Members of the large G protein-coupled receptor (GPCR) clan are implicated in many physiological and disease processes, making them important therapeutic drug targets. In the present study, we follow ...up on results of a pilot study suggesting a functional relationship between glucocorticoid (GC)-induced ocular hypertension and GPR158, one of three orphan members of the GPCR Family C. GC treatment increases levels of GPR158 mRNA and protein through transcriptional mechanisms, in cultured trabecular meshwork (TBM) cells derived from the eye's aqueous outflow pathway. Like treatment with GCs, transient overexpression of GPR158 stimulates cell proliferation, while siRNA knockdown of endogenous GPR158 has the opposite effect. Both endogenous and overexpressed GPR158 show an unusual subcellular localization pattern, being found almost entirely in the nucleus. However, when cells are treated with inhibitors of clathrin-mediated endocytosis, GPR158 is shifted to the plasma membrane. Mutation of a bipartite nuclear localization signal (NLS) in the 8(th) helix also shifts GPR158 out of the nucleus, but in this case the protein is found in vesicles localized in the cytoplasm. These results suggest that newly synthesized GPR158 first traffics to the plasma membrane, where it rapidly undergoes endocytosis and translocation to the nucleus. Significantly, mutation of the NLS abrogates GPR158-mediated enhancement of cell proliferation, indicating a functional requirement for nuclear localization. GPR158 overexpression upregulates levels of the cell cycle regulator cyclin D1, but mutation of the NLS reverses this. Overexpression of GPR158 enhances the barrier function of a TBM cell monolayer, which is associated with an increase in the levels of tight junction proteins ZO-1 and occludin, similar to reported studies on GC treatment. Regulated paracellular permeability controls aqueous outflow facility in vivo. Since GCs stimulate GPR158 expression, the result is consistent with a role for elevation of GPR158 expression in GC-induced ocular hypertension.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Numerous studies are exploring the use of cell adoptive therapies to treat hematological malignancies as well as solid tumors. However, there are numerous factors that dampen the immune response, ...including viruses like human immunodeficiency virus. In this study, we leverage human-derived microphysiological models to reverse-engineer the HIV-immune system interaction and evaluate the potential of memory-like natural killer cells for HIV
head and neck cancer, one of the most common tumors in patients living with human immunodeficiency virus. Here, we evaluate multiple aspects of the memory-like natural killer cell response in human-derived bioengineered environments, including immune cell extravasation, tumor penetration, tumor killing, T cell dependence, virus suppression, and compatibility with retroviral medication. Overall, these results suggest that memory-like natural killer cells are capable of operating without T cell assistance and could simultaneously destroy head and neck cancer cells as well as reduce viral latency.
Most studies of sleep and health outcomes rely on self-reported sleep duration, although correlation with objective measures is poor. In this study, we defined sociodemographic and sleep ...characteristics associated with misreporting and assessed whether accounting for these factors better explains variation in objective sleep duration among 2,086 participants in the Hispanic Community Health Study/Study of Latinos who completed more than 5 nights of wrist actigraphy and reported habitual bed/wake times from 2010 to 2013. Using linear regression, we examined self-report as a predictor of actigraphy-assessed sleep duration. Mean amount of time spent asleep was 7.85 (standard deviation, 1.12) hours by self-report and 6.74 (standard deviation, 1.02) hours by actigraphy; correlation between them was 0.43. For each additional hour of self-reported sleep, actigraphy time spent asleep increased by 20 minutes (95% confidence interval: 19, 22). Correlations between self-reported and actigraphy-assessed time spent asleep were lower with male sex, younger age, sleep efficiency <85%, and night-to-night variability in sleep duration ≥1.5 hours. Adding sociodemographic and sleep factors to self-reports increased the proportion of variance explained in actigraphy-assessed sleep slightly (18%-32%). In this large validation study including Hispanics/Latinos, we demonstrated a moderate correlation between self-reported and actigraphy-assessed time spent asleep. The performance of self-reports varied by demographic and sleep measures but not by Hispanic subgroup.
BACKGROUND:The Veterans Choice Program (VCP) was launched in 2014 to address the growing concerns about the timeliness and quality of Veterans Health Administration (VHA) care. Given that many ...sex-specific health services, such as mammography and maternity care, are not routinely provided in all VHA facilities, women Veterans may disproportionately rely on VCP care. Understanding the provision and coordination of VCP care is crucial in order to ensure that care is not fragmented across the 2 health care systems.
OBJECTIVES:The main objective of this study was to understand women Veterans’ experiences, perceptions, and challenges with VCP care.
DESIGN:This study was a semistructured interview with 148 women at 13 VHA facilities nationwide.
RESULTS:Four major themes emerged(1) eligibility information for the VCP was limited and confusing; (2) women experienced difficulty scheduling VCP appointments; (3) VCP care results were not shared with women Veterans or their VHA providers in a timely manner; and (4) concerns with unpaid VCP bills were common.
CONCLUSIONS:Our study highlights challenges women experienced with VCP care, and the need for improved care coordination. An ideal care coordination system would be the one in which all Veterans’ non-Veteran Affairs care, including scheduling, follow-up, communication with community providers, coordination of services, and transition back to Veteran Affairs care is ensured.
Estimates of Sun-Induced vegetation chlorophyll Fluorescence (SIF) using remote sensing techniques are commonly determined by exploiting solar and/or telluric absorption features. When SIF is ...retrieved in the strong oxygen (O2) absorption features, atmospheric effects must always be compensated. Whereas correction of atmospheric effects is a standard airborne or satellite data processing step, there is no consensus regarding whether it is required for SIF proximal-sensing measurements nor what is the best strategy to be followed. Thus, by using simulated data, this work provides a comprehensive analysis about how atmospheric effects impact SIF estimations on proximal sensing, regarding: (1) the sensor height above the vegetated canopy; (2) the SIF retrieval technique used, e.g., Fraunhofer Line Discriminator (FLD) family or Spectral Fitting Methods (SFM); and (3) the instrument's spectral resolution. We demonstrate that for proximal-sensing scenarios compensating for atmospheric effects by simply introducing the O2 transmittance function into the FLD or SFM formulations improves SIF estimations. However, these simplistic corrections still lead to inaccurate SIF estimations due to the multiplication of spectrally convolved atmospheric transfer functions with absorption features. Consequently, a more rigorous oxygen compensation strategy is proposed and assessed by following a classic airborne atmospheric correction scheme adapted to proximal sensing. This approach allows compensating for the O2 absorption effects and, at the same time, convolving the high spectral resolution data according to the corresponding Instrumental Spectral Response Function (ISRF) through the use of an atmospheric radiative transfer model. Finally, due to the key role of O2 absorption on the evaluated proximal-sensing SIF retrieval strategies, its dependency on surface pressure (p) and air temperature (T) was also assessed. we combined simulated spectral data with p and T measurements obtained for a one-year period in the Hyytiala Forestry Field Station in Finland. Of importance hereby is that seasonal dynamics in terms of T and p, if not appropriately considered as part of the retrieval strategy, can result in erroneous SIF seasonal trends that mimic those of known dynamics for temperature-dependent physiological responses of vegetation.
To quantify maternal, fetal and neonatal mortality in low- and middle-income countries, to identify when deaths occur and to identify relationships between maternal deaths and stillbirths and ...neonatal deaths.
A prospective study of pregnancy outcomes was performed in 106 communities at seven sites in Argentina, Guatemala, India, Kenya, Pakistan and Zambia. Pregnant women were enrolled and followed until six weeks postpartum.
Between 2010 and 2012, 214,070 of 220,235 enrolled women (97.2%) completed follow-up. The maternal mortality ratio was 168 per 100,000 live births, ranging from 69 per 100,000 in Argentina to 316 per 100,000 in Pakistan. Overall, 29% (98/336) of maternal deaths occurred around the time of delivery: most were attributed to haemorrhage (86/336), pre-eclampsia or eclampsia (55/336) or sepsis (39/336). Around 70% (4349/6213) of stillbirths were probably intrapartum; 34% (1804/5230) of neonates died on the day of delivery and 14% (755/5230) died the day after. Stillbirths were more common in women who died than in those alive six weeks postpartum (risk ratio, RR: 9.48; 95% confidence interval, CI: 7.97-11.27), as were perinatal deaths (RR: 4.30; 95% CI: 3.26-5.67) and 7-day (RR: 3.94; 95% CI: 2.74-5.65) and 28-day neonatal deaths (RR: 7.36; 95% CI: 5.54-9.77).
Most maternal, fetal and neonatal deaths occurred at or around delivery and were attributed to preventable causes. Maternal death increased the risk of perinatal and neonatal death. Improving obstetric and neonatal care around the time of birth offers the greatest chance of reducing mortality.
The core of micelles self-assembled from amphiphiles is hydrophobic and contains little water, whereas complex coacervate core micelles co-assembled from oppositely charged hydrophilic polymers have ...a hydrophilic core with a high water content. Co-assembly of ionic surfactants with ionic-neutral copolymers yields surfactant-copolymer complexes known to be capable of solubilizing both hydrophilic and hydrophobic cargo within the mixed core composed of a coacervate phase with polyelectrolyte-decorated surfactant micelles. Here we formed such complexes from asymmetric (
) and symmetric (
), sequence-controlled polyurethane ionomers and poly(
-methyl-2-vinylpyridinium iodide)
-
-poly(ethylene oxide)
copolymers. The complexes with
were 1.3-fold larger in mass and 1.8-fold larger in radius of gyration than the
complexes. Small-angle X-ray scattering revealed differences in the packing of the similarly sized PUI micelles within the core of the complexes. The
micelles were arranged in a more ordered fashion and were spaced further apart from each other (10 nm vs. 6 nm) than the
micelles. Hence, this work shows that the monomer sequence of amphiphiles can be varied to alter the internal structure of surfactant-copolymer complexes. Since the structure of the micellar core may affect both the cargo loading and release, our findings suggest that these properties may be tuned through control of the monomer sequence of the micellar constituents.
The importance of the epicardium covering the heart and the intrapericardial part of the great arteries has reached a new summit. It has evolved as a major cellular component with impact both in ...development, disease and more recently also repair potential. The role of the epicardium in development, its differentiation from a proepicardial organ at the venous pole (vPEO) and the differentiation capacities of the vPEO initiating cardiac epicardium (cEP) into epicardium derived cells (EPDCs) have been extensively described in recent reviews on growth and transcription factor pathways. In short, the epicardium is the source of the interstitial, the annulus fibrosus and the adventitial fibroblasts, and differentiates into the coronary arterial smooth muscle cells. Furthermore, EPDCs induce growth of the compact myocardium and differentiation of the Purkinje fibers. This review includes an arterial pole located PEO (aPEO) that provides the epicardium covering the intrapericardial great vessels. In avian and mouse models disturbance of epicardial outgrowth and maturation leads to a broad spectrum of cardiac anomalies with main focus on non-compaction of the myocardium, deficient annulus fibrosis, valve malformations and coronary artery abnormalities. The discovery that in disease both arterial and cardiac epicardium can again differentiate into EPDCs and thus reactivate its embryonic program and potential has highly broadened the scope of research interest. This reactivation is seen after myocardial infarction and also in aneurysm formation of the ascending aorta. Use of EPDCs for cell therapy show their positive function in paracrine mediated repair processes which can be additive when combined with the cardiac progenitor stem cells that probably share the same embryonic origin with EPDCs. Research into the many cell-autonomous and cell–cell-based capacities of the adult epicardium will open up new realistic therapeutic avenues.
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