1903 dose.

Abstract: CID infusion eliminated 85% to 95% of circulating CD3(+)CD19(+) T cells within 30 minutes, with no recurrence of GVHD within 90 days.

Abstract: In one patient, symptoms and signs of GVHD-associated cytokine release syndrome (CRS-hyperpyrexia, high levels of proinflammatory cytokines, and rash) resolved within 2 hours of AP1903 infusion.

Abstract: One patient with varicella zoster virus meningitis and acute GVHD had iC9-T cells present in the cerebrospinal fluid, which were reduced by >90% after CID.

Abstract: Notably, virus-specific T cells recovered even after AP1903 administration and continued to protect against infection.

Abstract: Hence, alloreplete iC9-T cells can reconstitute immunity posttransplant and administration of CID can eliminate them from both peripheral blood and the central nervous system (CNS), leading to rapid resolution of GVHD and CRS.

Abstract: The approach may therefore be useful for the rapid and effective treatment of toxicities associated with infusion of engineered T lymphocytes.

Abstract: This trial was registered at www.clinicaltrials.gov as #NCT01494103.


Clonal analysis of epiblast fate during germ layer formation in the mouse embryo.

Abstract: The fate of cells in the epiblast at prestreak and early primitive streak stages has been studied by injecting horseradish peroxidase (HRP) into single cells in situ of 6.7-day mouse embryos and identifying the labelled descendants at midstreak to neural plate stages after one day of culture.

Abstract: Ectoderm was composed of descendants of epiblast progenitors that had been located in the embryonic axis anterior to the primitive streak.

Abstract: Embryonic mesoderm was derived from all areas of the epiblast except the distal tip and the adjacent region anterior to it: the most anterior mesoderm cells originated posteriorly, traversing the primitive streak early; labelled cells in the posterior part of the streak at the neural plate stage were derived from extreme anterior axial and paraxial epiblast progenitors; head process cells were derived from epiblast at or near the anterior end of the primitive streak.

Abstract: Endoderm descendants were most frequently derived from a region that included, but extended beyond, the region producing the head process: descendants of epiblast were present in endoderm by the midstreak stage, as well as at later stages.

Abstract: Yolk sac and amnion mesoderm developed from posterolateral and posterior epiblast.

Abstract: The resulting fate map is essentially the same as those of the chick and urodele and indicates that, despite geometrical differences, topological fate relationships are conserved among these vertebrates.

Abstract: Clonal descendants were not necessarily confined to a single germ layer or to extraembryonic mesoderm, indicating that these lineages are not separated at the beginning of gastrulation.

Abstract: The embryonic axis lengthened up to the neural plate stage by (1) elongation of the primitive streak through progressive incorporation of the expanding lateral and initially more anterior regions of epiblast and, (2) expansion of the region of epiblast immediately cranial to the anterior end of the primitive streak.

Abstract: The population doubling time of labelled cells was 7.5 h; a calculated 43% were in, or had completed, a 4th cell cycle, and no statistically significant regional differences in the number of descendants were found.

Abstract: This clonal analysis also showed that (1) growth in the epiblast was noncoherent and in most regions anisotropic and directed towards the primitive streak and (2) the midline did not act as a barrier to clonal spread, either in the epiblast in the anterior half of the axis or in the primitive streak.

Abstract: These results taken together with the fate map indicate that, while individual cells in the epiblast sheet behave independently with respect to their neighbours, morphogenetic movement during germ layer formation is coordinated in the population as a whole.


Effects of a High-Intensity Functional Exercise Program on Dependence in Activities of Daily Living and Balance in Older Adults with Dementia

Abstract: OBJECTIVES To investigate the effects of a high-intensity functional exercise program on independence in activities of daily living (ADLs) and balance in older people with dementia and whether exercise effects differed between dementia types.

Abstract: DESIGN Cluster-randomized controlled trial: Umeå Dementia and Exercise (UMDEX) study.

Abstract: SETTING Residential care facilities, Umeå, Sweden.

Abstract: PARTICIPANTS Individuals aged 65 and older with a dementia diagnosis, a Mini-Mental State Examination score of 10 or greater, and dependence in ADLs (N=186).

Abstract: INTERVENTION Ninety-three participants each were allocated to the high-intensity functional exercise program, comprising lower limb strength and balance exercises, and 93 to a seated control activity.

Abstract: MEASUREMENTS Blinded assessors measured ADL independence using the Functional Independence Measure (FIM) and Barthel Index (BI) and balance using the Berg Balance Scale (BBS) at baseline and 4 (directly after intervention completion) and 7 months.

Abstract: RESULTS Linear mixed models showed no between-group effect on ADL independence at 4 (FIM=1.3, 95% confidence interval (CI)=-1.6-4.3; BI=0.6, 95% CI=-0.2-1.4) or 7 (FIM=0.8, 95% CI=-2.2-3.8; BI=0.6, 95% CI=-0.3-1.4) months.

Abstract: A significant between-group effect on balance favoring exercise was observed at 4 months (BBS=4.2, 95% CI=1.8-6.6).

Abstract: In interaction analyses, exercise effects differed significantly between dementia types.

Abstract: Positive between-group exercise effects were found in participants with non-Alzheimer's dementia according to the FIM at 7 months and BI and BBS at 4 and 7 months.

Abstract: CONCLUSION In older people with mild to moderate dementia living in residential care facilities, a 4-month high-intensity functional exercise program appears to slow decline in ADL independence and improve balance, albeit only in participants with non-Alzheimer's dementia.


Effect of Health Literacy on Quality of Life amongst Patients with Ischaemic Heart Disease in Australian General Practice

Abstract: BACKGROUND Appropriate understanding of health information by patients with cardiovascular disease (CVD) is fundamental for better management of risk factors and improved morbidity, which can also benefit their quality of life.

Abstract: OBJECTIVES To assess the relationship between health literacy and health-related quality of life (HRQoL) in patients with ischaemic heart disease (IHD), and to investigate the role of sociodemographic and clinical variables as possible confounders.

Abstract: METHODS Cross-sectional study of patients with IHD recruited from a stratified sample of general practices in two Australian states (Queensland and South Australia) between 2007 and 2009.

Abstract: Health literacy was measured using a validated questionnaire and classified as inadequate, marginal, or adequate.

Abstract: Physical and mental components of HRQoL were assessed using the Medical Outcomes Study Short Form (SF12) questionnaire.

Abstract: Analyses were adjusted for confounders (sociodemographic variables, clinical history of IHD, number of CVD comorbidities, and CVD risk factors) using multiple linear regression.

Abstract: RESULTS A total sample of 587 patients with IHD (mean age 72.0±8.4 years) was evaluated: 76.8% males, 84.2% retired or pensioner, and 51.4% with up to secondary educational level.

Abstract: Health literacy showed a mean of 39.6±6.7 points, with 14.3% (95%CI 11.8-17.3) classified as inadequate.

Abstract: Scores of the physical component of HRQoL were 39.6 (95%CI 37.1-42.1), 42.1 (95%CI 40.8-43.3) and 44.8 (95%CI 43.3-46.2) for inadequate, marginal, and adequate health literacy, respectively (p-value for trend = 0.001).

Abstract: This association persisted after adjustment for confounders.

Abstract: Health literacy was not associated with the mental component of HRQoL (p-value = 0.482).

Abstract: Advanced age, lower educational level, disadvantaged socioeconomic position, and a larger number of CVD comorbidities adversely affected both, health literacy and HRQoL.   CONCLUSION Inadequate health literacy is a contributing factor to poor physical functioning in patients with IHD.

Abstract: Increasing health literacy may improve HRQoL and reduce the impact of IHD among patients with this chronic CVD.


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Abstract: Transglutaminase 2 (TGase 2) is a Ca+2-dependent enzyme that catalyzes both intracellular and extracellular cross-linking reactions by transamidation of specific glutamine residues.

Abstract: TGase 2 is known to be involved in the membrane-mediated events required for glucose-stimulated insulin release from the pancreatic beta cells.

Abstract: Here we show that targeted disruption of TGase 2 impairs glucose-stimulated insulin secretion.

Abstract: TGase 2-/- mice show glucose intolerance after intraperitoneal glucose loading.

Abstract: TGase 2-/- mice manifest a tendency to develop hypoglycemia after administration of exogenous insulin as a consequence of enhanced insulin receptor substrate 2 (IRS-2) phosphorylation.

Abstract: We suggest that the increased peripheral sensitivity to insulin partially compensates for the defective secretion in this animal model.

Abstract: TGase 2-/- mouse phenotype resembles that of the maturity-onset diabetes of young (MODY) patients.

Abstract: In the course of screening for human TGase 2 gene in Italian subjects with the clinical features of MODY, we detected a missense mutation (N333S) in the active site of the enzyme.

Abstract: Collectively, these results identify TGase 2 as a potential candidate gene in type 2 diabetes.


Chromatin structure and gene expression programs of human embryonic and induced pluripotent stem cells.

Abstract: Knowledge of both the global chromatin structure and the gene expression programs of human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) should provide a robust means to assess whether the genomes of these cells have similar pluripotent states.

Abstract: Recent studies have suggested that ESCs and iPSCs represent different pluripotent states with substantially different gene expression profiles.

Abstract: We describe here a comparison of global chromatin structure and gene expression data for a panel of human ESCs and iPSCs.

Abstract: Genome-wide maps of nucleosomes with histone H3K4me3 and H3K27me3 modifications indicate that there is little difference between ESCs and iPSCs with respect to these marks.

Abstract: Gene expression profiles confirm that the transcriptional programs of ESCs and iPSCs show very few consistent differences.

Abstract: Although some variation in chromatin structure and gene expression was observed in these cell lines, these variations did not serve to distinguish ESCs from iPSCs.


Myeloid Cells Expressing VEGF and Arginase-1 Following Uptake of Damaged Retinal Pigment Epithelium Suggests Potential Mechanism That Drives the Onset of Choroidal Angiogenesis in Mice

Abstract: Whilst data recognise both myeloid cell accumulation during choroidal neovascularisation (CNV) as well as complement activation, none of the data has presented a clear explanation for the angiogenic drive that promotes pathological angiogenesis.

Abstract: One possibility that is a pre-eminent drive is a specific and early conditioning and activation of the myeloid cell infiltrate.

Abstract: Using a laser-induced CNV murine model, we have identified that disruption of retinal pigment epithelium (RPE) and Bruch's membrane resulted in an early recruitment of macrophages derived from monocytes and microglia, prior to angiogenesis and contemporaneous with lesional complement activation.

Abstract: Early recruited CD11b(+) cells expressed a definitive gene signature of selective inflammatory mediators particularly a pronounced Arg-1 expression.

Abstract: Accumulating macrophages from retina and peripheral blood were activated at the site of injury, displaying enhanced VEGF expression, and notably prior to exaggerated VEGF expression from RPE, or earliest stages of angiogenesis.

Abstract: All of these initial events, including distinct VEGF (+) Arg-1(+) myeloid cells, subsided when CNV was established and at the time RPE-VEGF expression was maximal.

Abstract: Depletion of inflammatory CCR2-positive monocytes confirmed origin of infiltrating monocyte Arg-1 expression, as following depletion Arg-1 signal was lost and CNV suppressed.

Abstract: Furthermore, our in vitro data supported a myeloid cell uptake of damaged RPE or its derivatives as a mechanism generating VEGF (+) Arg-1(+) phenotype in vivo.

Abstract: Our results reveal a potential early driver initiating angiogenesis via myeloid-derived VEGF drive following uptake of damaged RPE and deliver an explanation of why CNV develops during any of the stages of macular degeneration and can be explored further for therapeutic gain.


Monitoring Tumorigenesis and Senescence In Vivo with a p16INK4a-Luciferase Model

Abstract: Monitoring cancer and aging in vivo remains experimentally challenging.

Abstract: Here, we describe a luciferase knockin mouse (p16(LUC)), which faithfully reports expression of p16(INK4a), a tumor suppressor and aging biomarker.

Abstract: Lifelong assessment of luminescence in p16(+/LUC) mice revealed an exponential increase with aging, which was highly variable in a cohort of contemporaneously housed, syngeneic mice.

Abstract: Expression of p16(INK4a) with aging did not predict cancer development, suggesting that the accumulation of senescent cells is not a principal determinant of cancer-related death.

Abstract: In 14 of 14 tested tumor models, expression of p16(LUC) was focally activated by early neoplastic events, enabling visualization of tumors with sensitivity exceeding other imaging modalities.

Abstract: Activation of p16(INK4a) was noted in the emerging neoplasm and surrounding stromal cells.

Abstract: This work suggests that p16(INK4a) activation is a characteristic of all emerging cancers, making the p16(LUC) allele a sensitive, unbiased reporter of neoplastic transformation.


The Bacteroides sp. 3_1_23 Pif1 protein is a multifunctional helicase

Abstract: ScPif1 DNA helicase is the prototypical member of a 5'-to-3' helicase superfamily conserved from bacteria to human and plays various roles in the maintenance of genomic homeostasis.

Abstract: While many studies have been performed with eukaryotic Pif1 helicases, including yeast and human Pif1 proteins, the potential functions and biochemical properties of prokaryotic Pif1 helicases remain largely unknown.

Abstract: Here, we report the expression, purification and biochemical analysis of Pif1 helicase from Bacteroides sp. 3_1_23 (BsPif1).

Abstract: BsPif1 binds to a large panel of DNA substrates and, in particular, efficiently unwinds partial duplex DNAs with 5'-overhang, fork-like substrates, D-loop and flap-like substrates, suggesting that BsPif1 may act at stalled DNA replication forks and enhance Okazaki fragment maturation.

Abstract: Like its eukaryotic homologues, BsPif1 resolves R-loop structures and unwinds DNA-RNA hybrids.

Abstract: Furthermore, BsPif1 efficiently unfolds G-quadruplexes and disrupts nucleoprotein complexes.

Abstract: Altogether, these results highlight that prokaryotic Pif1 helicases may resolve common issues that arise during DNA transactions.

Abstract: Interestingly, we found that BsPif1 is different from yeast Pif1, but resembles more human Pif1 with regard to substrate specificity, helicase activity and mode of action.

Abstract: These findings are discussed in the context of the possible functions of prokaryotic Pif1 helicases in vivo.


Netting neutrophils in autoimmune small-vessel vasculitis

Abstract: Small-vessel vasculitis (SVV) is a chronic autoinflammatory condition linked to antineutrophil cytoplasm autoantibodies (ANCAs).

Abstract: Here we show that chromatin fibers, so-called neutrophil extracellular traps (NETs), are released by ANCA-stimulated neutrophils and contain the targeted autoantigens proteinase-3 (PR3) and myeloperoxidase (MPO).

Abstract: Deposition of NETs in inflamed kidneys and circulating MPO-DNA complexes suggest that NET formation triggers vasculitis and promotes the autoimmune response against neutrophil components in individuals with SVV.


Control of Nutrient Stress-Induced Metabolic Reprogramming by PKCζ in Tumorigenesis

Abstract: Tumor cells have high-energetic and anabolic needs and are known to adapt their metabolism to be able to survive and keep proliferating under conditions of nutrient stress.

Abstract: We show that PKCζ deficiency promotes the plasticity necessary for cancer cells to reprogram their metabolism to utilize glutamine through the serine biosynthetic pathway in the absence of glucose.

Abstract: PKCζ represses the expression of two key enzymes of the pathway, PHGDH and PSAT1, and phosphorylates PHGDH at key residues to inhibit its enzymatic activity.

Abstract: Interestingly, the loss of PKCζ in mice results in enhanced intestinal tumorigenesis and increased levels of these two metabolic enzymes, whereas patients with low levels of PKCζ have a poor prognosis.

Abstract: Furthermore, PKCζ and caspase-3 activities are correlated with PHGDH levels in human intestinal tumors.

Abstract: Taken together, this demonstrates that PKCζ is a critical metabolic tumor suppressor in mouse and human cancer.


XRCC4's interaction with XLF is required for coding (but not signal) end joining

Abstract: XRCC4 and XLF are structurally related proteins important for DNA Ligase IV function.

Abstract: XRCC4 forms a tight complex with DNA Ligase IV while XLF interacts directly with XRCC4.

Abstract: Both XRCC4 and XLF form homodimers that can polymerize as heterotypic filaments independently of DNA Ligase IV.

Abstract: Emerging structural and in vitro biochemical data suggest that XRCC4 and XLF together generate a filamentous structure that promotes bridging between DNA molecules.

Abstract: Here, we show that ablating XRCC4's affinity for XLF results in DNA repair deficits including a surprising deficit in VDJ coding, but not signal end joining.

Abstract: These data are consistent with a model whereby XRCC4/XLF complexes hold DNA ends together--stringently required for coding end joining, but dispensable for signal end joining.

Abstract: Finally, DNA-PK phosphorylation of XRCC4/XLF complexes disrupt DNA bridging in vitro, suggesting a regulatory role for DNA-PK's phosphorylation of XRCC4/XLF complexes.


Loss of imprinting in colorectal cancer linked to hypomethylation of H19 and IGF2.

Abstract: Epigenetic alterations in human cancers include global DNA hypomethylation,gene hypomethylation and promoter hypermethylation, and loss of imprinting (LOI) of the insulin-like growth factor-II gene (IGF2).

Abstract: A mechanism for LOI described previously is hypermethylation of a differentially methylated region (DMR) upstream of the H19 gene, allowing activation of the normally silent maternal allele of IGF2.

Abstract: Here we show that this mechanism does not apply to colorectal cancers, which show hypomethylation of the H19 DMR as well as a DMR upstream of exon 3 of IGF2.

Abstract: This hypomethylation is found in both colorectal cancers and normal mucosa from the same patients, and in cell lines with somatic cell knockout of DNA methyltransferases DNMT1 and DNMT3B.

Abstract: These data suggest that hypomethylation is a mechanism for LOI, that the popular IGF2-H19 enhancer competition model for IGF2 imprinting does not apply to the human colon, and that an alternative model for LOI would involve a transcriptional repressor acting on the normally silent maternal allele of IGF2.


Management of patients with sore throats in relation to guidelines: An interview study in Sweden

Abstract: OBJECTIVE To explore how a group of Swedish general practitioners (GPs) manage patients with a sore throat in relation to current guidelines as expressed in interviews.

Abstract: DESIGN Qualitative content analysis was used to analyse semi-structured interviews.

Abstract: SETTING Swedish primary care.

Abstract: SUBJECTS A strategic sample of 25 GPs.

Abstract: MAIN OUTCOME MEASURES Perceived management of sore throat patients.

Abstract: RESULTS It was found that nine of the interviewed GPs were adherent to current guidelines for sore throat and 16 were non-adherent.

Abstract: The two groups differed in terms of guideline knowledge, which was shared within the team for adherent GPs while idiosyncratic knowledge dominated for the non-adherent GPs.

Abstract: Adherent GPs had no or low concerns for bacterial infections and differential diagnosis whilst non-adherent GPs believed that in patients with a sore throat any bacterial infection should be identified and treated with antibiotics.

Abstract: Patient history and examination was mainly targeted by adherent GPs whilst for non-adherent GPs it was often redundant.

Abstract: Non-adherent GPs reported problems getting patients to abstain from antibiotics, whilst no such problems were reported in adherent GPs.

Abstract: CONCLUSION This interview study of sore throat management in a strategically sampled group of Swedish GPs showed that while two-thirds were non-adherent and had a liberal attitude to antibiotics one-third were guideline adherent with a restricted view on antibiotics.

Abstract: Non-adherent GPs revealed significant knowledge gaps.

Abstract: Adherent GPs had discussed guidelines within the primary care team while non-adherent GPs had not.

Abstract: Guideline implementation thus seemed to be promoted by knowledge shared in team discussions.


Catch and release: how do kinetochores hook the right microtubules during mitosis?

Abstract: Sport fishermen keep tension on their lines to prevent hooked fish from releasing.

Abstract: A molecular version of this angler's trick, operating at kinetochores, ensures accuracy during mitosis: the mitotic spindle attaches randomly to chromosomes and then correctly bioriented attachments are stabilized due to the tension exerted on them by opposing microtubules.

Abstract: Incorrect attachments, which lack tension, are unstable and release quickly, allowing another chance for biorientation.

Abstract: Stabilization of molecular interactions by tension also occurs in other physiological contexts, such as cell adhesion, motility, hemostasis, and tissue morphogenesis.

Abstract: Here, we review models for the stabilization of kinetochore attachments with an eye toward emerging models for other force-activated systems.

Abstract: Although attention in the mitosis field has focused mainly on one kinase-based mechanism, multiple mechanisms may act together to stabilize properly bioriented kinetochores and some principles governing other tension-sensitive systems may also apply to kinetochores.


Label-free in vivo imaging of myelinated axons in health and disease with spectral confocal reflectance microscopy

Abstract: We report a newly developed technique for high-resolution in vivo imaging of myelinated axons in the brain, spinal cord and peripheral nerve that requires no fluorescent labeling.

Abstract: This method, based on spectral confocal reflectance microscopy (SCoRe), uses a conventional laser-scanning confocal system to generate images by merging the simultaneously reflected signals from multiple lasers of different wavelengths.

Abstract: Striking color patterns unique to individual myelinated fibers are generated that facilitate their tracing in dense axonal areas.

Abstract: These patterns highlight nodes of Ranvier and Schmidt-Lanterman incisures and can be used to detect various myelin pathologies.

Abstract: Using SCoRe we carried out chronic brain imaging up to 400 μm deep, capturing de novo myelination of mouse cortical axons in vivo.

Abstract: We also established the feasibility of imaging myelinated axons in the human cerebral cortex.

Abstract: SCoRe adds a powerful component to the evolving toolbox for imaging myelination in living animals and potentially in humans.


Applicability of current staging/categorization of α-synuclein pathology and their clinical relevance

Abstract: In Parkinson's disease (PD) and dementia with Lewy bodies (DLB) alpha-synuclein (alphaS) pathology is seen that displays a predictable topographic distribution.

Abstract: There are two staging/categorization systems,

Abstract: i.e. Braak's and McKeith's, currently in use for the assessment of alphaS pathology.

Abstract: The aim of these diagnostic strategies in pathology is, in addition to assess the stage/severity of pathology, to assess the probabilities of the related clinical symptomatology i.e. dementia and extrapyramidal symptoms (EPS).

Abstract: Herein, we assessed the applicability of these two staging/categorization systems and the frequency of dementia and EPS in a cohort of 226 alphaS-positive-subjects.

Abstract: These subject were selected from a large autopsy sample (n = 1,720), irrespective of the clinical presentation, based on the detection of alphaS-immunoreactivity (IR) in one of the most vulnerable nuclei; in the dorsal motor nucleus of vagus, substantia nigra and basal forebrain.

Abstract: The frequency of alphaS-IR lesions in this large cohort was 14% (248 out of 1,720).

Abstract: If applicable, each of the 226 subjects with all required material available was assigned a neuropathological stage/category of PD/DLB and finally the neuropathological data was analyzed in relation to dementia and EPS.

Abstract: 83% of subjects showed a distribution pattern of alphaS-IR that was compatible with the current staging/categorization systems.

Abstract: Around 55% of subjects with widespread alphaS pathology (Braak's PD stages 5-6) lacked clinical signs of dementia or EPS.

Abstract: Similarly, in respect to those subjects that fulfilled the McKeith criteria for diffuse neocortical category and displaying only mild concomitant Alzheimer's disease-related pathology, only 48% were demented and 54% displayed EPS.

Abstract: It is noteworthy that some subjects (17%) deviated from the suggested caudo-rostral propagation suggesting alternative routes of progression, perhaps due to concomitant diseases and genetic predisposition.

Abstract: In conclusion, our results do indeed confirm that current staging/categorization systems can readily be applied to most of the subjects with alphaS pathology.

Abstract: However, finding that around half of the subjects with abundant alphaS pathology remain neurologically intact is intriguing and raises the question whether we do assess the actual disease process.


Batf is important for IL-4 expression in T follicular helper cells

Abstract: Apart from T helper (Th)-2 cells, T follicular helper (Tfh) cells are a major class of IL-4-producing T cells, required for regulation of type 2 humoral immunity; however, transcriptional control of IL-4 production in Tfh cells remains mainly unknown.

Abstract: Here, we show that the basic leucine zipper transcription factor ATF-like, Batf is important for IL-4 expression in Tfh cells rather than in canonical Th2 cells.

Abstract: Functionally, Batf in cooperation with interferon regulatory factor (IRF) 4 along with Stat3 and Stat6 trigger IL-4 production in Tfh cells by directly binding to and activation of the CNS2 region in the IL-4 locus.

Abstract: In addition, Batf-to-c-Maf signalling is an important determinant of IL-4 expression in Tfh cells.

Abstract: Batf deficiency impairs the generation of IL-4-producing Tfh cells that results in protection against allergic asthma.

Abstract: Our results thus indicate a positive role of Batf in promoting the generation of pro-allergic IL-4-producing Tfh cells.


Autocrine VEGF Signaling Synergizes with EGFR in Tumor Cells to Promote Epithelial Cancer Development

Abstract: It is established that tumor cell-derived VEGF acts on endothelial cells to promote angiogenesis and tumor growth.

Abstract: Here, we demonstrate that in K5-SOS-dependent mouse skin tumors, autocrine VEGF is required for tumor cell proliferation in a cell-autonomous and angiogenesis-independent manner.

Abstract: VEGF is upregulated in SOS-expressing tumors, and its deletion in epidermal cells delays tumorigenesis by suppressing angiogenesis and tumor cell proliferation.

Abstract: Epidermis-specific Flt1 deletion also impairs tumorigenesis and proliferation.

Abstract: Surprisingly, complete tumor inhibition occurs in the absence of VEGF in EGFR mutant mice, demonstrating that VEGFR and EGFR synergize in neoplastic cells to promote tumor growth.

Abstract: Mechanistically, K5-SOS upregulates VEGF, Flt1, and Neuropilin-1 in an Erk-dependent manner, thereby activating an autocrine proliferation loop, whereas EGFR prevents tumor cells from apoptosis.

Abstract: Moreover, Flt1 is upregulated in human SCC, and its inhibition in SCC cells impairs proliferation.

Abstract: Thus, in addition to regulating angiogenesis, VEGF has to be considered as a potent growth factor for epidermal tumors.


Discovery and development of the Polo-like kinase inhibitor volasertib in cancer therapy

Abstract: Owing to their integral involvement in cell cycle regulation, the Polo-like kinase (Plk) family, particularly Plk1, has emerged as an attractive therapeutic target in oncology.

Abstract: In recent years, several Plk1 inhibitors have been developed, with some agents showing encouraging results in early-phase clinical trials.

Abstract: This review focuses on volasertib (BI 6727; an investigational agent), a potent and selective Plk inhibitor.

Abstract: Volasertib has shown promising activity in various cancer cell lines and xenograft models of human cancer.

Abstract: Trials performed to date suggest that volasertib has clinical efficacy in a range of malignancies, with the most promising results seen in patients with acute myeloid leukemia (AML).

Abstract: Encouragingly, recent phase II data have demonstrated that volasertib combined with low-dose cytarabine (LDAC) was associated with higher response rates and improved event-free survival than LDAC alone in patients with previously untreated AML.

Abstract: Based on these observations, and its presumably manageable safety profile, volasertib is currently in phase III development as a potential treatment for patients with AML who are ineligible for intensive remission induction therapy.

Abstract: Given that many patients with AML are of an older age and frail, this constitutes an area of major unmet need.

Abstract: In this review, we discuss the biologic rationale for Plk1 inhibitors in cancer, the clinical development of volasertib to date in solid tumors and AML, and the future identification of biomarkers that might predict response to volasertib and help determine the role of this agent in the clinic.


Babies driving robots: self-generated mobility in very young infants

Abstract: Self-generated mobility via locomotion is a key for the cognitive, social and motor development of young infants.

Abstract: For certain children with special needs, self-generated mobility is only attained via assistive technology such as a power wheelchair.

Abstract: Up until recently, infants under 24 months of age were not considered candidates for training in power mobility.

Abstract: Recent work in our labs and others suggest that younger infants can utilize their reaching and grasping ability to learn power mobility.

Abstract: This interdisciplinary study combines our previous work in motor development and learning in infants with special needs, and the application of robot technology for rehabilitation to determine whether young infants without structured training, would drive a mobile robot, and if so, to determine how their driving would change over multiple sessions.

Abstract: The two infants that were seen for the most sessions were the focus of this pilot study.

Abstract: Both infants increased their total session time, percentage of session time spent driving, and total path length.

Abstract: These results suggest that, without training, young infants will independently move themselves using a mobile robot.

Abstract: These results provide the foundation for training studies to advance the self-generated mobility in young infants with special needs.

Abstract: Our future studies will explore the multiple training and technology combinations to reduce the barriers to exploration via self-generated mobility, and advance the general development of infants with special needs.


Effects of Abciximab on the architecture of platelet-rich clots in patients with acute myocardial infarction undergoing primary coronary intervention.

Abstract: BACKGROUND Abciximab plus aspirin improves the TIMI 3 flow rate of the infarct-related artery in patients treated with either percutaneous coronary intervention or thrombolysis.

Abstract: The present study investigated whether the reperfusion efficacy of abciximab relates to modifications of clot architecture in patients admitted for acute myocardial infarction (AMI).

Abstract: METHODS AND RESULTS A total of 23 AMI patients in the Abciximab before Direct angioplasty and stenting in Myocardial Infarction Regarding Acute and Long term follow-up (ADMIRAL) trial received, in a double-blind fashion, either abciximab (n=13) or placebo (n=10) before primary stenting.

Abstract: Viscoelastic (G' in dyne/cm(2)) and morphological (mean platelet aggregate surface area [SAG] in micrometer(2)) indexes of ex vivo platelet-rich clots (PRC) were assessed in a double-blind fashion before and after the bolus administration of abciximab or placebo.

Abstract: G' and SAG reflect the mechanical and morphological impact of activated platelets on the PRC fibrin network, respectively.

Abstract: Abciximab administration reduced G' by 63% (P=0.0001) and SAG by 65% (P=0.0007), and no effect was seen in the placebo group.

Abstract: These abciximab-related changes increased fibrin exposure as a consequence of the platelet-aggregate surface reduction and may have improved endogenous fibrinolysis.

Abstract: These effects were identified in all patients, independent of previous heparin administration.

Abstract: CONCLUSIONS Abciximab dramatically reduces platelet aggregate size and increases the fibrin accessibility of ex vivo PRC in AMI patients.

Abstract: These modifications could participate in the better coronary artery patency observed with abciximab.


Natural Mutagenesis of Human Genomes by Endogenous Retrotransposons

Abstract: Two abundant classes of mobile elements, namely Alu and L1 elements, continue to generate new retrotransposon insertions in human genomes.

Abstract: Estimates suggest that these elements have generated millions of new germline insertions in individual human genomes worldwide.

Abstract: Unfortunately, current technologies are not capable of detecting most of these young insertions, and the true extent of germline mutagenesis by endogenous human retrotransposons has been difficult to examine.

Abstract: Here, we describe technologies for detecting these young retrotransposon insertions and demonstrate that such insertions indeed are abundant in human populations.

Abstract: We also found that new somatic L1 insertions occur at high frequencies in human lung cancer genomes.

Abstract: Genome-wide analysis suggests that altered DNA methylation may be responsible for the high levels of L1 mobilization observed in these tumors.

Abstract: Our data indicate that transposon-mediated mutagenesis is extensive in human genomes and is likely to have a major impact on human biology and diseases.


Knowledge of young African American adults about heart disease: a cross-sectional survey

Abstract: BACKGROUND African Americans have higher rates of cardiovascular disease (CVD) mortality than other ethnic groups.

Abstract: Young adults are prime targets for intervention strategies to prevent and reduce disease risk.

Abstract: The study purpose was to determine the level of knowledge of lifestyle risk factors for CVD among young African American adults in Phoenix.

Abstract: The results will be used to guide the development of CVD outreach programs targeted to this population.

Abstract: The Health Belief Model was used as a conceptual framework.

Abstract: METHODS A convenience sample of 172 African American men and women aged 18-26 years completed a questionnaire adapted from the American Heart Association national surveys.

Abstract: Descriptive statistics were compared by age, gender, education level, and health status variables including BMI, smoking status, and physical activity.

Abstract: RESULTS Some aspects of heart-disease were well known among young adult African Americans.

Abstract: Knowledge of certain other important risk factors (menopause) and preventive behaviors (eating fewer animal products), however, was more variable and inconsistent among the respondents.

Abstract: Differences in knowledge of individual variables was greater by education level than by gender overall.

Abstract: Predictors of a summary CVD knowledge score included higher education, female gender, and high self-efficacy (adjusted R2 = 0.158, p < .001).

Abstract: Predictors of self-efficacy in changing CVD risk were higher education and perceived low risk of CVD (adjusted R2 = 0.064, p < .001), but these characteristics explained only 6% of the variance.

Abstract: CONCLUSIONS Evaluation of baseline knowledge of CVD is essential before designing and implementing health promotion programs.

Abstract: Existing strengths and weaknesses in knowledge can guide tailoring of programs to be more effective.

Abstract: Further research would help to identify the range of other characteristics that determine knowledge and risk perception.


Recent insights into the role of Notch signaling in tumorigenesis

Abstract: Members of the Notch family of transmembrane receptors play an important role in cell fate determination.

Abstract: Over the past decade, a role for Notch in the pathogenesis of hematologic and solid malignancies has become apparent.

Abstract: Numerous cellular functions and microenvironmental cues associated with tumorigenesis are modulated by Notch signaling, including proliferation, apoptosis, adhesion, epithelial-to-mesenchymal transition, and angiogenesis.

Abstract: It is becoming increasingly evident that Notch signaling can be both oncogenic and tumor suppressive.

Abstract: This review highlights recent findings regarding the molecular and functional aspects of Notch-mediated neoplastic transformation.

Abstract: In addition, cellular mechanisms that potentially explain the complex role of Notch in tumorigenesis are discussed.


BRIEFINGS IN FUNCTIONAL GENOMICS AND PROTEOMICS. VOL 5. NO 3. 209^221 doi:10.1093/bfgp/ell028 Histone acetylation in gene regulation

Abstract: Genetic information is packaged in the highly dynamic nucleoprotein structure called chromatin.

Abstract: Many biological processes are regulated via post-translational modifications of key proteins.

Abstract: Acetylation of lysine residues at the N-terminal histone tails is one of the most studied covalent modifications influencing gene regulation in eukaryotic cells.

Abstract: This review focuses on the role of enzymes involved in controlling both histone and non-histone proteins acetylation levels in the cell, with particular emphasis on their effects on cancer.


Efficacy of monthly tafenoquine for prophylaxis of Plasmodium vivax and multidrug-resistant P. falciparum malaria.

Abstract: We assessed monthly doses of tafenoquine for preventing Plasmodium vivax and multidrug-resistant P. falciparum malaria.

Abstract: In a randomized, double-blind, placebo-controlled study, 205 Thai soldiers received either a loading dose of tafenoquine 400 mg (base) daily for 3 days, followed by single monthly 400-mg doses (n = 104), or placebo (n = 101), for up to 5 consecutive months.

Abstract: In volunteers completing follow-up (96 tafenoquine and 91 placebo recipients), there were 22 P. vivax, 8 P. falciparum, and 1 mixed infection.

Abstract: All infections except 1 P. vivax occurred in placebo recipients, giving tafenoquine a protective efficacy of 97% for all malaria (95% confidence interval [CI], 82%-99%), 96% for P. vivax malaria (95% CI, 76%-99%), and 100% for P. falciparum malaria (95% CI, 60%-100%).

Abstract: Monthly tafenoquine was safe, well tolerated, and highly effective in preventing P. vivax and multidrug-resistant P. falciparum malaria in Thai soldiers during 6 months of prophylaxis.


Headache, migraine, and structural brain lesions and function: population based Epidemiology of Vascular Ageing-MRI study

Abstract: OBJECTIVE To evaluate the association of overall and specific headaches with volume of white matter hyperintensities, brain infarcts, and cognition.

Abstract: DESIGN Population based, cross sectional study.

Abstract: SETTING Epidemiology of Vascular Ageing study, Nantes, France.

Abstract: PARTICIPANTS 780 participants (mean age 69, 58.5% women) with detailed headache assessment.

Abstract: MAIN OUTCOME MEASURES Brain scans were evaluated for volume of white matter hyperintensities (by fully automated imaging processing) and for classification of infarcts (by visual reading with a standardised assessment grid).

Abstract: Cognitive function was assessed by a battery of tests including the mini-mental state examination.

Abstract: RESULTS 163 (20.9%) participants reported a history of severe headache and 116 had migraine, of whom 17 (14.7%) reported aura symptoms.

Abstract: An association was found between any history of severe headache and increasing volume of white matter hyperintensities.

Abstract: The adjusted odds ratio of being in the highest third for total volume of white matter hyperintensities was 2.0 (95% confidence interval 1.3 to 3.1, P for trend 0.002) for participants with any history of severe headache when compared with participants without severe headache being in the lowest third.

Abstract: The association pattern was similar for all headache types.

Abstract: Migraine with aura was the only headache type strongly associated with volume of deep white matter hyperintensities (highest third odds ratio 12.4, 1.6 to 99.4, P for trend 0.005) and with brain infarcts (3.4, 1.2 to 9.3).

Abstract: The location of infarcts was predominantly outside the cerebellum and brain stem.

Abstract: Evidence was lacking for cognitive impairment for any headache type with or without brain lesions.

Abstract: CONCLUSIONS In this population based study, any history of severe headache was associated with an increased volume of white matter hyperintensities.

Abstract: Migraine with aura was the only headache type associated with brain infarcts.

Abstract: Evidence that headache of any type by itself or in combination with brain lesions was associated with cognitive impairment was lacking.


Characterization of adipocytes derived from fibro/adipogenic progenitors resident in human skeletal muscle

Abstract: A population of fibro/adipogenic but non-myogenic progenitors located between skeletal muscle fibers was recently discovered.

Abstract: The aim of this study was to determine the extent to which these progenitors differentiate into fully functional adipocytes.

Abstract: The characterization of muscle progenitor-derived adipocytes is a central issue in understanding muscle homeostasis.

Abstract: They are considered as being the cellular origin of intermuscular adipose tissue that develops in several pathophysiological situations.

Abstract: Here fibro/adipogenic progenitors were isolated from a panel of 15 human muscle biopsies on the basis of the specific cell-surface immunophenotype CD15+/PDGFRα+CD56-.

Abstract: This allowed investigations of their differentiation into adipocytes and the cellular functions of terminally differentiated adipocytes.

Abstract: Adipogenic differentiation was found to be regulated by the same effectors as those regulating differentiation of progenitors derived from white subcutaneous adipose tissue.

Abstract: Similarly, basic adipocyte functions, such as triglyceride synthesis and lipolysis occurred at levels similar to those observed with subcutaneous adipose tissue progenitor-derived adipocytes.

Abstract: However, muscle progenitor-derived adipocytes were found to be insensitive to insulin-induced glucose uptake, in association with the impairment of phosphorylation of key insulin-signaling effectors.

Abstract: Our findings indicate that muscle adipogenic progenitors give rise to bona fide white adipocytes that have the unexpected feature of being insulin-resistant.


Membrane lipids in invadopodia and podosomes: Key structures for cancer invasion and metastasis

Abstract: Invadopodia are extracellular matrix (ECM)-degrading protrusions formed by invasive cancer cells.

Abstract: Podosomes are structures functionally similar to invadopodia that are found in oncogene-transformed fibroblasts and monocyte-derived cells, including macrophages and osteoclasts.

Abstract: These structures are thought to play important roles in the pericellular remodeling of ECM during cancer invasion and metastasis.

Abstract: Much effort has been directed toward identification of the molecular components and regulators of invadopodia/podosomes, which could be therapeutic targets in the treatment of malignant cancers.

Abstract: However, it remains largely unknown how these components are assembled into invadopodia/podosomes and how the assembly process is spatially and temporally regulated.

Abstract: This review will summarize recent progress on the molecular mechanisms of invadopodia/podosome formation, with strong emphasis on the roles of lipid rafts and phosphoinositides.


CCR2 and CXCR4 regulate peripheral blood monocyte pharmacodynamics and link to efficacy in experimental autoimmune encephalomyelitis

Abstract: BACKGROUND CCR2 plays a key role in regulating monocyte trafficking to sites of inflammation and therefore has been the focus of much interest as a target for inflammatory disease.

Abstract: METHODS Here we examined the effects of CCR2 blockade with a potent small molecule antagonist to determine the pharmacodynamic consequences on the peripheral blood monocyte compartment in the context of acute and chronic inflammatory processes.

Abstract: RESULTS We demonstrate that CCR2 antagonism in vivo led to a rapid decrease in the number of circulating Ly6Chi monocytes and that this decrease was largely due to the CXCR4-dependent sequestration of these cells in the bone marrow, providing pharmacological evidence for a mechanism by which monocyte dynamics are regulated in vivo.

Abstract: CCR2 antagonism led to an accumulation of circulating CCL2 and CCL7 levels in the blood, indicating a role for CCR2 in regulating the levels of its ligands under homeostatic conditions.

Abstract: Finally, we show that the pharmacodynamic changes due to CCR2 antagonism were apparent after chronic dosing in mouse experimental autoimmune encephalomyelitis, a model in which CCR2 blockade demonstrated a dramatic reduction in disease severity, manifest in a reduced accumulation of monocytes and other cells in the CNS.

Abstract: CONCLUSION CCR2 antagonism in vivo has tractable pharmacodynamic effects that can be used to align target engagement with biologic effects on disease activity.


Displacement of a DNA binding protein by Dda helicase

Abstract: Bacteriophage T4 Dda helicase has recently been shown to be active as a monomer for unwinding of short duplex oligonucleotides and for displacing streptavidin from 3′-biotinylated oligonucleotides.

Abstract: However, its activity for streptavidin displacement and DNA unwinding has been shown to increase as the number of Dda molecules bound to the substrate molecule increases.

Abstract: A substrate was designed to address the ability of Dda to displace DNA binding proteins.

Abstract: A DNA binding site for the Escherichia coli trp repressor was introduced into an oligonucleotide substrate for Dda helicase containing single-stranded overhang.

Abstract: Here we show that a Dda monomer is insufficient to displace the E.coli trp repressor from dsDNA under single turnover conditions, although the substrate is unwound and the repressor displaced when the single-stranded overhang is long enough to accommodate two Dda molecules.

Abstract: The quantity of product formed increases when the substrate is able to accommodate more than two Dda molecules.

Abstract: These results indicate that multiple Dda molecules act to displace DNA binding proteins in a manner that correlates with the DNA unwinding activity and streptavidin displacement activity.

Abstract: We suggest a cooperative inchworm model to describe the activities of Dda helicase.


Control of Developmental Regulators by Polycomb in Human Embryonic Stem Cells

Abstract: Polycomb group proteins are essential for early development in metazoans, but their contributions to human development are not well understood.

Abstract: We have mapped the Polycomb Repressive Complex 2 (PRC2) subunit SUZ12 across the entire nonrepeat portion of the genome in human embryonic stem (ES) cells.

Abstract: We found that SUZ12 is distributed across large portions of over two hundred genes encoding key developmental regulators.

Abstract: These genes are occupied by nucleosomes trimethylated at histone H3K27, are transcriptionally repressed, and contain some of the most highly conserved noncoding elements in the genome.

Abstract: We found that PRC2 target genes are preferentially activated during ES cell differentiation and that the ES cell regulators OCT4, SOX2, and NANOG cooccupy a significant subset of these genes.

Abstract: These results indicate that PRC2 occupies a special set of developmental genes in ES cells that must be repressed to maintain pluripotency and that are poised for activation during ES cell differentiation.


PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps

Abstract: Neutrophils trap and kill bacteria by forming highly decondensed chromatin structures, termed neutrophil extracellular traps (NETs).

Abstract: We previously reported that histone hypercitrullination catalyzed by peptidylarginine deiminase 4 (PAD4) correlates with chromatin decondensation during NET formation.

Abstract: However, the role of PAD4 in NET-mediated bacterial trapping and killing has not been tested.

Abstract: Here, we use PAD4 knockout mice to show that PAD4 is essential for NET-mediated antibacterial function.

Abstract: Unlike PAD4(+/+) neutrophils, PAD4(-/-) neutrophils cannot form NETs after stimulation with chemokines or incubation with bacteria, and are deficient in bacterial killing by NETs.

Abstract: In a mouse infectious disease model of necrotizing fasciitis, PAD4(-/-) mice are more susceptible to bacterial infection than PAD4(+/+) mice due to a lack of NET formation.

Abstract: Moreover, we found that citrullination decreased the bacterial killing activity of histones and nucleosomes, which suggests that PAD4 mainly plays a role in chromatin decondensation to form NETs instead of increasing histone-mediated bacterial killing.

Abstract: Our results define a role for histone hypercitrullination in innate immunity during bacterial infection.


Human ‘brite / beige’ adipocytes develop from capillary networks and their implantation improves metabolic homeostasis in mice

Abstract: Uncoupling protein 1 (UCP1) is highly expressed in brown adipose tissue, where it generates heat by uncoupling electron transport from ATP production.

Abstract: UCP1 is also found outside classical brown adipose tissue depots, in adipocytes that are termed 'brite' (brown-in-white) or 'beige'.

Abstract: In humans, the presence of brite or beige (brite/beige) adipocytes is correlated with a lean, metabolically healthy phenotype, but whether a causal relationship exists is not clear.

Abstract: Here we report that human brite/beige adipocyte progenitors proliferate in response to pro-angiogenic factors, in association with expanding capillary networks.

Abstract: Adipocytes formed from these progenitors transform in response to adenylate cyclase activation from being UCP1 negative to being UCP1 positive, which is a defining feature of the beige/brite phenotype, while displaying uncoupled respiration.

Abstract: When implanted into normal chow-fed, or into high-fat diet (HFD)-fed, glucose-intolerant NOD-scid IL2rg(null) (NSG) mice, brite/beige adipocytes activated in vitro enhance systemic glucose tolerance.

Abstract: These adipocytes express neuroendocrine and secreted factors, including the pro-protein convertase PCSK1, which is strongly associated with human obesity.

Abstract: Pro-angiogenic conditions therefore drive the proliferation of human beige/brite adipocyte progenitors, and activated beige/brite adipocytes can affect systemic glucose homeostasis, potentially through a neuroendocrine mechanism.