LATS1/2 kinases trigger self-renewal of cancer stem cells in aggressive oral cancer

Cancer stem cells (CSCs), which play important roles in tumor initiation and progression, are resistant to many types of therapies. However, the regulatory mechanisms underlying CSC-specific properties, including self-renewal, are poorly understood. Here, we found that LATS1/2, the core Hippo pathway-kinases, were highly expressed in the oral squamous cell carcinoma line SAS, which exhibits high capacity of CSCs, and that depletion of these kinases prevented SAS cells from forming spheres under serum-free conditions. Detailed examination of the expression and activation of LATS kinases and related proteins over a time course of sphere formation revealed that LATS1/2 were more highly expressed and markedly activated before initiation of self-renewal. Moreover, TAZ, SNAIL, CHK1/2, and Aurora-A were expressed in hierarchical, oscillating patterns during sphere formation, suggesting that the process consists of four sequential steps. Our results indicate that LATS1/2 trigger self-renewal of CSCs by regulating the Hippo pathway, the EMT, and cell division

Exogenous Interferon-α and Interferon-γ Increase Lethality of Murine Inhalational Anthrax

Bacillus anthracis, the etiologic agent of inhalational anthrax, is a facultative intracellular pathogen. Despite appropriate antimicrobial therapy, the mortality from inhalational anthrax approaches 45%, underscoring the need for better adjuvant therapies. The variable latency between exposure and development of disease suggests an important role for the host's innate immune response. Type I and Type II Interferons (IFN) are prominent members of the host innate immune response and are required for control of intracellular pathogens. We have previously described a protective role for exogenous Type I and Type II IFNs in attenuating intracellular B.anthracis germination and macrophage cell death in vitro.We sought to extend these findings in an in vivo model of inhalational anthrax, utilizing the Sterne strain (34F2) of B.anthracis. Mice devoid of STAT1, a component of IFN-alpha and IFN-gamma signaling, had a trend towards increased mortality, bacterial germination and extrapulmonary spread of B.anthracis at 24 hrs. This was associated with impaired IL-6, IL-10 and IL-12 production. However, administration of exogenous IFN-gamma, and to a lesser extent IFN-alpha, at the time of infection, markedly increased lethality. While IFNs were able to reduce the fraction of germinated spores within the lung, they increased both the local and systemic inflammatory response manifest by increases in IL-12 and reductions in IL-10. This was associated with an increase in extrapulmonary dissemination. The mechanism of IFN mediated inflammation appears to be in part due to STAT1 independent signaling.In conclusion, while endogenous IFNs are essential for control of B.anthracis germination and lethality, administration of exogenous IFNs appear to increase the local inflammatory response, thereby increasing mortality

Fitness versus Fatness and Insulin Resistance in U.S. Adolescents

Background. The present study examined the relationship between insulin resistance and both waist circumference and cardiorespiratory fitness in U.S. adolescents. Methods. NHANES assessed a nationally representative sample of U.S. adolescents (12–18 yrs) between 1999–2002. Abdominal adiposity was estimated by waist circumference, overall adiposity by BMI, and cardiorespiratory fitness (maximal oxygen uptake (VO2max) from a treadmill exercise test). Insulin resistance was estimated from fasting insulin and glucose using the homeostatic model assessment method (i.e., HOMA) and was log-transformed. Results. 1078 adolescents were included in the study. Positive correlations existed between lnHOMA and waist circumference (r = 0.59; r = 0.54) for boys and girls, respectively. lnHOMA and VO2max were inversely related in boys (r = −0.29) but not girls (r = −0.06). Gender-specific analyses by BMI category showed that the significant inverse relationship in lnHOMA and VO2max was primarily present in obese boys. Conclusion. Among adolescents, important gender and BMI differences exist in the relationship between insulin resistance and fitness. While waist circumference and BMI are important predictors in all children, fitness appears especially important in obese boys. These findings may have important implications for gender-specific interventions to prevent adult obesity and diabetes mellitus

Development and Validation of a Tool for Assessing Glucose Impairment in Adolescents

INTRODUCTION: Childhood obesity is associated with an increased risk for type 2 diabetes. Early identification of adolescents at risk for impaired fasting blood glucose may lead to earlier and more comprehensive evaluation and intervention. Because widespread blood glucose testing of adolescents is not recommended, community-based tools are needed to identify those who could benefit from further testing. One such tool, developed for adults, was the Tool for Assessing Glucose ImpairmenT (TAG-IT). Our objective was to validate whether a similar tool could be useful for community-based screening of glucose impairment risk among adolescents. METHODS: Our study sample consisted of 3,050 adolescents aged 12 to18 years who had participated in the 1999-2008 National Health and Nutrition Examination Survey (NHANES). Half of participants were female and 40% were nonwhite. NHANES measured fasting blood glucose and height, weight, and resting heart rate. We used Pearson correlations and regression analysis to determine key variables for predicting glucose impairment. From these measurements, we created a composite TAG-IT score for adolescents called TAG-IT-A. We then applied the TAG-IT-A model to 1988-1994 NHANES data, using linear regression analysis and receiver operating characteristic analysis to determine how well the TAG-IT-A score predicted a fasting blood glucose at or above 100 mg/dL. RESULTS: We determined that age, sex, body mass index, and resting heart rate were predictors of impaired fasting blood glucose and that TAG-IT-A was a better predictor of impaired fasting blood glucose than body mass index alone (area under the curve, 0.61, P < .001 vs 0.55, P = .10, respectively). A TAG-IT-A score of 3 or higher correctly identified 50% of adolescents with impaired fasting blood glucose, while a score of 5 or higher correctly identified 76% . CONCLUSION: The TAG-IT-A score is a simple screening tool that clinicians and public health professionals could use to easily identify adolescents who may have impaired fasting blood glucose and need a more comprehensive evaluation

The Multiple Roles of Mps1 in Drosophila Female Meiosis

The Drosophila gene ald encodes the fly ortholog of mps1, a conserved kinetochore-associated protein kinase required for the meiotic and mitotic spindle assembly checkpoints. Using live imaging, we demonstrate that oocytes lacking Ald/Mps1 (hereafter referred to as Ald) protein enter anaphase I immediately upon completing spindle formation, in a fashion that does not allow sufficient time for nonexchange homologs to complete their normal partitioning to opposite half spindles. This observation can explain the heightened sensitivity of nonexchange chromosomes to the meiotic effects of hypomorphic ald alleles. In one of the first studies of the female meiotic kinetochore, we show that Ald localizes to the outer edge of meiotic kinetochores after germinal vesicle breakdown, where it is often observed to be extended well away from the chromosomes. Ald also localizes to numerous filaments throughout the oocyte. These filaments, which are not observed in mitotic cells, also contain the outer kinetochore protein kinase Polo, but not the inner kinetochore proteins Incenp or Aurora-B. These filaments polymerize during early germinal vesicle breakdown, perhaps as a means of storing excess outer kinetochore kinases during early embryonic development

MosAIck: Staging Contemporary AI Performance - Connecting Live Coding, E-Textiles and Movement

This paper introduces our collective work “Patterns in Between Intelligences”, a performance piece that builds an artistic practice between live coding sounds and coding through dance, mediated and shaped through e-textile sensors. This creates a networked system of which both live coded processes and human bodies are part. The paper describes in detail the implementations of technology used in the prototype performance performed at No Bounds Festival in Sheffield UK, October 2022, as well as discussions and concerns the team had related to the use of AI technology on stage. The paper concludes with a narrative reflection on the Sheffield performance, and reflections on it

Changes in histoanatomical distribution of types I, III and V collagen promote adaptative remodeling in posterior tibial tendon rupture

INTRODUCTION: Posterior tibial tendon dysfunction is a common cause of adult flat foot deformity, and its etiology is unknown. PURPOSE: In this study, we characterized the morphologic pattern and distribution of types I, III and V collagen in posterior tibial tendon dysfunction. METHOD: Tendon samples from patients with and without posterior tibial tendon dysfunction were stained by immunofluorescence using antibodies against types I, III and V collagen. RESULTS: Control samples showed that type V deposited near the vessels only, while surgically obtained specimens displayed type V collagen surrounding other types of collagen fibers in thicker adventitial layers. Type III collagen levels were also increased in pathological specimens. On the other hand, amounts of collagen type I, which represents 95% of the total collagen amount in normal tendon, were decreased in pathological specimens. CONCLUSION: Fibrillogenesis in posterior tibial tendon dysfunction is altered due to higher expression of types III and V collagen and a decreased amount of collagen type I, which renders the originating fibrils structurally less resistant to mechanical forces

Biomarkers of aging in Drosophila

Low environmental temperature and dietary restriction (DR) extend lifespan in diverse organisms. In the fruit fly Drosophila, switching flies between temperatures alters the rate at which mortality subsequently increases with age but does not reverse mortality rate. In contrast, DR acts acutely to lower mortality risk; flies switched between control feeding and DR show a rapid reversal of mortality rate. Dietary restriction thus does not slow accumulation of aging-related damage. Molecular species that track the effects of temperatures on mortality but are unaltered with switches in diet are therefore potential biomarkers of aging-related damage. However, molecular species that switch upon instigation or withdrawal of DR are thus potential biomarkers of mechanisms underlying risk of mortality, but not of aging-related damage. Using this approach, we assessed several commonly used biomarkers of aging-related damage. Accumulation of fluorescent advanced glycation end products (AGEs) correlated strongly with mortality rate of flies at different temperatures but was independent of diet. Hence, fluorescent AGEs are biomarkers of aging-related damage in flies. In contrast, five oxidized and glycated protein adducts accumulated with age, but were reversible with both temperature and diet, and are therefore not markers either of acute risk of dying or of aging-related damage. Our approach provides a powerful method for identification of biomarkers of aging.This work was supported by the Wellcome Trust and in part by I+D grants from the Spanish Ministry of Education and Science (BFU2006-14495 ⁄ BFI), the Spanish Ministry of Health (ISCIII, Red de Envejecimiento y Fragilidad, RD06 ⁄ 0013 ⁄ 0012), and the Generalitat of Catalunya (2005SGR00101) to R.P; the Spanish Ministry of Health (FIS PI081843), Spanish Ministry of Education and Science (AGL2006-12433), and ‘‘La Caixa’’ Foundation to M.P.O. Also supported by the Max Planck Society (J.J. and L.P), COST B-35 Action; Research into Ageing (A.J.L.) and the Medical Research Council and National Institutes of Health (P01 AG025901, PL1 AG032118 and P30 AG025708) (M.D.B.)

Changes in Histoanatomical Distribution Of Types I, III And V Collagen Promote Adaptative Remodeling in Posterior Tibial Tendon Rupture

INTRODUCTION: Posterior tibial tendon dysfunction is a common cause of adult flat foot deformity, and its etiology is unknown. PURPOSE: In this study, we characterized the morphologic pattern and distribution of types I, III and V collagen in posterior tibial tendon dysfunction. METHOD: Tendon samples from patients with and without posterior tibial tendon dysfunction were stained by immunofluorescence using antibodies against types I, III and V collagen. RESULTS: Control samples showed that type V deposited near the vessels only, while surgically obtained specimens displayed type V collagen surrounding other types of collagen fibers in thicker adventitial layers. Type III collagen levels were also increased in pathological specimens. On the other hand, amounts of collagen type I, which represents 95% of the total collagen amount in normal tendon, were decreased in pathological specimens. CONCLUSION: Fibrillogenesis in posterior tibial tendon dysfunction is altered due to higher expression of types III and V collagen and a decreased amount of collagen type I, which renders the originating fibrils structurally less resistant to mechanical forces