Tumor-derived extracellular vesicles (tEVs) are important signals in tumor–host cell communication, yet it remains unclear how endogenously produced tEVs affect the host in different areas of the ...body. We combined imaging and genetic analysis to track melanoma-derived vesicles at organismal, cellular, and molecular scales to show that endogenous tEVs efficiently disseminate via lymphatics and preferentially bind subcapsular sinus (SCS) CD169⁺ macrophages in tumor-draining lymph nodes (tdLNs) in mice and humans. The CD169⁺ macrophage layer physically blocks tEV dissemination but is undermined during tumor progression and by therapeutic agents. A disrupted SCS macrophage barrier enables tEVs to enter the lymph node cortex, interact with B cells, and foster tumor-promoting humoral immunity. Thus, CD169⁺ macrophages may act as tumor suppressors by containing tEV spread and ensuing cancer-enhancing immunity.
Abstract Introduction Post-traumatic stress disorder (PTSD) is associated with an increased risk of dementia in male veterans, but little is known in females and civilians. Methods PTSD and ...comorbidities were abstracted from medical records from 1/1/1996 to 12/31/2001. Dementia incidence from 1/1/2002 to 12/31/2014 in 499,844 health care members aged 60+ years over an average of 8.2 years. Cox proportional hazard models were adjusted for age, demographics, and comorbidities. Results PTSD was associated with increased risk of dementia over an average of 8 years of follow-up (females: hazard ratio HR = 1.59, 95% confidence interval CI = 1.30–1.95; males: HR = 1.96, 95% CI = 1.51–2.55). There was a two-fold risk of dementia in those with both PTSD and depression (females: HR = 2.08; 95% CI = 1.66–2.59; males: HR = 2.06; 95% CI = 1.47–2.91) versus those without. Discussion PTSD was a risk factor for dementia in both sexes, with a heightened risk in those with comorbid depression.
Addictive disorders are partly heritable, chronic, relapsing conditions that account for a tremendous disease burden. Currently available addiction pharmacotherapies are only moderately successful, ...continue to be viewed with considerable scepticism outside the scientific community and have not become widely adopted as treatments. More effective medical treatments are needed to transform addiction treatment and address currently unmet medical needs. Emerging evidence from alcoholism research suggests that no single advance can be expected to fundamentally change treatment outcomes. Rather, studies of opioid, corticotropin-releasing factor, GABA and serotonin systems suggest that incremental advances in treatment outcomes will result from an improved understanding of the genetic heterogeneity among patients with alcohol addiction, and the development of personalized treatments.
'Gold standard' reference sets of human muscle architecture are based on elderly cadaveric specimens, which are unlikely to be representative of a large proportion of the human population. This is ...important for musculoskeletal modeling, where the muscle force-generating properties of generic models are defined by these data but may not be valid when applied to models of young, healthy individuals. Obtaining individualized muscle architecture data in vivo is difficult, however diffusion tensor magnetic resonance imaging (DTI) has recently emerged as a valid method of achieving this. DTI was used here to provide an architecture data set of 20 lower limb muscles from 10 healthy adults, including muscle fiber lengths, which are important inputs for Hill-type muscle models commonly used in musculoskeletal modeling. Maximum isometric force and muscle fiber lengths were found not to scale with subject anthropometry, suggesting that these factors may be difficult to predict using scaling or optimization algorithms. These data also highlight the high level of anatomical variation that exists between individuals in terms of lower limb muscle architecture, which supports the need of incorporating subject-specific force-generating properties into musculoskeletal models to optimize their accuracy for clinical evaluation.
Extracellular Vesicles ZABOROWSKI, MIKOŁAJ P.; BALAJ, LEONORA; BREAKEFIELD, XANDRA O. ...
Bioscience,
08/2015, Letnik:
65, Številka:
8
Journal Article
Recenzirano
Odprti dostop
The release of extracellular vesicles (EVs), including exosomes and microvesicles, is a phenomenon shared by many cell types as a means of communicating with other cells and also potentially removing ...cell contents. The cargo of EVs includes the proteins, lipids, nucleic acids, and membrane receptors of the cells from which they originate. EVs released into the extracellular space can enter body fluids and potentially reach distant tissues. Once taken up by neighboring and/or distal cells, EVs can transfer functional cargo that may alter the status of recipient cells, thereby contributing to both physiological and pathological processes. In this article, we will focus on EV composition, mechanisms of uptake, and their biological effects on recipient cells. We will also discuss established and recently developed methods used to study EVs, including isolation, quantification, labeling and imaging protocols, as well as RNA analysis.
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•We present a fuzzy smart controller for hybrid renewable and conventional energy system.•The rules are based on human intelligence and implemented in the smart controller.•Efficient ...tracking capability of the proposed controller is proofed in this paper by an example.•Excess produced renewable energy is converted to hydrogen for household use .•Considerable electric grid energy saving is highlighted in the proposed controller system.
This study concerns the conception and development of an efficient multi input-output fuzzy logic smart controller, to manage the energy flux of a sustainable hybrid power system, based on renewable power sources, integrating solar panels and a wind turbine associated with storage, applied to a typical residential habitat. In the suggested topology, the energy surplus is redirected to an electrolysis system to produce hydrogen suitable for household utilities. To assume a constant access to electricity in case of consumption peak, connection to the grid is also considered as an exceptional rescue resource. The objective of the presented controller is to exploit instantaneously the produced renewable electric energy and insure savings of electric grid energy. The proposed multi input-output fuzzy logic smart controller has been achieved and verified, outcome switches command signals are discussed and the renewable energy system integration ratio is highlighted.
Alcohol dependence comorbid with posttraumatic stress disorder (PTSD) has been found to be resistant to treatment. In addition, there is a concern that prolonged exposure therapy for PTSD may ...exacerbate alcohol use.
To compare the efficacy of an evidence-based treatment for alcohol dependence (naltrexone) plus an evidence-based treatment for PTSD (prolonged exposure therapy), their combination, and supportive counseling.
A single-blind, randomized clinical trial of 165 participants with PTSD and alcohol dependence conducted at the University of Pennsylvania and the Philadelphia Veterans Administration. Participant enrollment began on February 8, 2001, and ended on June 25, 2009. Data collection was completed on August 12, 2010.
Participants were randomly assigned to (1) prolonged exposure therapy plus naltrexone (100 mg/d), (2) prolonged exposure therapy plus pill placebo, (3) supportive counseling plus naltrexone (100 mg/d), or (4) supportive counseling plus pill placebo. Prolonged exposure therapy was composed of 12 weekly 90-minute sessions followed by 6 biweekly sessions. All participants received supportive counseling.
The Timeline Follow-Back Interview and the PTSD Symptom Severity Interview were used to assess the percentage of days drinking alcohol and PTSD severity, respectively, and the Penn Alcohol Craving Scale was used to assess alcohol craving. Independent evaluations occurred prior to treatment (week 0), at posttreatment (week 24), and at 6 months after treatment discontinuation (week 52).
Participants in all 4 treatment groups had large reductions in the percentage of days drinking (mean change, -63.9% 95% CI, -73.6% to -54.2% for prolonged exposure therapy plus naltrexone; -63.9% 95% CI, -73.9% to -53.8% for prolonged exposure therapy plus placebo; -69.9% 95% CI, -78.7% to -61.2% for supportive counseling plus naltrexone; and -61.0% 95% CI, -68.9% to -53.0% for supportive counseling plus placebo). However, those who received naltrexone had lower percentages of days drinking than those who received placebo (mean difference, 7.93%; P = .008). There was also a reduction in PTSD symptoms in all 4 groups, but the main effect of prolonged exposure therapy was not statistically significant. Six months after the end of treatment, participants in all 4 groups had increases in percentage of days drinking. However, those in the prolonged exposure therapy plus naltrexone group had the smallest increases.
In this study of patients with alcohol dependence and PTSD, naltrexone treatment resulted in a decrease in the percentage of days drinking. Prolonged exposure therapy was not associated with an exacerbation of alcohol use disorder.
clinicaltrials.gov Identifier: NCT00006489.
•SWAT prediction of soil temperature during winter has errors in areas with substantial snow cover.•A physically-based soil-temperature module was developed and integrated with SWAT.•The new module ...does not require additional inputs.•The new module was validated in a small watershed in Atlantic Canada.•The new module could simulate freeze-thaw cycles in soil profile.
Accurate estimates of soil temperature are important for quantifying hydrological and biological processes in hydrological models. Soil temperature predictions in the widely used Soil and Water Assessment Tool (SWAT) have large prediction errors when applied to regions with significant snow cover during winter. In this study, a new physically-based soil-temperature module is developed as an alternative to the empirical soil-temperature module currently used in SWAT. The physically-based module simulates soil temperature in different soil layers as a result of energy transfer between the atmosphere and soil (or snow) interface. The modified version of SWAT with the new soil-temperature module in place, introduces only three new parameters over the original soil-temperature module. Both the original and new soil-temperature modules are tested against field data from the Black Brook Watershed, a small watershed in Atlantic Canada. The results indicate that both versions of soil-temperature module are able to provide acceptable predictions of temperature in different layers of the soil during non-winter seasons. However, the original module severely underestimates soil temperatures in winter (within −10 to −20°C), while the new module produces results that are more consistent with field measurements (within −2 to 2°C). In addition, unlike its counterpart, the new module is able to simulate freeze–thaw cycles in the soil profile. Ice-water content variations in winter are reasonably simulated by the new module for different snow cover scenarios. In general, modified-SWAT improves prediction accuracy on baseflow discharge compared with the original-SWAT, due to improved estimates of soil temperature during winter. The new physically-based soil-temperature module has greatly improved the ability of SWAT to predict soil temperatures under seasonal snow cover, which is essential to the application of the model in regions like Atlantic Canada.
Hedgehogs (Hhs) are key signaling regulators of stem cell maintenance and tissue patterning in embryos, and activating mutations in the pathway that increase Gli transcriptional activity are causal ...in a diversity of cancers. Here, we report that phosphoinositide 3-kinase (P13-kinase)-dependent Akt activation is essential for Sonic Hedgehog (Shh) signaling in the specification of neuronal fates in chicken neural explants, chondrogenic differentiation of 10T1/2 cells, and Gli activation in NIH 3T3 cells. Stimulation of PI3-kinase/Akt by insulin-like growth factor I potentiates Gli activation induced by low levels of Shh; however, insulin-like growth factor I alone is insufficient to induce Gli-dependent transcription. Protein kinase A (PKA) and glycogen synthase kinase 3β sequentially phosphorylate Gli2 at multiple sites, identified by mutagenesis, thus resulting in a reduction of its transcriptional activity. Gli2 mutant proteins in which the major PKA and glycogen synthase kinase 3β phosphorylation sites were mutated to alanine remain fully transcriptionally active; however, PKA-mutant Gli2 functions independently of Akt signaling, indicating that Akt positively regulates Shh signaling by controlling PKA-mediated Gli inactivation. Our findings provide a basis for the synergistic role of PI3-kinase/Akt in Hh signaling in embryonic development and Hh-dependent tumors.
Cerebral blood flow (CBF) reductions in Alzheimer's disease patients and related mouse models have been recognized for decades, but the underlying mechanisms and resulting consequences for ...Alzheimer's disease pathogenesis remain poorly understood. In APP/PS1 and 5xFAD mice we found that an increased number of cortical capillaries had stalled blood flow as compared to in wild-type animals, largely due to neutrophils that had adhered in capillary segments and blocked blood flow. Administration of antibodies against the neutrophil marker Ly6G reduced the number of stalled capillaries, leading to both an immediate increase in CBF and rapidly improved performance in spatial and working memory tasks. This study identified a previously uncharacterized cellular mechanism that explains the majority of the CBF reduction seen in two mouse models of Alzheimer's disease and demonstrated that improving CBF rapidly enhanced short-term memory function. Restoring cerebral perfusion by preventing neutrophil adhesion may provide a strategy for improving cognition in Alzheimer's disease patients.
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