Comparison of Maximal Oxygen Consumption Between Black and White Prepubertal and Pubertal Children

Abstract: The purpose of this investigation was to determine whether maximal oxygen consumption (VO2max) differed between two selected groups of black and white children and whether a difference existed to determine whether it was related to hematologic profiles, body composition, and/or physical activity/inactivity level.

Abstract: Forty-five prepubertal and 42 pubertal, clinically normal black and white children participated.

Abstract: Dual-energy x-ray absorptiometry was used to determine body composition.

Abstract: A computed tomography scan of the abdomen was used to determine visceral adipose tissue and s.c.

Abstract: adipose tissue.

Abstract: Daily physical activity/inactivity was assessed by questionnaire.

Abstract: Black prepubertal and pubertal children had lower VO2max values when compared with white children (28.8 ± 7.8 versus 35.0 ± 6.5 mL · kg−1 · min−1, p < 0.01; 33.7 ± 6.4 versus 40.4 ± 10.2 mL · kg−1 · min−1, p < 0.05; respectively).

Abstract: Black prepubertal and pubertal children had lower Hb concentrations ([Hb]) and hematocrits than white children (prepubertal: 12.1 ± 0.5 versus 12.8 ± 0.9 g/dL, p < 0.001; 35.6 ± 1.4 versus 37.4 ± 2.3%, p < 0.01, respectively; pubertal: 13.0 ± 0.9 versus 13.6 ± 0.7 g/dL, p < 0.05; 37.7 ± 2.5 versus 39.5 ± 2.1%, p < 0.05, respectively).

Abstract: In conclusion, these findings indicate that black prepubertal and pubertal children had lower VO2max when compared with their white peers matched for age, pubertal stage, and body mass index.

Abstract: This difference in VO2max could be attributed at least in part to comparatively lower [Hb] and more sedentary lifestyle in the black children.

Abstract: Further investigations should study Hb flow rate (a function of [Hb] × maximal cardiac output) in black and white children as it relates to VO2max.


Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway.

Abstract: CD4(+) helper T (Th) cells play a crucial role in the delicate balance between host defense and autoimmune disease.

Abstract: Two important populations of helper T cells are the proinflammatory, interleukin-17 (IL-17)-producing (Th17) cells and the anti-inflammatory forkhead box P3-positive (FoxP3(+)) T regulatory (Treg) cells.

Abstract: Here we show that all-trans retinoic acid (ATRA) and other agonists of the retinoic acid receptor alpha (RARalpha) inhibit the formation of Th17 cells and promote FoxP3 expression.

Abstract: Conversely, inhibition of retinoic acid signaling constrains transforming growth factor beta (TGF-beta1) induction of FoxP3.

Abstract: The effect of ATRA is mediated independently of IL-2, signal transducer and activator of transcription 5 (Stat5) and Stat3, representing a novel mechanism for the induction of FoxP3 in CD4 T cells.

Abstract: As previous studies have shown that vitamin A derivatives are protective in animal models of autoimmune disease, the current data suggest a previously unrecognized role for RARalpha in the regulation of CD4(+) T-cell differentiation and provide a mechanism for the anti-inflammatory effects of retinoic acid.


British Journal of Nutrition (2003), 89, 295–301 q The Authors 2003 DOI: 10.1079/BJN2002776 Plasma homocysteine concentration is decreased by dietary intervention*

Abstract: High plasma total homocysteine (tHcy) concentration is reported to be a risk factor for vascular diseases.

Abstract: We investigated the extent to which serum folate and plasma tHcy respond to a high intake of natural folate from food.

Abstract: Thirty-seven healthy females volunteered t o participate in a crossover dietary intervention.

Abstract: The study included a baseline period and two 5-week diet periods (low- and high-folate diets) with a 3-week washout in between.

Abstract: The low-folate diet contained one serving of both vegetables and fruit/d, while during the high-folate diet the subjects ate at least seven servings of vegetables, berries, and citrus fruit/d.

Abstract: Serum and erythrocyte (RBC) folate, serum vitamin B (12), and plasma tHcy concentrations were measured at the base-line and at the end of each diet period.

Abstract: The mean concentrations of serum and RBC folate were 11.0 (SD 3.0) nmol/l and 412 (SD 120) nmol/l at the end of the low-folate diet and 78 (95 % CI 62, 94) % and 14 (95 % CI 8, 20) % higher in response to the high-folate diet (P< 0.001).

Abstract: The serum concentration of vitamin B12 remained unchanged during the intervention.

Abstract: The mean plasma tHcy concentration was 8.0 pmol/ at the end of the low-folate diet and decreased by 13 (95% CI 9, 18) % in response to the high-folate diet (P<0.001).

Abstract: In conclusion, a diet high in fresh berries, citrus fruit, and vegetables effectively increases serum and RBC folate and decreases plasma homocysteine.


Achieving increased resolution and more pixels with Superresolution Optical Fluctuation Imaging (SOFI)

Abstract: Superresolution Optical Fluctuation Imaging (SOFI) as initially demonstrated allows for a resolution enhancement in imaging by a factor of square-root of two.

Abstract: Here, we demonstrate how to increase the resolution of SOFI images by re-weighting the Optical Transfer Function (OTF).

Abstract: Furthermore, we demonstrate how cross-cumulants can be exploited to obtain a fair approximation of the underlying Point-Spread Function.

Abstract: We show a two-fold increase of resolution (over the diffraction limit) of near-infrared quantum dot labeled tubulin-network of 3T3 fibroblasts.


Evaluation of reagent strips in detecting asymptomatic bacteriuria in early pregnancy: prospective case series.

Abstract: OBJECTIVE To evaluate the performance of reagent test strips in screening pregnant women for asymptomatic bacteriuria at their first visit to an antenatal clinic.

Abstract: DESIGN Prospective case series.

Abstract: SETTING Antenatal clinic of a large inner city maternity hospital.

Abstract: SUBJECTS All women attending for their first antenatal clinic.

Abstract: Patients taking antibiotics for any reason and those with urinary tract symptoms were excluded.

Abstract: INTERVENTION A midstream urine specimen was divided; half was sent for microscopy and formal bacteriological culture and the other half was tested with a commercial reagent strip test for the presence of blood, protein, nitrite, and leucocyte esterase.

Abstract: MAIN OUTCOME MEASURES Sensitivity, specificity, and positive and negative predictive values of the reagent strips in diagnosing asymptomatic bacteriuria (defined as 10(5) colony forming units/ml urine).

Abstract: RESULTS Sensitivity was low, with a maximum of 33% when all four tests were used in combination.

Abstract: Specificity was high, with typical values of 99% or more.

Abstract: Positive predictive value reached a maximum of 69% and negative predictive value was typically 95% or more.

Abstract: CONCLUSION Urine reagent strips are not sufficiently sensitive to be of use in the screening for asymptomatic bacteriuria and therefore many patients would be missed.

Abstract: In view of the potentially serious sequelae of this condition in pregnant women we recommend that formal bacteriological investigation remain the investigation of choice in this group of patients.


Wnt5a functions in planar cell polarity regulation in mice.

Abstract: Planar cell polarity (PCP) refers to the polarization of cells within the plane of a cell sheet.

Abstract: A distinctive epithelial PCP in vertebrates is the uniform orientation of stereociliary bundles of the sensory hair cells in the mammalian cochlea.

Abstract: In addition to establishing epithelial PCP, planar polarization is also required for convergent extension (CE); a polarized cellular movement that occurs during neural tube closure and cochlear extension.

Abstract: Studies in Drosophila and vertebrates have revealed a conserved PCP pathway, including Frizzled (Fz) receptors.

Abstract: Here we use the cochlea as a model system to explore the involvement of known ligands of Fz, Wnt morphogens, in PCP regulation.

Abstract: We show that Wnt5a forms a reciprocal expression pattern with a Wnt antagonist, the secreted frizzled-related protein 3 (Sfrp3 or Frzb), along the axis of planar polarization in the cochlear epithelium.

Abstract: We further demonstrate that Wnt5a antagonizes Frzb in regulating cochlear extension and stereociliary bundle orientation in vitro, and that Wnt5a(-/-) animals have a shortened and widened cochlea.

Abstract: Finally, we show that Wnt5a is required for proper subcellular distribution of a PCP protein, Ltap/Vangl2, and that Wnt5a interacts genetically with Ltap/Vangl2 for uniform orientation of stereocilia, cochlear extension, and neural tube closure.

Abstract: Together, these findings demonstrate that Wnt5a functions in PCP regulation in mice.


The RNA Polymerase “Switch Region” Is a Target for Inhibitors

Abstract: The alpha-pyrone antibiotic myxopyronin (Myx) inhibits bacterial RNA polymerase (RNAP).

Abstract: Here, through a combination of genetic, biochemical, and structural approaches, we show that Myx interacts with the RNAP "switch region"--the hinge that mediates opening and closing of the RNAP active center cleft--to prevent interaction of RNAP with promoter DNA.

Abstract: We define the contacts between Myx and RNAP and the effects of Myx on RNAP conformation and propose that Myx functions by interfering with opening of the RNAP active-center cleft during transcription initiation.

Abstract: We further show that the structurally related alpha-pyrone antibiotic corallopyronin (Cor) and the structurally unrelated macrocyclic-lactone antibiotic ripostatin (Rip) function analogously to Myx.

Abstract: The RNAP switch region is distant from targets of previously characterized RNAP inhibitors, and, correspondingly, Myx, Cor, and Rip do not exhibit crossresistance with previously characterized RNAP inhibitors.

Abstract: The RNAP switch region is an attractive target for identification of new broad-spectrum antibacterial therapeutic agents.


How reliable are light traps in estimating biting rates of adult Anopheles gambiae s.l. (Diptera: Culicidae) in the presence of treated bed nets?

Abstract: The sampling efficiency of light trap catches relative to human bait catches in estimating biting rates of the mosquito Anopheles gambiae Giles was investigated in two types of community in southern Sierra Leone: (i) where most of the inhabitants slept under treated bed nets; and (ii) where most of the inhabitants slept without bed nets.

Abstract: The number of female A. gambiae mosquitoes caught in these communities by light trap was strongly correlated (r > or = 0.72) with those from corresponding human biting catches performed either on the same or adjacent nights.

Abstract: It was found that the relative sampling efficiency of light traps varied slightly but significantly with mosquito abundance in villages with treated bed nets, but not in those without them.

Abstract: Nevertheless, the relationship between relative sampling efficiency and mosquito abundance did not differ significantly between the two types of village.

Abstract: Overall, there was insufficient evidence to show that the presence of treated nets altered the relative efficiency of light traps and any bias was only slight, and unlikely to be of any practical importance.

Abstract: Hence, it was concluded that light traps can be used as a surrogate for human bait catches in estimating biting rates of A. gambiae mosquitoes in the two communities.


Development of a novel mouse glioma model using lentiviral vectors

Abstract: We report the development of a new method to induce glioblastoma multiforme in adult immunocompetent mice by injecting Cre-loxP–controlled lentiviral vectors expressing oncogenes.

Abstract: Cell type- or region-specific expression of activated forms of the oncoproteins Harvey-Ras and AKT in fewer than 60 glial fibrillary acidic protein–positive cells in the hippocampus, subventricular zone or cortex of mice heterozygous for the gene encoding the tumor suppressor Tp53 were tested.

Abstract: Mice developed glioblastoma multiforme when transduced either in the subventricular zone or the hippocampus.

Abstract: However, tumors were rarely detected when the mice were transduced in the cortex.

Abstract: Transplantation of brain tumor cells into naive recipient mouse brain resulted in the formation of glioblastoma multiforme–like tumors, which contained CD133+ cells, formed tumorspheres and could differentiate into neurons and astrocytes.

Abstract: We suggest that the use of Cre-loxP–controlled lentiviral vectors is a novel way to generate a mouse glioblastoma multiforme model in a region- and cell type-specific manner in adult mice.


Research Letters

Abstract: We report a case of preclinical variant Creutzfeldt-Jakob disease (vCJD) in a patient who died from a non-neurological disorder 5 years after receiving a blood transfusion from a donor who subsequently developed vCJD.

Abstract: Protease-resistant prion protein (PrP(res)) was detected by western blot, paraffin-embedded tissue blot, and immunohistochemistry in the spleen, but not in the brain.

Abstract: Immunohistochemistry for prion protein was also positive in a cervical lymph node.

Abstract: The patient was a heterozygote at codon 129 of PRNP, suggesting that susceptibility to vCJD infection is not confined to the methionine homozygous PRNP genotype.

Abstract: These findings have major implications for future estimates and surveillance of vCJD in the UK.


Swi1Timeless Prevents Repeat Instability at Fission Yeast Telomeres

Abstract: Genomic instability associated with DNA replication stress is linked to cancer and genetic pathologies in humans.

Abstract: If not properly regulated, replication stress, such as fork stalling and collapse, can be induced at natural replication impediments present throughout the genome.

Abstract: The fork protection complex (FPC) is thought to play a critical role in stabilizing stalled replication forks at several known replication barriers including eukaryotic rDNA genes and the fission yeast mating-type locus.

Abstract: However, little is known about the role of the FPC at other natural impediments including telomeres.

Abstract: Telomeres are considered to be difficult to replicate due to the presence of repetitive GT-rich sequences and telomere-binding proteins.

Abstract: However, the regulatory mechanism that ensures telomere replication is not fully understood.

Abstract: Here, we report the role of the fission yeast Swi1(Timeless), a subunit of the FPC, in telomere replication.

Abstract: Loss of Swi1 causes telomere shortening in a telomerase-independent manner.

Abstract: Our epistasis analyses suggest that heterochromatin and telomere-binding proteins are not major impediments for telomere replication in the absence of Swi1.

Abstract: Instead, repetitive DNA sequences impair telomere integrity in swi1Δ mutant cells, leading to the loss of repeat DNA.

Abstract: In the absence of Swi1, telomere shortening is accompanied with an increased recruitment of Rad52 recombinase and more frequent amplification of telomere/subtelomeres, reminiscent of tumor cells that utilize the alternative lengthening of telomeres pathway (ALT) to maintain telomeres.

Abstract: These results suggest that Swi1 ensures telomere replication by suppressing recombination and repeat instability at telomeres.

Abstract: Our studies may also be relevant in understanding the potential role of Swi1(Timeless) in regulation of telomere stability in cancer cells.


Prediction of guide strand of microRNAs from its sequence and secondary structure

Abstract: BACKGROUND MicroRNAs (miRNAs) are produced by the sequential processing of a long hairpin RNA transcript by Drosha and Dicer, an RNase III enzymes, and form transitory small RNA duplexes.

Abstract: One strand of the duplex, which incorporates into RNA-induced silencing complex (RISC) and silences the gene expression is called guide strand, or miRNA; while the other strand of duplex is degraded and called the passenger strand, or miRNA*. Predicting the guide strand of miRNA is important for better understanding the RNA interference pathways.

Abstract: RESULTS This paper describes support vector machine (SVM) models developed for predicting the guide strands of miRNAs.

Abstract: All models were trained and tested on a dataset consisting of 329 miRNA and 329 miRNA* pairs using five fold cross validation technique.

Abstract: Firstly, models were developed using mono-, di-, and tri-nucleotide composition of miRNA strands and achieved the highest accuracies of 0.588, 0.638 and 0.596 respectively.

Abstract: Secondly, models were developed using split nucleotide composition and achieved maximum accuracies of 0.553, 0.641 and 0.602 for mono-, di-, and tri-nucleotide respectively.

Abstract: Thirdly, models were developed using binary pattern and achieved the highest accuracy of 0.708.

Abstract: Furthermore, when integrating the secondary structure features with binary pattern, an accuracy of 0.719 was seen.

Abstract: Finally, hybrid models were developed by combining various features and achieved maximum accuracy of 0.799 with sensitivity 0.781 and specificity 0.818.

Abstract: Moreover, the performance of this model was tested on an independent dataset that achieved an accuracy of 0.80.

Abstract: In addition, we also compared the performance of our method with various siRNA-designing methods on miRNA and siRNA datasets.

Abstract: CONCLUSION In this study, first time a method has been developed to predict guide miRNA strands, of miRNA duplex.

Abstract: This study demonstrates that guide and passenger strand of miRNA precursors can be distinguished using their nucleotide sequence and secondary structure.

Abstract: This method will be useful in understanding microRNA processing and can be implemented in RNA silencing technology to improve the biological and clinical research.

Abstract: A web server has been developed based on SVM models described in this study (http://crdd.osdd.net:8081/RISCbinder/).


NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome

Abstract: Cornelia de Lange syndrome (CdLS) is a multiple malformation disorder characterized by dysmorphic facial features, mental retardation, growth delay and limb reduction defects.

Abstract: We indentified and characterized a new gene, NIPBL, that is mutated in individuals with CdLS and determined its structure and the structures of mouse, rat and zebrafish homologs.

Abstract: We named its protein product delangin.

Abstract: Vertebrate delangins have substantial homology to orthologs in flies, worms, plants and fungi, including Scc2-type sister chromatid cohesion proteins, and D. melanogaster Nipped-B. We propose that perturbed delangin function may inappropriately activate DLX genes, thereby contributing to the proximodistal limb patterning defects in CdLS.

Abstract: Genome analyses typically identify individual delangin or Nipped-B-like orthologs in diploid animal and plant genomes.

Abstract: The evolution of an ancestral sister chromatid cohesion protein to acquire an additional role in developmental gene regulation suggests that there are parallels between CdLS and Roberts syndrome.


Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely characterize Fanconi anemia complementation group M.

Abstract: FANCM is a component of the Fanconi anemia (FA) core complex and one FA patient (EUFA867) with biallelic mutations in FANCM has been described.

Abstract: Strikingly, we found that EUFA867 also carries biallelic mutations in FANCA.

Abstract: After correcting the FANCA defect in EUFA867 lymphoblasts, a "clean" FA-M cell line was generated.

Abstract: These cells were hypersensitive to mitomycin C, but unlike cells defective in other core complex members, FANCM(-/-) cells were proficient in monoubiquitinating FANCD2 and were sensitive to the topoisomerase inhibitor camptothecin, a feature shared only with the FA subtype D1 and N. In addition, FANCM(-/-) cells were sensitive to UV light.

Abstract: FANCM and a C-terminal deletion mutant rescued the cross-linker sensitivity of FANCM(-/-) cells, whereas a FANCM ATPase mutant did not.

Abstract: Because both mutants restored the formation of FANCD2 foci, we conclude that FANCM functions in an FA core complex-dependent and -independent manner.


Vesicular Glycolysis Provides On-Board Energy for Fast Axonal Transport

Abstract: Fast axonal transport (FAT) requires consistent energy over long distances to fuel the molecular motors that transport vesicles.

Abstract: We demonstrate that glycolysis provides ATP for the FAT of vesicles.

Abstract: Although inhibiting ATP production from mitochondria did not affect vesicles motility, pharmacological or genetic inhibition of the glycolytic enzyme GAPDH reduced transport in cultured neurons and in Drosophila larvae.

Abstract: GAPDH localizes on vesicles via a huntingtin-dependent mechanism and is transported on fast-moving vesicles within axons.

Abstract: Purified motile vesicles showed GAPDH enzymatic activity and produced ATP.

Abstract: Finally, we show that vesicular GAPDH is necessary and sufficient to provide on-board energy for fast vesicular transport.

Abstract: Although detaching GAPDH from vesicles reduced transport, targeting GAPDH to vesicles was sufficient to promote FAT in GAPDH deficient neurons.

Abstract: This specifically localized glycolytic machinery may supply constant energy, independent of mitochondria, for the processive movement of vesicles over long distances in axons.


RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer

Abstract: Tyrosine kinase inhibitors are effective treatments for non-small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations.

Abstract: However, relapse typically occurs after an average of 1 year of continuous treatment.

Abstract: A fundamental histological transformation from NSCLC to small-cell lung cancer (SCLC) is observed in a subset of the resistant cancers, but the molecular changes associated with this transformation remain unknown.

Abstract: Analysis of tumour samples and cell lines derived from resistant EGFR mutant patients revealed that Retinoblastoma (RB) is lost in 100% of these SCLC transformed cases, but rarely in those that remain NSCLC.

Abstract: Further, increased neuroendocrine marker and decreased EGFR expression as well as greater sensitivity to BCL2 family inhibition are observed in resistant SCLC transformed cancers compared with resistant NSCLCs.

Abstract: Together, these findings suggest that this subset of resistant cancers ultimately adopt many of the molecular and phenotypic characteristics of classical SCLC.


Periostin Deficiency Increases Bone Damage and Impairs Injury Response to Fatigue Loading in Adult Mice

Abstract: Bone damage removal and callus formation in response to fatigue loading are essential to prevent fractures.

Abstract: Periostin (Postn) is a matricellular protein that mediates adaptive response of cortical bone to loading.

Abstract: Whether and how periostin influences damage and the injury response to fatigue remains unknown.

Abstract: We investigated the skeletal response of Postn(-/-) and Postn(+/+) mice after fatigue stimulus by axial compression of their tibia.

Abstract: In Postn(+/+) mice, cracks number and surface (CsNb, CsS) increased 1h after fatigue, with a decrease in strength compared to non-fatigued tibia.

Abstract: At 15 days, CsNb had started to decline, while CtTV and CtBV increased in fatigued vs non-fatigued tibia, reflecting a woven bone response that was present in 75% of the fatigued bones.

Abstract: Cortical porosity and remodelling also prominently increased in the fatigued tibia of Postn(+/+) mice.

Abstract: At 30 days, paralleling a continuous removal of cortical damage, strength of the fatigued tibia was similar to the non-fatigue tibia.

Abstract: In Postn(-/-) mice, cracks were detectable even in the absence of fatigue, while the amount of collagen crosslinks and tissue hardness was decreased compared to Postn(+/+).

Abstract: Fatigue significantly increased CsNb and CsS in Postn(-/-), but was not associated with changes in CtTV and CtBV, as only 16% of the fatigued bones formed some woven bone.

Abstract: Cortical porosity and remodelling did not increase either after fatigue in Postn(-/-), and the level of damage remained high even after 30 days.

Abstract: As a result, strength remained compromised in Postn(-/-) mice.

Abstract: Contrary to Postn(+/+), which osteocytic lacunae showed a change in the degree of anisotropy (DA) after fatigue, Postn(-/-) showed no DA change.

Abstract: Hence periostin appears to influence bone materials properties, damage accumulation and repair, including local modeling/remodeling processes in response to fatigue.

Abstract: These observations suggest that the level of periostin expression could influence the propensity to fatigue fractures.


Preferential occupancy of histone variant H2AZ at inactive promoters influences local histone modifications and chromatin remodeling.

Abstract: The yeast histone variant H2AZ (Htz1) is implicated in transcription activation, prevention of the ectopic spread of heterochromatin, and genome integrity.

Abstract: Our genome-wide localization analysis revealed that Htz1 is widely, but nonrandomly, distributed throughout the genome in an SWR1-dependent manner.

Abstract: We found that Htz1 is enriched in intergenic regions compared with coding regions.

Abstract: Its occupancy is inversely proportional to transcription rates and the enrichment of the RNA polymerase II under different growth conditions.

Abstract: However, Htz1 does not seem to directly regulate transcription repression genome-wide; instead, the presence of Htz1 under the inactivated condition is essential for optimal activation of a subset of genes.

Abstract: In addition, Htz1 is not generally responsible for nucleosome positioning, even at those promoters where Htz1 is highly enriched.

Abstract: Finally, using a biochemical approach, we demonstrate that incorporation of Htz1 into nucleosomes inhibits activities of histone modifiers associated with transcription, Dot1, Set2, and NuA4 and reduces the nucleosome mobilization driven by chromatin remodeling complexes.

Abstract: These lines of evidence collectively suggest that Htz1 may serve to mark quiescent promoters for proper activation.


Genomic organisation and transcription characterisation of the gene encoding Leishmania (Leishmania) amazonensis arginase and its protein structure prediction.

Abstract: The genomic organisation of the gene encoding Leishmania (Leishmania) amazonensis arginase as well as its flanking regions were characterised.

Abstract: The size of the transcribed RNA was determined, allowing us to map the genomic sites signalling for RNA trans-splicing and putative polyadenylation regions.

Abstract: The general organisation was compared with genes encoding other proteins already described in organisms of the Trypanosomatid family.

Abstract: The complete nucleotide sequence of the arginase open reading frame was obtained and the three-dimensional structure of the enzyme was inferred by a computational analysis of the deduced amino acid sequence, based on the established crystal structure described for Rattus norvergicus arginase.

Abstract: The human liver arginase sequence was analysed in the same way and the comparison of the presumed structure of both the Leishmania and human enzymes identified some differences that may be exploited in chemotherapeutic studies.


Endometrial carcinoma risk among women diagnosed with endometrial hyperplasia: the 34-year experience in a large health plan

Abstract: Classifying endometrial hyperplasia (EH) according to the severity of glandular crowding (simple hyperplasia (SH) vs complex hyperplasia (CH)) and nuclear atypia (simple atypical hyperplasia (SAH) vs complex atypical hyperplasia (CAH)) should predict subsequent endometrial carcinoma risk, but data on progression are lacking.

Abstract: Our nested case–control study of EH progression included 138 cases, who were diagnosed with EH and then with carcinoma (1970–2003) at least 1 year (median, 6.5 years) later, and 241 controls, who were individually matched on age, date, and follow-up duration and counter-matched on EH classification.

Abstract: After centralised pathology panel and medical record review, we generated rate ratios (RRs) and 95% confidence intervals (CIs), adjusted for treatment and repeat biopsies.

Abstract: With disordered proliferative endometrium (DPEM) as the referent, AH significantly increased carcinoma risk (RR=14, 95% CI, 5–38).

Abstract: Risk was highest 1–5 years after AH (RR=48, 95% CI, 8–294), but remained elevated 5 or more years after AH (RR=3.5, 95% CI, 1.0–9.6).

Abstract: Progression risks for SH (RR=2.0, 95% CI, 0.9–4.5) and CH (RR=2.8, 95% CI, 1.0–7.9) were substantially lower and only slightly higher than the progression risk for DPEM.

Abstract: The higher progression risks for AH could foster management guidelines based on markedly different progression risks for atypical vs non-atypical EH.


Redefining the Genetic Hierarchies Controlling Skeletal Myogenesis: Pax-3 and Myf-5 Act Upstream of MyoD

Abstract: We analyzed Pax-3 (splotch), Myf-5 (targeted with nlacZ), and splotch/Myf-5 homozygous mutant mice to investigate the roles that these genes play in programming skeletal myogenesis.

Abstract: In splotch and Myf-5 homozygous embryos, myogenic progenitor cell perturbations and early muscle defects are distinct.

Abstract: Remarkably, splotch/Myf-5 double homozygotes have a dramatic phenotype not seen in the individual mutants: body muscles are absent.

Abstract: MyoD does not rescue this double mutant phenotype since activation of this gene proves to be dependent on either Pax-3 or Myf-5.

Abstract: Therefore, Pax-3 and Myf-5 define two distinct myogenic pathways, and MyoD acts genetically downstream of these genes for myogenesis in the body.

Abstract: This genetic hierarchy does not appear to operate for head muscle formation.


Assessment of Volume Depletion in Children with Malaria

Abstract: Background The degree of volume depletion in severe malaria is currently unknown, although knowledge of fluid compartment volumes can guide therapy.

Abstract: To assist management of severely ill children, and to test the hypothesis that volume changes in fluid compartments reflect disease severity, we measured body compartment volumes in Gabonese children with malaria.

Abstract: Methods and Findings Total body water volume (TBW) and extracellular water volume (ECW) were estimated in children with severe or moderate malaria and in convalescence by tracer dilution with heavy water and bromide, respectively.

Abstract: Intracellular water volume (ICW) was derived from these parameters.

Abstract: Bioelectrical impedance analysis estimates of TBW and ECW were calibrated against dilution methods, and bioelectrical impedance analysis measurements were taken daily until discharge.

Abstract: Sixteen children had severe and 19 moderate malaria.

Abstract: Severe childhood malaria was associated with depletion of TBW (mean [SD] of 37 [33] ml/kg, or 6.7% [6.0%]) relative to measurement at discharge.

Abstract: This is defined as mild dehydration in other conditions.

Abstract: ECW measurements were normal on admission in children with severe malaria and did not rise in the first few days of admission.

Abstract: Volumes in different compartments (TBW, ECW, and ICW) were not related to hyperlactataemia or other clinical and laboratory markers of disease severity.

Abstract: Moderate malaria was not associated with a depletion of TBW.


NSOM/QD-Based Direct Visualization of CD3-Induced and CD28-Enhanced Nanospatial Coclustering of TCR and Coreceptor in Nanodomains in T Cell Activation

Abstract: Direct molecular imaging of nano-spatial relationship between T cell receptor (TCR)/CD3 and CD4 or CD8 co-receptor before and after activation of a primary T cell has not been reported.

Abstract: We have recently innovated application of near-field scanning optical microscopy (NSOM) and immune-labeling quantum dots (QD) to image Ag-specific TCR response during in vivo clonal expansion, and now up-graded the NSOM/QD-based nanotechnology through dipole-polarization and dual-color imaging.

Abstract: Using this imaging system scanning cell-membrane molecules at a best-optical lateral resolution, we demonstrated that CD3, CD4 or CD8 molecules were distinctly distributed as single QD-bound molecules or nano-clusters equivalent to 2-4 QD fluorescence-intensity/size on cell-membrane of un-stimulated primary T cells, and approximately 6-10% of CD3 were co-clustering with CD4 or CD8 as 70-110 nm nano-clusters without forming nano-domains.

Abstract: The ligation of TCR/CD3 on CD4 or CD8 T cells led to CD3 nanoscale co-clustering or interaction with CD4 or CD8 co-receptors forming 200-500 nm nano-domains or >500 nm micro-domains.

Abstract: Such nano-spatial co-clustering of CD3 and CD4 or CD3 and CD8 appeared to be an intrinsic event of TCR/CD3 ligation, not purely limited to MHC engagement, and be driven by Lck phosphorylation.

Abstract: Importantly, CD28 co-stimulation remarkably enhanced TCR/CD3 nanoscale co-clustering or interaction with CD4 co-receptor within nano- or micro-domains on the membrane.

Abstract: In contrast, CD28 co-stimulation did not enhance CD8 clustering or CD3-CD8 co-clustering in nano-domains although it increased molecular number and density of CD3 clustering in the enlarged nano-domains.

Abstract: These nanoscale findings provide new insights into TCR/CD3 interaction with CD4 or CD8 co-receptor in T-cell activation.


Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b.

Abstract: Hoxa9, Meis1 and Pbx1 encode homeodomaincontaining proteins implicated in leukemic transformation in both mice and humans.

Abstract: Hoxa9, Meis1 and Pbx1 proteins have been shown to physically interact with each other, as Hoxa9 cooperatively binds consensus DNA sequences with Meis1 and with Pbx1, while Meis1 and Pbx1 form heterodimers in both the presence and absence of DNA.

Abstract: In this study, we sought to determine if Hoxa9 could transform hemopoietic cells in collaboration with either Pbx1 or Meis1.

Abstract: Primary bone marrow cells, retrovirally engineered to overexpress Hoxa9 and Meis1a simultaneously, induced growth factor-dependent oligoclonal acute myeloid leukemia in <3 months when transplanted into syngenic mice.

Abstract: In contrast, overexpression of Hoxa9, Meis1a or Pbx1b alone, or the combination of Hoxa9 and Pbx1b failed to transform these cells acutely within 6 months post-transplantation.

Abstract: Similar results were obtained when FDC-P1 cells, engineered to overexpress these genes, were transplanted to syngenic recipients.

Abstract: Thus, these studies demonstrate a selective collaboration between a member of the Hox family and one of its DNA-binding partners in transformation of hemopoietic cells.


Tyr26 phosphorylation of PGAM1 provides a metabolic advantage to tumours by stabilizing the active conformation

Abstract: How oncogenic signalling coordinates glycolysis and anabolic biosynthesis in cancer cells remains unclear.

Abstract: We recently reported that the glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) regulates anabolic biosynthesis by controlling intracellular levels of its substrate 3-phosphoglycerate and product 2-phosphoglycerate.

Abstract: Here we report a novel mechanism in which Y26 phosphorylation enhances PGAM1 activation through release of inhibitory E19 that blocks the active site, stabilising cofactor 2,3-bisphosphoglycerate binding and H11 phosphorylation.

Abstract: We also report the crystal structure of H11-phosphorylated PGAM1 and find that phospho-H11 activates PGAM1 at least in part by promoting substrate 3-phosphoglycerate binding.

Abstract: Moreover, Y26 phosphorylation of PGAM1 is common in human cancer cells and contributes to regulation of 3-phosphoglycerate and 2-phosphoglycerate levels, promoting cancer cell proliferation and tumour growth.

Abstract: As PGAM1 is a negative transcriptional target of TP53, and is therefore commonly upregulated in human cancers, these findings suggest that Y26 phosphorylation represents an additional acute mechanism underlying phosphoglycerate mutase 1 upregulation.


Spatial and Temporal Clustering of Dengue Virus Transmission in Thai Villages

Abstract: BACKGROUND Transmission of dengue viruses (DENV), the leading cause of arboviral disease worldwide, is known to vary through time and space, likely owing to a combination of factors related to the human host, virus, mosquito vector, and environment.

Abstract: An improved understanding of variation in transmission patterns is fundamental to conducting surveillance and implementing disease prevention strategies.

Abstract: To test the hypothesis that DENV transmission is spatially and temporally focal, we compared geographic and temporal characteristics within Thai villages where DENV are and are not being actively transmitted.

Abstract: METHODS AND FINDINGS Cluster investigations were conducted within 100 m of homes where febrile index children with (positive clusters) and without (negative clusters) acute dengue lived during two seasons of peak DENV transmission.

Abstract: Data on human infection and mosquito infection/density were examined to precisely (1) define the spatial and temporal dimensions of DENV transmission, (2) correlate these factors with variation in DENV transmission, and (3) determine the burden of inapparent and symptomatic infections.

Abstract: Among 556 village children enrolled as neighbors of 12 dengue-positive and 22 dengue-negative index cases, all 27 DENV infections (4.9% of enrollees) occurred in positive clusters (p < 0.01; attributable risk [AR] = 10.4 per 100; 95% confidence interval 1-19.8 per 100].

Abstract: In positive clusters, 12.4% of enrollees became infected in a 15-d period and DENV infections were aggregated centrally near homes of index cases.

Abstract: As only 1 of 217 pairs of serologic specimens tested in positive clusters revealed a recent DENV infection that occurred prior to cluster initiation, we attribute the observed DENV transmission subsequent to cluster investigation to recent DENV transmission activity.

Abstract: Of the 1,022 female adult Ae.

Abstract: aegypti collected, all eight (0.8%) dengue-infected mosquitoes came from houses in positive clusters; none from control clusters or schools.

Abstract: Distinguishing features between positive and negative clusters were greater availability of piped water in negative clusters (p < 0.01) and greater number of Ae.

Abstract: aegypti pupae per person in positive clusters (p = 0.04).

Abstract: During primarily DENV-4 transmission seasons, the ratio of inapparent to symptomatic infections was nearly 1:1 among child enrollees.

Abstract: Study limitations included inability to sample all children and mosquitoes within each cluster and our reliance on serologic rather than virologic evidence of interval infections in enrollees given restrictions on the frequency of blood collections in children.

Abstract: CONCLUSIONS Our data reveal the remarkably focal nature of DENV transmission within a hyperendemic rural area of Thailand.

Abstract: These data suggest that active school-based dengue case detection prompting local spraying could contain recent virus introductions and reduce the longitudinal risk of virus spread within rural areas.

Abstract: Our results should prompt future cluster studies to explore how host immune and behavioral aspects may impact DENV transmission and prevention strategies.

Abstract: Cluster methodology could serve as a useful research tool for investigation of other temporally and spatially clustered infectious diseases.


Secondary T cell–T cell synaptic interactions drive the differentiation of protective CD8+ T cells

Abstract: Immunization results in the differentiation of CD8+ T cells, such that they acquire effector abilities and convert into a memory pool.

Abstract: Priming of T cells takes place via an immunological synapse formed with an antigen-presenting cell (APC).

Abstract: By disrupting synaptic stability at different times, we found that the differentiation of CD8+ T cells required cell interactions beyond those made with APCs.

Abstract: We identified a critical differentiation period that required interactions between primed T cells.

Abstract: We found that T cell–T cell synapses had a major role in the generation of protective CD8+ T cell memory.

Abstract: T cell–T cell synapses allowed T cells to polarize critical secretion of interferon-γ (IFN-γ) toward each other.

Abstract: Collective activation and homotypic clustering drove cytokine sharing and acted as regulatory stimuli for T cell differentiation.


The Histone H3 Lysine-27 Demethylase Jmjd3 Links Inflammation to Inhibition of Polycomb-Mediated Gene Silencing

Abstract: Epigenetic chromatin marks restrict the ability of differentiated cells to change gene expression programs in response to environmental cues and to transdifferentiate.

Abstract: Polycomb group (PcG) proteins mediate gene silencing and repress transdifferentiation in a manner dependent on histone H3 lysine 27 trimethylation (H3K27me3).

Abstract: However, macrophages migrated into inflamed tissues can transdifferentiate, but it is unknown whether inflammation alters PcG-dependent silencing.

Abstract: Here we show that the JmjC-domain protein Jmjd3 is a H3K27me demethylase expressed in macrophages in response to bacterial products and inflammatory cytokines.

Abstract: Jmjd3 binds PcG target genes and regulates their H3K27me3 levels and transcriptional activity.

Abstract: The discovery of an inducible enzyme that erases a histone mark controlling differentiation and cell identity provides a link between inflammation and reprogramming of the epigenome, which could be the basis for macrophage plasticity and might explain the differentiation abnormalities in chronic inflammation.


Apolipoprotein E and atherosclerosis: beyond lipid effect.

Abstract: In humans, apolipoprotein E (apoE) is a polymorphic multifunctional protein.1 It is coded by three alleles (e2, e3, e4) of a modulator gene (level, variability, and susceptibility gene) at the apoE locus on chromosome 19, determining six apoE genotypes and plasma phenotypes.

Abstract: Its pleiotropic effects are exerted on plasma lipoprotein metabolism, coagulation, oxidative processes, macrophage, glial cell and neuronal cell homeostasis, adrenal function, central nervous system physiology, inflammation, and cell proliferation.2,3 ApoE polymorphism modulates susceptibility to many diseases.

Abstract: It is, however, particularly notorious for its role in neurodegenerative disorders4 and atherosclerotic arterial disease.5,6 The e4 allele (phenotypes E4/4 and E4/3) that is associated with higher low density lipoprotein cholesterol (LDL-C) is considered proatherogenic, whereas the presence of the e2 allele (E3/2, E2/2), being associated with lower LDL-C levels, is deemed to have the opposite effect (although it may be associated with increased plasma triglycerides and lipoprotein remnants).

Abstract: This simple equation, however, is an oversimplification because these properties are subject to many environmental and genetic influences.

Abstract: ApoE has allele- and gender-dependent effects on reverse cholesterol transport, platelet aggregation, and oxidative processes that are likely to affect the overall atherogenic potential ascribed to modulation of lipoprotein metabolism.2,3,6 Notwithstanding the context dependency, a recent meta-analysis fully supports the presence of the e4 allele as a significant risk factor for coronary artery disease.7 Several mechanisms have been evoked to link apoE with atherosclerosis, but the relationship is not fully unraveled in humans.

Abstract: Nevertheless, some apoE mimetic peptides that promote LDL clearance are currently tested in animals for potential clinical applications.8,9  See page 436   The situation is relatively simpler in animals.

Abstract: The mouse model has been prominently useful to test mechanisms …


Exploitative and Hierarchical Antagonism in a Cooperative Bacterium

Abstract: Social organisms that cooperate with some members of their own species, such as close relatives, may fail to cooperate with other genotypes of the same species.

Abstract: Such noncooperation may take the form of outright antagonism or social exploitation.

Abstract: Myxococcus xanthus is a highly social prokaryote that cooperatively develops into spore-bearing, multicellular fruiting bodies in response to starvation.

Abstract: Here we have characterized the nature of social interactions among nine developmentally proficient strains of M. xanthus isolated from spatially distant locations.

Abstract: Strains were competed against one another in all possible pairwise combinations during starvation-induced development.

Abstract: In most pairings, at least one competitor exhibited strong antagonism toward its partner and a majority of mixes showed bidirectional antagonism that decreased total spore production, even to the point of driving whole populations to extinction.

Abstract: Differential response to mixing was the primary determinant of competitive superiority rather than the sporulation efficiencies of unmixed populations.

Abstract: In some competitive pairings, the dominant partner sporulated more efficiently in mixed populations than in clonal isolation.

Abstract: This finding represents a novel form of exploitation in bacteria carried out by socially competent genotypes and is the first documentation of social exploitation among natural bacterial isolates.

Abstract: Patterns of antagonistic superiority among these strains form a highly linear dominance hierarchy.

Abstract: At least some competition pairs construct chimeric, rather than segregated, fruiting bodies.

Abstract: The cooperative prokaryote M. xanthus has diverged into a large number of distinct social types that cooperate with clone-mates but exhibit intense antagonism toward distinct social types of the same species.

Abstract: Most lengthy migration events in nature may thus result in strong antagonism between migratory and resident populations, and this antagonism may have large effects on local population sizes and dynamics.

Abstract: Intense mutual antagonism appears to be more prevalent in this prokaryotic social species than has been observed in the eukaryotic social slime mold Dictyostelium discoideum, which also exhibits multicellular development.

Abstract: The finding of several cases of facultative social exploitation among these natural isolates suggests that such exploitation may occur frequently in nature in many prokaryotes with cooperative traits.


Mental Health Conditions Among Patients Seeking and Undergoing Bariatric Surgery: A Meta-analysis.

Abstract: IMPORTANCE Bariatric surgery is associated with sustained weight loss and improved physical health status for severely obese individuals.

Abstract: Mental health conditions may be common among patients seeking bariatric surgery; however, the prevalence of these conditions and whether they are associated with postoperative outcomes remains unknown.

Abstract: OBJECTIVE To determine the prevalence of mental health conditions among bariatric surgery candidates and recipients, to evaluate the association between preoperative mental health conditions and health outcomes following bariatric surgery, and to evaluate the association between surgery and the clinical course of mental health conditions.

Abstract: DATA SOURCES We searched PubMed, MEDLINE on OVID, and PsycINFO for studies published between January 1988 and November 2015.

Abstract: Study quality was assessed using an adapted tool for risk of bias; quality of evidence was rated based on GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria.

Abstract: FINDINGS We identified 68 publications meeting inclusion criteria: 59 reporting the prevalence of preoperative mental health conditions (65,363 patients) and 27 reporting associations between preoperative mental health conditions and postoperative outcomes (50,182 patients).

Abstract: Among patients seeking and undergoing bariatric surgery, the most common mental health conditions, based on random-effects estimates of prevalence, were depression (19% [95% CI, 14%-25%]) and binge eating disorder (17% [95% CI, 13%-21%]).

Abstract: There was conflicting evidence regarding the association between preoperative mental health conditions and postoperative weight loss.

Abstract: Neither depression nor binge eating disorder was consistently associated with differences in weight outcomes.

Abstract: Bariatric surgery was, however, consistently associated with postoperative decreases in the prevalence of depression (7 studies; 8%-74% decrease) and the severity of depressive symptoms (6 studies; 40%-70% decrease).

Abstract: CONCLUSIONS AND RELEVANCE Mental health conditions are common among bariatric surgery patients-in particular, depression and binge eating disorder.

Abstract: There is inconsistent evidence regarding the association between preoperative mental health conditions and postoperative weight loss.

Abstract: Moderate-quality evidence supports an association between bariatric surgery and lower rates of depression postoperatively.


The Nuclear Effector of Wnt-Signaling, Tcf1, Functions as a T-Cell–Specific Tumor Suppressor for Development of Lymphomas

Abstract: The HMG-box factor Tcf1 is required during T-cell development in the thymus and mediates the nuclear response to Wnt signals.

Abstract: Tcf1(-/-) mice have previously been characterized and show developmental blocks at the CD4-CD8- double negative (DN) to CD4+CD8+ double positive transition.

Abstract: Due to the blocks in T-cell development, Tcf1(-/-) mice normally have a very small thymus.

Abstract: Unexpectedly, a large proportion of Tcf1(-/-) mice spontaneously develop thymic lymphomas with 50% of mice developing a thymic lymphoma/leukemia at the age of 16 wk.

Abstract: These lymphomas are clonal, highly metastatic, and paradoxically show high Wnt signaling when crossed with Wnt reporter mice and have high expression of Wnt target genes Lef1 and Axin2.

Abstract: In wild-type thymocytes, Tcf1 is higher expressed than Lef1, with a predominance of Wnt inhibitory isoforms.

Abstract: Loss of Tcf1 as repressor of Lef1 leads to high Wnt activity and is the initiating event in lymphoma development, which is exacerbated by activating Notch1 mutations.

Abstract: Thus, Notch1 and loss of Tcf1 functionally act as collaborating oncogenic events.

Abstract: Tcf1 deficiency predisposes to the development of thymic lymphomas by ectopic up-regulation of Lef1 due to lack of Tcf1 repressive isoforms and frequently by cooperating activating mutations in Notch1.

Abstract: Tcf1 therefore functions as a T-cell-specific tumor suppressor gene, besides its established role as a Wnt responsive transcription factor.

Abstract: Thus, Tcf1 acts as a molecular switch between proliferative and repressive signals during T-lymphocyte development in the thymus.


Activator Control of Nucleosome Occupancy in Activation and Repression of Transcription

Abstract: The relationship between chromatin structure and gene expression is a subject of intense study.

Abstract: The universal transcriptional activator Gal4 removes promoter nucleosomes as it triggers transcription, but how it does so has remained obscure.

Abstract: The reverse process, repression of transcription, has often been correlated with the presence of nucleosomes.

Abstract: But it is not known whether nucleosomes are required for that effect.

Abstract: A new quantitative assay describes, for any given location, the fraction of DNA molecules in the population that bears a nucleosome at any given instant.

Abstract: This allows us to follow the time courses of nucleosome removal and reformation, in wild-type and mutant cells, upon activation (by galactose) and repression (by glucose) of the GAL genes of yeast.

Abstract: We show that upon being freed of its inhibitor Gal80 by the action of galactose, Gal4 quickly recruits SWI/SNF to the genes, and that nucleosome "remodeler" rapidly removes promoter nucleosomes.

Abstract: In the absence of SWI/SNF, Gal4's action also results in nucleosome removal and the activation of transcription, but both processes are significantly delayed.

Abstract: Addition of glucose to cells growing in galactose represses transcription.

Abstract: But if galactose remains present, Gal4 continues to work, recruiting SWI/SNF and maintaining the promoter nucleosome-free despite it being repressed.

Abstract: This requirement for galactose is obviated in a mutant in which Gal4 works constitutively.

Abstract: These results show how an activator's recruiting function can control chromatin structure both during gene activation and repression.

Abstract: Thus, both under activating and repressing conditions, the activator can recruit an enzymatic machine that removes promoter nucleosomes.

Abstract: Our results show that whereas promoter nucleosome removal invariably accompanies activation, reformation of nucleosomes is not required for repression.

Abstract: The finding that there are two routes to nucleosome removal and activation of transcription-one that requires the action of SWI/SNF recruited by the activator, and a slower one that does not-clarifies our understanding of the early events of gene activation, and in particular corrects earlier reports that SWI/SNF plays no role in GAL gene induction.

Abstract: Our finding that chromatin structure is irrelevant for repression as studied here-that is, repression sets in as efficiently whether or not promoter nucleosomes are allowed to reform-contradicts the widely held, but little tested, idea that nucleosomes are required for repression.

Abstract: These findings were made possible by our nucleosome occupancy assay.

Abstract: The assay, we believe, will prove useful in studying other outstanding issues in the field.


Contractile forces sustain and polarize hematopoiesis from stem and progenitor cells.

Abstract: Self-renewal and differentiation of stem cells depend on asymmetric division and polarized motility processes that in other cell types are modulated by nonmuscle myosin-II (MII) forces and matrix mechanics.

Abstract: Here, mass spectrometry-calibrated intracellular flow cytometry of human hematopoiesis reveals MIIB to be a major isoform that is strongly polarized in hematopoietic stem cells and progenitors (HSC/Ps) and thereby downregulated in differentiated cells via asymmetric division.

Abstract: MIIA is constitutive and activated by dephosphorylation during cytokine-triggered differentiation of cells grown on stiff, endosteum-like matrix, but not soft, marrow-like matrix.

Abstract: In vivo, MIIB is required for generation of blood, while MIIA is required for sustained HSC/P engraftment.

Abstract: Reversible inhibition of both isoforms in culture with blebbistatin enriches for long-term hematopoietic multilineage reconstituting cells by 5-fold or more as assessed in vivo.

Abstract: Megakaryocytes also become more polyploid, producing 4-fold more platelets.

Abstract: MII is thus a multifunctional node in polarized division and niche sensing.


Critical Role of the Virus-Encoded MicroRNA-155 Ortholog in the Induction of Marek's Disease Lymphomas

Abstract: Notwithstanding the well-characterised roles of a number of oncogenes in neoplastic transformation, microRNAs (miRNAs) are increasingly implicated in several human cancers.

Abstract: Discovery of miRNAs in several oncogenic herpesviruses such as KSHV has further highlighted the potential of virus-encoded miRNAs to contribute to their oncogenic capabilities.

Abstract: Nevertheless, despite the identification of several possible cancer-related genes as their targets, the direct in vivo role of virus-encoded miRNAs in neoplastic diseases such as those induced by KSHV is difficult to demonstrate in the absence of suitable models.

Abstract: However, excellent natural disease models of rapid-onset Marek's disease (MD) lymphomas in chickens allow examination of the oncogenic potential of virus-encoded miRNAs.

Abstract: Using viruses modified by reverse genetics of the infectious BAC clone of the oncogenic RB-1B strain of MDV, we show that the deletion of the six-miRNA cluster 1 from the viral genome abolished the oncogenicity of the virus.

Abstract: This loss of oncogenicity appeared to be primarily due to the single miRNA within the cluster, miR-M4, the ortholog of cellular miR-155, since its deletion or a 2-nucleotide mutation within its seed region was sufficient to inhibit the induction of lymphomas.

Abstract: The definitive role of this miR-155 ortholog in oncogenicity was further confirmed by the rescue of oncogenic phenotype by revertant viruses that expressed either the miR-M4 or the cellular homolog gga-miR-155.

Abstract: This is the first demonstration of the direct in vivo role of a virus-encoded miRNA in inducing tumors in a natural infection model.

Abstract: Furthermore, the use of viruses deleted in miRNAs as effective vaccines against virulent MDV challenge, enables the prospects of generating genetically defined attenuated vaccines.


Functional insights into the role of nuclear-retained long noncoding RNAs in gene expression control in mammalian cells

Abstract: The mammalian genome harbors thousands of long noncoding RNA (lncRNA) genes.

Abstract: Recent studies have indicated the involvement of several of these lncRNAs in the regulation of gene expression.

Abstract: lncRNAs play crucial roles in various biological processes ranging from epigenetic gene regulation, transcriptional control, to post-transcriptional regulation.

Abstract: lncRNAs are localized in various subcellular compartments, and major proportion of these are retained in the cell nucleus and could be broadly classified as nuclear-retained lncRNAs (nrRNAs).

Abstract: Based on the identified functions, members of the nrRNAs execute diverse roles, including providing architectural support to the hierarchical subnuclear organization and influencing the recruitment of chromatin modifier factors to specific chromatin sites.

Abstract: In this review, we will summarize the recently described roles of mammalian nrRNAs in controlling gene expression by influencing chromatin organization, transcription, pre-mRNA processing, nuclear organization, and their involvement in disease.


Downregulation of TAP1 in B lymphocytes by cellular and Epstein-Barr virus-encoded interleukin-10.

Abstract: Virally infected cells degrade intracellular viral proteins proteolytically and present the resulting peptides in association with major histocompatibility complex (MHC) class I molecules to CD8+ cytotoxic T lymphocytes (CTLs).

Abstract: These cells are normally prone to CTL-mediated elimination.

Abstract: However, several viruses have evolved strategies to avoid detection by the immune system that interfere with the pathway of antigen presentation.

Abstract: Epstein-Barr virus (EBV) expresses a predominantly late protein, the BCRF1 gene product vIL-10, that is similar in sequence to the human interleukin-10 (hIL-10).

Abstract: We show here that vIL-10 affects the expression of one of the two transporter proteins (TAPs) associated with antigen presentation.

Abstract: Similarly, hIL-10 showed the same activity.

Abstract: Expression of the LMP2 and TAP1 genes but not expression of TAP2 or LMP7 is efficiently downregulated, indicating a specific IL-10 effect on the two divergently transcribed TAP1 and LMP2 genes.

Abstract: Downregulation of TAP1 by IL-10 hampers the transport of peptide antigens into the endoplasmatic reticulum, as shown in the TAP-specific peptide transporter assay, their loading onto empty MHC I molecules, and the subsequent translocation to the cell surface.

Abstract: As a consequence, IL-10 causes a general reduction of surface MHC I molecules on B lymphocytes that might also affect the recognition of EBV-infected cells by cytotoxic T cells.


TGF-β and Insulin Signaling Regulate Reproductive Aging via Oocyte and Germline Quality Maintenance

Abstract: Reproductive cessation is perhaps the earliest aging phenotype that humans experience.

Abstract: Similarly, reproduction of Caenorhabditis elegans ceases in mid-adulthood.

Abstract: Although somatic aging has been studied in both worms and humans, mechanisms regulating reproductive aging are not yet understood.

Abstract: Here, we show that TGF-β Sma/Mab and Insulin/IGF-1 signaling regulate C. elegans reproductive aging by modulating multiple aspects of the reproductive process, including embryo integrity, oocyte fertilizability, chromosome segregation fidelity, DNA damage resistance, and oocyte and germline morphology.

Abstract: TGF-β activity regulates reproductive span and germline/oocyte quality noncell-autonomously and is temporally and transcriptionally separable from its regulation of growth.

Abstract: Chromosome segregation, cell cycle, and DNA damage response genes are upregulated in TGF-β mutant oocytes, decline in aged mammalian oocytes, and are critical for oocyte quality maintenance.

Abstract: Our data suggest that C. elegans and humans share many aspects of reproductive aging, including the correlation between reproductive aging and declining oocyte quality and mechanisms determining oocyte quality.


The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells

Abstract: The epithelial-mesenchymal transition (EMT) is a key developmental program that is often activated during cancer invasion and metastasis.

Abstract: We here report that the induction of an EMT in immortalized human mammary epithelial cells (HMLEs) results in the acquisition of mesenchymal traits and in the expression of stem-cell markers.

Abstract: Furthermore, we show that those cells have an increased ability to form mammospheres, a property associated with mammary epithelial stem cells.

Abstract: Independent of this, stem cell-like cells isolated from HMLE cultures form mammospheres and express markers similar to those of HMLEs that have undergone an EMT.

Abstract: Moreover, stem-like cells isolated either from mouse or human mammary glands or mammary carcinomas express EMT markers.

Abstract: Finally, transformed human mammary epithelial cells that have undergone an EMT form mammospheres, soft agar colonies, and tumors more efficiently.

Abstract: These findings illustrate a direct link between the EMT and the gain of epithelial stem cell properties.


NEMO Prevents RIP Kinase 1-Mediated Epithelial Cell Death and Chronic Intestinal Inflammation by NF-κB-Dependent and -Independent Functions

Abstract: Intestinal epithelial cells (IECs) regulate gut immune homeostasis, and impaired epithelial responses are implicated in the pathogenesis of inflammatory bowel diseases (IBD).

Abstract: IEC-specific ablation of nuclear factor κB (NF-κB) essential modulator (NEMO) caused Paneth cell apoptosis and impaired antimicrobial factor expression in the ileum, as well as colonocyte apoptosis and microbiota-driven chronic inflammation in the colon.

Abstract: Combined RelA, c-Rel, and RelB deficiency in IECs caused Paneth cell apoptosis but not colitis, suggesting that NEMO prevents colon inflammation by NF-κB-independent functions.

Abstract: Inhibition of receptor-interacting protein kinase 1 (RIPK1) kinase activity or combined deficiency of Fas-associated via death domain protein (FADD) and RIPK3 prevented epithelial cell death, Paneth cell loss, and colitis development in mice with epithelial NEMO deficiency.

Abstract: Therefore, NEMO prevents intestinal inflammation by inhibiting RIPK1 kinase activity-mediated IEC death, suggesting that RIPK1 inhibitors could be effective in the treatment of colitis in patients with NEMO mutations and possibly in IBD.


Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency

Abstract: The Myc oncogene regulates the expression of several components of the protein synthetic machinery, including ribosomal proteins, initiation factors of translation, RNA polymerase III and ribosomal DNA.

Abstract: Whether and how increasing the cellular protein synthesis capacity affects the multistep process leading to cancer remains to be addressed.

Abstract: Here we use ribosomal protein heterozygote mice as a genetic tool to restore increased protein synthesis in Emu-Myc/+ transgenic mice to normal levels, and show that the oncogenic potential of Myc in this context is suppressed.

Abstract: Our findings demonstrate that the ability of Myc to increase protein synthesis directly augments cell size and is sufficient to accelerate cell cycle progression independently of known cell cycle targets transcriptionally regulated by Myc.

Abstract: In addition, when protein synthesis is restored to normal levels, Myc-overexpressing precancerous cells are more efficiently eliminated by programmed cell death.

Abstract: Our findings reveal a new mechanism that links increases in general protein synthesis rates downstream of an oncogenic signal to a specific molecular impairment in the modality of translation initiation used to regulate the expression of selective messenger RNAs.

Abstract: We show that an aberrant increase in cap-dependent translation downstream of Myc hyperactivation specifically impairs the translational switch to internal ribosomal entry site (IRES)-dependent translation that is required for accurate mitotic progression.

Abstract: Failure of this translational switch results in reduced mitotic-specific expression of the endogenous IRES-dependent form of Cdk11 (also known as Cdc2l and PITSLRE), which leads to cytokinesis defects and is associated with increased centrosome numbers and genome instability in Emu-Myc/+ mice.

Abstract: When accurate translational control is re-established in Emu-Myc/+ mice, genome instability is suppressed.

Abstract: Our findings demonstrate how perturbations in translational control provide a highly specific outcome for gene expression, genome stability and cancer initiation that have important implications for understanding the molecular mechanism of cancer formation at the post-genomic level.


Susceptibility to exacerbation in chronic obstructive pulmonary disease.

Abstract: BACKGROUND Although we know that exacerbations are key events in chronic obstructive pulmonary disease (COPD), our understanding of their frequency, determinants, and effects is incomplete.

Abstract: In a large observational cohort, we tested the hypothesis that there is a frequent-exacerbation phenotype of COPD that is independent of disease severity.

Abstract: METHODS We analyzed the frequency and associations of exacerbation in 2138 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study.

Abstract: Exacerbations were defined as events that led a care provider to prescribe antibiotics or corticosteroids (or both) or that led to hospitalization (severe exacerbations).

Abstract: Exacerbation frequency was observed over a period of 3 years.

Abstract: RESULTS Exacerbations became more frequent (and more severe) as the severity of COPD increased; exacerbation rates in the first year of follow-up were 0.85 per person for patients with stage 2 COPD (with stage defined in accordance with Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages), 1.34 for patients with stage 3, and 2.00 for patients with stage 4.

Abstract: Overall, 22% of patients with stage 2 disease, 33% with stage 3, and 47% with stage 4 had frequent exacerbations (two or more in the first year of follow-up).

Abstract: The single best predictor of exacerbations, across all GOLD stages, was a history of exacerbations.

Abstract: The frequent-exacerbation phenotype appeared to be relatively stable over a period of 3 years and could be predicted on the basis of the patient's recall of previous treated events.

Abstract: In addition to its association with more severe disease and prior exacerbations, the phenotype was independently associated with a history of gastroesophageal reflux or heartburn, poorer quality of life, and elevated white-cell count.

Abstract: CONCLUSIONS Although exacerbations become more frequent and more severe as COPD progresses, the rate at which they occur appears to reflect an independent susceptibility phenotype.

Abstract: This has implications for the targeting of exacerbation-prevention strategies across the spectrum of disease severity.

Abstract: (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT00292552.)


Sympathetic baroreflex gain in normotensive pregnant women.

Abstract: Muscle sympathetic nerve activity is increased during normotensive pregnancy while mean arterial pressure is maintained or reduced, suggesting baroreflex resetting.

Abstract: We hypothesized spontaneous sympathetic baroreflex gain would be reduced in normotensive pregnant women relative to nonpregnant matched controls.

Abstract: Integrated muscle sympathetic burst incidence and total sympathetic activity (microneurography), blood pressure (Finometer), and R-R interval (ECG) were assessed at rest in 11 pregnant women (33 ± 1 wk gestation, 31 ± 1 yr, prepregnancy BMI: 23.5 ± 0.9 kg/m(2)) and 11 nonpregnant controls (29 ± 1 yr; BMI: 25.2 ± 1.7 kg/m(2)).

Abstract: Pregnant women had elevated baseline sympathetic burst incidence (43 ± 2 vs. 33 ± 2 bursts/100 heart beats, P = 0.01) and total sympathetic activity (1,811 ± 148 vs. 1,140 ± 55 au, P < 0.01) relative to controls.

Abstract: Both mean (88 ± 3 vs. 91 ± 2 mmHg, P = 0.4) and diastolic (DBP) (72 ± 3 vs. 73 ± 2 mmHg, P = 0.7) pressures were similar between pregnant and nonpregnant women, respectively, indicating an upward resetting of the baroreflex set point with pregnancy.

Abstract: Baroreflex gain, calculated as the linear relationship between sympathetic burst incidence and DBP, was reduced in pregnant women relative to controls (-3.7 ± 0.5 vs. -5.4 ± 0.5 bursts·100 heart beats(-1)·mmHg(-1), P = 0.03), as was baroreflex gain calculated with total sympathetic activity (-294 ± 24 vs. -210 ± 24 au·100 heart beats(-1)·mmHg(-1); P = 0.03).

Abstract: Cardiovagal baroreflex gain (sequence method) was not different between nonpregnant controls and pregnant women (49 ± 8 vs. 36 ± 8 ms/mmHg; P = 0.2).

Abstract: However, sympathetic (burst incidence) and cardiovagal gains were negatively correlated in pregnant women (R = -0.7; P = 0.02).

Abstract: Together, these data indicate that the influence of the sympathetic nervous system over arterial blood pressure is reduced in normotensive pregnancy, in terms of both long-term and beat-to-beat regulation of arterial pressure, likely through a baroreceptor-dependent mechanism.


Facilitators and Impediments of the Pluripotency Reprogramming Factors' Initial Engagement with the Genome

Abstract: The ectopic expression of transcription factors can reprogram cell fate, yet it is unknown how the initial binding of factors to the genome relates functionally to the binding seen in the minority of cells that become reprogrammed.

Abstract: We report a map of Oct4, Sox2, Klf4, and c-Myc (O, S, K, and M) on the human genome during the first 48 hr of reprogramming fibroblasts to pluripotency.

Abstract: Three striking aspects of the initial chromatin binding events include an unexpected role for c-Myc in facilitating OSK chromatin engagement, the primacy of O, S, and K as pioneer factors at enhancers of genes that promote reprogramming, and megabase-scale chromatin domains spanned by H3K9me3, including many genes required for pluripotency, that prevent initial OSKM binding and impede the efficiency of reprogramming.

Abstract: We find diverse aspects of initial factor binding that must be overcome in the minority of cells that become reprogrammed.


Fibrillar Collagen Inhibits Arterial Smooth Muscle Proliferation through Regulation of Cdk2 Inhibitors

Abstract: Arterial smooth muscle cells (SMCs) are arrested in the G1 phase of the cell cycle on polymerized type I collagen fibrils, while monomer collagen supports SMC proliferation.

Abstract: Cyclin E-associated kinase and cyclin-dependent kinase 2 (cdk2) phosphorylation are inhibited on polymerized collagen, and levels of the cdk2 inhibitors p27Kip1 and p21Cip1/Waf1 are increased compared with SMCs on monomer collagen.

Abstract: p27Kip1 associates with the cyclin E-cdk2-p21Cip1/Waf1 complex in SMCs on polymerized collagen.

Abstract: Monovalent blocking antibodies to alpha2 integrins, integrins that mediate adhesion to both forms of collagen, mimic these effects on monomer collagen.

Abstract: Furthermore, polymerized collagen rapidly suppresses p70 S6 kinase, a possible regulator of p27Kip1.

Abstract: Thus, fibrillar collagen specifically regulates early integrin signaling that may lead to up-regulation of cdk2 inhibitors and inhibition of SMC proliferation.


Memory CD4+ T cells induce innate responses independently of pathogen

Abstract: Inflammation induced by recognition of pathogen-associated molecular patterns markedly affects subsequent adaptive responses.

Abstract: We asked whether the adaptive immune system can also affect the character and magnitude of innate inflammatory responses.

Abstract: We found that the response of memory, but not naive, CD4+ T cells enhances production of multiple innate inflammatory cytokines and chemokines (IICs) in the lung and that, during influenza infection, this leads to early control of virus.

Abstract: Memory CD4+ T cell–induced IICs and viral control require cognate antigen recognition and are optimal when memory cells are either T helper type 1 (TH1) or TH17 polarized but are independent of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) production and do not require activation of conserved pathogen recognition pathways.

Abstract: This represents a previously undescribed mechanism by which memory CD4+ T cells induce an early innate response that enhances immune protection against pathogens.


Direct Upregulation of STAT3 by MicroRNA-551b-3p Deregulates Growth and Metastasis of Ovarian Cancer.

Abstract: 3q26.2 amplification in high-grade serous ovarian cancer leads to increased expression of mature microRNA miR551b-3p, which is associated with poor clinical outcome.

Abstract: Importantly, miR551b-3p contributes to resistance to apoptosis and increased survival and proliferation of cancer cells in vitro and in vivo.

Abstract: miR551b-3p upregulates STAT3 protein levels, and STAT3 is required for the effects of miR551b-3p on cell proliferation.

Abstract: Rather than decreasing levels of target mRNA as expected, we demonstrate that miR551b-3p binds a complementary sequence on the STAT3 promoter, recruiting RNA polymerase II and the TWIST1 transcription factor to activate STAT3 transcription, and thus directly upregulates STAT3 expression.

Abstract: Furthermore, anti-miR551b reduced STAT3 expression in ovarian cancer cells in vitro and in vivo and reduced ovarian cancer growth in vivo.

Abstract: Together, our data demonstrate a role for miR551b-3p in transcriptional activation.

Abstract: Thus, miR551b-3p represents a promising candidate biomarker and therapeutic target in ovarian cancer.


Human albumin administration in critically ill patients: systematic review of randomised controlled trials.

Abstract: OBJECTIVE To quantify effect on mortality of administering human albumin or plasma protein fraction during management of critically ill patients.

Abstract: DESIGN Systematic review of randomised controlled trials comparing administration of albumin or plasma protein fraction with no administration or with administration of crystalloid solution in critically ill patients with hypovolaemia, burns, or hypoalbuminaemia.

Abstract: SUBJECTS 30 randomised controlled trials including 1419 randomised patients.

Abstract: MAIN OUTCOME MEASURE Mortality from all causes at end of follow up for each trial.

Abstract: RESULTS For each patient category the risk of death in the albumin treated group was higher than in the comparison group.

Abstract: For hypovolaemia the relative risk of death after albumin administration was 1.46 (95% confidence interval 0.97 to 2.22), for burns the relative risk was 2.40 (1.11 to 5.19), and for hypoalbuminaemia

Abstract: it was 1.69 (1.07 to 2.67).

Abstract: Pooled relative risk of death with albumin administration was 1.68 (1.26 to 2.23).

Abstract: Pooled difference in the risk of death with albumin was 6% (95% confidence interval 3% to 9%) with a fixed effects model.

Abstract: These data suggest that for every 17 critically ill patients treated with albumin there is one additional death.

Abstract: CONCLUSIONS There is no evidence that albumin administration reduces mortality in critically ill patients with hypovolaemia, burns, or hypoalbuminaemia and a strong suggestion that it may increase mortality.

Abstract: These data suggest that use of human albumin in critically ill patients should be urgently reviewed and that it should not be used outside the context of rigorously conducted, randomised controlled trials.


A fine-scale map of recombination rates and hotspots across the human genome.

Abstract: Genetic maps, which document the way in which recombination rates vary over a genome, are an essential tool for many genetic analyses.

Abstract: We present a high-resolution genetic map of the human genome, based on statistical analyses of genetic variation data, and identify more than 25,000 recombination hotspots, together with motifs and sequence contexts that play a role in hotspot activity.

Abstract: Differences between the behavior of recombination rates over large (megabase) and small (kilobase) scales lead us to suggest a two-stage model for recombination in which hotspots are stochastic features, within a framework in which large-scale rates are constrained.


Mental Health Support Provided Throughout the Bariatric Surgery Clinical Pathway in French Specialized Care Centers for Obesity

Abstract: Pre-operative psychological assessment is recommended by international guidelines for bariatric surgery candidates.

Abstract: Thereby, service teams caring for bariatric patients should include at least one mental health provider (e.g., a psychologist or psychiatrist).

Abstract: The objective of this study was to evaluate the psychology and psychiatry resources and practices in the 37 specialized obesity centers (CSOs) created by the French Ministry of Health.

Abstract: CSO coordinators were contacted by e-mail to collect general information on the centers (e.g., number of bariatric operations).

Abstract: Secondly, psychologists and psychiatrists of each center completed an anonymous questionnaire assessing their professional practices and their organization of care pathways.

Abstract: The vast majority of CSO coordinators (81%, n = 26/32) answered our survey.

Abstract: These results show significant differences and shortages in terms of the psychology/psychiatry resources available.

Abstract: Most of the psychologists (n = 26/31) and psychiatrists (n = 10/10) stated that they systematically meet new patients only before surgery (56%) or both before and after the operation (30%); however, some psychologists and psychiatrists (14%) do not systematically meet all the patients (before and/or after surgery).

Abstract: Nevertheless, all the professionals provide psychology assessments, and about 75% of them offer a psychological follow-up, indicating a similarity regarding the practices of psychologists and psychiatrists.

Abstract: Our results highlight the place of psychological/psychiatric evaluations in French CSOs and emphasize the absence of mental health providers in several of these services.

Abstract: Post-operative psychological follow-up is not usually provided.

Abstract: It would be appropriate to create clear recommendations for post-operative psychological or psychiatric long-term follow-up.


Calcium: Regulation of cell death: the calcium–apoptosis link

Abstract: To live or to die?

Abstract: This crucial question eloquently reflects the dual role of Ca2+ in living organisms – survival factor or ruthless killer.

Abstract: It has long been known that Ca2+ signals govern a host of vital cell functions and so are necessary for cell survival.

Abstract: However, more recently it has become clear that cellular Ca2+ overload, or perturbation of intracellular Ca2+ compartmentalization, can cause cytotoxicity and trigger either apoptotic or necrotic cell death.


Breaking the code of DNA binding specificity of TAL-type III effectors.

Abstract: The pathogenicity of many bacteria depends on the injection of effector proteins via type III secretion into eukaryotic cells in order to manipulate cellular processes.

Abstract: TAL (transcription activator-like) effectors from plant pathogenic Xanthomonas are important virulence factors that act as transcriptional activators in the plant cell nucleus, where they directly bind to DNA via a central domain of tandem repeats.

Abstract: Here, we show how target DNA specificity of TAL effectors is encoded.

Abstract: Two hypervariable amino acid residues in each repeat recognize one base pair in the target DNA.

Abstract: Recognition sequences of TAL effectors were predicted and experimentally confirmed.

Abstract: The modular protein architecture enabled the construction of artificial effectors with new specificities.

Abstract: Our study describes the functionality of a distinct type of DNA binding domain and allows the design of DNA binding domains for biotechnology.


Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion

Abstract: Interferon-gamma (IFN-γ) is a pleiotropic molecule with associated antiproliferative, pro-apoptotic and antitumor mechanisms.

Abstract: This effector cytokine, often considered as a major effector of immunity, has been used in the treatment of several diseases, despite its adverse effects.

Abstract: Although broad evidence implicating IFN-γ in tumor immune surveillance, IFN-γ-based therapies undergoing clinical trials have been of limited success.

Abstract: In fact, recent reports suggested that it may also play a protumorigenic role, namely, through IFN-γ signaling insensitivity, downregulation of major histocompatibility complexes, and upregulation of indoleamine 2,3-dioxygenase and of checkpoint inhibitors, as programmed cell-death ligand 1.

Abstract: However, the IFN-γ-mediated responses are still positively associated with patient's survival in several cancers.

Abstract: Consequently, major research efforts are required to understand the immune contexture in which IFN-γ induces its intricate and highly regulated effects in the tumor microenvironment.

Abstract: This review discusses the current knowledge on the pro- and antitumorigenic effects of IFN-γ as part of the complex immune response to cancer, highlighting the relevance to identify IFN-γ responsive patients for the improvement of therapies that exploit associated signaling pathways.


Role of antioxidants in paraquat toxicity.

Abstract: Paraquat, a quarternary nitrogen herbicide, is a highly toxic compound for humans and animals and many cases of acute poisoning and death have been reported over the past few decades.

Abstract: The mechanisms of paraquat toxicity involve: the generation of the superoxide anion, which can lead to the formation of more toxic reactive oxygen species, such as hydrogen peroxide and hydroxyl radical; and the oxidation of the cellular NADPH, the major source of reducing equivalents for the intracellular reduction of paraquat, which results in the disruption of important NADPH-requiring biochemical processes.

Abstract: The major cause of death in paraquat poisoning is respiratory failure due to an oxidative insult to the alveolar epithelium with subsequent obliterating fibrosis.

Abstract: Management of paraquat poisoning has remained mostly supportive and has been directed towards the modification of the toxicokinetics of the poison.

Abstract: Currently, there are no true pharmacological antagonists for paraquat and there are no chelating agents capable of binding the poison in the blood or other tissues.

Abstract: Recognizing the fact that paraquat induces its toxic effects via oxidative stress-mediated mechanisms, innovations in the management of paraquat poisoning are directed towards the use of antioxidants.

Abstract: In this review, the status of antioxidants in ameliorating or treating the toxic effects produced by paraquat is presented.


Nucleation of nuclear bodies by RNA

Abstract: The biogenesis of the many functional compartments contained in the mammalian cell nucleus is poorly understood.

Abstract: More specifically, little is known regarding the initial nucleation step required for nuclear body formation.

Abstract: Here we show that RNA can function as a structural element and a nucleator of nuclear bodies.

Abstract: We find that several types of coding and noncoding RNAs are sufficient to de novo assemble, and are physiologically enriched in, histone locus bodies (with associated Cajal bodies), nuclear speckles, paraspeckles and nuclear stress bodies.

Abstract: Formation of nuclear bodies occurs through recruitment and accumulation of proteins resident in the nuclear bodies by nucleating RNA.

Abstract: These results demonstrate that transcription is a driving force in nuclear body formation and RNA transcripts can function as a scaffold in the formation of major nuclear bodies.

Abstract: Together, these data suggest that RNA-primed biogenesis of nuclear bodies is a general principle of nuclear organization.


Evaluation of human papillomavirus testing in primary screening for cervical abnormalities: comparison of sensitivity, specificity, and frequency of referral.

Abstract: CONTEXT Human papillomavirus (HPV) DNA testing of women having Papanicolaou (Pap) smears showing atypical squamous cells of undetermined significance (ASCUS) has clinical usefulness.

Abstract: Whether HPV DNA testing alone is useful in primary screening remains to be determined.

Abstract: OBJECTIVE To determine the accuracy of HPV DNA testing for detecting cervical intraepithelial neoplasia (CIN) grade 3 or cancer (the criterion standard).

Abstract: DESIGN, SETTING, AND PARTICIPANTS Between December 1997 and October 2000, 4075 women who attended Planned Parenthood clinics in Washington State were screened simultaneously using thin-layer Pap and HPV DNA testing by a polymerase chain reaction (PCR)-based method and by a liquid-based RNA-DNA hybridization capture with signal amplification assay (signal amplification).

Abstract: Women who were positive for high-risk HPV types, or had Pap results of ASCUS or higher, were considered to have positive screening test results and were referred for colposcopy and biopsy.

Abstract: Additionally, a random sample of women with negative screening test results was referred for colposcopy.

Abstract: Based on individual and combined thin-layer Pap, HPV PCR, and HPV signal amplification test results from the screening and the colposcopy visits, 7 colposcopy triage strategies were defined and evaluated.

Abstract: MAIN OUTCOME MEASURE Sensitivity and specificity for detecting cervical lesions graded CIN 3 or higher for each of the 7 triage strategies.

Abstract: RESULTS The estimated prevalence of CIN 3 or higher was 3.2%.

Abstract: The sensitivity (95% confidence interval) of thin-layer Pap (with a result of > or = ASCUS) for identifying women with CIN 3 or higher was only 61.3% (48.5%-70.9%) compared with 88.2% (78.9%-93.8%) for HPV testing by PCR and 90.8% (83.1%-95.8%) by signal amplification.

Abstract: Differences in specificities were also observed: 82.4% (81.8%-83.1%) for thin-layer Pap (with a result of > or = ASCUS), 78.8% (77.9%-79.7%) for PCR, and 72.6% (69.4%-75.0%) for signal amplification.

Abstract: Compared with referral for colposcopy of all women with ASCUS or higher, signal amplification testing of women with ASCUS and referral of those with a positive result was about as sensitive (61.3% vs 60.3%, respectively) and significantly more specific (82.4% vs 88.9%, respectively).

Abstract: The strategy requiring repeat positive PCR tests on 2 visits had a sensitivity of 84.2% (75.3%-91.0%) and a specificity of 86.2% (85.1%-87.3%).

Abstract: All tests were more specific and less sensitive in older (> or = 30 years) vs younger women.

Abstract: CONCLUSIONS Testing for HPV has higher sensitivity but lower specificity than thin-layer Pap screening.

Abstract: In some settings, particularly where screening intervals are long or haphazard, screening for HPV DNA may be a reasonable alternative to cytology-based screening of reproductive-age women.


Breaking the chains: structure and function of the deubiquitinases

Abstract: Ubiquitylation is a reversible protein modification that is implicated in many cellular functions.

Abstract: Recently, much progress has been made in the characterization of a superfamily of isopeptidases that remove ubiquitin: the deubiquitinases (DUBs; also known as deubiquitylating or deubiquitinating enzymes).

Abstract: Far from being uniform in structure and function, these enzymes display a myriad of distinct mechanistic features.

Abstract: The small number (<100) of DUBs might at first suggest a low degree of selectivity; however, DUBs are subject to multiple layers of regulation that modulate both their activity and their specificity.

Abstract: Due to their wide-ranging involvement in key regulatory processes, these enzymes might provide new therapeutic targets.


Replication protein A: a heterotrimeric, single-stranded DNA-binding protein required for eukaryotic DNA metabolism.

Abstract: Replication protein A [RPA; also known as replication factor A (RFA) and human single-stranded DNA-binding protein] is a single-stranded DNA-binding protein that is required for multiple processes in eukaryotic DNA metabolism, including DNA replication, DNA repair, and recombination.

Abstract: RPA homologues have been identified in all eukaryotic organisms examined and are all abundant heterotrimeric proteins composed of subunits of approximately 70, 30, and 14 kDa.

Abstract: Members of this family bind nonspecifically to single-stranded DNA and interact with and/or modify the activities of multiple proteins.

Abstract: In cells, RPA is phosphorylated by DNA-dependent protein kinase when RPA is bound to single-stranded DNA (during S phase and after DNA damage).

Abstract: Phosphorylation of RPA may play a role in coordinating DNA metabolism in the cell.

Abstract: RPA may also have a role in modulating gene expression.


Internal fixation versus nonoperative treatment of displaced 3-part proximal humeral fractures in elderly patients: a randomized controlled trial.

Abstract: BACKGROUND The aim of the study was to report the 2-year outcome after a displaced 3-part fracture of the proximal humerus in elderly patients randomized to treatment with a locking plate or nonoperative treatment.

Abstract: PATIENTS AND METHODS We included 60 patients, mean age 74 years (range, 56-92), 81% being women.

Abstract: The main outcome measures were the Constant and Disabilities of the Arm, Shoulder and Hand (DASH) scores and the health-related quality of life (HRQoL) according to the EQ-5D.

Abstract: RESULTS At the final 2-year follow-up, the results for range of motion (ROM), function and HRQoL were all in favor of the locking plate group.

Abstract: The mean flexion in the locking plate group was 120° compared to 111° in the nonoperative group (P = .36) and the mean abduction was 114° compared to 106° (P = .28).

Abstract: The corresponding values for the Constant score were 61 versus 58 (P = .64), for DASH 26 versus 35 (P = .19), and the mean EQ-5D (index) score was 0.70 compared to 0.59 (P = .26).

Abstract: In spite of good primary reduction in 86% of the fractures in the locking plate group, 13% of the patients had a fracture complication requiring a major reoperation and 17% had a minor reoperation.

Abstract: CONCLUSION The results of our study indicate an advantage in functional outcome and HRQoL in favor of the locking plate compared to nonoperative treatment in elderly patients with a displaced 3-part fracture of the proximal humerus, but at the cost of additional surgery in 30% of the patients.


Good and bad consequences of altered fatty acid metabolism in heart failure: evidence from mouse models.

Abstract: The shift in substrate preference away from fatty acid oxidation (FAO) towards increased glucose utilization in heart failure has long been interpreted as an oxygen-sparing mechanism.

Abstract: Inhibition of FAO has therefore evolved as an accepted approach to treat heart failure.

Abstract: However, recent data indicate that increased reliance on glucose might be detrimental rather than beneficial for the failing heart.

Abstract: This review discusses new insights into metabolic adaptations in heart failure.

Abstract: A particular focus lies on data obtained from mouse models with modulations of cardiac FA metabolism at different levels of the FA metabolic pathway and how these differently affect cardiac function.

Abstract: Based on studies in which these mouse models were exposed to ischaemic and non-ischaemic heart failure, we discuss whether and when modulations in FA metabolism are protective against heart failure.


Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells

Abstract: Cells derived from blood vessels of human skeletal muscle can regenerate skeletal muscle, similarly to embryonic mesoangioblasts.

Abstract: However, adult cells do not express endothelial markers, but instead express markers of pericytes, such as NG2 proteoglycan and alkaline phosphatase (ALP), and can be prospectively isolated from freshly dissociated ALP+ cells.

Abstract: Unlike canonical myogenic precursors (satellite cells), pericyte-derived cells express myogenic markers only in differentiated myotubes, which they form spontaneously with high efficiency.

Abstract: When transplanted into severe combined immune deficient–X-linked, mouse muscular dystrophy (scid–mdx) mice, pericyte-derived cells colonize host muscle and generate numerous fibres expressing human dystrophin.

Abstract: Similar cells isolated from Duchenne patients, and engineered to express human mini-dystrophin, also give rise to many dystrophin-positive fibres in vivo.

Abstract: These data show that myogenic precursors, distinct from satellite cells, are associated with microvascular walls in the human skeletal muscle, may represent a correlate of embryonic 'mesoangioblasts' present after birth and may be a promising candidate for future cell-therapy protocols in patients.


Ten years' experience with alendronate for osteoporosis in postmenopausal women.

Abstract: BACKGROUND Antiresorptive agents are widely used to treat osteoporosis.

Abstract: We report the results of a multinational randomized, double-blind study, in which postmenopausal women with osteoporosis were treated with alendronate for up to 10 years.

Abstract: METHODS The initial three-year phase of the study compared three daily doses of alendronate with placebo.

Abstract: Women in the original placebo group received alendronate in years 4 and 5 and then were discharged.

Abstract: Women in the original active-treatment groups continued to receive alendronate during the initial extension (years 4 and 5).

Abstract: In two further extensions (years 6 and 7, and 8 through 10), women who had received 5 mg or 10 mg of alendronate daily continued on the same treatment.

Abstract: Women in the discontinuation group received 20 mg of alendronate daily for two years and 5 mg daily in years 3, 4, and 5, followed by five years of placebo.

Abstract: Randomized group assignments and blinding were maintained throughout the 10 years.

Abstract: We report results for the 247 women who participated in all four phases of the study.

Abstract: RESULTS Treatment with 10 mg of alendronate daily for 10 years produced mean increases in bone mineral density of 13.7 percent at the lumbar spine (95 percent confidence interval, 12.0 to 15.5 percent), 10.3 percent at the trochanter (95 percent confidence interval, 8.1 to 12.4 percent), 5.4 percent at the femoral neck (95 percent confidence interval, 3.5 to 7.4 percent), and 6.7 percent at the total proximal femur (95 percent confidence interval, 4.4 to 9.1 percent) as compared with base-line values; smaller gains occurred in the group given 5 mg daily.

Abstract: The discontinuation of alendronate resulted in a gradual loss of effect, as measured by bone density and biochemical markers of bone remodeling.

Abstract: Safety data, including fractures and stature, did not suggest that prolonged treatment resulted in any loss of benefit.

Abstract: CONCLUSIONS The therapeutic effects of alendronate were sustained, and the drug was well tolerated over a 10-year period.

Abstract: The discontinuation of alendronate resulted in the gradual loss of its effects.


UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis

Abstract: Uncoupling protein 1 (UCP1) plays a central role in nonshivering thermogenesis in brown fat; however, its role in beige fat remains unclear.

Abstract: Here we report a robust UCP1-independent thermogenic mechanism in beige fat that involves enhanced ATP-dependent Ca2+ cycling by sarco/endoplasmic reticulum Ca2+-ATPase 2b (SERCA2b) and ryanodine receptor 2 (RyR2).

Abstract: Inhibition of SERCA2b impairs UCP1-independent beige fat thermogenesis in humans and mice as well as in pigs, a species that lacks a functional UCP1 protein.

Abstract: Conversely, enhanced Ca2+ cycling by activation of α1- and/or β3-adrenergic receptors or the SERCA2b-RyR2 pathway stimulates UCP1-independent thermogenesis in beige adipocytes.

Abstract: In the absence of UCP1, beige fat dynamically expends glucose through enhanced glycolysis, tricarboxylic acid metabolism and pyruvate dehydrogenase activity for ATP-dependent thermogenesis through the SERCA2b pathway; beige fat thereby functions as a 'glucose sink' and improves glucose tolerance independently of body weight loss.

Abstract: Our study uncovers a noncanonical thermogenic mechanism through which beige fat controls whole-body energy homeostasis via Ca2+ cycling.