Question: Pro-inflammatory cytokines are up regulated during tumor development.

Paraneoplastic thrombocytosis: the secrets of tumor self-promotion.
Paraneoplastic thrombocytosis is associated with many solid tumors and often correlates with reduced survival. Recent studies suggest that a pathogenic feed back loop may be operative between platelets and tumor cells, with reciprocal interactions between tumor growth/metastasis and thrombocytosis/platelet activation. Specific molecular pathways have been identified in which tumors can stimulate platelet production and activation; activated platelets can, in turn, promote tumor growth and metastasis. Taken together, these findings provide exciting new potential targets for therapeutic intervention.

Progression of preclinical diastolic dysfunction to the development of symptoms.
BACKGROUND Preclinical diastolic dysfunction (PDD) has been defined as subjects with normal systolic function, diastolic dysfunction but no symptoms of heart failure (HF). The clinical phenotype and natural history of the syndrome remains poorly defined. This study's objective was to determine the clinical phenotype and progression to HF in a group of patients with normal systolic function and moderate or severe diastolic dysfunction as determinate by Doppler criteria without any clinical diagnosis of HF according to the Framingham criteria or any symptoms of HF, specifically dyspnoea, oedema or fatigue at the time of echocardiography. METHODS The authors used resources of the Mayo Clinic echocardiography database to consecutively select among patients who had an echocardiogram in 2005, a cohort with moderate or severe diastolic dysfunction by Doppler criteria and EF >or=50%. Patients could not have a diagnosis of HF, or any HF symptoms-specifically dyspnoea, oedema or fatigue-at the time of echocardiography; nor grade 3 or greater valvular dysfunction (except tricuspid valve). A total of 82 patients had their medical chart reviewed. Primary endpoint was the time to the development of (1) HF according to the Framingham criteria or (2) any symptoms of dyspnoea, oedema or fatigue. RESULTS The mean age of the cohort of PDD subjects was 69+/-10 years with a female (67%) preponderance. Presence of hypertension was 76%, coronary artery disease was 29%, paroxysmal atrial fibrillation was 26%, estimated creatinine clearance <60 ml/min was 51%. The 2-year cumulative probability of development of HF according to the Framingham criteria was 1.9%; however, the 2-year cumulative probability of development of any symptoms was 31.1%. The 2-year cumulative probability for cardiac hospitalisation was 21.2%. Peripheral vascular disease and hypertension were independently associated with increased likelihood for the development of symptoms. CONCLUSION The study demonstrates that hypertension, hyperlipidaemia, CAD and renal dysfunction are prevalent in patients with PDD. More importantly, although the progression to the development of clinical HF over 2 years was low, there was a moderate degree of progression to development of symptoms and cardiac hospitalisations over 2 years. Based on the finding that only PVD and hypertension were independently associated with the progression to the development of symptoms in subject with PDD, the authors speculate that ventricular-arterial interaction may be important to the progression of diastolic dysfunction to the development of symptoms.

Multiple-dose activated charcoal in acute self-poisoning: a randomised controlled trial
BACKGROUND The case-fatality for intentional self-poisoning in the rural developing world is 10-50-fold higher than that in industrialised countries, mostly because of the use of highly toxic pesticides and plants. We therefore aimed to assess whether routine treatment with multiple-dose activated charcoal, to interrupt enterovascular or enterohepatic circulations, offers benefit compared with no charcoal in such an environment. METHODS We did an open-label, parallel group, randomised, controlled trial of six 50 g doses of activated charcoal at 4-h intervals versus no charcoal versus one 50 g dose of activated charcoal in three Sri Lankan hospitals. 4632 patients were randomised to receive no charcoal (n=1554), one dose of charcoal (n=1545), or six doses of charcoal (n=1533); outcomes were available for 4629 patients. 2338 (51%) individuals had ingested pesticides, whereas 1647 (36%) had ingested yellow oleander (Thevetia peruviana) seeds. Mortality was the primary outcome measure. Analysis was by intention to treat. The trial is registered with controlled-trials.com as ISRCTN02920054. FINDINGS Mortality did not differ between the groups. 97 (6.3%) of 1531 participants in the multiple-dose group died, compared with 105 (6.8%) of 1554 in the no charcoal group (adjusted odds ratio 0.96, 95% CI 0.70-1.33). No differences were noted for patients who took particular poisons, were severely ill on admission, or who presented early. INTERPRETATION We cannot recommend the routine use of multiple-dose activated charcoal in rural Asia Pacific; although further studies of early charcoal administration might be useful, effective affordable treatments are urgently needed.

Exercise-induced asthma screening of elite athletes: field versus laboratory exercise challenge.
PURPOSE The purpose of this study was to compare a laboratory based exercise challenge (LBC) to a field based exercise challenge (FBC) for pulmonary function test (PFT) exercise-induced asthma (EIA) screening of elite athletes. METHODS Twenty-three elite cold weather athletes (14 men, 9 women) PFT positive for EIA (FBC screened) served as subjects. Twenty-three gender and sport matched controls (nonasthmatics) were randomly selected to establish PFT reference values for normal elite athletes. Before FBC, athletes completed a medical history questionnaire for EIA symptoms. FBC evaluations consisted of baseline spirometry, actual or simulated competition, and 5, 10, and 15 min postexercise spirometry. PFT positive athletes were evaluated in the laboratory using an exercise challenge simulating race intensity (ambient conditions: 21 degrees C, 60% relative humidity). PFT procedures were identical to FBC. RESULTS 91% of PFT positive and 48% of PFT normal athletes reported at least one symptom of EIA, with postrace cough most frequent. Baseline spirometry was the same for PFT positives and normal controls. Lower limit reference range (MN - 2 SD) of FEV1 for controls suggests that postexercise decrements of greater than approximately -7% indicate abnormal airway response in this population. Exercise time duration did not effect bronchial reactivity; 78% of FBC PFT positives were PFT normal post-LBC. CONCLUSION Self-reported symptoms by elite athletes are not reliable in identifying EIA. Reference range criterion for FEV1 decrement in the elite athlete postexercise contrasts current recommended guidelines. Moreover, a large number of false negatives may occur in this population if EIA screening is performed with inadequate exercise and environmental stress.

Advances in brain tumor surgery.
Advances in the fields of molecular and translational research, oncology, and surgery have emboldened the medical community to believe that intrinsic brain tumors may be treatable. Intraoperative imaging and brain mapping allow operations adjacent to eloquent cortex and more radical resection of tumors with increased confidence and safety. Despite these advances, the infiltrating edge of a neoplasm and distant microscopic satellite lesions will never be amendable to a surgical cure. Indeed, it is continued research into the delivery of an efficacious chemobiologic agent that will eventually allows us to manage this primary cause of treatment failure.

Cell fusion hypothesis of the cancer stem cell.
A major advance in recent cancer research is the identification of tumor cells with stem cell-like properties. Cancer stem cells (CSCs) often represent a rare population in the tumor mass and possess the exclusive ability to initiate the growth of a heterogeneous tumor. The origin of CSCs remains elusive and is likely to be cancer type specific. One possible but under-appreciated potential mechanism for the generation of CSCs is through fusion between stem cells and differentiated cells. The cell fusion hypothesis of CSCs adds an important functional underpinning to the potential multifaceted roles of cell fusion in the initiation and progression of cancer.

Behavioral effects of estrogen receptor gene disruption in male mice.
Gonadal steroid hormones regulate sexually dimorphic development of brain functions and behaviors. Their nuclear receptors offer the opportunity to relate molecular events in neurons to simple instinctive mammalian behaviors. We have determined the role of estrogen receptor (ER) activation by endogenous estrogen in the development of male-typical behaviors by the use of transgenic estrogen-receptor-deficient (ERKO) mice. Surprisingly, in spite of the fact that they are infertile, ERKO mice showed normal motivation to mount females but they achieved less intromissions and virtually no ejaculations. Aggressive behaviors were dramatically reduced and male-typical offensive attacks were rarely displayed by ERKO males. Moreover, ER gene disruption demasculinized open-field behaviors. In the brain, despite the evident loss of functional ER protein, the androgen-dependent system appears to be normally present in ERKO mice. Together, these findings indicate that ER gene expression during development plays a major role in the organization of male-typical aggressive and emotional behaviors in addition to simple sexual behaviors.

Very small embryonic-like stem cells with maximum regenerative potential get discarded during cord blood banking and bone marrow processing for autologous stem cell therapy.
Very small embryonic-like stem cells (VSELs) are possibly lost during cord blood banking and bone marrow (BM) processing for autologus stem cell therapy mainly because of their small size. The present study was conducted on human umbilical cord blood (UCB, n=6) and discarded red blood cells (RBC) fraction obtained after separation of mononuclear cells from human BM (n=6), to test this hypothesis. The results show that VSELs, which are pluripotent stem cells with maximum regenerative potential, settle along with the RBCs during Ficoll-Hypaque density separation. These cells are very small in size (3-5 μm), have high nucleo-cytoplasmic ratio, and express nuclear Oct-4, cell surface protein SSEA-4, and other pluripotent markers such as Nanog, Sox-2, Rex-1, and Tert as indicated by immunolocalization and quantitative polymerase chain reaction (Q-PCR) studies. Interestingly, a distinct population of slightly larger, round hematopoietic stem cells (HSCs) with cytoplasmic Oct-4 were detected in the "buffy" coat, which usually gets banked or used during autologus stem cell therapy. Immunohistochemical studies on the umbilical cord tissue (UCT) sections (n=3) showed the presence of nuclear Oct-4-positive VSELs and many fibroblast-like mesenchymal stem cells (MSCs) with cytoplasmic Oct-4. These VSELs with nuclear Oct-4, detected in UCB, UCT, and discarded RBC fraction obtained after BM processing, may persist throughout life, maintain tissue homeostasis, and undergo asymmetric cell division to self-renew as well as produce larger progenitor stem cells, viz. HSCs or MSCs, which follow differentiation trajectories depending on the somatic niche. Hence, it can be concluded that the true stem cells in adult body tissues are the VSELs, whereas the HSCs and MSCs are actually progenitor stem cells that arise by asymmetric cell division of VSELs. The results of the present study may help explain low efficacy reported during adult autologous stem cell trials, wherein unknowingly progenitor stem cells are injected rather than the pluripotent stem cells with maximum regenerative potential.

Prognostic impact of minimal pleural effusion in non-small-cell lung cancer.
PURPOSE Minimal (< 10 mm thick) pleural effusion (PE) may represent an early phase of malignant PE, but its clinical relevance has rarely been studied. Therefore, we examined the proportion of minimal PE in patients with non-small-cell lung cancer (NSCLC) and its impact on survival. We also considered possible accumulation mechanisms in our data set. PATIENTS AND METHODS On the basis of PE status from chest computed tomography scans at diagnosis, 2,061 patients were classified into three groups: no PE, minimal PE, and malignant PE. Twenty-one variables associated with four factors-patient, stage migration, tumor, and treatment-were investigated for correlation with survival. RESULTS Minimal PE presented in 272 patients (13.2%). Of 2,061 patients, the proportion of each stage was the following: 5.2% stage I, 10.9% stage II, 13.2% stage IIIA, 23.8% stage IIIB, and 13.9% stage IV. Minimal PE correlated significantly with shorter survival time than did no PE (median survival time, 7.7 v 17.7 months; log-rank P < .001), even after full adjustment with all variables (adjusted hazard ratio, 1.40; 95% CI, 1.21 to 1.62). Prognostic impact of minimal PE was higher in early versus advanced stages (Pinteraction = .001). In 237 patients (87.8%) with minimal PE, pleural invasion or attachment as a direct mechanism was observed, and it was an independent factor predicting worse survival (P = .03). CONCLUSION Minimal PE is a commonly encountered clinical concern in staging NSCLCs. Its presence is an important prognostic factor of worse survival, especially in early-stage disease.

Autoimmunity due to molecular mimicry as a cause of neurological disease
One hypothesis that couples infection with autoimmune disease is molecular mimicry. Molecular mimicry is characterized by an immune response to an environmental agent that cross-reacts with a host antigen, resulting in disease. This hypothesis has been implicated in the pathogenesis of diabetes, lupus and multiple sclerosis (MS). There is limited direct evidence linking causative agents with pathogenic immune reactions in these diseases. Our study establishes a clear link between viral infection, autoimmunity and neurological disease in humans. As a model for molecular mimicry, we studied patients with human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a disease that can be indistinguishable from MS (refs. 5,6,7). HAM/TSP patients develop antibodies to neurons. We hypothesized these antibodies would identify a central nervous system (CNS) autoantigen. Immunoglobulin G isolated from HAM/TSP patients identified heterogeneous nuclear ribonuclear protein-A1 (hnRNP-A1) as the autoantigen. Antibodies to hnRNP-A1 cross-reacted with HTLV-1-tax, the immune response to which is associated with HAM/TSP (refs. 5,9). Immunoglobulin G specifically stained human Betz cells, whose axons are preferentially damaged. Infusion of autoantibodies in brain sections inhibited neuronal firing, indicative of their pathogenic nature. These data demonstrate the importance of molecular mimicry between an infecting agent and hnRNP-A1 in autoimmune disease of the CNS.

GFI1 and GFI1B control the loss of endothelial identity of hemogenic endothelium during hematopoietic commitment.
Recent studies have established that during embryonic development, hematopoietic progenitors and stem cells are generated from hemogenic endothelium precursors through a process termed endothelial to hematopoietic transition (EHT). The transcription factor RUNX1 is essential for this process, but its main downstream effectors remain largely unknown. Here, we report the identification of Gfi1 and Gfi1b as direct targets of RUNX1 and critical regulators of EHT. GFI1 and GFI1B are able to trigger, in the absence of RUNX1, the down-regulation of endothelial markers and the formation of round cells, a morphologic change characteristic of EHT. Conversely, blood progenitors in Gfi1- and Gfi1b-deficient embryos maintain the expression of endothelial genes. Moreover, those cells are not released from the yolk sac and disseminated into embryonic tissues. Taken together, our findings demonstrate a critical and specific role of the GFI1 transcription factors in the first steps of the process leading to the generation of hematopoietic progenitors from hemogenic endothelium.

Instruction: Given a scientific claim, retrieve documents that support or refute the claim


Question: Pro-inflammatory cytokines are up regulated during tumor development.

Impact of TNF-alpha and IL-6 levels on development of cachexia in newly diagnosed NSCLC patients.
OBJECTIVES We investigated the role of cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in cachexia development in newly diagnosed nonsmall cell lung cancer (NSCLC) patients. METHODS : We evaluated 44 (M/F:41/3) NSCLC patients and 12 (M/F:10/2) age matched healthy smokers. NSCLC cases with a weight loss of > or =10% consisted the cachectic group (n:23, M/F:21/2) and the ones with <10% weight loss consisted the noncachectic group (n:21, M/F:19/2). RESULTS Body mass index (BMI) of cachectics was significantly lower than that of noncachectics (21.0 +/- 2.9 versus 24.5 +/- 3.6, P = 0.02) and controls (21.0 +/- 2.9 versus 25.5 +/- 2.6, P = 0.01). Serum TNF-alpha level did not differ between cachectic and noncachectics (37.3 +/- 39.1 and 51.6 +/- 84.2 pg/mL, respectively). However, it was significantly higher in NSCLC patients compared with controls (44.1 +/- 64.3 and 15.1 +/- 14.3 pg/mL, P = 0.03). Serum IL-6 level was not different between 3 groups (6.4 +/- 4.1, 8.9 +/- 16.3, and 4.1 +/- 3.5 pg/mL, respectively) but it correlated significantly with TNF-alpha (r = 0.4, P = 0.006) and BMI (r = -0.3, P = 0.03). Erythrocyte sedimentation rate (ESR) correlated significantly with TNF-alpha (r = 0.4, P = 0.003) and BMI (r = -0.3, P = 0.03). Among 44 cases, survival of 12 and 17 patients was recorded in cachectics and noncachectics, with no statistical difference (12.2 +/- 3.7 and 11.2 +/- 1.0 months, respectively). CONCLUSIONS TNF-alpha and IL-6 levels did not differ significantly between cachectics and noncachectics. However, significant correlations between IL-6, BMI, and TNF-alpha suggested that these cytokines acted as cofactors in weight loss. Survival was neither influenced by BMI, nor the cytokine levels in the present study. The significant correlation of ESR with TNF-alpha suggested that ESR could provide valuable clue for considerable weight loss in the follow-up of NSCLC patients.

Identification of Epstein-Barr virus nuclear antigen 1 protein domains that direct interactions at a distance between DNA-bound proteins.
The EBNA1 protein of Epstein-Barr virus (EBV) binds to and activates DNA replication from the EBV latent origin of replication, oriP, via a direct interaction with the two noncontiguous subelements of oriP. The EBNA1 molecules bound to the oriP subelements interact efficiently with each other by a DNA looping mechanism. We have previously mapped a region of EBNA1 (termed the looping region) that is required to mediate the interaction of the EBNA1 molecules bound to the oriP subelements. We now demonstrate that two fragments of this region of EBNA1, which consist largely of an eight amino acid repeat, can mediate homotypic interactions when transferred to another DNA-binding protein. Protein interactions mediated by the EBNA1 looping region appear to be dependent on DNA binding since these interactions were detected between DNA-bound forms of the proteins only.

Peroxisome proliferator-activated receptor gamma agonists for the Prevention of Adverse events following percutaneous coronary Revascularization--results of the PPAR study.
BACKGROUND Patients with metabolic syndrome are at increased risk for cardiovascular complications. We sought to determine whether peroxisome proliferator-activated receptor gamma agonists had any beneficial effect on patients with metabolic syndrome undergoing percutaneous coronary intervention (PCI). METHODS A total of 200 patients with metabolic syndrome undergoing PCI were randomized to rosiglitazone or placebo and followed for 1 year. Carotid intima-medial thickness (CIMT), inflammatory markers, lipid levels, brain natriuretic peptide, and clinical events were measured at baseline, 6 months, and 12 months. RESULTS There was no significant difference in CIMT between the 2 groups. There was no difference in the 12-month composite end point of death, myocardial infarction (MI), stroke, or any recurrent ischemia (31.4% vs 30.2%, P = .99). The rate of death, MI, or stroke at 12 months was numerically lower in the rosiglitazone group (11.9% vs 6.4%, P = .19). There was a trend toward a greater decrease over time in high-sensitivity C-reactive protein values compared with baseline in the group randomized to rosiglitazone versus placebo both at 6 months (-35.4% vs -15.8%, P = .059) and 12 months (-40.0% vs -20.9%, P = .089) and higher change in high-density lipoprotein (+15.5% vs +4.1%, P = .05) and lower triglycerides (-13.9% vs +14.9%, P = .004) in the rosiglitazone arm. There was a trend toward less new onset diabetes in the rosiglitazone group (0% vs 3.3%, P = .081) and no episodes of symptomatic hypoglycemia. There was no excess of new onset of clinical heart failure in the rosiglitazone group, nor was there a significant change in brain natriuretic peptide levels. CONCLUSIONS Patients with metabolic syndrome presenting for PCI are at increased risk for subsequent cardiovascular events. Rosiglitazone for 12 months did not appear to affect CIMT in this population, although it did have beneficial effects on high-sensitivity C-reactive protein, high-density lipoprotein, and triglycerides. Further study of peroxisome proliferator-activated receptor agonism in patients with metabolic syndrome undergoing PCI may be warranted.

Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015
BACKGROUND Healthy life expectancy (HALE) and disability-adjusted life-years (DALYs) provide summary measures of health across geographies and time that can inform assessments of epidemiological patterns and health system performance, help to prioritise investments in research and development, and monitor progress toward the Sustainable Development Goals (SDGs). We aimed to provide updated HALE and DALYs for geographies worldwide and evaluate how disease burden changes with development. METHODS We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2015. We calculated DALYs by summing years of life lost (YLLs) and years of life lived with disability (YLDs) for each geography, age group, sex, and year. We estimated HALE using the Sullivan method, which draws from age-specific death rates and YLDs per capita. We then assessed how observed levels of DALYs and HALE differed from expected trends calculated with the Socio-demographic Index (SDI), a composite indicator constructed from measures of income per capita, average years of schooling, and total fertility rate. FINDINGS Total global DALYs remained largely unchanged from 1990 to 2015, with decreases in communicable, neonatal, maternal, and nutritional (Group 1) disease DALYs offset by increased DALYs due to non-communicable diseases (NCDs). Much of this epidemiological transition was caused by changes in population growth and ageing, but it was accelerated by widespread improvements in SDI that also correlated strongly with the increasing importance of NCDs. Both total DALYs and age-standardised DALY rates due to most Group 1 causes significantly decreased by 2015, and although total burden climbed for the majority of NCDs, age-standardised DALY rates due to NCDs declined. Nonetheless, age-standardised DALY rates due to several high-burden NCDs (including osteoarthritis, drug use disorders, depression, diabetes, congenital birth defects, and skin, oral, and sense organ diseases) either increased or remained unchanged, leading to increases in their relative ranking in many geographies. From 2005 to 2015, HALE at birth increased by an average of 2·9 years (95% uncertainty interval 2·9-3·0) for men and 3·5 years (3·4-3·7) for women, while HALE at age 65 years improved by 0·85 years (0·78-0·92) and 1·2 years (1·1-1·3), respectively. Rising SDI was associated with consistently higher HALE and a somewhat smaller proportion of life spent with functional health loss; however, rising SDI was related to increases in total disability. Many countries and territories in central America and eastern sub-Saharan Africa had increasingly lower rates of disease burden than expected given their SDI. At the same time, a subset of geographies recorded a growing gap between observed and expected levels of DALYs, a trend driven mainly by rising burden due to war, interpersonal violence, and various NCDs. INTERPRETATION Health is improving globally, but this means more populations are spending more time with functional health loss, an absolute expansion of morbidity. The proportion of life spent in ill health decreases somewhat with increasing SDI, a relative compression of morbidity, which supports continued efforts to elevate personal income, improve education, and limit fertility. Our analysis of DALYs and HALE and their relationship to SDI represents a robust framework on which to benchmark geography-specific health performance and SDG progress. Country-specific drivers of disease burden, particularly for causes with higher-than-expected DALYs, should inform financial and research investments, prevention efforts, health policies, and health system improvement initiatives for all countries along the development continuum. FUNDING Bill & Melinda Gates Foundation.

Human cytomegalovirus encodes an MHC class I-like molecule (UL142) that functions to inhibit NK cell lysis.
Clinical and low passage strains of human CMV (HCMV) encode an additional MHC class I-related molecule UL142, in addition to the previously described UL18. The UL142 open reading frame is encoded within the ULb' region which is missing from a number of common high passage laboratory strains. Cells expressing UL142 following transfection, and fibroblasts infected with a recombinant adenovirus-expressing UL142, were used to screen both polyclonal NK cells and NK cell clones, in a completely autologous system. Analysis of 100 NK cell clones derived from five donors, revealed 23 clones that were inhibited by fibroblasts expressing UL142 alone. Small-interfering RNA-mediated knockdown of UL142 mRNA expression in HCMV-infected cells resulted in increased sensitivity to lysis. From these data we conclude that UL142 is a novel HCMV-encoded MHC class I-related molecule which inhibits NK cell killing in a clonally dependent manner.

Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case-control study.
OBJECTIVE To examine whether past high sun exposure is associated with a reduced risk of multiple sclerosis. DESIGN Population based case-control study. SETTING Tasmania, latitudes 41-3 degrees S.   PARTICIPANTS 136 cases with multiple sclerosis and 272 controls randomly drawn from the community and matched on sex and year of birth. MAIN OUTCOME MEASURE Multiple sclerosis defined by both clinical and magnetic resonance imaging criteria. RESULTS Higher sun exposure when aged 6-15 years (average 2-3 hours or more a day in summer during weekends and holidays) was associated with a decreased risk of multiple sclerosis (adjusted odds ratio 0.31, 95% confidence interval 0.16 to 0.59). Higher exposure in winter seemed more important than higher exposure in summer. Greater actinic damage was also independently associated with a decreased risk of multiple sclerosis (0.32, 0.11 to 0.88 for grades 4-6 disease). A dose-response relation was observed between multiple sclerosis and decreasing sun exposure when aged 6-15 years and with actinic damage. CONCLUSION Higher sun exposure during childhood and early adolescence is associated with a reduced risk of multiple sclerosis. Insufficient ultraviolet radiation may therefore influence the development of multiple sclerosis.

BMP/SMAD1 signaling sets a threshold for the left/right pathway in lateral plate mesoderm and limits availability of SMAD4.
Bistability in developmental pathways refers to the generation of binary outputs from graded or noisy inputs. Signaling thresholds are critical for bistability. Specification of the left/right (LR) axis in vertebrate embryos involves bistable expression of transforming growth factor beta (TGFbeta) member NODAL in the left lateral plate mesoderm (LPM) controlled by feed-forward and feedback loops. Here we provide evidence that bone morphogenetic protein (BMP)/SMAD1 signaling sets a repressive threshold in the LPM essential for the integrity of LR signaling. Conditional deletion of Smad1 in the LPM led to precocious and bilateral pathway activation. NODAL expression from both the left and right sides of the node contributed to bilateral activation, indicating sensitivity of mutant LPM to noisy input from the LR system. In vitro, BMP signaling inhibited NODAL pathway activation and formation of its downstream SMAD2/4-FOXH1 transcriptional complex. Activity was restored by overexpression of SMAD4 and in embryos, elevated SMAD4 in the right LPM robustly activated LR gene expression, an effect reversed by superactivated BMP signaling. We conclude that BMP/SMAD1 signaling sets a bilateral, repressive threshold for NODAL-dependent Nodal activation in LPM, limiting availability of SMAD4. This repressive threshold is essential for bistable output of the LR system.

Expansion and deletion of CTG repeats from human disease genes are determined by the direction of replication in E. coli
Several human hereditary neurological and neurodegenerative disease genes are associated with the expansion of CTG repeats. Here we show that the frequency of genetic expansions or deletions in Escherichia coli depends on the direction of replication. Large expansions occur predominantly when the CTGs are in the leading strand template rather than the lagging strand. However, deletions are more prominant when the CTGs are in the opposite orientation. Most deletions generated products of defined size classes. Strand slippage coupled with non–classical DMA structures may account for these observations and relate to expansion–deletion mechanisms in eukaryotic chromosomes for disease genes.

Intimal smooth muscle cell proliferation after balloon catheter injury. The role of basic fibroblast growth factor.
The localization and synthesis of basic fibroblast growth factor (bFGF) in the rat carotid artery were investigated at times of chronic smooth muscle cell proliferation. Immunocytochemical staining showed the presence of bFGF in the uninjured arterial wall, and after balloon injury, this cellular staining was decreased. Western and northern blot analyses likewise showed that the amount of bFGF protein and mRNA decreased after injury. A neutralizing antibody to bFGF was administered 4 and 5 days after injury and was found to have no effect on intimal smooth muscle cell proliferation. These data suggest that an increase in the expression of bFGF is not necessary for chronic smooth muscle cell proliferation observed after balloon catheter injury and that bFGF is not the major mitogen responsible for intimal smooth muscle cell proliferation.

Air pollution and cardiovascular disease: a statement for healthcare professionals from the Expert Panel on Population and Prevention Science of the American Heart Association.
Air pollution is a heterogeneous, complex mixture of gases, liquids, and particulate matter. Epidemiological studies have demonstrated a consistent increased risk for cardiovascular events in relation to both short- and long-term exposure to present-day concentrations of ambient particulate matter. Several plausible mechanistic pathways have been described, including enhanced coagulation/thrombosis, a propensity for arrhythmias, acute arterial vasoconstriction, systemic inflammatory responses, and the chronic promotion of atherosclerosis. The purpose of this statement is to provide healthcare professionals and regulatory agencies with a comprehensive review of the literature on air pollution and cardiovascular disease. In addition, the implications of these findings in relation to public health and regulatory policies are addressed. Practical recommendations for healthcare providers and their patients are outlined. In the final section, suggestions for future research are made to address a number of remaining scientific questions.

Baby hands that move to the rhythm of language: hearing babies acquiring sign languages babble silently on the hands
The "ba, ba, ba" sound universal to babies' babbling around 7 months captures scientific attention because it provides insights into the mechanisms underlying language acquisition and vestiges of its evolutionary origins. Yet the prevailing mystery is what is the biological basis of babbling, with one hypothesis being that it is a non-linguistic motoric activity driven largely by the baby's emerging control over the mouth and jaw, and another being that it is a linguistic activity reflecting the babies' early sensitivity to specific phonetic-syllabic patterns. Two groups of hearing babies were studied over time (ages 6, 10, and 12 months), equal in all developmental respects except for the modality of language input (mouth versus hand): three hearing babies acquiring spoken language (group 1: "speech-exposed") and a rare group of three hearing babies acquiring sign language only, not speech (group 2: "sign-exposed"). Despite this latter group's exposure to sign, the motoric hypothesis would predict similar hand activity to that seen in speech-exposed hearing babies because language acquisition in sign-exposed babies does not involve the mouth. Using innovative quantitative Optotrak 3-D motion-tracking technology, applied here for the first time to study infant language acquisition, we obtained physical measurements similar to a speech spectrogram, but for the hands. Here we discovered that the specific rhythmic frequencies of the hands of the sign-exposed hearing babies differed depending on whether they were producing linguistic activity, which they produced at a low frequency of approximately 1 Hz, versus non-linguistic activity, which they produced at a higher frequency of approximately 2.5 Hz - the identical class of hand activity that the speech-exposed hearing babies produced nearly exclusively. Surprisingly, without benefit of the mouth, hearing sign-exposed babies alone babbled systematically on their hands. We conclude that babbling is fundamentally a linguistic activity and explain why the differentiation between linguistic and non-linguistic hand activity in a single manual modality (one distinct from the human mouth) could only have resulted if all babies are born with a sensitivity to specific rhythmic patterns at the heart of human language and the capacity to use them.

Instruction: Given a scientific claim, retrieve documents that support or refute the claim


Question: Pro-inflammatory cytokines are up repressed during tumor development.

Paraneoplastic thrombocytosis: the secrets of tumor self-promotion.
Paraneoplastic thrombocytosis is associated with many solid tumors and often correlates with reduced survival. Recent studies suggest that a pathogenic feed back loop may be operative between platelets and tumor cells, with reciprocal interactions between tumor growth/metastasis and thrombocytosis/platelet activation. Specific molecular pathways have been identified in which tumors can stimulate platelet production and activation; activated platelets can, in turn, promote tumor growth and metastasis. Taken together, these findings provide exciting new potential targets for therapeutic intervention.

N- and E-cadherins in Xenopus are specifically required in the neural and non-neural ectoderm, respectively, for F-actin assembly and morphogenetic movements.
Transmembrane cadherins are calcium-dependent intercellular adhesion molecules. Recently, they have also been shown to be sites of actin assembly during adhesive contact formation. However, the roles of actin assembly on transmembrane cadherins during development are not fully understood. We show here, using the developing ectoderm of the Xenopus embryo as a model, that F-actin assembly is a primary function of both N-cadherin in the neural ectoderm and E-cadherin in the non-neural (epidermal) ectoderm, and that each cadherin is essential for the characteristic morphogenetic movements of these two tissues. However, depletion of N-cadherin and E-cadherin did not cause dissociation in these tissues at the neurula stage, probably owing to the expression of C-cadherin in each tissue. Depletion of each of these cadherins is not rescued by the other, nor by the expression of C-cadherin, which is expressed in both tissues. One possible reason for this is that each cadherin is expressed in a different domain of the cell membrane. These data indicate the combinatorial nature of cadherin function, the fact that N- and E-cadherin play primary roles in F-actin assembly in addition to roles in cell adhesion, and that this function is specific to individual cadherins. They also show how cell adhesion and motility can be combined in morphogenetic tissue movements that generate the form and shape of the embryonic organs.

A psychometric evaluation of the Beck Depression Inventory–II.
This article provides psychometric information on the second edition of the Beck Depression Inventory (BDI-II; A. T. Beck, R. A. Steer, & G. K. Brown, 1996), with respect to internal consistency, factorial validity, and gender differences. Both measures demonstrated high internal reliability in the full student sample. Significant differences between the mean BDI and BDI-II scores necessitated the development of new cutoffs for analogue research on the BDI-II. Results from exploratory and confirmatory factor analyses indicated that a 2-factor solution optimally summarized the data for both versions of the inventory and accounted for a cumulative 41% and 46% of the common variance in BDI and BDI-II responses, respectively. These factor solutions were reliably cross-validated, although the importance of each factor varied by gender. The authors conclude that the BDI-II is a stronger instrument than the BDI in terms of its factor structure.

Fusion proteins for versatile antigen targeting to cell surface receptors reveal differential capacity to prime immune responses.
Targeting of proteins to APCs is an attractive strategy for eliciting adaptive immune responses. However, the relationship between the choice of the targeted receptor and the quality and quantity of responses remains poorly understood. We describe a strategy for expression of Ags including hydrophobic proteins as soluble fusion proteins that are optimized for proteasome-dependent MHC class I-restricted cross-presentation and form stable complexes with a wide variety of targeting Abs. Upon s.c. immunization, these complexes were initially taken up by CD169+ lymph node subcapsular sinus macrophages. In the OVA model system, receptor-targeted antigenic complexes primed specific T and B cell responses in vitro and in vivo at least 100-fold more efficiently than Ag alone. Comparison of 10 targeting receptors allowed us to establish a ranking with respect to priming of CD8+ T cell responses and demonstrated striking differences with respect to the relative efficacy of CD8+ and CD4+ T cell subset and B cell priming. The described fusion proteins should help in developing optimized strategies for targeted delivery of protein Ags in the context of tolerization or vaccination.

Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells.
Interleukin(IL)-2 and inflammation regulate effector and memory cytolytic T-lymphocyte (CTL) generation during infection. We demonstrate a complex interplay between IL-2 and inflammatory signals during CTL differentiation. IL-2 stimulation induced the transcription factor eomesodermin (Eomes), upregulated perforin (Prf1) transcription, and repressed re-expression of memory CTL markers Bcl6 and IL-7Ralpha. Binding of Eomes and STAT5 to Prf1 cis-regulatory regions correlated with transcriptional initiation (increased recruitment of RNA polymerase II to the Prf1 promoter). Inflammation (CpG, IL-12) enhanced expression of IL-2Ralpha and the transcription factor T-bet, but countered late Eomes and perforin induction while preventing IL-7Ralpha repression by IL-2. After infection of mice with lymphocytic choriomeningitis virus, IL-2Ralpha-deficient effector CD8(+) T cells expressed more Bcl6 but less perforin and granzyme B, formed fewer KLRG-1(+) and T-bet-expressing CTL, and killed poorly. Thus, inflammation influences both effector and memory CTL differentiation, whereas persistent IL-2 stimulation promotes effector at the expense of memory CTL development.

A library of yeast transcription factor motifs reveals a widespread function for Rsc3 in targeting nucleosome exclusion at promoters.
The sequence specificity of DNA-binding proteins is the primary mechanism by which the cell recognizes genomic features. Here, we describe systematic determination of yeast transcription factor DNA-binding specificities. We obtained binding specificities for 112 DNA-binding proteins representing 19 distinct structural classes. One-third of the binding specificities have not been previously reported. Several binding sequences have striking genomic distributions relative to transcription start sites, supporting their biological relevance and suggesting a role in promoter architecture. Among these are Rsc3 binding sequences, containing the core CGCG, which are found preferentially approximately 100 bp upstream of transcription start sites. Mutation of RSC3 results in a dramatic increase in nucleosome occupancy in hundreds of proximal promoters containing a Rsc3 binding element, but has little impact on promoters lacking Rsc3 binding sequences, indicating that Rsc3 plays a broad role in targeting nucleosome exclusion at yeast promoters.

Beta interferon controls West Nile virus infection and pathogenesis in mice.
Studies with mice lacking the common plasma membrane receptor for type I interferon (IFN-αβR(-)(/)(-)) have revealed that IFN signaling restricts tropism, dissemination, and lethality after infection with West Nile virus (WNV) or several other pathogenic viruses. However, the specific functions of individual IFN subtypes remain uncertain. Here, using IFN-β(-)(/)(-) mice, we defined the antiviral and immunomodulatory function of this IFN subtype in restricting viral infection. IFN-β(-)(/)(-) mice were more vulnerable to WNV infection than wild-type mice, succumbing more quickly and with greater overall mortality, although the phenotype was less severe than that of IFN-αβR(-)(/)(-) mice. The increased susceptibility of IFN-β(-)(/)(-) mice was accompanied by enhanced viral replication in different tissues. Consistent with a direct role for IFN-β in control of WNV replication, viral titers in ex vivo cultures of macrophages, dendritic cells, fibroblasts, and cerebellar granule cell neurons, but not cortical neurons, from IFN-β(-)(/)(-) mice were greater than in wild-type cells. Although detailed immunological analysis revealed no major deficits in the quality or quantity of WNV-specific antibodies or CD8(+) T cells, we observed an altered CD4(+) CD25(+) FoxP3(+) regulatory T cell response, with greater numbers after infection. Collectively, these results suggest that IFN-β controls WNV pathogenesis by restricting infection in key cell types and by modulating T cell regulatory networks.

Cell Stem Cell Article In Vivo Fate Analysis Reveals the Multipotent and Self-Renewal Capacities of Sox2 + Neural Stem Cells in the Adult Hippocampus
To characterize the properties of adult neural stem cells (NSCs), we generated and analyzed Sox2-GFP transgenic mice. Sox2-GFP cells in the subgranular zone (SGZ) express markers specific for progenitors, but they represent two morphologically distinct populations that differ in proliferation levels. Lentivirus- and retrovirus-mediated fate-tracing studies showed that Sox2+ cells in the SGZ have potential to give rise to neurons and astrocytes, revealing their multipotency at the population as well as at a single-cell level. A subpopulation of Sox2+ cells gives rise to cells that retain Sox2, highlighting Sox2+ cells as a primary source for adult NSCs. In response to mitotic signals, increased proliferation of Sox2+ cells is coupled with the generation of Sox2+ NSCs as well as neuronal precursors. An asymmetric contribution of Sox2+ NSCs may play an important role in maintaining the constant size of the NSC pool and producing newly born neurons during adult neurogenesis.

DIASPORA BONDS: TAPPING THE DIASPORA DURING DIFFICULT TIMES
India and Israel have raised over US$35 billion by tapping into the wealth of their diaspora communities. These diaspora bonds represent a stable and cheap source of external finance, often when countries lost access to international capital markets. For diaspora investors, these bonds offer the opportunity to help their country of origin while also providing an investment opportunity. The potential for diaspora bonds is significant for many countries with large diasporas abroad. However, diaspora bond issuance from countries with weak governance and high sovereign risk may require support for institutional capacity building and credit enhancement from multilateral or bilateral agencies. Haiti, for instance, could raise several hundred million dollars by issuing diaspora bonds provided a guarantee structure is created to build trust in the country's public institutions.

IFI16 and cGAS cooperate in the activation of STING during DNA sensing in human keratinocytes
Many human cells can sense the presence of exogenous DNA during infection though the cytosolic DNA receptor cyclic GMP-AMP synthase (cGAS), which produces the second messenger cyclic GMP-AMP (cGAMP). Other putative DNA receptors have been described, but whether their functions are redundant, tissue-specific or integrated in the cGAS-cGAMP pathway is unclear. Here we show that interferon-γ inducible protein 16 (IFI16) cooperates with cGAS during DNA sensing in human keratinocytes, as both cGAS and IFI16 are required for the full activation of an innate immune response to exogenous DNA and DNA viruses. IFI16 is also required for the cGAMP-induced activation of STING, and interacts with STING to promote STING phosphorylation and translocation. We propose that the two DNA sensors IFI16 and cGAS cooperate to prevent the spurious activation of the type I interferon response.

Prostaglandin E2 mediates sensory nerve regulation of bone homeostasis
Whether sensory nerve can sense bone density or metabolic activity to control bone homeostasis is unknown. Here we found prostaglandin E2 (PGE2) secreted by osteoblastic cells activates PGE2 receptor 4 (EP4) in sensory nerves to regulate bone formation by inhibiting sympathetic activity through the central nervous system. PGE2 secreted by osteoblasts increases when bone density decreases as demonstrated in osteoporotic animal models. Ablation of sensory nerves erodes the skeletal integrity. Specifically, knockout of the EP4 gene in the sensory nerves or cyclooxygenase-2 (COX2) in the osteoblastic cells significantly reduces bone volume in adult mice. Sympathetic tone is increased in sensory denervation models, and propranolol, a β2-adrenergic antagonist, rescues bone loss. Furthermore, injection of SW033291, a small molecule to increase PGE2 level locally, significantly boostes bone formation, whereas the effect is obstructed in EP4 knockout mice. Thus, we show that PGE2 mediates sensory nerve to control bone homeostasis and promote regeneration.

Instruction: Given a scientific claim, retrieve documents that support or refute the claim


Question: Progerin induces premature aging in stem cells.

Human iPSC-based modeling of late-onset disease via progerin-induced aging.
Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) resets their identity back to an embryonic age and, thus, presents a significant hurdle for modeling late-onset disorders. In this study, we describe a strategy for inducing aging-related features in human iPSC-derived lineages and apply it to the modeling of Parkinson's disease (PD). Our approach involves expression of progerin, a truncated form of lamin A associated with premature aging. We found that expression of progerin in iPSC-derived fibroblasts and neurons induces multiple aging-related markers and characteristics, including dopamine-specific phenotypes such as neuromelanin accumulation. Induced aging in PD iPSC-derived dopamine neurons revealed disease phenotypes that require both aging and genetic susceptibility, such as pronounced dendrite degeneration, progressive loss of tyrosine hydroxylase (TH) expression, and enlarged mitochondria or Lewy-body-precursor inclusions. Thus, our study suggests that progerin-induced aging can be used to reveal late-onset age-related disease features in hiPSC-based disease models.

GSK-3-mediated phosphorylation enhances Maf-transforming activity.
The Maf oncoproteins are b-Zip transcription factors of the AP-1 superfamily. They are involved in developmental, metabolic, and tumorigenic processes. Maf proteins are overexpressed in about 50% of human multiple myelomas. Here, we show that Maf-transforming activity is controlled by GSK-3-dependent phosphorylation and that phosphorylation by GSK-3 can increase the oncogenic activity of a protein. Using microarray analysis, we identify a gene-expression subprogram regulated by GSK-3-mediated Maf phosphorylation involved in extracellular matrix remodeling and relevant to cancer progression. We also demonstrate that GSK-3 triggers MafA sequential phosphorylation on residues S61, T57, T53, and S49, inducing its ubiquitination and degradation. Paradoxically, this phosphorylation increases MafA-transcriptional activity through the recruitment of the coactivator P/CAF. We further demonstrate that P/CAF protects MafA from ubiquitination and degradation, suggesting that, upon the release of the coactivator complex, MafA becomes polyubiquitinated and degraded to allow the response to terminate.

Serum high-density lipoprotein cholesterol, metabolic profile, and breast cancer risk.
BACKGROUND The prevalence of metabolic syndrome (obesity, glucose intolerance, low serum high-density lipoprotein cholesterol [HDL-C], high serum triglycerides, hypertension) is high and increasing in parallel with an increasing breast cancer incidence worldwide. HDL-C represents an important aspect of the syndrome, yet its role in breast cancer is still undefined. METHODS In two population-based screening surveys during 1977-1983 and 1985-1987, serum HDL-C was assayed enzymatically among 38,823 Norwegian women aged 17-54 years at entry. Height, weight, blood pressure, serum lipids, fat and energy intake, physical activity, parity, oral contraceptive use, hormone therapy use, alcohol intake, and tobacco use were also assessed. We used Cox proportional hazards modeling to estimate the relative risk (RR) of breast cancer associated with serum HDL-C levels and to adjust for potential confounding variables. We performed stratified analyses to evaluate effect modification by body mass index (BMI) and menopausal status. All statistical tests were two-sided. RESULTS During a median follow-up of 17.2 years, we identified 708 cases of invasive breast cancer. In multivariable analysis, the risk of postmenopausal breast cancer was inversely related to quartile of HDL-C (P(trend) =.02). Among women with HDL-C above 1.64 mmol/L (highest quartile) versus below 1.20 mmol/L (lowest quartile), the relative risk was 0.75 (95% confidence interval [CI] = 0.58 to 0.97). The HDL-C association was confined to women in the heavier subgroup (BMI > or =25 kg/m2), for whom the relative risk of postmenopausal breast cancer in those with HDL-C above 1.64 mmol/L versus below 1.20 mmol/L was 0.43 (95% CI = 0.28 to 0.67; P(trend)<.001; P(interaction) =.001). CONCLUSION Low HDL-C, as part of the metabolic syndrome, is associated with increased postmenopausal breast cancer risk.

Predominance of Type 1 Innate Lymphoid Cells in the Rectal Mucosa of Patients With Non-Celiac Wheat Sensitivity: Reversal After a Wheat-Free Diet
OBJECTIVES Non-celiac wheat sensitivity (NCWS) is defined as a reaction to ingested wheat after exclusion of celiac disease and wheat allergy. As its pathogenesis is incompletely understood, we evaluated the inflammatory response in the rectal mucosa of patients with well-defined NCWS. METHODS The prospective study included 22 patients with irritable bowel syndrome (IBS)-like clinical presentation, diagnosed with NCWS by double-blind placebo-controlled challenge. Eight IBS patients not improving on wheat-free diet were used as controls. Two weeks after oral challenge was performed with 80 grams of wheat daily, cells were isolated from rectal biopsies and thoroughly characterized by fluorescence-activated cell sorting analysis for intracellular cytokines and surface markers. RESULTS Rectal biopsies from wheat-challenged NCWS patients showed that a significant mucosal CD45(+) infiltrate consisted of CD3(+) and CD3(-) lymphocytes, with the latter spontaneously producing more interferon (IFN)-γ than IBS controls. About 30% of IFN-γ-producing CD45(+) cells were T-bet(+), CD56(-), NKP44(-), and CD117(-), defining them as a type-1 innate lymphoid cells (ILC1). IFN-γ-producing ILC1 cells significantly decreased in 10 patients analyzed 2 weeks after they resumed a wheat-free diet. CONCLUSIONS These data indicate that, in patients with active NCWS, IFN-γ-producing ILC1 cells infiltrate rectal mucosa and support a role for this innate lymphoid cell population in the pathogenesis of NCWS.

The pecking order of free radicals and antioxidants: lipid peroxidation, alpha-tocopherol, and ascorbate.
Free radicals vary widely in their thermodynamic properties, ranging from very oxidizing to very reducing. These thermodynamic properties can be used to predict a pecking order, or hierarchy, for free radical reactions. Using one-electron reduction potentials, the predicted pecking order is in agreement with experimentally observed free radical electron (hydrogen atom) transfer reactions. These potentials are also in agreement with experimental data that suggest that vitamin E, the primary lipid soluble small molecule antioxidant, and vitamin C, the terminal water soluble small molecule antioxidant, cooperate to protect lipids and lipid structures against peroxidation. Although vitamin E is located in membranes and vitamin C is located in aqueous phases, vitamin C is able to recycle vitamin E; i.e., vitamin C repairs the tocopheroxyl (chromanoxyl) radical of vitamin E, thereby permitting vitamin E to function again as a free radical chain-breaking antioxidant. This review discusses: (i) the thermodynamics of free radical reactions that are of interest to the health sciences; (ii) the fundamental thermodynamic and kinetic properties that are associated with chain-breaking antioxidants; (iii) the unique interfacial nature of the apparent reaction of the tocopherol free radical (vitamin E radical) and vitamin C; and (iv) presents a hierarchy, or pecking order, for free radical electron (hydrogen atom) transfer reactions.

The curious case of the tumour virus: 50 years of Burkitt's lymphoma
Burkitt's lymphoma (BL) was first described 50 years ago, and the first human tumour virus Epstein–Barr virus (EBV) was discovered in BL tumours soon after. Since then, the role of EBV in the development of BL has become more and more enigmatic. Only recently have we finally begun to understand, at the cellular and molecular levels, the complex and interesting interaction of EBV with B cells that creates a predisposition for the development of BL. Here, we discuss the intertwined histories of EBV and BL and their relationship to the cofactors in BL pathogenesis: malaria and the MYC translocation.

Single-Cell RNA-Seq Reveals Dynamic, Random Monoallelic Gene Expression in Mammalian Cells
Expression from both alleles is generally observed in analyses of diploid cell populations, but studies addressing allelic expression patterns genome-wide in single cells are lacking. Here, we present global analyses of allelic expression across individual cells of mouse preimplantation embryos of mixed background (CAST/EiJ × C57BL/6J). We discovered abundant (12 to 24%) monoallelic expression of autosomal genes and that expression of the two alleles occurs independently. The monoallelic expression appeared random and dynamic because there was considerable variation among closely related embryonic cells. Similar patterns of monoallelic expression were observed in mature cells. Our allelic expression analysis also demonstrates the de novo inactivation of the paternal X chromosome. We conclude that independent and stochastic allelic transcription generates abundant random monoallelic expression in the mammalian cell.

The First Myriapod Genome Sequence Reveals Conservative Arthropod Gene Content and Genome Organisation in the Centipede Strigamia maritima
Myriapods (e.g., centipedes and millipedes) display a simple homonomous body plan relative to other arthropods. All members of the class are terrestrial, but they attained terrestriality independently of insects. Myriapoda is the only arthropod class not represented by a sequenced genome. We present an analysis of the genome of the centipede Strigamia maritima. It retains a compact genome that has undergone less gene loss and shuffling than previously sequenced arthropods, and many orthologues of genes conserved from the bilaterian ancestor that have been lost in insects. Our analysis locates many genes in conserved macro-synteny contexts, and many small-scale examples of gene clustering. We describe several examples where S. maritima shows different solutions from insects to similar problems. The insect olfactory receptor gene family is absent from S. maritima, and olfaction in air is likely effected by expansion of other receptor gene families. For some genes S. maritima has evolved paralogues to generate coding sequence diversity, where insects use alternate splicing. This is most striking for the Dscam gene, which in Drosophila generates more than 100,000 alternate splice forms, but in S. maritima is encoded by over 100 paralogues. We see an intriguing linkage between the absence of any known photosensory proteins in a blind organism and the additional absence of canonical circadian clock genes. The phylogenetic position of myriapods allows us to identify where in arthropod phylogeny several particular molecular mechanisms and traits emerged. For example, we conclude that juvenile hormone signalling evolved with the emergence of the exoskeleton in the arthropods and that RR-1 containing cuticle proteins evolved in the lineage leading to Mandibulata. We also identify when various gene expansions and losses occurred. The genome of S. maritima offers us a unique glimpse into the ancestral arthropod genome, while also displaying many adaptations to its specific life history.

Pharmacological Blockade of ASCT2-dependent Glutamine Transport Leads To Anti-tumor Efficacy in Preclinical Models
The unique metabolic demands of cancer cells underscore potentially fruitful opportunities for drug discovery in the era of precision medicine. However, therapeutic targeting of cancer metabolism has led to surprisingly few new drugs to date. The neutral amino acid glutamine serves as a key intermediate in numerous metabolic processes leveraged by cancer cells, including biosynthesis, cell signaling, and oxidative protection. Herein we report the preclinical development of V-9302, a competitive small molecule antagonist of transmembrane glutamine flux that selectively and potently targets the amino acid transporter ASCT2. Pharmacological blockade of ASCT2 with V-9302 resulted in attenuated cancer cell growth and proliferation, increased cell death, and increased oxidative stress, which collectively contributed to antitumor responses in vitro and in vivo. This is the first study, to our knowledge, to demonstrate the utility of a pharmacological inhibitor of glutamine transport in oncology, representing a new class of targeted therapy and laying a framework for paradigm-shifting therapies targeting cancer cell metabolism.

Ultrarapid drug metabolism: PCR-based detection of CYP2D6 gene duplication.
The enzyme debrisoquine 4-hydroxylase (CYP2D6), which metabolizes many widely used drugs, is highly polymorphic. The activity of the enzyme ranges between subjects from ultrafast to a complete absence. Therefore, metabolic capacity varies, producing intersubject differences in therapeutic efficacy and side effects at standard recommended doses. Up to 7% of Caucasians may demonstrate ultrarapid drug metabolism (UM) because of inherited alleles with multiplicate functional CYP2D6 genes, causing an increased amount of enzyme to be expressed. Identification of UM subjects is of potential clinical importance for adjustment of doses in drug therapy, as well as to avoid misidentification of noncompliance. In our study, we tested recently designed PCR assays for the detection of the UM genotype. We found a 3.5% prevalence of UMs carrying duplicate active CYP2D6 genes in a population consisting of 202 psychiatric patients.

Angiogenesis therapy: amidst the hype, the neglected potential for serious side effects.
Although essentially unknown as a therapeutic concept as recently as a decade ago, it is difficult now to open a cardiology journal, attend a cardiology meeting, or scan a newspaper without being caught up in the excitement generated by the thought that angiogenesis therapy may soon have a major impact on the treatment of patients with atherosclerotic lesions obstructing arteries that supply the myocardium or legs. Potent therapeutic interventions, however, are rarely free of at least the potential for causing harmful effects. Angiogenesis therapy is no exception. Despite this and despite the fact that the only reasonably powered, randomized, double-blind clinical studies to date have failed to demonstrate primary end-point efficacy,1 thoughtful consideration of the serious side effects that might accompany any therapeutic benefit has been largely missing from scientific communications. For the lay media, a switch from this unbounded enthusiasm to profound skepticism occurred recently after a report of the tragic death of a young man caused by injection of large amounts of an adenoviral vector into the hepatic artery (unrelated to angiogenesis therapy).2 For the scientific community, however, there has been a general lack of in-depth discussion of the potential dangers inherent in angiogenesis interventions. Such a discussion is appropriate not only because of the event cited above but also because considerable mechanistic data are available that actually permit us to identify specific side effects that we might anticipate as potential complications of angiogenesis therapy. The following therefore is a discussion of potential complications based predominantly on our knowledge of the underlying biological activities of 2 of the most potent angiogenic cytokines, vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). Angiogenic agents are thought to have the potential to induce neovascularization in many different tissues. This becomes important in that under clinical circumstances it …

Instruction: Given a scientific claim, retrieve documents that support or refute the claim


Question: Propriospinal interneurons that play a role in the plastic reorganization of spinal circuits are integral for recovery from spinal cord injury.

Recovery of supraspinal control of stepping via indirect propriospinal relay connections after spinal cord injury
Spinal cord injuries (SCIs) in humans and experimental animals are often associated with varying degrees of spontaneous functional recovery during the first months after injury. Such recovery is widely attributed to axons spared from injury that descend from the brain and bypass incomplete lesions, but its mechanisms are uncertain. To investigate the neural basis of spontaneous recovery, we used kinematic, physiological and anatomical analyses to evaluate mice with various combinations of spatially and temporally separated lateral hemisections with or without the excitotoxic ablation of intrinsic spinal cord neurons. We show that propriospinal relay connections that bypass one or more injury sites are able to mediate spontaneous functional recovery and supraspinal control of stepping, even when there has been essentially total and irreversible interruption of long descending supraspinal pathways in mice. Our findings show that pronounced functional recovery can occur after severe SCI without the maintenance or regeneration of direct projections from the brain past the lesion and can be mediated by the reorganization of descending and propriospinal connections. Targeting interventions toward augmenting the remodeling of relay connections may provide new therapeutic strategies to bypass lesions and restore function after SCI and in other conditions such as stroke and multiple sclerosis.

Crizotinib in ROS1-rearranged non-small-cell lung cancer.
BACKGROUND Chromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase (ROS1) define a distinct molecular subgroup of non-small-cell lung cancers (NSCLCs) that may be susceptible to therapeutic ROS1 kinase inhibition. Crizotinib is a small-molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and another proto-oncogene receptor tyrosine kinase, MET. METHODS We enrolled 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement in an expansion cohort of the phase 1 study of crizotinib. Patients were treated with crizotinib at the standard oral dose of 250 mg twice daily and assessed for safety, pharmacokinetics, and response to therapy. ROS1 fusion partners were identified with the use of next-generation sequencing or reverse-transcriptase-polymerase-chain-reaction assays. RESULTS The objective response rate was 72% (95% confidence interval [CI], 58 to 84), with 3 complete responses and 33 partial responses. The median duration of response was 17.6 months (95% CI, 14.5 to not reached). Median progression-free survival was 19.2 months (95% CI, 14.4 to not reached), with 25 patients (50%) still in follow-up for progression. Among 30 tumors that were tested, we identified 7 ROS1 fusion partners: 5 known and 2 novel partner genes. No correlation was observed between the type of ROS1 rearrangement and the clinical response to crizotinib. The safety profile of crizotinib was similar to that seen in patients with ALK-rearranged NSCLC. CONCLUSIONS In this study, crizotinib showed marked antitumor activity in patients with advanced ROS1-rearranged NSCLC. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).

Macrophages in the Pathogenesis of Atherosclerosis
In atherosclerosis, the accumulation of apolipoprotein B-lipoproteins in the matrix beneath the endothelial cell layer of blood vessels leads to the recruitment of monocytes, the cells of the immune system that give rise to macrophages and dendritic cells. Macrophages derived from these recruited monocytes participate in a maladaptive, nonresolving inflammatory response that expands the subendothelial layer due to the accumulation of cells, lipid, and matrix. Some lesions subsequently form a necrotic core, triggering acute thrombotic vascular disease, including myocardial infarction, stroke, and sudden cardiac death. This Review discusses the central roles of macrophages in each of these stages of disease pathogenesis.

Identification of genes associated with the astrocyte-specific gene Gfap during astrocyte differentiation.
Chromosomes and genes are non-randomly arranged within the mammalian cell nucleus, and gene clustering is of great significance in transcriptional regulation. However, the relevance of gene clustering and their expression during the differentiation of neural precursor cells (NPCs) into astrocytes remains unclear. We performed a genome-wide enhanced circular chromosomal conformation capture (e4C) to screen for genes associated with the astrocyte-specific gene glial fibrillary acidic protein (Gfap) during astrocyte differentiation. We identified 18 genes that were specifically associated with Gfap and expressed in NPC-derived astrocytes. Our results provide additional evidence for the functional significance of gene clustering in transcriptional regulation during NPC differentiation.

Accuracy of weighed dietary records in studies of diet and health.
OBJECTIVE To provide an independent evaluation of seven day weighed dietary records, which are currently accepted as the most accurate technique for assessing habitual dietary intake in studies investigating the links between diet and health. DESIGN Subjects who had previously participated in the Northern Ireland diet and health study were reselected by stratified random sampling to represent the range of energy intakes in the study as assessed by the seven day weighed dietary record. SETTING Northern Ireland. SUBJECTS 31 Free living adults (16 men and 15 women). MAIN OUTCOME MEASURES Energy intake as measured by the seven day weighed dietary record and total energy expenditure estimated concurrently by the doubly labelled water technique. RESULTS Average recorded energy intakes were significantly lower than measured expenditure in the group overall (9.66 MJ/day v 12.15 MJ/day, 95% confidence interval 1.45 to 3.53 MJ/day). Among those in the upper third of energy intakes the mean (SE) ratio of intake to expenditure was close to 1.0, indicating accurate records (men 1.01 (0.11), women 0.96 (0.08]. In the middle and lower thirds the ratios for men were only 0.74 (0.05) and 0.70 (0.07) respectively and for women 0.89 (0.07) and 0.61 (0.07). CONCLUSIONS These results show a serious bias in reporting habitual energy intake. If substantiated they may have wide implications for the interpretation of many nutritional studies.

Key role of Ubc5 and lysine-63 polyubiquitination in viral activation of IRF3.
The mitochondrial antiviral signaling protein (MAVS; also known as IPS-1, VISA, and CARDIF) is essential for innate immune response against RNA viruses. MAVS transduces signals from the cytosolic RIG-I-like receptors, which bind to viral RNAs. But how MAVS activates downstream transcription factors such as IRF3 to induce type-I interferons is not well understood. We have established a cell-free system in which mitochondria derived from virus-infected cells activate IRF3 in the cytosol. Fractionation of the cytosol led to the identification of Ubc5 as a ubiquitin-conjugating enzyme (E2) required for IRF3 activation. Using an inducible RNAi strategy, we demonstrate that catalytically active Ubc5 is required for IRF3 activation by viral infection. The activation of IRF3 also requires two ubiquitin-binding domains of NEMO. Furthermore, we show that replacement of endogenous ubiquitin with its K63R mutant abolishes viral activation of IRF3, demonstrating that K63 polyubiquitination plays a key role in IRF3 activation.

Outcome of repeated radiosurgery for recurrent metastatic brain tumors.
OBJECTIVE We investigated the outcome of repeated gamma knife radiosurgery (GKS) for local or remote recurrence after initial radiosurgery. MATERIAL AND METHODS We retrospectively reviewed 204 patients who were treated with GKS. Among them 43 patients (21%) underwent GKS more than once. The second GKS was given for recurrence at the previously treated sites in 16 patients, new lesions at remote sites in 13, and both local recurrence and new lesions in 14. RESULTS The median survival from the first GKS was 36 (7-190) weeks in all patients and 68 (16-156) weeks in 43 patients with repeated GKS. The median time from the first GKS to the second was 37 weeks. The median survival from the second radiosurgical intervention was 32 (7-132) weeks. Local control rate at 6 months after salvage GKS was 90.7%. RPA class was the commonly dominant prognostic factor in both initial and salvage GKS. CONCLUSION Recurrence is common for patients with metastatic brain tumors after initial radiosurgery. Local control and survival time after salvage treatment are comparable with those after initial radiosurgery. GKS as a salvage treatment may provide additional survival benefit in selected patients.

Feasibility assessment of desalination application in Australian traditional agriculture
Abstract Within some data limitations, the paper provides a first assessment of areas in Australia with potential for implementing desalination technologies to supply agricultural water. At the national scale, these areas were identified based on a set of selected criteria: distance from land currently used for irrigated agriculture and feedlots; distance from town sites; exclusion of areas of environmental protection; exclusion of areas with surface elevation greater than 600 m AHD; and exclusion of regions with limited groundwater resources. Industries involved in the production of high-value crops are most likely to benefit from desalinated water as they use more-efficient irrigation practices and have the highest gross value of irrigated agricultural production. Groundwater was identified as the most likely feedwater source for cost-effective desalination, which is also the case worldwide. Brine disposal is a major factor in overall cost effectiveness of desalination. When feedwater salinity is relatively low, mixing permeate with feedwater leads to an increase in water production and a reduction in water cost. It was estimated that Australian farmers are unlikely to pay more than AU$1.2/kL for agricultural water. Generally for agriculture, desalinated water is still more expensive than water from other sources; however, there are likely to be circumstances when the costs could be comparable.

Gene targeting using zinc finger nucleases
The ability to achieve site-specific manipulation of the mammalian genome has widespread implications for basic and applied research. Gene targeting is a process in which a DNA molecule introduced into a cell replaces the corresponding chromosomal segment by homologous recombination, and thus presents a precise way to manipulate the genome. In the past, the application of gene targeting to mammalian cells has been limited by its low efficiency. Zinc finger nucleases (ZFNs) show promise in improving the efficiency of gene targeting by introducing DNA double-strand breaks in target genes, which then stimulate the cell's endogenous homologous recombination machinery. Recent results have shown that ZFNs can be used to create targeting frequencies of up to 20% in a human disease-causing gene. Future work will be needed to translate these in vitro findings to in vivo applications and to determine whether zinc finger nucleases create undesired genomic instability.

Mutant SOD1 inhibits ER-Golgi transport in amyotrophic lateral sclerosis.
Cu/Zn-superoxide dismutase is misfolded in familial and sporadic amyotrophic lateral sclerosis, but it is not clear how this triggers endoplasmic reticulum (ER) stress or other pathogenic processes. Here, we demonstrate that mutant SOD1 (mSOD1) is predominantly found in the cytoplasm in neuronal cells. Furthermore, we show that mSOD1 inhibits secretory protein transport from the ER to Golgi apparatus. ER-Golgi transport is linked to ER stress, Golgi fragmentation and axonal transport and we also show that inhibition of ER-Golgi trafficking preceded ER stress, Golgi fragmentation, protein aggregation and apoptosis in cells expressing mSOD1. Restoration of ER-Golgi transport by over-expression of coatomer coat protein II subunit Sar1 protected against inclusion formation and apoptosis, thus linking dysfunction in ER-Golgi transport to cellular pathology. These findings thus link several cellular events in amyotrophic lateral sclerosis into a single mechanism occurring early in mSOD1 expressing cells.

Thirty-One Novel Biomarkers as Predictors for Clinically Incident Diabetes
BACKGROUND The prevalence of diabetes is increasing in all industrialized countries and its prevention has become a public health priority. However, the predictors of diabetes risk are insufficiently understood. We evaluated, whether 31 novel biomarkers could help to predict the risk of incident diabetes. METHODS AND FINDINGS The biomarkers were evaluated primarily in the FINRISK97 cohort (n = 7,827; 417 cases of clinically incident diabetes during the follow-up). The findings were replicated in the Health 2000 cohort (n = 4,977; 179 cases of clinically incident diabetes during the follow-up). We used Cox proportional hazards models to calculate the relative risk of diabetes, after adjusting for the classic risk factors, separately for each biomarker. Next, we assessed the discriminatory ability of single biomarkers using receiver operating characteristic curves and C-statistics, integrated discrimination improvement (IDI) and net reclassification improvement (NRI). Finally, we derived a biomarker score in the FINRISK97 cohort and validated it in the Health 2000 cohort. A score consisting of adiponectin, apolipoprotein B, C-reactive protein and ferritin almost doubled the relative risk of diabetes in the validation cohort (HR per one standard deviation increase 1.88, p = 2.8 e-5). It also improved discrimination of the model (IDI = 0.0149, p<0.0001) and reclassification of diabetes risk (NRI = 11.8%, p = 0.006). Gender-specific analyses suggested that the best score differed between men and women. Among men, the best results were obtained with the score of four biomarkers: adiponectin, apolipoprotein B, ferritin and interleukin-1 receptor antagonist, which gave an NRI of 25.4% (p<0.0001). Among women, the best score included adiponectin, apolipoprotein B, C-reactive protein and insulin. It gave an NRI of 13.6% (p = 0.041). CONCLUSIONS We identified novel biomarkers that were associated with the risk of clinically incident diabetes over and above the classic risk factors. This gives new insights into the pathogenesis of diabetes and may help with targeting prevention and treatment.

Instruction: Given a scientific claim, retrieve documents that support or refute the claim


Question: Pseudogene PTENP1 encodes a transcript that regulates PTEN expression.

A coding-independent function of gene and pseudogene mRNAs regulates tumour biology
The canonical role of messenger RNA (mRNA) is to deliver protein-coding information to sites of protein synthesis. However, given that microRNAs bind to RNAs, we hypothesized that RNAs could possess a regulatory role that relies on their ability to compete for microRNA binding, independently of their protein-coding function. As a model for the protein-coding-independent role of RNAs, we describe the functional relationship between the mRNAs produced by the PTEN tumour suppressor gene and its pseudogene PTENP1 and the critical consequences of this interaction. We find that PTENP1 is biologically active as it can regulate cellular levels of PTEN and exert a growth-suppressive role. We also show that the PTENP1 locus is selectively lost in human cancer. We extended our analysis to other cancer-related genes that possess pseudogenes, such as oncogenic KRAS. We also demonstrate that the transcripts of protein-coding genes such as PTEN are biologically active. These findings attribute a novel biological role to expressed pseudogenes, as they can regulate coding gene expression, and reveal a non-coding function for mRNAs.

Modulation of cellular and viral promoters by mutant human p53 proteins found in tumor cells.
Wild-type p53 has recently been shown to repress transcription from several cellular and viral promoters. Since p53 mutations are the most frequently reported genetic defects in human cancers, it becomes important to study the effects of mutations of p53 on promoter functions. We, therefore, have studied the effects of wild-type and mutant human p53 on the human proliferating-cell nuclear antigen (PCNA) promoter and on several viral promoters, including the herpes simplex virus type 1 UL9 promoter, the human cytomegalovirus major immediate-early promoter-enhancer, and the long terminal repeat promoters of Rous sarcoma virus and human T-cell lymphotropic virus type I. HeLa cells were cotransfected with a wild-type or mutant p53 expression vector and a plasmid containing a chloramphenicol acetyltransferase reporter gene under viral (or cellular) promoter control. As expected, expression of the wild-type p53 inhibited promoter function. Expression of a p53 with a mutation at any one of the four amino acid positions 175, 248, 273, or 281, however, correlated with a significant increase of the PCNA promoter activity (2- to 11-fold). The viral promoters were also activated, although to a somewhat lesser extent. We also showed that activation by a mutant p53 requires a minimal promoter containing a lone TATA box. A more significant increase (25-fold) in activation occurs when the promoter contains a binding site for the activating transcription factor or cyclic AMP response element-binding protein. Using Saos-2 cells that do not express p53, we showed that activation by a mutant p53 was a direct enhancement. The mutant forms of p53 used in this study are found in various cancer cells. The activation of PCNA by mutant p53s may indicate a way to increase cell proliferation by the mutant p53s. Thus, our data indicate a possible functional role for the mutants of p53 found in cancer cells in activating several important loci, including PCNA.

Inhibition of limb regeneration in the axolotl after treatment of the skin with actinomycin D.
In this experiment actinomycin D was used to explore the action of the wound epidermis on underlying tissues during limb regeneration. In axolotl forelimbs the skin was removed from the elbow to the shoulder. Skin from the right limbs was soaked for three hours in actinomycin D (5.0 or 10.0 μg/ml 0.6% NaCl). For controls, skin from left limbs was soaked in 0.6% NaCl for the same period of time. Each piece of skin was orthotopically replanted, and both limbs were amputated through the treated skin, proximal to the elbow. After an initial healing period, the control limbs regenerated normally. Except for a slightly paler color, limbs bearing actinomycin-treated skin were indistinguishable from the controls, both grossly and histologically, during the first week following amputation. While the control limbs formed early blastemas, no grossly visible evidence of regeneration was apparent in the experimental limbs, but histologically some dedifferentiation was occurring. Normally three to four digits were seen in the control regenerates before blastemas appeared on the experimental limbs. By 35–40 days blastemas had appeared on most experimental limbs. These developed very rapidly, and within a short time many of them had attained levels of development close to the controls. Actinomycin D temporarily suppresses formation of the apical epidermal cap and the subsequent aggregation of dedifferentiated cells into a blastema. When the effect wears off, an apical cap forms and the dedifferentiated cells quickly organize into a blastema and begin to differentiate.

KLF1-null neonates display hydrops fetalis and a deranged erythroid transcriptome.
We describe a case of severe neonatal anemia with kernicterus caused by compound heterozygosity for null mutations in KLF1, each inherited from asymptomatic parents. One of the mutations is novel. This is the first described case of a KLF1-null human. The phenotype of severe nonspherocytic hemolytic anemia, jaundice, hepatosplenomegaly, and marked erythroblastosis is more severe than that present in congenital dyserythropoietic anemia type IV as a result of dominant mutations in the second zinc-finger of KLF1. There was a very high level of HbF expression into childhood (>70%), consistent with a key role for KLF1 in human hemoglobin switching. We performed RNA-seq on circulating erythroblasts and found that human KLF1 acts like mouse Klf1 to coordinate expression of many genes required to build a red cell including those encoding globins, cytoskeletal components, AHSP, heme synthesis enzymes, cell-cycle regulators, and blood group antigens. We identify novel KLF1 target genes including KIF23 and KIF11 which are required for proper cytokinesis. We also identify new roles for KLF1 in autophagy, global transcriptional control, and RNA splicing. We suggest loss of KLF1 should be considered in otherwise unexplained cases of severe neonatal NSHA or hydrops fetalis.

An actomyosin-based barrier inhibits cell mixing at compartmental boundaries in Drosophila embryos
Partitioning tissues into compartments that do not intermix is essential for the correct morphogenesis of animal embryos and organs. Several hypotheses have been proposed to explain compartmental cell sorting, mainly differential adhesion, but also regulation of the cytoskeleton or of cell proliferation. Nevertheless, the molecular and cellular mechanisms that keep cells apart at boundaries remain unclear. Here we demonstrate, in early Drosophila melanogaster embryos, that actomyosin-based barriers stop cells from invading neighbouring compartments. Our analysis shows that cells can transiently invade neighbouring compartments, especially when they divide, but are then pushed back into their compartment of origin. Actomyosin cytoskeletal components are enriched at compartmental boundaries, forming cable-like structures when the epidermis is mitotically active. When MyoII (non-muscle myosin II) function is inhibited, including locally at the cable by chromophore-assisted laser inactivation (CALI), in live embryos, dividing cells are no longer pushed back, leading to compartmental cell mixing. We propose that local regulation of actomyosin contractibility, rather than differential adhesion, is the primary mechanism sorting cells at compartmental boundaries.

Reprogramming of human fibroblasts to pluripotency with lineage specifiers.
Since the initial discovery that OCT4, SOX2, KLF4, and c-MYC overexpression sufficed for the induction of pluripotency in somatic cells, methodologies replacing the original factors have enhanced our understanding of the reprogramming process. However, unlike in mouse, OCT4 has not been replaced successfully during reprogramming of human cells. Here we report on a strategy to accomplish this replacement. Through a combination of transcriptome and bioinformatic analysis we have identified factors previously characterized as being lineage specifiers that are able to replace OCT4 and SOX2 in the reprogramming of human fibroblasts. Our results show that it is possible to replace OCT4 and SOX2 simultaneously with alternative lineage specifiers in the reprogramming of human cells. At a broader level, they also support a model in which counteracting lineage specification networks underlies the induction of pluripotency.

Developmental Analysis of Bone Marrow Neutrophils Reveals Populations Specialized in Expansion, Trafficking, and Effector Functions
Summary Neutrophils are specialized innate cells that require constant replenishment from proliferative bone marrow (BM) precursors as a result of their short half‐life. Although it is established that neutrophils are derived from the granulocyte‐macrophage progenitor (GMP), the differentiation pathways from GMP to functional mature neutrophils are poorly defined. Using mass cytometry (CyTOF) and cell‐cycle‐based analysis, we identified three neutrophil subsets within the BM: a committed proliferative neutrophil precursor (preNeu) which differentiates into non‐proliferating immature neutrophils and mature neutrophils. Transcriptomic profiling and functional analysis revealed that preNeu require the C/EBP&egr; transcription factor for their generation from the GMP, and their proliferative program is substituted by a gain of migratory and effector function as they mature. preNeus expand under microbial and tumoral stress, and immature neutrophils are recruited to the periphery of tumor‐bearing mice. In summary, our study identifies specialized BM granulocytic populations that ensure supply under homeostasis and stress responses. Graphical Abstract Figure. No Caption available. HighlightsProliferation activity identifies committed neutrophil precursor in mice and humansNeutrophil subsets possess distinct transcriptomic and functional signaturesDefect in neutrophil development leads to impaired neutrophil‐mediated responsesIncreased circulating immature neutrophils are associated with cancer progression &NA; The neutrophil differentiation pathway is poorly defined. Evrard et. al. demonstrate a workflow of characterizing bone marrow neutrophil subsets on the basis of their proliferative capacity and molecular signatures and thereby define the developmental trajectory and functional properties of neutrophils.

Mesenchymal Inflammation Drives Genotoxic Stress in Hematopoietic Stem Cells and Predicts Disease Evolution in Human Pre-leukemia.
Mesenchymal niche cells may drive tissue failure and malignant transformation in the hematopoietic system, but the underlying molecular mechanisms and relevance to human disease remain poorly defined. Here, we show that perturbation of mesenchymal cells in a mouse model of the pre-leukemic disorder Shwachman-Diamond syndrome (SDS) induces mitochondrial dysfunction, oxidative stress, and activation of DNA damage responses in hematopoietic stem and progenitor cells. Massive parallel RNA sequencing of highly purified mesenchymal cells in the SDS mouse model and a range of human pre-leukemic syndromes identified p53-S100A8/9-TLR inflammatory signaling as a common driving mechanism of genotoxic stress. Transcriptional activation of this signaling axis in the mesenchymal niche predicted leukemic evolution and progression-free survival in myelodysplastic syndrome (MDS), the principal leukemia predisposition syndrome. Collectively, our findings identify mesenchymal niche-induced genotoxic stress in heterotypic stem and progenitor cells through inflammatory signaling as a targetable determinant of disease outcome in human pre-leukemia.

CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis.
Cancer stem cells drive tumor formation and metastasis, but how they acquire metastatic traits is not well understood. Here, we show that all colorectal cancer stem cells (CR-CSCs) express CD44v6, which is required for their migration and generation of metastatic tumors. CD44v6 expression is low in primary tumors but demarcated clonogenic CR-CSC populations. Cytokines hepatocyte growth factor (HGF), osteopontin (OPN), and stromal-derived factor 1α (SDF-1), secreted from tumor associated cells, increase CD44v6 expression in CR-CSCs by activating the Wnt/β-catenin pathway, which promotes migration and metastasis. CD44v6(-) progenitor cells do not give rise to metastatic lesions but, when treated with cytokines, acquire CD44v6 expression and metastatic capacity. Importantly, phosphatidylinositol 3-kinase (PI3K) inhibition selectively killed CD44v6 CR-CSCs and reduced metastatic growth. In patient cohorts, low levels of CD44v6 predict increased probability of survival. Thus, the metastatic process in colorectal cancer is initiated by CSCs through the expression of CD44v6, which is both a functional biomarker and therapeutic target.

Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections.
Health professionals and the public need to understand the natural history of human papillomavirus (HPV) infections of the cervix to best use the information provided by new molecular screening tests. We investigated outcomes of 800 carcinogenic HPV infections detected in 599 women at enrollment into a population-based cohort (Guanacaste, Costa Rica). For individual infections, we calculated cumulative proportions of three outcomes (viral clearance, persistence without cervical intraepithelial neoplasia grade 2 or worse [CIN2+], or persistence with new diagnosis of CIN2+) at successive 6-month time points for the first 30 months of follow-up. Cervical specimens were tested for carcinogenic HPV genotypes using an L1 degenerate-primer polymerase chain reaction method. Infections typically cleared rapidly, with 67% (95% confidence interval [CI] = 63% to 70%) clearing by 12 months. However, among infections that persisted at least 12 months, the risk of CIN2+ diagnosis by 30 months was 21% (95% CI = 15% to 28%). The risk of CIN2+ diagnosis was highest among women younger than 30 years with HPV-16 infections that persisted for at least 12 months (53%; 95% CI = 29% to 76%). These findings suggest that the medical community should emphasize persistence of cervical HPV infection, not single-time detection of HPV, in management strategies and health messages.

Viral interleukin-10 expressed by human cytomegalovirus during the latent phase of infection modulates latently infected myeloid cell differentiation.
The human cytomegalovirus UL111A gene is expressed during latent and productive infections, and it codes for homologs of interleukin-10 (IL-10). We examined whether viral IL-10 expressed during latency altered differentiation of latently infected myeloid progenitors. In comparison to infection with parental virus or mock infection, latent infection with a virus in which the gene encoding viral IL-10 has been deleted upregulated cytokines associated with dendritic cell (DC) formation and increased the proportion of myeloid DCs. These data demonstrate that viral IL-10 restricts the ability of latently infected myeloid progenitors to differentiate into DCs and identifies an immunomodulatory role for viral IL-10 which may limit the host's ability to clear latent virus.

Instruction: Given a scientific claim, retrieve documents that support or refute the claim