Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies.

Abstract: OBJECTIVE To assess the effect of 25-hydroxyvitamin D (25-OHD) levels on pregnancy outcomes and birth variables.

Abstract: DESIGN Systematic review and meta-analysis.

Abstract: DATA SOURCES Medline (1966 to August 2012), PubMed (2008 to August 2012), Embase (1980 to August 2012), CINAHL (1981 to August 2012), the Cochrane database of systematic reviews, and the Cochrane database of registered clinical trials.

Abstract: STUDY SELECTION Studies reporting on the association between serum 25-OHD levels during pregnancy and the outcomes of interest (pre-eclampsia, gestational diabetes, bacterial vaginosis, caesarean section, small for gestational age infants, birth weight, birth length, and head circumference).

Abstract: DATA EXTRACTION Two authors independently extracted data from original research articles, including key indicators of study quality.

Abstract: We pooled the most adjusted odds ratios and weighted mean differences.

Abstract: Associations were tested in subgroups representing different patient characteristics and study quality.

Abstract: RESULTS 3357 studies were identified and reviewed for eligibility.

Abstract: 31 eligible studies were included in the final analysis.

Abstract: Insufficient serum levels of 25-OHD were associated with gestational diabetes (pooled odds ratio 1.49, 95% confidence interval 1.18 to 1.89), pre-eclampsia (1.79, 1.25 to 2.58), and small for gestational age infants (1.85, 1.52 to 2.26).

Abstract: Pregnant women with low serum 25-OHD levels had an increased risk of bacterial vaginosis and low birthweight infants but not delivery by caesarean section.

Abstract: CONCLUSION Vitamin D insufficiency is associated with an increased risk of gestational diabetes, pre-eclampsia, and small for gestational age infants.

Abstract: Pregnant women with low 25-OHD levels had an increased risk of bacterial vaginosis and lower birth weight infants, but not delivery by caesarean section.


β-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat.

Abstract: Psychosocial stress is associated with altered immune function and development of psychological disorders including anxiety and depression.

Abstract: Here we show that repeated social defeat in mice increased c-Fos staining in brain regions associated with fear and threat appraisal and promoted anxiety-like behavior in a β-adrenergic receptor-dependent manner.

Abstract: Repeated social defeat also significantly increased the number of CD11b(+)/CD45(high)/Ly6C(high) macrophages that trafficked to the brain.

Abstract: In addition, several inflammatory markers were increased on the surface of microglia (CD14, CD86, and TLR4) and macrophages (CD14 and CD86) after social defeat.

Abstract: Repeated social defeat also increased the presence of deramified microglia in the medial amygdala, prefrontal cortex, and hippocampus.

Abstract: Moreover, mRNA analysis of microglia indicated that repeated social defeat increased levels of interleukin (IL)-1β and reduced levels of glucocorticoid responsive genes [glucocorticoid-induced leucine zipper (GILZ) and FK506 binding protein-51 (FKBP51)].

Abstract: The stress-dependent changes in microglia and macrophages were prevented by propranolol, a β-adrenergic receptor antagonist.

Abstract: Microglia isolated from socially defeated mice and cultured ex vivo produced markedly higher levels of IL-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1 after stimulation with lipopolysaccharide compared with microglia from control mice.

Abstract: Last, repeated social defeat increased c-Fos activation in IL-1 receptor type-1-deficient mice, but did not promote anxiety-like behavior or microglia activation in the absence of functional IL-1 receptor type-1.

Abstract: These findings indicate that repeated social defeat-induced anxiety-like behavior and enhanced reactivity of microglia was dependent on activation of β-adrenergic and IL-1 receptors.


In vitro differentiation of transplantable neural precursors from human embryonic stem cells

Abstract: The remarkable developmental potential and replicative capacity of human embryonic stem (ES) cells promise an almost unlimited supply of specific cell types for transplantation therapies.

Abstract: Here we describe the in vitro differentiation, enrichment, and transplantation of neural precursor cells from human ES cells.

Abstract: Upon aggregation to embryoid bodies, differentiating ES cells formed large numbers of neural tube–like structures in the presence of fibroblast growth factor 2 (FGF-2).

Abstract: Neural precursors within these formations were isolated by selective enzymatic digestion and further purified on the basis of differential adhesion.

Abstract: Following withdrawal of FGF-2, they differentiated into neurons, astrocytes, and oligodendrocytes.

Abstract: After transplantation into the neonatal mouse brain, human ES cell–derived neural precursors were incorporated into a variety of brain regions, where they differentiated into both neurons and astrocytes.

Abstract: No teratoma formation was observed in the transplant recipients.

Abstract: These results depict human ES cells as a source of transplantable neural precursors for possible nervous system repair.


Characterization of prostaglandin E2 production by Candida albicans.

Abstract: Candida albicans produces lipid metabolites that are functionally similar to host prostaglandins.

Abstract: These studies, using mass spectrometry, demonstrate that C. albicans produces authentic prostaglandin E(2) (PGE(2)) from arachidonic acid.

Abstract: Maximal PGE(2) production was achieved at 37 degrees C in stationary-phase culture supernatants and in cell-free lysates generated from stationary-phase cells.

Abstract: Interestingly, PGE(2) production is inhibited by both nonspecific cyclooxygenase and lipoxygenase inhibitors but not by inhibitors specific for the cyclooxygenase 2 isoenzyme.

Abstract: The C. albicans genome does not possess a cyclooxygenase homolog; however, several genes that may play a role in prostaglandin production from C. albicans were investigated.

Abstract: It was found that a C. albicans fatty acid desaturase homolog (Ole2) and a multicopper oxidase homolog (Fet3) play roles in prostaglandin production, with ole2/ole2 and fet3/fet3 mutant strains exhibiting reduced PGE(2) levels compared with parent strains.

Abstract: This work demonstrates that the synthesis of PGE(2) in C. albicans proceeds via novel pathways.


A global role for KLF1 in erythropoiesis revealed by ChIP-seq in primary erythroid cells.

Abstract: KLF1 regulates a diverse suite of genes to direct erythroid cell differentiation from bipotent progenitors.

Abstract: To determine the local cis-regulatory contexts and transcription factor networks in which KLF1 operates, we performed KLF1 ChIP-seq in the mouse.

Abstract: We found at least 945 sites in the genome of E14.5 fetal liver erythroid cells which are occupied by endogenous KLF1.

Abstract: Many of these recovered sites reside in erythroid gene promoters such as Hbb-b1, but the majority are distant to any known gene.

Abstract: Our data suggests KLF1 directly regulates most aspects of terminal erythroid differentiation including production of alpha- and beta-globin protein chains, heme biosynthesis, coordination of proliferation and anti-apoptotic pathways, and construction of the red cell membrane and cytoskeleton by functioning primarily as a transcriptional activator.

Abstract: Additionally, we suggest new mechanisms for KLF1 cooperation with other transcription factors, in particular the erythroid transcription factor GATA1, to maintain homeostasis in the erythroid compartment.


KOBAS 2.0: a web server for annotation and identification of enriched pathways and diseases

Abstract: High-throughput experimental technologies often identify dozens to hundreds of genes related to, or changed in, a biological or pathological process.

Abstract: From these genes one wants to identify biological pathways that may be involved and diseases that may be implicated.

Abstract: Here, we report a web server, KOBAS 2.0, which annotates an input set of genes with putative pathways and disease relationships based on mapping to genes with known annotations.

Abstract: It allows for both ID mapping and cross-species sequence similarity mapping.

Abstract: It then performs statistical tests to identify statistically significantly enriched pathways and diseases.

Abstract: KOBAS 2.0 incorporates knowledge across 1327 species from 5 pathway databases (KEGG PATHWAY, PID, BioCyc, Reactome and Panther) and 5 human disease databases (OMIM, KEGG DISEASE, FunDO, GAD and NHGRI GWAS Catalog).

Abstract: KOBAS 2.0 can be accessed at http://kobas.cbi.pku.edu.cn.


Translocation of sickle cell erythrocyte microRNAs into Plasmodium falciparum inhibits parasite translation and contributes to malaria resistance.

Abstract: Erythrocytes carrying a variant hemoglobin allele (HbS), which causes sickle cell disease and resists infection by the malaria parasite Plasmodium falciparum.

Abstract: The molecular basis of this resistance, which has long been recognized as multifactorial, remains incompletely understood.

Abstract: Here we show that the dysregulated microRNA (miRNA) composition, of either heterozygous HbAS or homozygous HbSS erythrocytes, contributes to resistance against P. falciparum.

Abstract: During the intraerythrocytic life cycle of P. falciparum, a subset of erythrocyte miRNAs translocate into the parasite.

Abstract: Two miRNAs, miR-451 and let-7i, were highly enriched in HbAS and HbSS erythrocytes, and these miRNAs, along with miR-223, negatively regulated parasite growth.

Abstract: Surprisingly, we found that miR-451 and let-7i integrated into essential parasite messenger RNAs and, via impaired ribosomal loading, resulted in translational inhibition.

Abstract: Hence, sickle cell erythrocytes exhibit cell-intrinsic resistance to malaria in part through an atypical miRNA activity, which may represent a unique host defense strategy against complex eukaryotic pathogens.


CD28 and ITK signals regulate autoreactive T cell trafficking

Abstract: Activation of self-reactive T cells and their trafficking to target tissues leads to autoimmune organ destruction.

Abstract: Mice lacking the co-inhibitory receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) develop fatal autoimmunity characterized by lymphocytic infiltration into nonlymphoid tissues.

Abstract: Here, we demonstrate that the CD28 co-stimulatory pathway regulates the trafficking of self-reactive Ctla4(-/-) T cells to tissues.

Abstract: Concurrent ablation of the CD28-activated Tec family kinase ITK does not block spontaneous T cell activation but instead causes self-reactive Ctla4(-/-) T cells to accumulate in secondary lymphoid organs.

Abstract: Despite excessive spontaneous T cell activation and proliferation in lymphoid organs, Itk(-/-); Ctla4(-/-) mice are otherwise healthy, mount antiviral immune responses and exhibit a long lifespan.

Abstract: We propose that ITK specifically licenses autoreactive T cells to enter tissues to mount destructive immune responses.

Abstract: Notably, ITK inhibitors mimic the null mutant phenotype and also prevent pancreatic islet infiltration by diabetogenic T cells in mouse models of type 1 diabetes, highlighting their potential utility for the treatment of human autoimmune disorders.


Delayed and Accelerated Aging Share Common Longevity Assurance Mechanisms

Abstract: Mutant dwarf and calorie-restricted mice benefit from healthy aging and unusually long lifespan.

Abstract: In contrast, mouse models for DNA repair-deficient progeroid syndromes age and die prematurely.

Abstract: To identify mechanisms that regulate mammalian longevity, we quantified the parallels between the genome-wide liver expression profiles of mice with those two extremes of lifespan.

Abstract: Contrary to expectation, we find significant, genome-wide expression associations between the progeroid and long-lived mice.

Abstract: Subsequent analysis of significantly over-represented biological processes revealed suppression of the endocrine and energy pathways with increased stress responses in both delayed and premature aging.

Abstract: To test the relevance of these processes in natural aging, we compared the transcriptomes of liver, lung, kidney, and spleen over the entire murine adult lifespan and subsequently confirmed these findings on an independent aging cohort.

Abstract: The majority of genes showed similar expression changes in all four organs, indicating a systemic transcriptional response with aging.

Abstract: This systemic response included the same biological processes that are triggered in progeroid and long-lived mice.

Abstract: However, on a genome-wide scale, transcriptomes of naturally aged mice showed a strong association to progeroid but not to long-lived mice.

Abstract: Thus, endocrine and metabolic changes are indicative of "survival" responses to genotoxic stress or starvation, whereas genome-wide associations in gene expression with natural aging are indicative of biological age, which may thus delineate pro- and anti-aging effects of treatments aimed at health-span extension.


Arginine depletion as a mechanism for the immune privilege of corneal allografts

Abstract: The cornea is an immune privileged tissue.

Abstract: Since arginase has been found to modulate T-cell function by depleting arginine, we investigated the expression of arginase in the cornea and its possible role in immune privilege using a murine transplant model.

Abstract: We found that both the endothelium and epithelium of murine corneas express functional arginase I, capable of down-regulating T-cell proliferation in an in vitro culture system.

Abstract: The administration of the specific arginase inhibitor N-hydroxy-nor-L-Arg to recipient mice resulted in an accelerated rejection of allogeneic C57BL/6 (B6) corneal grafts.

Abstract: In contrast, in vivo blockade of arginase activity had no effect in altering the course of rejection of primary skin grafts that express little, if any, arginase.

Abstract: In addition, the inhibition of arginase did not alter systemic T-cell proliferation.

Abstract: These data show that arginase is functional in the cornea and contributes to the immune privilege of the eye, and that modulation of arginase contributes to graft survival.


Once-a-day Concerta methylphenidate versus three-times-daily methylphenidate in laboratory and natural settings.

Abstract: OBJECTIVE Methylphenidate (MPH), the most commonly prescribed drug for attention-deficit/hyperactivity disorder (ADHD), has a short half-life, which necessitates multiple daily doses.

Abstract: The need for multiple doses produces problems with medication administration during school and after-school hours, and therefore with compliance.

Abstract: Previous long-acting stimulants and preparations have shown effects equivalent to twice-daily dosing of MPH.

Abstract: This study tests the efficacy and duration of action, in natural and laboratory settings, of an extended-release MPH preparation designed to last 12 hours and therefore be equivalent to 3-times-daily dosing.

Abstract: METHODS Sixty-eight children with ADHD, 6 to 12 years old, participated in a within-subject, double-blind comparison of placebo, immediate-release (IR) MPH 3 times a day (tid), and Concerta, a once-daily MPH formulation.

Abstract: Three dosing levels of medication were used: 5 mg IR MPH tid/18 mg Concerta once a day (qd);

Abstract: 10 mg IR MPH tid/36 mg Concerta qd;

Abstract: and 15 mg IR MPH tid/54 mg Concerta qd.

Abstract: All children were currently medicated with MPH at enrollment, and each child's dose level was based on that child's MPH dosing before the study.

Abstract: The doses of Concerta were selected to be comparable to the daily doses of MPH that each child received.

Abstract: To achieve the ascending rate of MPH delivery determined by initial investigations to provide the necessary continuous coverage, Concerta doses were 20% higher on a daily basis than a comparable tid regimen of IR MPH.

Abstract: Children received each medication condition for 7 days.

Abstract: The investigation was conducted in the context of a background clinical behavioral intervention in both the natural environment and the laboratory setting.

Abstract: Parents received behavioral parent training and teachers were taught to establish a school-home daily report card (DRC).

Abstract: A DRC is a list of individual target behaviors that represent a child's most salient areas of impairment.

Abstract: Teachers set daily goals for each child's impairment targets, and parents provided rewards at home for goal attainment.

Abstract: Each weekday, teachers completed the DRC, and it was used as a dependent measure of individualized medication response.

Abstract: Teachers and parents also completed weekly standardized ratings of behavior and treatment effectiveness.

Abstract: To evaluate the time course of medication effects, children spent 12 hours in a laboratory setting on Saturdays and medication effects were measured using procedures and methods adapted from our summer treatment program.

Abstract: Measures of classroom behavior and academic productivity/accuracy were taken in a laboratory classroom setting during which children completed independent math and reading worksheets.

Abstract: Measures of social behavior were taken in structured, small-group board game settings and unstructured recess settings.

Abstract: Measures included behavior frequency counts, academic problems completed and accuracy, independent observations, teacher and counselor ratings, and individualized behavioral target goals.

Abstract: Reports of adverse events, sleep quality, and appetite were collected.

Abstract: RESULTS On virtually all measures in all settings, both drug conditions were significantly different from placebo, and the 2 drugs were not different from each other.

Abstract: In children's regular school settings, both medications improved behavior as measured by teacher ratings and individualized target behaviors (the DRC); these effects were seen into the evening as measured by parent ratings.

Abstract: In the laboratory setting, effects of Concerta were equivalent to tid MPH and lasted at least through 12 hours after dosing.

Abstract: Concerta was significantly superior to tid MPH on 2 parent rating scores, and when asked, more parents preferred Concerta than preferred tid IR MPH or placebo.

Abstract: Side effects on children's sleep and appetite were similar for the 2 preparations.

Abstract: In the lab setting, both medications improved productivity and accuracy on arithmetic seatwork assignments, disruptive and on-task behavior, and classroom rule following.

Abstract: Both medications improved children's rule following and negative behavior in small group board games, as well as in unstructured recess settings.

Abstract: Individual target behaviors also showed significant improvement with medication across domains in the laboratory setting.

Abstract: Children's behavior across settings deteriorated across the laboratory day, and the primary effect of medication was to prevent this deterioration as the day wore on.

Abstract: Results support the use of background behavioral treatment in clinical trials of stimulant medication, and illustrate the utility of a measure of individualized daily target goals (ie, the DRC) as an objective measure of medication response in both the laboratory and natural school settings.

Abstract: CONCLUSION This investigation clearly supports the efficacy of the Concerta long-acting formulation of MPH for parents who desire to have medication benefits for their child throughout the day and early evening.

Abstract: (ABSTRACT TRUNCATED)


Leaderless genes in bacteria: clue to the evolution of translation initiation mechanisms in prokaryotes

Abstract: BACKGROUND Shine-Dalgarno (SD) signal has long been viewed as the dominant translation initiation signal in prokaryotes.

Abstract: Recently, leaderless genes, which lack 5'-untranslated regions (5'-UTR) on their mRNAs, have been shown abundant in archaea.

Abstract: However, current large-scale in silico analyses on initiation mechanisms in bacteria are mainly based on the SD-led initiation way, other than the leaderless one.

Abstract: The study of leaderless genes in bacteria remains open, which causes uncertain understanding of translation initiation mechanisms for prokaryotes.

Abstract: RESULTS Here, we study signals in translation initiation regions of all genes over 953 bacterial and 72 archaeal genomes, then make an effort to construct an evolutionary scenario in view of leaderless genes in bacteria.

Abstract: With an algorithm designed to identify multi-signal in upstream regions of genes for a genome, we classify all genes into SD-led, TA-led and atypical genes according to the category of the most probable signal in their upstream sequences.

Abstract: Particularly, occurrence of TA-like signals about 10 bp upstream to translation initiation site (TIS) in bacteria most probably means leaderless genes.

Abstract: CONCLUSIONS Our analysis reveals that leaderless genes are totally widespread, although not dominant, in a variety of bacteria.

Abstract: Especially for Actinobacteria and Deinococcus-Thermus, more than twenty percent of genes are leaderless.

Abstract: Analyzed in closely related bacterial genomes, our results imply that the change of translation initiation mechanisms, which happens between the genes deriving from a common ancestor, is linearly dependent on the phylogenetic relationship.

Abstract: Analysis on the macroevolution of leaderless genes further shows that the proportion of leaderless genes in bacteria has a decreasing trend in evolution.


Neuronal Sirt1 deficiency increases insulin sensitivity in both brain and peripheral tissues.

Abstract: Sirt1 is a NAD(+)-dependent class III deacetylase that functions as a cellular energy sensor.

Abstract: In addition to its well-characterized effects in peripheral tissues, emerging evidence suggests that neuronal Sirt1 activity plays a role in the central regulation of energy balance and glucose metabolism.

Abstract: To assess this idea, we generated Sirt1 neuron-specific knockout (SINKO) mice.

Abstract: On both standard chow and HFD, SINKO mice were more insulin sensitive than Sirt1(f/f) mice.

Abstract: Thus, SINKO mice had lower fasting insulin levels, improved glucose tolerance and insulin tolerance, and enhanced systemic insulin sensitivity during hyperinsulinemic euglycemic clamp studies.

Abstract: Hypothalamic insulin sensitivity of SINKO mice was also increased over controls, as assessed by hypothalamic activation of PI3K, phosphorylation of Akt and FoxO1 following systemic insulin injection.

Abstract: Intracerebroventricular injection of insulin led to a greater systemic effect to improve glucose tolerance and insulin sensitivity in SINKO mice compared with controls.

Abstract: In line with the in vivo results, insulin-induced AKT and FoxO1 phosphorylation were potentiated by inhibition of Sirt1 in a cultured hypothalamic cell line.

Abstract: Mechanistically, this effect was traced to a reduced effect of Sirt1 to directly deacetylate and repress IRS-1 function.

Abstract: The enhanced central insulin signaling in SINKO mice was accompanied by increased insulin receptor signal transduction in liver, muscle, and adipose tissue.

Abstract: In summary, we conclude that neuronal Sirt1 negatively regulates hypothalamic insulin signaling, leading to systemic insulin resistance.

Abstract: Interventions that reduce neuronal Sirt1 activity have the potential to improve systemic insulin action and limit weight gain on an obesigenic diet.


Candidate Causal Regulatory Effects by Integration of Expression QTLs with Complex Trait Genetic Associations

Abstract: The recent success of genome-wide association studies (GWAS) is now followed by the challenge to determine how the reported susceptibility variants mediate complex traits and diseases.

Abstract: Expression quantitative trait loci (eQTLs) have been implicated in disease associations through overlaps between eQTLs and GWAS signals.

Abstract: However, the abundance of eQTLs and the strong correlation structure (LD) in the genome make it likely that some of these overlaps are coincidental and not driven by the same functional variants.

Abstract: In the present study, we propose an empirical methodology, which we call Regulatory Trait Concordance (RTC) that accounts for local LD structure and integrates eQTLs and GWAS results in order to reveal the subset of association signals that are due to cis eQTLs.

Abstract: We simulate genomic regions of various LD patterns with both a single or two causal variants and show that our score outperforms SNP correlation metrics, be they statistical (r(2)) or historical (D').

Abstract: Following the observation of a significant abundance of regulatory signals among currently published GWAS loci, we apply our method with the goal to prioritize relevant genes for each of the respective complex traits.

Abstract: We detect several potential disease-causing regulatory effects, with a strong enrichment for immunity-related conditions, consistent with the nature of the cell line tested (LCLs).

Abstract: Furthermore, we present an extension of the method in trans, where interrogating the whole genome for downstream effects of the disease variant can be informative regarding its unknown primary biological effect.

Abstract: We conclude that integrating cellular phenotype associations with organismal complex traits will facilitate the biological interpretation of the genetic effects on these traits.


Gender-dependent differences in outcome after the treatment of infection in hospitalized patients.

Abstract: CONTEXT While it is established that management strategies and outcomes differ by gender for many diseases, its effect on infection has not been adequately studied.

Abstract: OBJECTIVE To investigate the role of gender among hospitalized patients treated for infection.

Abstract: DESIGN Observational cohort study conducted during a 26-month period from December 1996 through January 1999.

Abstract: SETTING University-affiliated hospital.

Abstract: PARTICIPANTS A total of 892 patients in the surgical units of the hospital with 1470 consecutive infectious episodes (782 in men and 688 in women).

Abstract: MAIN OUTCOME MEASURES Mortality during hospitalization by gender for infection episodes overall and for specific infectious sites, including lung, peritoneum, bloodstream, catheter, urine, surgical site, and skin/soft tissue.

Abstract: RESULTS Among all infections, there was no significant difference in mortality based on gender (men, 11.1% vs women, 14.2%; P = .07).

Abstract: After logistic regression analysis, factors independently associated with mortality included higher APACHE (Acute Physiology and Chronic Health Evaluation) II score, older age, malignancy, blood transfusion, and diagnosis of infection more than 7 days after admission, but not gender (female odds ratio [OR] for death, 1.32; 95% confidence interval [CI], 0.90-1.94; P = .16).

Abstract: Mortality was higher in women for lung (men, 18% vs women, 34%; P = .002) and soft tissue (men, 2% vs women, 10%; P < or = .05) infection; for other infectious sites, mortality did not differ by gender.

Abstract: Factors associated with mortality due to pneumonia by logistic regression included higher APACHE II score, malignancy, diabetes mellitus, diagnosis of infection more than 7 days after admission, older age, transplantation, and female gender (OR for death, 2.25; 95% CI, 1.17-4.32; P = .02).

Abstract: CONCLUSIONS Although gender may not be predictive of mortality among all infections, women appear to be at increased risk for death from hospital-acquired pneumonia, even after controlling for other comorbidities.


Comparative Safety of Targeted Therapies for Metastatic Colorectal Cancer between Elderly and Younger Patients: a Study Using the International Pharmacovigilance Database

Abstract: Metastatic colorectal cancer (mCRC) is increasingly treated using targeted therapies.

Abstract: Post-marketing safety of these agents is understudied, especially in the elderly.

Abstract: This study aimed to compare, according to age, the adverse drug reactions (ADRs) of targeted therapies used for mCRC in real life.

Abstract: An extraction of VigiBase, which contains World Health Organization individual case safety reports (ICSRs), was performed.

Abstract: All ADR reports with aflibercept, bevacizumab, cetuximab, panitumumab, or regorafenib used in CRC were considered.

Abstract: For all drugs, chi-square tests were used to compare frequencies of serious ADRs between patients aged ≥75 and <75 years.

Abstract: For selected ADRs and each drug, the drug-ADR association compared to other anticancer drugs was estimated through the proportional reporting ratio (PRR) in both age groups.

Abstract: There were 21,565 ICSRs included, among which 74% were serious and 11% were fatal.

Abstract: Median age was 64 years (Inter Quartile Range = 56–71) and 15% of patients were aged ≥75; 57% were male.

Abstract: Serious ICSRs accounted for 47,292 ADRs.

Abstract: Neutropenia was not more reported in elderly for all drugs while diarrhea was more reported in elderly for panitumumab.

Abstract: Cardiac disorders were more reported in elderly patients, in particular heart failure, especially for bevacizumab, cetuximab, and regorafenib, as were respiratory, thoracic, and mediastinal disorders.

Abstract: Most of PRR were not different between the two groups, except encephalopathies, which were significantly associated with bevacizumab in the elderly only.

Abstract: ADRs related to targeted therapies used for mCRC treatment were different across age groups; yet, not systematically more reported or worse in elderly patients.

Abstract: Selected elderly patients could, therefore, be treated with these targeted therapies.


CpG island methylation in premalignant stages of gastric carcinoma.

Abstract: There are limited reports on methylation analysis of the premalignant lesions of gastric carcinoma thus far.

Abstract: This is despite the fact that gastric carcinoma is one of the tumors with a high frequency of CpG island hypermethylation.

Abstract: To determine the frequency and timing of hypermethylation during multistep gastric carcinogenesis, non-neoplastic gastric mucosa (n = 118), adenomas (n = 61), and carcinomas (n = 64) were analyzed for their p16, human Mut L homologue 1 (hMLH1), death-associated protein (DAP)-kinase, thromobospondin-1 (THBS1), and tissue inhibitor of metalloproteinase 3 (TIMP-3) methylation status using methylation-specific PCR.

Abstract: Three different classes of methylation behaviors were found in the five tested genes.

Abstract: DAP-kinase was methylated at a similar frequency in all four stages, whereas hMLH1 and p16 were methylated in cancer samples (20.3% and 42.2%, respectively) more frequently than in intestinal metaplasia (6.3% and 2.1%, respectively) or adenomas (9.8% and 11.5%, respectively).

Abstract: However, hMLH1 and p16 were not methylated in chronic gastritis.

Abstract: THBS-1 and TIMP-3 were methylated in all stages but showed a marked increase in hypermethylation frequency from chronic gastritis (10.1% and 14.5%, respectively) to intestinal metaplasia (34.7% and 36.7%, respectively; P < 0.05) and from adenomas (28.3% and 26.7%, respectively) to carcinomas (48.4% and 57.4%, respectively: P < 0.05).

Abstract: The hMLH1, THBS1, and TIMP-3 hypermethylation frequencies were similar in both intestinal metaplasia and adenomas, but the p16 hypermethylation frequency tended to be higher in adenomas (11.5%) than in intestinal metaplasia (2.1%; P = 0.073).

Abstract: The average number of methylated genes was 0.6, 1.1, 1.1, and 2.0 per five genes per sample in chronic gastritis, intestinal metaplasia, adenomas, and carcinomas, respectively.

Abstract: This shows a marked increase in methylated genes from non-metaplastic mucosa to intestinal metaplasia (P = 0.001) as well as from premalignant lesions to carcinomas (P = 0.002).

Abstract: These results suggest that CpG island hypermethylation occur early in multistep gastric carcinogenesis and tend to accumulate along the multistep carcinogenesis.


Familial amyloidotic polyneuropathy: current and emerging treatment options for transthyretin-mediated amyloidosis

Abstract: Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a fatal clinical disorder characterized by extracellular deposition of abnormal fibrils derived from misfolded, normally soluble transthyretin (TTR) molecules.

Abstract: The disease is most commonly caused by a point mutation within the TTR gene inherited in an autosomal dominant fashion.

Abstract: Over 100 of such mutations have been identified, leading to destabilization of the physiological TTR tetramer.

Abstract: As a result, many monomers originate with a tendency for spontaneous conformational changes and self-aggregation.

Abstract: The main clinical feature of TTR-FAP is progressive sensorimotor and autonomic neuropathy.

Abstract: In the beginning, this polyneuropathy predominantly involves small unmyelinated nerve fibers with the result of dissociated sensory loss disproportionately affecting sensation of pain and temperature.

Abstract: Autonomic neuropathy typically accompanies sensory deficits early in the disease course.

Abstract: The symptoms include orthostatic hypotension, constipation alternating with diarrhea, erectile dysfunction, anhydrosis, and urinary retention or incontinence.

Abstract: Later, involvement of motor fibers causes rapidly progressive weakness and gait disturbances.

Abstract: In addition to the peripheral nervous system, the heart and the gut are frequently affected.

Abstract: Onset of symptoms is bimodal, with one peak at age 33 years (early onset) and another distinct peak in the sixth decade of life (late onset).

Abstract: The course of TTR-FAP is uniformly progressive and fatal.

Abstract: Death occurs an average of 10.8 years after the onset of symptoms in Portuguese patients, and 7.3 years in late-onset Japanese patients.

Abstract: Common causes include cachexia, cardiac failure, arrhythmia, and secondary infections.

Abstract: Liver transplantation is the standard therapy for patients who are in a clinical condition good enough to tolerate this intervention because it stops progression of neuropathy by removing the main source of mutant TTR.

Abstract: Recently, orally administered tafamidis meglumine has been approved by European authorities for treatment of FAP.

Abstract: The substance has been shown to stabilize the TTR tetramer, thereby improving the outcome of patients with TTR-FAP.

Abstract: Various other strategies have been studied in vitro to prevent TTR amyloidosis, including gene therapy, immunization, dissolution of TTR aggregates, and free radical scavengers, but none of them is ready for clinical use so far.


Invariant natural killer T cells: bridging innate and adaptive immunity

Abstract: Cells of the innate immune system interact with pathogens via conserved pattern-recognition receptors, whereas cells of the adaptive immune system recognize pathogens through diverse, antigen-specific receptors that are generated by somatic DNA rearrangement.

Abstract: Invariant natural killer T (iNKT) cells are a subset of lymphocytes that bridge the innate and adaptive immune systems.

Abstract: Although iNKT cells express T cell receptors that are generated by somatic DNA rearrangement, these receptors are semi-invariant and interact with a limited set of lipid and glycolipid antigens, thus resembling the pattern-recognition receptors of the innate immune system.

Abstract: Functionally, iNKT cells most closely resemble cells of the innate immune system, as they rapidly elicit their effector functions following activation, and fail to develop immunological memory.

Abstract: iNKT cells can become activated in response to a variety of stimuli and participate in the regulation of various immune responses.

Abstract: Activated iNKT cells produce several cytokines with the capacity to jump-start and modulate an adaptive immune response.

Abstract: A variety of glycolipid antigens that can differentially elicit distinct effector functions in iNKT cells have been identified.

Abstract: These reagents have been employed to test the hypothesis that iNKT cells can be harnessed for therapeutic purposes in human diseases.

Abstract: Here, we review the innate-like properties and functions of iNKT cells and discuss their interactions with other cell types of the immune system.


Olmesartan-based therapies: an effective way to improve blood pressure control and cardiovascular protection.

Abstract: The main purpose in hypertension treatment is the reduction of cardiovascular disease burden.

Abstract: Among different first-line antihypertensive drug classes, angiotensin-receptor blockers are characterized by their both good effectiveness and tolerability.

Abstract: Furthermore, the interruption of the renin-angiotensin cascade is related with several benefits in target organ protection and cardiovascular prevention.

Abstract: Among different angiotensin-receptor blockers, olmesartan has been examined in several trial of organ protection, showing improvements in several disease markers, such as microinflammation, regression of both plaque volume and vascular hypertrophy, as well as microalbuminuria prevention.

Abstract: Olmesartan has been also widely examined in combination of either hydrochlorothiazide or amlodipine, as well as with both drugs in a single-pill triple combination, showing improvements in antihypertensive efficacy without significant effects on tolerability.

Abstract: This treatment strategy based on a drug with such characteristics and the availability of different types of combinations with other first-line drug classes may represent an effective way for achieving blood pressure control in a majority of hypertensive patients and this could also be related with a better cardiovascular disease prevention.


Manslaughter by Fake Artesunate in Asia—Will Africa Be Next?

Abstract: Falciparum malaria kills, and it particularly kills the rural poor.

Abstract: Artemisinin derivatives, such as artesunate, are a vital component of Plasmodium falciparum malaria treatment and control in the face of globally increasing antimalarial drug resistance.

Abstract: Since 1998 a worsening epidemic of sophisticated counterfeit “artesunate” tablets (containing no artesunate) has plagued mainland Southeast Asia (see Figure S1).

Abstract: In some countries, most of the available artesunate is fake [ 1–5].

Abstract: Artemisinin derivatives are remarkably rapid in their antimalarial effects, and they are very well tolerated.

Abstract: So where these medicines are available, they are sought after.

Abstract: But as they are relatively expensive, a demand is created for cheaper versions amongst the poorest and most vulnerable people, upon whom the counterfeiters have preyed–with fatal results.


Workshop: endothelial cell dysfunction leading to diabetic nephropathy : focus on nitric oxide.

Abstract: Clinical manifestations of diabetic nephropathy are an expression of diabetic microangiopathy.

Abstract: This review revisits the previously proposed Steno hypothesis and advances our hypothesis that development of endothelial cell dysfunction represents a common pathophysiological pathway of diabetic complications.

Abstract: Specifically, the ability of glucose to scavenge nitric oxide is proposed as the initiation phase of endothelial dysfunction.

Abstract: Gradual accumulation of advanced glycated end products and induction of plasminogen activator inhibitor-1, resulting in the decreased expression of endothelial nitric oxide synthase and reduced generation of nitric oxide, are proposed to be pathophysiologically critical for the maintenance phase of endothelial dysfunction.

Abstract: The proposed conceptual shift toward the role of endothelial dysfunction in diabetic complications may provide new strategies for their prevention.


A nuclear Argonaute promotes multi-generational epigenetic inheritance and germline immortality

Abstract: Epigenetic information is frequently erased near the start of each new generation.

Abstract: In some cases, however, epigenetic information can be transmitted from parent to progeny (multigenerational epigenetic inheritance).

Abstract: A particularly notable example of this type of epigenetic inheritance is double-stranded RNA-mediated gene silencing in Caenorhabditis elegans.

Abstract: This RNA-mediated interference (RNAi) can be inherited for more than five generations.

Abstract: To understand this process, here we conduct a genetic screen for nematodes defective in transmitting RNAi silencing signals to future generations.

Abstract: This screen identified the heritable RNAi defective 1 (hrde-1) gene.

Abstract: hrde-1 encodes an Argonaute protein that associates with small interfering RNAs in the germ cells of progeny of animals exposed to double-stranded RNA.

Abstract: In the nuclei of these germ cells, HRDE-1 engages the nuclear RNAi defective pathway to direct the trimethylation of histone H3 at Lys 9 (H3K9me3) at RNAi-targeted genomic loci and promote RNAi inheritance.

Abstract: Under normal growth conditions, HRDE-1 associates with endogenously expressed short interfering RNAs, which direct nuclear gene silencing in germ cells.

Abstract: In hrde-1- or nuclear RNAi-deficient animals, germline silencing is lost over generational time.

Abstract: Concurrently, these animals exhibit steadily worsening defects in gamete formation and function that ultimately lead to sterility.

Abstract: These results establish that the Argonaute protein HRDE-1 directs gene-silencing events in germ-cell nuclei that drive multigenerational RNAi inheritance and promote immortality of the germ-cell lineage.

Abstract: We propose that C. elegans use the RNAi inheritance machinery to transmit epigenetic information, accrued by past generations, into future generations to regulate important biological processes.


Autophagic programmed cell death by selective catalase degradation.

Abstract: Autophagy plays a central role in regulating important cellular functions such as cell survival during starvation and control of infectious pathogens.

Abstract: Recently, it has been shown that autophagy can induce cells to die; however, the mechanism of the autophagic cell death program is unclear.

Abstract: We now show that caspase inhibition leading to cell death by means of autophagy involves reactive oxygen species (ROS) accumulation, membrane lipid oxidation, and loss of plasma membrane integrity.

Abstract: Inhibition of autophagy by chemical compounds or knocking down the expression of key autophagy proteins such as ATG7, ATG8, and receptor interacting protein (RIP) blocks ROS accumulation and cell death.

Abstract: The cause of abnormal ROS accumulation is the selective autophagic degradation of the major enzymatic ROS scavenger, catalase.

Abstract: Caspase inhibition directly induces catalase degradation and ROS accumulation, which can be blocked by autophagy inhibitors.

Abstract: These findings unveil a molecular mechanism for the role of autophagy in cell death and provide insight into the complex relationship between ROS and nonapoptotic programmed cell death.


Human epidermal stem cell function is regulated by circadian oscillations.

Abstract: Human skin copes with harmful environmental factors that are circadian in nature, yet how circadian rhythms modulate the function of human epidermal stem cells is mostly unknown.

Abstract: Here we show that in human epidermal stem cells and their differentiated counterparts, core clock genes peak in a successive and phased manner, establishing distinct temporal intervals during the 24 hr day period.

Abstract: Each of these successive clock waves is associated with a peak in the expression of subsets of transcripts that temporally segregate the predisposition of epidermal stem cells to respond to cues that regulate their proliferation or differentiation, such as TGFβ and calcium.

Abstract: Accordingly, circadian arrhythmia profoundly affects stem cell function in culture and in vivo.

Abstract: We hypothesize that this intricate mechanism ensures homeostasis by providing epidermal stem cells with environmentally relevant temporal functional cues during the course of the day and that its perturbation may contribute to aging and carcinogenesis.


Engraftment of engineered ES cell–derived cardiomyocytes but not BM cells restores contractile function to the infarcted myocardium

Abstract: Cellular cardiomyoplasty is an attractive option for the treatment of severe heart failure.

Abstract: It is, however, still unclear and controversial which is the most promising cell source.

Abstract: Therefore, we investigated and examined the fate and functional impact of bone marrow (BM) cells and embryonic stem cell (ES cell)–derived cardiomyocytes after transplantation into the infarcted mouse heart.

Abstract: This proved particularly challenging for the ES cells, as their enrichment into cardiomyocytes and their long-term engraftment and tumorigenicity are still poorly understood.

Abstract: We generated transgenic ES cells expressing puromycin resistance and enhanced green fluorescent protein cassettes under control of a cardiac-specific promoter.

Abstract: Puromycin selection resulted in a highly purified (>99%) cardiomyocyte population, and the yield of cardiomyocytes increased 6–10-fold because of induction of proliferation on purification.

Abstract: Long-term engraftment (4–5 months) was observed when co-transplanting selected ES cell–derived cardiomyocytes and fibroblasts into the injured heart of syngeneic mice, and no teratoma formation was found (n = 60).

Abstract: Although transplantation of ES cell–derived cardiomyocytes improved heart function, BM cells had no positive effects.

Abstract: Furthermore, no contribution of BM cells to cardiac, endothelial, or smooth muscle neogenesis was detected.

Abstract: Hence, our results demonstrate that ES-based cell therapy is a promising approach for the treatment of impaired myocardial function and provides better results than BM-derived cells.


Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer

Abstract: OBJECTIVE Pancreatic ductal adenocarcinoma (PDA) is characterised by stromal desmoplasia and vascular dysfunction, which critically impair drug delivery.

Abstract: This study examines the role of an abundant extracellular matrix component, the megadalton glycosaminoglycan hyaluronan (HA), as a novel therapeutic target in PDA.

Abstract: METHODS Using a genetically engineered mouse model of PDA, the authors enzymatically depleted HA by a clinically formulated PEGylated human recombinant PH20 hyaluronidase (PEGPH20) and examined tumour perfusion, vascular permeability and drug delivery.

Abstract: The preclinical utility of PEGPH20 in combination with gemcitabine was assessed by short-term and survival studies.

Abstract: RESULTS PEGPH20 rapidly and sustainably depleted HA, inducing the re-expansion of PDA blood vessels and increasing the intratumoral delivery of two chemotherapeutic agents, doxorubicin and gemcitabine.

Abstract: Moreover, PEGPH20 triggered fenestrations and interendothelial junctional gaps in PDA tumour endothelia and promoted a tumour-specific increase in macromolecular permeability.

Abstract: Finally, combination therapy with PEGPH20 and gemcitabine led to inhibition of PDA tumour growth and prolonged survival over gemcitabine monotherapy, suggesting immediate clinical utility.

Abstract: CONCLUSIONS The authors demonstrate that HA impedes the intratumoral vasculature in PDA and propose that its enzymatic depletion be explored as a means to improve drug delivery and response in patients with pancreatic cancer.


Ribose 2′-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5

Abstract: The 5′ cap structures of higher eukaryote mRNAs have ribose 2′-O-methylation.

Abstract: Likewise, many viruses that replicate in the cytoplasm of eukaryotes have evolved 2′-O-methyltransferases to autonomously modify their mRNAs.

Abstract: However, a defined biological role for 2′-O-methylation of mRNA remains elusive.

Abstract: Here we show that 2′-O-methylation of viral mRNA was critically involved in subverting the induction of type I interferon.

Abstract: We demonstrate that human and mouse coronavirus mutants lacking 2′-O-methyltransferase activity induced higher expression of type I interferon and were highly sensitive to type I interferon.

Abstract: Notably, the induction of type I interferon by viruses deficient in 2′-O-methyltransferase was dependent on the cytoplasmic RNA sensor Mda5.

Abstract: This link between Mda5-mediated sensing of viral RNA and 2′-O-methylation of mRNA suggests that RNA modifications such as 2′-O-methylation provide a molecular signature for the discrimination of self and non-self mRNA.


Relationship between activity levels, aerobic fitness, and body fat in 8- to 10-yr-old children.

Abstract: The relationships between children's activity, aerobic fitness, and fatness are unclear.

Abstract: Indirect estimates of activity, e.g., heart rate (HR) and recall, may mask any associations.

Abstract: The purpose of this study was to assess these relationships by using the Tritrac-R3D, a pedometer, and heart rate.

Abstract: Thirty-four children, ages 8-10 yr, participated in the study.

Abstract: The Tritrac and pedometer were worn for up to 6 days.

Abstract: HR was measured for 1 day.

Abstract: Activity measured by Tritrac or pedometer correlated positively to fitness in the whole group (Tritrac, r = 0.66; pedometer, r = 0.59; P < 0.01) and in boys and girls separately (P < 0.05) and correlated negatively to fatness in the whole group (r = -0.42, P < 0.05).

Abstract: In contrast, HR did not correlate significantly to fitness, and HR of >139 beats/min correlated positively to fatness in girls (r = 0.64, P < 0.05).

Abstract: This suggests that HR is misleading as a measure of activity.

Abstract: This study supports a positive relationship between activity and fitness and suggests a negative relationship between fatness and activity.


Junctional actin assembly is mediated by Formin-like 2 downstream of Rac1

Abstract: Epithelial integrity is vitally important, and its deregulation causes early stage cancer.

Abstract: De novo formation of an adherens junction (AJ) between single epithelial cells requires coordinated, spatial actin dynamics, but the mechanisms steering nascent actin polymerization for cell-cell adhesion initiation are not well understood.

Abstract: Here we investigated real-time actin assembly during daughter cell-cell adhesion formation in human breast epithelial cells in 3D environments.

Abstract: We identify formin-like 2 (FMNL2) as being specifically required for actin assembly and turnover at newly formed cell-cell contacts as well as for human epithelial lumen formation.

Abstract: FMNL2 associates with components of the AJ complex involving Rac1 activity and the FMNL2 C terminus.

Abstract: Optogenetic control of Rac1 in living cells rapidly drove FMNL2 to epithelial cell-cell contact zones.

Abstract: Furthermore, Rac1-induced actin assembly and subsequent AJ formation critically depends on FMNL2.

Abstract: These data uncover FMNL2 as a driver for human epithelial AJ formation downstream of Rac1.


Inhibition of HDM2 and activation of p53 by ribosomal protein L23.

Abstract: The importance of coordinating cell growth with proliferation has been recognized for a long time.

Abstract: The molecular basis of this relationship, however, is poorly understood.

Abstract: Here we show that the ribosomal protein L23 interacts with HDM2.

Abstract: The interaction involves the central acidic domain of HDM2 and an N-terminal domain of L23.

Abstract: L23 and L11, another HDM2-interacting ribosomal protein, can simultaneously yet distinctly interact with HDM2 together to form a ternary complex.

Abstract: We show that, when overexpressed, L23 inhibits HDM2-induced p53 polyubiquitination and degradation and causes a p53-dependent cell cycle arrest.

Abstract: On the other hand, knocking down L23 causes nucleolar stress and triggers translocation of B23 from the nucleolus to the nucleoplasm, leading to stabilization and activation of p53.

Abstract: Our data suggest that cells may maintain a steady-state level of L23 during normal growth; alternating the levels of L23 in response to changing growth conditions could impinge on the HDM2-p53 pathway by interrupting the integrity of the nucleolus.


Association of Blood Monocyte and Platelet Markers with Carotid Artery Characteristics: The Atherosclerosis Risk in Communities Carotid MRI Study

Abstract: Background: Atherosclerosis is characterized by infiltration of inflammatory cells from circulating blood.

Abstract: Blood cell activation could play an important role in plaque formation.

Abstract: Methods: We analyzed the relationship between blood cellular markers and quantitative measures of carotid wall components in 1,546 participants from the ARIC (Atherosclerosis Risk in Communities)

Abstract: Carotid MRI Study.

Abstract: Carotid imaging was performed using a gadolinium contrast-enhanced MRI and cellular phenotyping by flow cytometry.

Abstract: Results: Monocyte Toll-like receptor (TLR)-2 is associated with larger plaques, while CD14, myeloperoxidase, and TLR-4 associate with smaller.

Abstract: Platelet CD40L is associated with smaller plaques and thinner caps, while P-selectin is associated with smaller core size.

Abstract: Conclusions: Blood cell activation is significantly associated with atherosclerotic changes of the carotid wall.


Vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments

Abstract: Receptor endocytosis is a fundamental step in controlling the magnitude, duration, and nature of cell signaling events.

Abstract: Confluent endothelial cells are contact inhibited in their growth and respond poorly to the proliferative signals of vascular endothelial growth factor (VEGF).

Abstract: In a previous study, we found that the association of vascular endothelial cadherin (VEC) with VEGF receptor (VEGFR) type 2 contributes to density-dependent growth inhibition (Lampugnani, G.M., A. Zanetti, M. Corada, T. Takahashi, G. Balconi, F. Breviario, F. Orsenigo, A. Cattelino, R. Kemler, T.O. Daniel, and E. Dejana.

Abstract: J. Cell Biol.

Abstract: In the present study, we describe the mechanism through which VEC reduces VEGFR-2 signaling.

Abstract: We found that VEGF induces the clathrin-dependent internalization of VEGFR-2.

Abstract: When VEC is absent or not engaged at junctions, VEGFR-2 is internalized more rapidly and remains in endosomal compartments for a longer time.

Abstract: Internalization does not terminate its signaling; instead, the internalized receptor is phosphorylated, codistributes with active phospholipase C–γ, and activates p44/42 mitogen-activated protein kinase phosphorylation and cell proliferation.

Abstract: Inhibition of VEGFR-2 internalization reestablishes the contact inhibition of cell growth, whereas silencing the junction-associated density-enhanced phosphatase-1/CD148 phosphatase restores VEGFR-2 internalization and signaling.

Abstract: Thus, VEC limits cell proliferation by retaining VEGFR-2 at the membrane and preventing its internalization into signaling compartments.


Diversification in the HIV-1 Envelope Hyper-variable Domains V2, V4, and V5 and Higher Probability of Transmitted/Founder Envelope Glycosylation Favor the Development of Heterologous Neutralization Breadth

Abstract: A recent study of plasma neutralization breadth in HIV-1 infected individuals at nine International AIDS Vaccine Initiative (IAVI) sites reported that viral load, HLA-A*03 genotype, and subtype C infection were strongly associated with the development of neutralization breadth.

Abstract: Here, we refine the findings of that study by analyzing the impact of the transmitted/founder (T/F) envelope (Env), early Env diversification, and autologous neutralization on the development of plasma neutralization breadth in 21 participants identified during recent infection at two of those sites: Kigali, Rwanda (n = 9) and Lusaka, Zambia (n = 12).

Abstract: Single-genome analysis of full-length T/F Env sequences revealed that all 21 individuals were infected with a highly homogeneous population of viral variants, which were categorized as subtype C (n = 12), A1 (n = 7), or recombinant AC (n = 2).

Abstract: An extensive amino acid sequence-based analysis of variable loop lengths and glycosylation patterns in the T/F Envs revealed that a lower ratio of NXS to NXT-encoded glycan motifs correlated with neutralization breadth.

Abstract: Further analysis comparing amino acid sequence changes, insertions/deletions, and glycan motif alterations between the T/F Env and autologous early Env variants revealed that extensive diversification focused in the V2, V4, and V5 regions of gp120, accompanied by contemporaneous viral escape, significantly favored the development of breadth.

Abstract: These results suggest that more efficient glycosylation of subtype A and C T/F Envs through fewer NXS-encoded glycan sites is more likely to elicit antibodies that can transition from autologous to heterologous neutralizing activity following exposure to gp120 diversification.

Abstract: This initiates an Env-antibody co-evolution cycle that increases neutralization breadth, and is further augmented over time by additional viral and host factors.

Abstract: These findings suggest that understanding how variation in the efficiency of site-specific glycosylation influences neutralizing antibody elicitation and targeting could advance the design of immunogens aimed at inducing antibodies that can transition from autologous to heterologous neutralizing activity.


Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity

Abstract: Oligodendrocytes, the myelin-forming glial cells of the central nervous system, maintain long-term axonal integrity.

Abstract: However, the underlying support mechanisms are not understood.

Abstract: Here we identify a metabolic component of axon–glia interactions by generating conditional Cox10 (protoheme IX farnesyltransferase) mutant mice, in which oligodendrocytes and Schwann cells fail to assemble stable mitochondrial cytochrome c oxidase (COX, also known as mitochondrial complex IV).

Abstract: In the peripheral nervous system, Cox10 conditional mutants exhibit severe neuropathy with dysmyelination, abnormal Remak bundles, muscle atrophy and paralysis.

Abstract: Notably, perturbing mitochondrial respiration did not cause glial cell death.

Abstract: In the adult central nervous system, we found no signs of demyelination, axonal degeneration or secondary inflammation.

Abstract: Unlike cultured oligodendrocytes, which are sensitive to COX inhibitors, post-myelination oligodendrocytes survive well in the absence of COX activity.

Abstract: More importantly, by in vivo magnetic resonance spectroscopy, brain lactate concentrations in mutants were increased compared with controls, but were detectable only in mice exposed to volatile anaesthetics.

Abstract: This indicates that aerobic glycolysis products derived from oligodendrocytes are rapidly metabolized within white matter tracts.

Abstract: Because myelinated axons can use lactate when energy-deprived, our findings suggest a model in which axon–glia metabolic coupling serves a physiological function.


Siglec-1 Is a Novel Dendritic Cell Receptor That Mediates HIV-1 Trans-Infection Through Recognition of Viral Membrane Gangliosides

Abstract: Dendritic cells (DCs) are essential antigen-presenting cells for the induction of immunity against pathogens.

Abstract: However, HIV-1 spread is strongly enhanced in clusters of DCs and CD4(+) T cells.

Abstract: Uninfected DCs capture HIV-1 and mediate viral transfer to bystander CD4(+) T cells through a process termed trans-infection.

Abstract: Initial studies identified the C-type lectin DC-SIGN as the HIV-1 binding factor on DCs, which interacts with the viral envelope glycoproteins.

Abstract: Upon DC maturation, however, DC-SIGN is down-regulated, while HIV-1 capture and trans-infection is strongly enhanced via a glycoprotein-independent capture pathway that recognizes sialyllactose-containing membrane gangliosides.

Abstract: Here we show that the sialic acid-binding Ig-like lectin 1 (Siglec-1, CD169), which is highly expressed on mature DCs, specifically binds HIV-1 and vesicles carrying sialyllactose.

Abstract: Furthermore, Siglec-1 is essential for trans-infection by mature DCs.

Abstract: These findings identify Siglec-1 as a key factor for HIV-1 spread via infectious DC/T-cell synapses, highlighting a novel mechanism that mediates HIV-1 dissemination in activated tissues.


The composition of the gut microbiota throughout life, with an emphasis on early life

Abstract: The intestinal microbiota has become a relevant aspect of human health.

Abstract: Microbial colonization runs in parallel with immune system maturation and plays a role in intestinal physiology and regulation.

Abstract: Increasing evidence on early microbial contact suggest that human intestinal microbiota is seeded before birth.

Abstract: Maternal microbiota forms the first microbial inoculum, and from birth, the microbial diversity increases and converges toward an adult-like microbiota by the end of the first 3-5 years of life.

Abstract: Perinatal factors such as mode of delivery, diet, genetics, and intestinal mucin glycosylation all contribute to influence microbial colonization.

Abstract: Once established, the composition of the gut microbiota is relatively stable throughout adult life, but can be altered as a result of bacterial infections, antibiotic treatment, lifestyle, surgical, and a long-term change in diet.

Abstract: Shifts in this complex microbial system have been reported to increase the risk of disease.

Abstract: Therefore, an adequate establishment of microbiota and its maintenance throughout life would reduce the risk of disease in early and late life.

Abstract: This review discusses recent studies on the early colonization and factors influencing this process which impact on health.


Intrauterine protein restriction combined with early postnatal overfeeding was not associated with adult-onset obesity but produced glucose intolerance by pancreatic dysfunction

Abstract: We investigated if whether intrauterine protein restriction in combination with overfeeding during lactation would cause adult-onset obesity and metabolic disorders.

Abstract: After birth, litters from dams fed with control (17% protein) and low protein (6% protein) diets were adjusted to a size of four (CO and LO groups, respectively) or eight (CC and LC groups, respectively) pups.

Abstract: All of the offspring were fed a diet containing 12% protein from the time of weaning until they were 90 d old.

Abstract: Compared to the CC and LC groups, the CO and LO groups had higher relative and absolute food intakes, oxygen consumption and carbon dioxide production; lower brown adipose tissue weight and lipid content and greater weight gain and absolute and relative white adipose tissue weight and absolute lipid content.

Abstract: Compared with the CO and CC rats, the LC and LO rats exhibited higher relative food intake, brown adipose tissue weight and lipid content, reduced oxygen consumption, carbon dioxide production and spontaneous activity, increased relative retroperitoneal adipose tissue weight and unaltered absolute white adipose tissue weight and lipid content.

Abstract: The fasting serum glucose was similar among the groups.

Abstract: The area under the glucose curve was higher in the LO and CO rats than in the LC and CC rats.

Abstract: The basal insulinemia and homeostasis model assessment of insulin resistance (HOMA-IR) were lower in the LO group than in the other groups.

Abstract: The total area under the insulin curve for the LO rats was similar to the CC rats, and both were lower than the CO and LC rats.

Abstract: Kitt was higher in the LO, LC and CO groups than in the CC group.

Abstract: Thus, intrauterine protein restriction followed by overfeeding during lactation did not induce obesity, but produced glucose intolerance by impairing pancreatic function in adulthood.


Somatic coding mutations in human induced pluripotent stem cells

Abstract: Defined transcription factors can induce epigenetic reprogramming of adult mammalian cells into induced pluripotent stem cells.

Abstract: Although DNA factors are integrated during some reprogramming methods, it is unknown whether the genome remains unchanged at the single nucleotide level.

Abstract: Here we show that 22 human induced pluripotent stem (hiPS) cell lines reprogrammed using five different methods each contained an average of five protein-coding point mutations in the regions sampled (an estimated six protein-coding point mutations per exome).

Abstract: The majority of these mutations were non-synonymous, nonsense or splice variants, and were enriched in genes mutated or having causative effects in cancers.

Abstract: At least half of these reprogramming-associated mutations pre-existed in fibroblast progenitors at low frequencies, whereas the rest occurred during or after reprogramming.

Abstract: Thus, hiPS cells acquire genetic modifications in addition to epigenetic modifications.

Abstract: Extensive genetic screening should become a standard procedure to ensure hiPS cell safety before clinical use.


Cell cycle, CDKs and cancer: a changing paradigm

Abstract: Tumour-associated cell cycle defects are often mediated by alterations in cyclin-dependent kinase (CDK) activity.

Abstract: Misregulated CDKs induce unscheduled proliferation as well as genomic and chromosomal instability.

Abstract: According to current models, mammalian CDKs are essential for driving each cell cycle phase, so therapeutic strategies that block CDK activity are unlikely to selectively target tumour cells.

Abstract: However, recent genetic evidence has revealed that, whereas CDK1 is required for the cell cycle, interphase CDKs are only essential for proliferation of specialized cells.

Abstract: Emerging evidence suggests that tumour cells may also require specific interphase CDKs for proliferation.

Abstract: Thus, selective CDK inhibition may provide therapeutic benefit against certain human neoplasias.


Sudden infant death syndrome.

Abstract: Despite declines in prevalence during the past two decades, sudden infant death syndrome (SIDS) continues to be the leading cause of death for infants aged between 1 month and 1 year in developed countries.

Abstract: Behavioural risk factors identified in epidemiological studies include prone and side positions for infant sleep, smoke exposure, soft bedding and sleep surfaces, and overheating.

Abstract: Evidence also suggests that pacifier use at sleep time and room sharing without bed sharing are associated with decreased risk of SIDS.

Abstract: Although the cause of SIDS is unknown, immature cardiorespiratory autonomic control and failure of arousal responsiveness from sleep are important factors.

Abstract: Gene polymorphisms relating to serotonin transport and autonomic nervous system development might make affected infants more vulnerable to SIDS.

Abstract: Campaigns for risk reduction have helped to reduce SIDS incidence by 50-90%.

Abstract: However, to reduce the incidence even further, greater strides must be made in reducing prenatal smoke exposure and implementing other recommended infant care practices.

Abstract: Continued research is needed to identify the pathophysiological basis of SIDS.


Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi.

Abstract: Eukaryotic heterochromatin is characterized by a high density of repeats and transposons, as well as by modified histones, and influences both gene expression and chromosome segregation.

Abstract: In the fission yeast Schizosaccharomyces pombe, we deleted the argonaute, dicer, and RNA-dependent RNA polymerase gene homologs, which encode part of the machinery responsible for RNA interference (RNAi).

Abstract: Deletion results in the aberrant accumulation of complementary transcripts from centromeric heterochromatic repeats.

Abstract: This is accompanied by transcriptional de-repression of transgenes integrated at the centromere, loss of histone H3 lysine-9 methylation, and impairment of centromere function.

Abstract: We propose that double-stranded RNA arising from centromeric repeats targets formation and maintenance of heterochromatin through RNAi.


Conformational Changes during Pore Formation by the Perforin-Related Protein Pleurotolysin

Abstract: Membrane attack complex/perforin-like (MACPF) proteins comprise the largest superfamily of pore-forming proteins, playing crucial roles in immunity and pathogenesis.

Abstract: Soluble monomers assemble into large transmembrane pores via conformational transitions that remain to be structurally and mechanistically characterised.

Abstract: Here we present an 11 Å resolution cryo-electron microscopy (cryo-EM) structure of the two-part, fungal toxin Pleurotolysin (Ply), together with crystal structures of both components (the lipid binding PlyA protein and the pore-forming MACPF component PlyB).

Abstract: These data reveal a 13-fold pore 80 Å in diameter and 100 Å in height, with each subunit comprised of a PlyB molecule atop a membrane bound dimer of PlyA. The resolution of the EM map, together with biophysical and computational experiments, allowed confident assignment of subdomains in a MACPF pore assembly.

Abstract: The major conformational changes in PlyB are a ∼70° opening of the bent and distorted central β-sheet of the MACPF domain, accompanied by extrusion and refolding of two α-helical regions into transmembrane β-hairpins (TMH1 and TMH2).

Abstract: We determined the structures of three different disulphide bond-trapped prepore intermediates.

Abstract: Analysis of these data by molecular modelling and flexible fitting allows us to generate a potential trajectory of β-sheet unbending.

Abstract: The results suggest that MACPF conformational change is triggered through disruption of the interface between a conserved helix-turn-helix motif and the top of TMH2.

Abstract: Following their release we propose that the transmembrane regions assemble into β-hairpins via top down zippering of backbone hydrogen bonds to form the membrane-inserted β-barrel.

Abstract: The intermediate structures of the MACPF domain during refolding into the β-barrel pore establish a structural paradigm for the transition from soluble monomer to pore, which may be conserved across the whole superfamily.

Abstract: The TMH2 region is critical for the release of both TMH clusters, suggesting why this region is targeted by endogenous inhibitors of MACPF function.


The widespread regulation of microRNA biogenesis, function and decay

Abstract: MicroRNAs (miRNAs) are a large family of post-transcriptional regulators of gene expression that are ∼21 nucleotides in length and control many developmental and cellular processes in eukaryotic organisms.

Abstract: Research during the past decade has identified major factors participating in miRNA biogenesis and has established basic principles of miRNA function.

Abstract: More recently, it has become apparent that miRNA regulators themselves are subject to sophisticated control.

Abstract: Many reports over the past few years have reported the regulation of miRNA metabolism and function by a range of mechanisms involving numerous protein–protein and protein–RNA interactions.

Abstract: Such regulation has an important role in the context-specific functions of miRNAs.


The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA

Abstract: High mutation frequency during reverse transcription has a principal role in the genetic variation of primate lentiviral populations.

Abstract: It is the main driving force for the generation of drug resistance and the escape from immune surveillance.

Abstract: G to A hypermutation is one of the characteristics of primate lentiviruses, as well as other retroviruses, during replication in vivo and in cell culture.

Abstract: The molecular mechanisms of this process, however, remain to be clarified.

Abstract: Here, we demonstrate that CEM15 (also known as apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G; APOBEC3G), an endogenous inhibitor of human immunodeficiency virus type 1 (HIV-1) replication, is a cytidine deaminase and is able to induce G to A hypermutation in newly synthesized viral DNA.

Abstract: This effect can be counteracted by the HIV-1 virion infectivity factor (Vif).

Abstract: It seems that this viral DNA mutator is a viral defence mechanism in host cells that may induce either lethal hypermutation or instability of the incoming nascent viral reverse transcripts, which could account for the Vif-defective phenotype.

Abstract: Importantly, the accumulation of CEM15-mediated non-lethal hypermutation in the replicating viral genome could potently contribute to the genetic variation of primate lentiviral populations.


Variants in the Toll-interacting protein gene are associated with susceptibility to sepsis in the Chinese Han population

Abstract: INTRODUCTION Deregulated or excessive host immune responses contribute to the pathogenesis of sepsis.

Abstract: Toll-like receptor (TLR) signaling pathways and their negative regulators play a pivotal role in the modulation of host immune responses and the development of sepsis.

Abstract: The objective of this study was to investigate the association of variants in the TLR signaling pathway genes and their negative regulator genes with susceptibility to sepsis in the Chinese Han population.

Abstract: METHODS Patients with severe sepsis (n = 378) and healthy control subjects (n = 390) were enrolled.

Abstract: Five genes, namely TLR2, TLR4, TLR9, MyD88 and TOLLIP, were investigated for their association with sepsis susceptibility by a tag single nucleotide polymorphism (SNP) strategy.

Abstract: Twelve tag SNPs were selected based on the data of Chinese Han in Beijing from the HapMap project and genotyped by direct sequencing.

Abstract: The mRNA expression levels of TOLLIP were determined using real-time quantitative Polymerase Chain Reaction (PCR) assays, and concentrations of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA).

Abstract: RESULTS Our results showed that the minor C-allele of rs5743867 in TOLLIP was significantly associated with the decreased risk of sepsis (Padj = 0.00062, odds ratio (OR)adj = 0.71, 95% confidence interval (CI) 0.59 to 0.86) after adjustment for covariates in multiple logistic regression analysis.

Abstract: A 3-SNP haplotype block harboring the associated SNP rs5743867 also displayed strong association with omnibus test P value of 0.00049.

Abstract: Haplotype GTC showed a protective role against sepsis (Padj = 0.0012), while haplotype GCT showed an increased risk for sepsis (Padj = 0.00092).

Abstract: After exposure to lipopolysaccharide (LPS), TOLLIP mRNA expression levels in peripheral blood mononuclear cells (PBMCs) from homozygotes for the rs5743867C allele were significantly higher than in heterozygotes and homozygotes for the rs5743867T allele (P = 0.013 and P = 0.01, respectively).

Abstract: Moreover, the concentrations of TNF-α and IL-6 in culture supernatants were significantly lower in the subjects of rs5743867CC genotype than in CT and TT genotype subjects (P = 0.016 and P = 0.003 for TNF-α; P = 0.01 and P = 0.002 for IL-6, respectively).

Abstract: CONCLUSIONS Our findings indicated that the variants in TOLLIP were significantly associated with sepsis susceptibility in the Chinese Han population.


Children's estimates of food portion size: the development and evaluation of three portion size assessment tools for use with children.

Abstract: A number of methods have been developed to assist subjects in providing an estimate of portion size but their application in improving portion size estimation by children has not been investigated systematically.

Abstract: The aim was to develop portion size assessment tools for use with children and to assess the accuracy of children's estimates of portion size using the tools.

Abstract: The tools were food photographs, food models and an interactive portion size assessment system (IPSAS).

Abstract: Children (n 201), aged 4-16 years, were supplied with known quantities of food to eat, in school.

Abstract: Food leftovers were weighed.

Abstract: Children estimated the amount of each food using each tool, 24 h after consuming the food.

Abstract: The age-specific portion sizes represented were based on portion sizes consumed by children in a national survey.

Abstract: Significant differences were found between the accuracy of estimates using the three tools.

Abstract: Children of all ages performed well using the IPSAS and food photographs.

Abstract: The accuracy and precision of estimates made using the food models were poor.

Abstract: For all tools, estimates of the amount of food served were more accurate than estimates of the amount consumed.

Abstract: Issues relating to reporting of foods left over which impact on estimates of the amounts of foods actually consumed require further study.

Abstract: The IPSAS has shown potential for assessment of dietary intake with children.

Abstract: Before practical application in assessment of dietary intake of children the tool would need to be expanded to cover a wider range of foods and to be validated in a 'real-life' situation.


A 3D Map of the Yeast Kinetochore Reveals the Presence of Core and Accessory Centromere-Specific Histone

Abstract: The budding yeast kinetochore is ~68 nm in length with a diameter slightly larger than a 25 nm microtubule.

Abstract: The kinetochores from the 16 chromosomes are organized in a stereotypic cluster encircling central spindle microtubules.

Abstract: Quantitative analysis of the inner kinetochore cluster (Cse4, COMA) reveals structural features not apparent in singly attached kinetochores.

Abstract: The cluster of Cse4-containing kinetochores is physically larger perpendicular to the spindle axis relative to the cluster of Ndc80 molecules.

Abstract: If there was a single Cse4 (molecule or nucleosome) at the kinetochore attached to each microtubule plus end, the cluster of Cse4 would appear geometrically identical to Ndc80.

Abstract: Thus, the structure of the inner kinetochore at the surface of the chromosomes remains unsolved.

Abstract: We have used point fluorescence microscopy and statistical probability maps to deduce the two-dimensional mean position of representative components of the yeast kinetochore relative to the mitotic spindle in metaphase.

Abstract: Comparison of the experimental images to three-dimensional architectures from convolution of mathematical models reveals a pool of Cse4 radially displaced from Cse4 at the kinetochore and kinetochore microtubule plus ends.

Abstract: The pool of displaced Cse4 can be experimentally depleted in mRNA processing pat1Δ or xrn1Δ mutants.

Abstract: The peripheral Cse4 molecules do not template outer kinetochore components.

Abstract: This study suggests an inner kinetochore plate at the centromere-microtubule interface in budding yeast and yields information on the number of Ndc80 molecules at the microtubule attachment site.


American Society of Clinical Oncology policy statement: the role of the oncologist in cancer prevention and risk assessment.

Abstract: Oncologists have a critical opportunity to utilize risk assessment and cancer prevention strategies to interrupt the initiation or progression of cancer in cancer survivors and individuals at high risk of developing cancer.

Abstract: Expanding knowledge about the natural history and prognosis of cancers positions oncologists to advise patients regarding the risk of second malignancies and treatment-related cancers.

Abstract: In addition, as recognized experts in the full spectrum of cancer care, oncologists are afforded opportunities for involvement in community-based cancer prevention activities.

Abstract: Although oncologists are currently providing many cancer prevention and risk assessment services to their patients, economic barriers exist, including inadequate or lack of insurance, that may compromise uniform patient access to these services.

Abstract: Additionally, insufficient reimbursement for existing and developing interventions may discourage patient access to these services.

Abstract: The American Society of Clinical Oncology (ASCO), the medical society representing cancer specialists involved in patient care and clinical research, is committed to supporting oncologists in their wide-ranging involvement in cancer prevention.

Abstract: This statement on risk assessment and prevention counseling, although not intended to be a comprehensive overview of cancer prevention describes the current role of oncologists in risk assessment and prevention; provides examples of risk assessment and prevention activities that should be offered by oncologists; identifies potential opportunities for coordination between oncologists and primary care physicians in prevention education and coordination of care for cancer survivors; describes ASCO's involvement in education and training of oncologists regarding prevention; and proposes improvement in the payment environment to encourage patient access to these services.


The BLM helicase contributes to telomere maintenance through processing of late-replicating intermediate structures

Abstract: Werner's syndrome (WS) and Bloom's syndrome (BS) are cancer predisposition disorders caused by loss of function of the RecQ helicases WRN or BLM, respectively.

Abstract: BS and WS are characterized by replication defects, hyperrecombination events and chromosomal aberrations, which are hallmarks of cancer.

Abstract: Inefficient replication of the G-rich telomeric strand contributes to chromosome aberrations in WS cells, demonstrating a link between WRN, telomeres and genomic stability.

Abstract: Herein, we provide evidence that BLM also contributes to chromosome-end maintenance.

Abstract: Telomere defects (TDs) are observed in BLM-deficient cells at an elevated frequency, which is similar to cells lacking a functional WRN helicase.

Abstract: Loss of both helicases exacerbates TDs and chromosome aberrations, indicating that BLM and WRN function independently in telomere maintenance.

Abstract: BLM localization, particularly its recruitment to telomeres, changes in response to replication dysfunction, such as in WRN-deficient cells or after aphidicolin treatment.

Abstract: Exposure to replication challenge causes an increase in decatenated deoxyribonucleic acid (DNA) structures and late-replicating intermediates (LRIs), which are visible as BLM-covered ultra-fine bridges (UFBs) in anaphase.

Abstract: A subset of UFBs originates from telomeric DNA and their frequency correlates with telomere replication defects.

Abstract: We propose that the BLM complex contributes to telomere maintenance through its activity in resolving LRIs.


Formation of a thymus from rat ES cells in xenogeneic nude mouse↔rat ES chimeras.

Abstract: Various conditions for differentiating embryonic stem (ES) cells or induced pluripotent stem (iPS) cells into specific kinds of cell lines are under intensive investigation.

Abstract: However, the production of a functional organ with a three-dimensional structure from ES or iPS cells is difficult to achieve in vitro.

Abstract: In the present paper, we describe the establishment of a green fluorescent protein-expressing rat ES cell line and production of mouse↔rat ES chimera by injecting rat ES cells into mouse blastocysts.

Abstract: The rat ES cells contributed to various organs in the chimera, including germ cells.

Abstract: When we injected ES cells into blastocysts of nu/nu mice lacking a thymus, the resultant chimeras produced thymus derived from rat ES cells in their bodies.

Abstract: The chimeric animals may provide a method for the derivation of various organs from ES or iPS cells.


Wnt/beta-catenin signaling is required for CNS, but not non-CNS, angiogenesis.

Abstract: Despite the importance of CNS blood vessels, the molecular mechanisms that regulate CNS angiogenesis and blood-brain barrier (BBB) formation are largely unknown.

Abstract: Here we analyze the role of Wnt/beta-catenin signaling in regulating the formation of CNS blood vessels.

Abstract: First, through the analysis of TOP-Gal Wnt reporter mice, we identify that canonical Wnt/beta-catenin signaling is specifically activated in CNS, but not non-CNS, blood vessels during development.

Abstract: This activation correlates with the expression of different Wnt ligands by neural progenitor cells in distinct locations throughout the CNS, including Wnt7a and Wnt7b in ventral regions and Wnt1, Wnt3, Wnt3a, and Wnt4 in dorsal regions.

Abstract: Blockade of Wnt/beta-catenin signaling in vivo specifically disrupts CNS, but not non-CNS, angiogenesis.

Abstract: These defects include reduction in vessel number, loss of capillary beds, and the formation of hemorrhagic vascular malformations that remain adherent to the meninges.

Abstract: Furthermore, we demonstrate that Wnt/beta-catenin signaling regulates the expression of the BBB-specific glucose transporter glut-1.

Abstract: Taken together these experiments reveal an essential role for Wnt/beta-catenin signaling in driving CNS-specific angiogenesis and provide molecular evidence that angiogenesis and BBB formation are in part linked.


Cyanidin-3-rutinoside, a natural polyphenol antioxidant, selectively kills leukemic cells by induction of oxidative stress.

Abstract: Anthocyanins are a group of naturally occurring phenolic compounds widely available in fruits and vegetables in human diets.

Abstract: They have broad biological activities including anti-mutagenesis and anticarcinogenesis, which are generally attributed to their antioxidant activities.

Abstract: We studied the effects and the mechanisms of the most common type of anthocyanins, cyanidin-3-rutinoside, in several leukemia and lymphoma cell lines.

Abstract: We found that cyanidin-3-rutinoside extracted and purified from the black raspberry cultivar Jewel induced apoptosis in HL-60 cells in a dose- and time-dependent manner.

Abstract: Paradoxically, this compound induced the accumulation of peroxides, which are involved in the induction of apoptosis in HL-60 cells.

Abstract: In addition, cyanidin-3-rutinoside treatment resulted in reactive oxygen species (ROS)-dependent activation of p38 MAPK and JNK, which contributed to cell death by activating the mitochondrial pathway mediated by Bim.

Abstract: Down-regulation of Bim or overexpression of Bcl-2 or Bcl-x(L) considerably blocked apoptosis.

Abstract: Notably, cyanidin-3-rutinoside treatment did not lead to increased ROS accumulation in normal human peripheral blood mononuclear cells and had no cytotoxic effects on these cells.

Abstract: These results indicate that cyanidin-3-rutinoside has the potential to be used in leukemia therapy with the advantages of being widely available and selective against tumors.


Gout-associated uric acid crystals activate the NALP3 inflammasome

Abstract: Development of the acute and chronic inflammatory responses known as gout and pseudogout are associated with the deposition of monosodium urate (MSU) or calcium pyrophosphate dihydrate (CPPD) crystals, respectively, in joints and periarticular tissues.

Abstract: Although MSU crystals were first identified as the aetiological agent of gout in the eighteenth century and more recently as a ‘danger signal’ released from dying cells, little is known about the molecular mechanisms underlying MSU- or CPPD-induced inflammation.

Abstract: Here we show that MSU and CPPD engage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome, resulting in the production of active interleukin (IL)-1β and IL-18.

Abstract: Macrophages from mice deficient in various components of the inflammasome such as caspase-1, ASC and NALP3 are defective in crystal-induced IL-1β activation.

Abstract: Moreover, an impaired neutrophil influx is found in an in vivo model of crystal-induced peritonitis in inflammasome-deficient mice or mice deficient in the IL-1β receptor (IL-1R).

Abstract: These findings provide insight into the molecular processes underlying the inflammatory conditions of gout and pseudogout, and further support a pivotal role of the inflammasome in several autoinflammatory diseases.


Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis.

Abstract: Most adult stem cells, including hematopoietic stem cells (HSCs), are maintained in a quiescent or resting state in vivo.

Abstract: Quiescence is widely considered to be an essential protective mechanism for stem cells that minimizes endogenous stress caused by cellular respiration and DNA replication.

Abstract: We demonstrate that HSC quiescence can also have detrimental effects.

Abstract: We found that HSCs have unique cell-intrinsic mechanisms ensuring their survival in response to ionizing irradiation (IR), which include enhanced prosurvival gene expression and strong activation of p53-mediated DNA damage response.

Abstract: We show that quiescent and proliferating HSCs are equally radioprotected but use different types of DNA repair mechanisms.

Abstract: We describe how nonhomologous end joining (NHEJ)-mediated DNA repair in quiescent HSCs is associated with acquisition of genomic rearrangements, which can persist in vivo and contribute to hematopoietic abnormalities.

Abstract: Our results demonstrate that quiescence is a double-edged sword that renders HSCs intrinsically vulnerable to mutagenesis following DNA damage.


Recruitment of Nck by CD3ϵ Reveals a Ligand-Induced Conformational Change Essential for T Cell Receptor Signaling and Synapse Formation

Abstract: How membrane receptors initiate signal transduction upon ligand binding is a matter of intense scrutiny.

Abstract: The T cell receptor complex (TCR-CD3) is composed of TCR alpha/beta ligand binding subunits bound to the CD3 subunits responsible for signal transduction.

Abstract: Although it has long been speculated that TCR-CD3 may undergo a conformational change, confirmation is still lacking.

Abstract: We present strong evidence that ligand engagement of TCR-CD3 induces a conformational change that exposes a proline-rich sequence in CD3 epsilon and results in recruitment of the adaptor protein Nck.

Abstract: This occurs earlier than and independently of tyrosine kinase activation.

Abstract: Finally, by interfering with Nck-CD3 epsilon association in vivo, we demonstrate that TCR-CD3 recruitment of Nck is critical for maturation of the immune synapse and for T cell activation.


Pseudo-Seq: Genome-Wide Detection of Pseudouridine Modifications in RNA.

Abstract: RNA molecules contain a variety of chemically diverse, posttranscriptionally modified bases.

Abstract: The most abundant modified base found in cellular RNAs, pseudouridine (Ψ), has recently been mapped to hundreds of sites in mRNAs, many of which are dynamically regulated.

Abstract: Though the pseudouridine landscape has been determined in only a few cell types and growth conditions, the enzymes responsible for mRNA pseudouridylation are universally conserved, suggesting many novel pseudouridylated sites remain to be discovered.

Abstract: Here, we present Pseudo-seq, a technique that allows the identification of sites of pseudouridylation genome-wide with single-nucleotide resolution.

Abstract: In this chapter, we provide a detailed description of Pseudo-seq.

Abstract: We include protocols for RNA isolation from Saccharomyces cerevisiae, Pseudo-seq library preparation, and data analysis, including descriptions of processing and mapping of sequencing reads, computational identification of sites of pseudouridylation, and assignment of sites to specific pseudouridine synthases.

Abstract: The approach presented here is readily adaptable to any cell or tissue type from which high-quality mRNA can be isolated.

Abstract: Identification of novel pseudouridylation sites is an important first step in elucidating the regulation and functions of these modifications.


The Mammalian Epigenome

Abstract: Chemical modifications to DNA and histone proteins form a complex regulatory network that modulates chromatin structure and genome function.

Abstract: The epigenome refers to the complete description of these potentially heritable changes across the genome.

Abstract: The composition of the epigenome within a given cell is a function of genetic determinants, lineage, and environment.

Abstract: With the sequencing of the human genome completed, investigators now seek a comprehensive view of the epigenetic changes that determine how genetic information is made manifest across an incredibly varied background of developmental stages, tissue types, and disease states.

Abstract: Here we review current research efforts, with an emphasis on large-scale studies, emerging technologies, and challenges ahead.


Microtubule-associated histone deacetylase 6 supports the calcium store sensor STIM1 in mediating malignant cell behaviors.

Abstract: Stromal-interaction molecule 1 (STIM1) is an endoplasmic reticulum Ca(2+) storage sensor that promotes cell growth, migration, and angiogenesis in breast and cervical cancers.

Abstract: Here, we report that the microtubule-associated histone deacetylase 6 (HDAC6) differentially regulates activation of STIM1-mediated store-operated Ca(2+) entry (SOCE) between cervical cancer cells and normal cervical epithelial cells.

Abstract: Confocal microscopy of living cells indicated that microtubule integrity was necessary for STIM1 trafficking to the plasma membrane and interaction with Orai1, an essential pore subunit of SOCE.

Abstract: Cancer cells overexpressed both STIM1 and Orai1 compared with normal cervical epithelial cells.

Abstract: HDAC6 upregulation in cancer cells was accompanied by hypoacetylated α-tubulin.

Abstract: Tubastatin-A, a specific HDAC6 inhibitor, inhibited STIM1 translocation to plasma membrane and blocked SOCE activation in cancer cells but not normal epithelial cells.

Abstract: Genetic or pharmacologic inhibition of HDAC6 blocked STIM1 membrane trafficking and downstream Ca(2+) influx, as evidenced by total internal reflection fluorescent images and intracellular Ca(2+) determination.

Abstract: In contrast, HDAC6 inhibition did not affect interactions between STIM1 and the microtubule plus end-binding protein EB1.

Abstract: Analysis of surgical specimens confirmed that most cervical cancer tissues overexpressed STIM1 and Orai1, accompanied by hypoacetylated α-tubulin.

Abstract: Together, our results identify HDAC6 as a candidate target to disrupt STIM1-mediated SOCE as a general strategy to block malignant cell behavior.


The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance.

Abstract: Medullary thymic epithelial cells (mTECs) establish T cell self-tolerance through the expression of autoimmune regulator (Aire) and peripheral tissue-specific self-antigens.

Abstract: However, signals underlying mTEC development remain largely unclear.

Abstract: Here, we demonstrate crucial regulation of mTEC development by receptor activator of NF-kappaB (RANK) and CD40 signals.

Abstract: Whereas only RANK signaling was essential for mTEC development during embryogenesis, in postnatal mice, cooperation between CD40 and RANK signals was required for mTEC development to successfully establish the medullary microenvironment.

Abstract: Ligation of RANK or CD40 on fetal thymic stroma in vitro induced mTEC development in a tumor necrosis factor-associated factor 6 (TRAF6)-, NF-kappaB inducing kinase (NIK)-, and IkappaB kinase beta (IKKbeta)-dependent manner.

Abstract: These results show that developmental-stage-dependent cooperation between RANK and CD40 promotes mTEC development, thereby establishing self-tolerance.


Rare and common variants: twenty arguments

Abstract: Genome-wide association studies have greatly improved our understanding of the genetic basis of disease risk.

Abstract: The fact that they tend not to identify more than a fraction of the specific causal loci has led to divergence of opinion over whether most of the variance is hidden as numerous rare variants of large effect or as common variants of very small effect.

Abstract: Here I review 20 arguments for and against each of these models of the genetic basis of complex traits and conclude that both classes of effect can be readily reconciled.


DNA methylation status predicts cell type-specific enhancer activity.

Abstract: Cell-selective glucocorticoid receptor (GR) binding to distal regulatory elements is associated with cell type-specific regions of locally accessible chromatin.

Abstract: These regions can either pre-exist in chromatin (pre-programmed) or be induced by the receptor (de novo).

Abstract: Mechanisms that create and maintain these sites are not well understood.

Abstract: We observe a global enrichment of CpG density for pre-programmed elements, and implicate their demethylated state in the maintenance of open chromatin in a tissue-specific manner.

Abstract: In contrast, sites that are actively opened by GR (de novo) are characterized by low CpG density, and form a unique class of enhancers devoid of suppressive effect of agglomerated methyl-cytosines.

Abstract: Furthermore, treatment with glucocorticoids induces rapid changes in methylation levels at selected CpGs within de novo sites.

Abstract: Finally, we identify GR-binding elements with CpGs at critical positions, and show that methylation can affect GR-DNA interactions in vitro.

Abstract: The findings present a unique link between tissue-specific chromatin accessibility, DNA methylation and transcription factor binding and show that DNA methylation can be an integral component of gene regulation by nuclear receptors.