MicroRNAs are often associated with the pathogenesis of many cancers, including head and neck squamous cell carcinoma (HNSCC). In particular, microRNA-21 (miR-21) appears to have a critical role in ...tumor cell survival, chemoresistance and HNSCC progression. In this study, we investigated matrix hyaluronan (HA)-induced CD44 (a primary HA receptor) interaction with the stem cell markers, Nanog and Stat-3, in HNSCC cells (HSC-3 cells). Our results indicate that HA binding to CD44 promotes Nanog-Stat-3 (also tyrosine phosphorylated Stat-3) complex formation, nuclear translocation and transcriptional activation. Further analyses reveal that miR-21 is controlled by an upstream promoter containing Stat-3 binding site(s), while chromatin immunoprecipitation assays demonstrate that stimulation of miR-21 expression by HA/CD44 signaling is Nanog/Stat-3-dependent in HNSCC cells. This process results in a decrease of a tumor suppressor protein (PDCD4), and an upregulation of i nhibitors of the apoptosis family of proteins (IAPs) as well as chemoresistance in HSC-3 cells. Treatment of HSC-3 cells with Nanog- and/or Stat-3-specific small interfering RNAs effectively blocks HA-mediated Nanog-Stat-3 signaling events, abrogates miR-21 production and increases PDCD4 expression. Subsequently, this Nanog-Stat-3 signaling inhibition causes downregulation of survival protein (IAP) expression and enhancement of chemosensitivity. To further evaluate the role of miR-21 in tumor cell-specific functions, HSC-3 cells were also transfected with a specific anti-miR-21 inhibitor in order to silence miR-21 expression and block its target functions. Our results demonstrate that anti-miR-21 inhibitor not only upregulates PDCD4 expression but also decreases IAP expression and enhances chemosensitivity in HA-treated HNSCC cells. Together, these findings indicate that the HA-induced CD44 interaction with Nanog and Stat-3 has a pivotal role in miR-21 production leading to PDCD4 reduction, IAP upregulation and chemoresistance in HNSCC cells. This novel Nanog/Stat-3 signaling pathway-specific mechanism involved in miR-21 production is significant for the formation of future intervention strategies in the treatment of HA/CD44-activated HNSCC.
Flavin-containing monooxygenase (FMO) oxygenates drugs and xenobiotics containing a "soft-nucleophile", usually nitrogen or sulfur. FMO, like cytochrome P450 (CYP), is a monooxygenase, utilizing the ...reducing equivalents of NADPH to reduce 1 atom of molecular oxygen to water, while the other atom is used to oxidize the substrate. FMO and CYP also exhibit similar tissue and cellular location, molecular weight, substrate specificity, and exist as multiple enzymes under developmental control. The human FMO functional gene family is much smaller (5 families each with a single member) than CYP. FMO does not require a reductase to transfer electrons from NADPH and the catalytic cycle of the 2 monooxygenases is strikingly different. Another distinction is the lack of induction of FMOs by xenobiotics. In general, CYP is the major contributor to oxidative xenobiotic metabolism. However, FMO activity may be of significance in a number of cases and should not be overlooked. FMO and CYP have overlapping substrate specificities, but often yield distinct metabolites with potentially significant toxicological/pharmacological consequences. The physiological function(s) of FMO are poorly understood. Three of the 5 expressed human FMO genes, FMO1, FMO2 and FMO3, exhibit genetic polymorphisms. The most studied of these is FMO3 (adult human liver) in which mutant alleles contribute to the disease known as trimethylaminuria. The consequences of these FMO genetic polymorphisms in drug metabolism and human health are areas of research requiring further exploration.
Globally, clouds are known to warm the climate system in the thermal infrared because they typically emit thermal radiation to space at effective temperatures lower than the combined cloud‐free ...atmosphere and surface. However, here we show that ∼40% of low‐level clouds over sea ice tend to cool the Arctic system at TOA and contribute to a radiative cooling of the Arctic winter climate by −2.3 Wm−2, or a ∼16% reduction over the infrared warming effect of all clouds during winter. Based on satellite observations, low‐level clouds residing in surface‐based temperature inversions emit more longwave radiation to space than would occur in cloudless skies. While these clouds are known to significantly warm the surface, they cool the Arctic climate system overall. Our results imply that accurately representing the cloud radiative effects unique to the Arctic could help to constrain the regional energy budget.
Plain Language Summary
The Arctic has become emblematic of climate change, with rapid warming that is at least twice as fast as the rest of the planet. However, major uncertainties in our confidence to understand and predict Arctic climate persist, particularly regarding the radiative effects of clouds. Here we use satellite data to quantify the radiative effects of Arctic low‐level clouds, and find approximately 40% of low‐level clouds over sea ice tend to radiatively cool the Arctic climate system (Earth's surface and the atmosphere) in winter, rather than warm the climate system as is typical for most clouds in the thermal infrared regime. This cooling effect is governed by the widespread surface temperature inversions (layers in which temperature increases with altitude), which cap these low‐level clouds and allow more longwave radiation to escape from the Earth to space compared to clear skies. This finding reveals a fundamental, but overlooked, characteristic of cloud radiative effects in the wintertime Arctic and establishes a new perspective for understanding Arctic climate change.
Key Points
A full range of radiative effects for Arctic wintertime low clouds over sea ice is investigated
About 40% of low clouds over sea ice tends to cool the Arctic at the top of the atmosphere in the polar night
These low clouds with a cooling effect at the top of the atmosphere reside within frequent surface‐based temperature inversions
Leads are a key feature of the Arctic ice pack during the winter owing to their substantial contribution to the surface energy balance. According to the present understanding, enhanced heat and ...moisture fluxes from high lead concentrations tend to produce more boundary layer clouds. However, described here in our composite analyses of diverse surface- and satellite-based observations, we find that abundant boundary layer clouds are associated with low lead flux periods, while fewer boundary layer clouds are observed for high lead flux periods. Motivated by these counterintuitive results, we conducted three-dimensional cloud-resolving simulations to investigate the underlying physics. We find that newly frozen leads with large sensible heat flux but low latent heat flux tend to dissipate low clouds. This finding indicates that the observed high lead fractions likely consist of mostly newly frozen leads that reduce any pre-existing low-level cloudiness, which in turn decreases downwelling infrared flux and accelerates the freezing of sea ice.
Summary
Background Because psoriatic arthritis (PsA) usually develops years after the first manifestation of skin symptoms, in many cases the initial diagnosis of PsA depends on the dermatologist.
...Objectives To investigate the prevalence and clinical pattern of PsA in a daily practice population of patients with psoriasis.
Methods Patients were enrolled in an observational prospective cross‐sectional cohort study at 48 community and academic centres. Demographic and medical parameters were recorded, including severity of skin symptoms (Psoriasis Area and Severity Index, PASI), previous and current treatments, concomitant diseases, and the impact of psoriasis on productivity and health‐related quality of life (Dermatology Life Quality Index, DLQI). Patients with joint symptoms were referred to a rheumatologist for diagnosis and to record the activity and pattern of arthritis.
Results Among 1511 patients 20·6% had PsA; in 85% of the cases PsA was newly diagnosed. Of these patients more than 95% had active arthritis and 53·0% had five or more joints affected. Polyarthritis (58·7%) was the most common manifestation pattern, followed by oligoarthritis (31·6%) and arthritis mutilans (4·9%). Distal interphalangeal involvement was present in 41·0% and dactylitis in 23·7% of the patients. Compared with patients without arthritis, patients with PsA had more severe skin symptoms (mean PASI 14·3 vs. 11·5), a lower quality of life (mean DLQI 11·6 vs. 7·7) and greater impairment of productivity parameters.
Conclusions The findings are consistent with a high prevalence of undiagnosed cases of active PsA among patients with psoriasis seen by dermatologists. As many of these patients also have significant skin symptoms, treatment strategies are required that are equally effective in the control of skin and joint symptoms of psoriasis.
The self-assembly of complex structures from a set of non-identical building blocks is a hallmark of soft matter and biological systems, including protein complexes, colloidal clusters, and DNA-based ...assemblies. Predicting the dependence of the equilibrium assembly yield on the concentrations and interaction energies of building blocks is highly challenging, owing to the difficulty of computing the entropic contributions to the free energy of the many structures that compete with the ground state configuration. While these calculations yield well known results for spherically symmetric building blocks, they do not hold when the building blocks have internal rotational degrees of freedom. Here we present an approach for solving this problem that works with arbitrary building blocks, including proteins with known structure and complex colloidal building blocks. Our algorithm combines classical statistical mechanics with recently developed computational tools for automatic differentiation. Automatic differentiation allows efficient evaluation of equilibrium averages over configurations that would otherwise be intractable. We demonstrate the validity of our framework by comparison to molecular dynamics simulations of simple examples, and apply it to calculate the yield curves for known protein complexes and for the assembly of colloidal shells.
White-nose syndrome (WNS) is an infectious disease that disrupts hibernation in bats, leading to premature exhaustion of fat stores. Though we know WNS does impact reproduction in hibernating female ...bats, we are unsure how these impacts are exacerbated by local climate factors. We compiled data from four southeastern U.S. states and used generalized linear mixed effects models to compare effects of WNS, pre-hibernation climate variables, and winter duration on the number of reproductive females in species across the range of WNS susceptibility. We predicted we would see a decline in the number of reproductive females in WNS-susceptible species, with the effect exaggerated by longer winter durations and pre-hibernation climate variables that lead to reductions in foraging. We found that the number of reproductive females in WNS-susceptible species was positively correlated with pre-hibernation local climate conditions conducive to foraging; however, WNS-susceptible species experienced an overall decline with the presence of WNS and as winter duration increased. Our long-term dataset provides evidence that pre-hibernation climate, specifically favorable summer weather conditions for foraging, greatly influences the reproduction, regardless of WNS status.
Abstract Previous studies have suggested beneficial effects of physical activity on cognition. Here, we asked in an interventional approach if physical activity performed at different intensity ...levels would differentially affect episodic memory function. Additionally, we tried to identify mechanisms mediating these changes. Sixty-two healthy elderly individuals were assessed for level of physical activity, aerobic fitness, episodic memory score, neurotrophin and catecholamine levels, and received a magnetic resonance image of the brain at baseline and after a six months intervention of medium or low-intensity physical activity or control. Increase in total physical activity was positively associated with increase in memory score over the entire cohort, without significant differences between intensity groups. It was also positively associated with increases in local gray matter volume in prefrontal and cingulate cortex, and BDNF levels (trend). In conclusion, we showed that physical activity conveys the beneficial effects on memory function independently of its intensity, possibly mediated by local gray matter volume and neurotrophic factors. Our findings may carry significant implications for prevention of cognitive decline in the elderly.
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