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BACKGROUND Social media has emerged as a prominent approach for health education and promotion. However, it is challenging to understand how to best promote health-related information on social media platforms such as Twitter. Despite commercial tools and prior studies attempting to analyze influence, there is a gap to fill in developing a publicly accessible and consolidated framework to measure influence and analyze dissemination strategies. OBJECTIVE This study aims to develop a theoretical framework to measure topic-specific user influence on Twitter for public use and support public health agencies in improving their dissemination strategies. METHODS We designed a consolidated framework for measuring influence that can capture topic-specific tweeting behaviors. The core of the framework is a summary indicator of influence decomposable into four-dimensional measures: activity, priority, originality, and popularity. These measures can be easily visualized and computed efficiently for any Twitter account without the need for private access. We demonstrated the proposed methods using a case study on dietary sodium with sampled stakeholders, then compared the framework with a traditional measure of influence. RESULTS More than half a million sodium tweets from 2006 to 2022 were retrieved from Twitter for sixteen U.S. domestic and international stakeholders in four categories, including public agencies, academic institutions, professional associations, and experts. We discovered that the World Health Organization (WHO), the American Heart Association (AHA), the Food and Agriculture Organization of the United Nations (UN-FAO), and World Action on Salt (WASH) were the top four sodium influencers in the sample. Each had different strengths and weaknesses in their dissemination strategies, and two stakeholders with similar overall influence, such as UN-FAO and WASH, could have significantly different tweeting patterns. In addition, we identified exemplars in each dimension of influence. Regarding tweeting activity, a dedicated expert published more sodium tweets in the past 16 years than any organizations in the sample. In terms of priority, WASH had more than half of its tweets dedicated to sodium. UN-FAO had both the highest proportion of original sodium tweets and posted the most popular sodium tweets among all sampled stakeholders. Regardless of excellence in one dimension, the four most influential stakeholders excelled at least two out of four dimensions of influence. CONCLUSIONS Results from the case study demonstrated that our method not only aligned with a traditional measure of influence but also advanced influence analysis by composing topic-specific influence into four dimensions. We also provided quantifiable measures for users to optimize their time and financial investments on Twitter and for public health entities to refine their social media campaign strategies. Our framework can be applied to improve the dissemination of other health topics, as well as assist policymakers and public campaign experts to maximize population impact.

Our previous study demonstrated that peroxisome proliferator-activated receptor (PPAR) agonists downregulated cereblon (CRBN) expression and reduced the anti-myeloma activity of lenalidomide in vitro and in vivo. We aimed to determine whether DNA methylation and protein degradation contribute to the effects of PPAR agonists. CRBN promoter methylation status was detected using methylation-specific polymerase chain reaction. The CRBN protein degradation rate was measured using a cycloheximide chase assay. Metabolomic analysis was performed in multiple myeloma (MM) cells treated with PPAR agonists and/or lenalidomide. Our retrospective study determined the effect of co-administration of PPAR agonists with immunomodulatory drugs on the outcomes of patients with MM. CpG islands of the CRBN promoter region became highly methylated upon treatment with PPAR agonists, whereas treatment with PPAR antagonists resulted in unmethylation. The CRBN protein was rapidly degraded after treatment with PPAR agonists. Lenalidomide and fenofibrate showed opposite effects on acylcarnitines and amino acids. Co-administration of immunomodulatory drugs and PPAR agonists was associated with inferior treatment responses and poor survival. Our study provides the first evidence that PPAR agonists reduce CRBN expression through various mechanisms including inducing methylation of CRBN promoter CpG island, enhancing CRBN protein degradation, and affecting metabolomics of MM cells.

Background Thioredoxin-1 (TXN1) is one of the major cellular antioxidants in mammals and is involved in a wide range of physiological cellular responses. However, little is known about the roles and the underlying molecular mechanisms of TXN1 in the regulation of hematopoietic stem/progenitor cells (HSPCs). Methods TXN1 conditional knockout mice (ROSA-CreER-TXN1fl/fl) and TXN1fl/fl control mice were used. The mice were treated with tamoxifen and the number and biological functions of HSPCs were measured by flow cytometry, PCR and western blot. Limiting dilution competitive transplantation with sorted HSCs and serial transplantations were performed to assess the effects of TXN1 knockout on HSC self-renewal and long-term reconstitutional capacity. RNA sequencing (RNA-seq) was performed to investigate the downstream molecular pathways of TXN1 deletion in murine HSPCs. CRISPR/Cas9 knockout experiments were performed in vitro in EML murine hematopoietic stem/progenitor cell line to investigate the effects of TXN1 and/or TP53 deletion on cell survival, senescence and colony forming units. TP53 protein degradation assay, CHiP PCR and PGL3 firefly/renilla reporter assay were performed. The effects of TXN1 on various molecular pathways relevant to HSC radiation protection were examined in vitro and in vivo. Results TXN1-TP53 tumor suppressor axis regulates HSPC biological fitness. Deletion of TXN1 in HSPCs using in vivo and in vitro models activates TP53 signaling pathway, and attenuates HSPC capacity to reconstitute hematopoiesis. Furthermore, we found that knocking out of TXN1 renders HSPCs more sensitive to radiation and treatment with recombinant TXN1 promotes the proliferation and expansion of HSPCs. Conclusions Our findings suggest that TXN1-TP53 axis acts as a regulatory mechanism in HSPC biological functions. Additionally, our study demonstrates the clinical potential of TXN1 for enhancing hematopoietic recovery in hematopoietic stem cell transplant and protecting HSPCs from radiation injury.

Perceptual decision-making has been shown to be influenced by reward expected from alternative options or actions, but the underlying neural mechanisms are currently unknown. More specifically, it is debated whether reward effects are mediated through changes in sensory processing, later stages of decision-making, or both. To address this question, we conducted two experiments in which human participants made saccades to what they perceived to be either the first or second of two visually identical but asynchronously presented targets while we manipulated expected reward from correct and incorrect responses on each trial. By comparing reward-induced bias in target selection (i.e., reward bias) during the two experiments, we determined whether reward caused changes in sensory or decision-making processes. We found similar reward biases in the two experiments indicating that reward information mainly influenced later stages of decision-making. Moreover, the observed reward biases were independent of the individual's sensitivity to sensory signals. This suggests that reward effects were determined heuristically via modulation of decision-making processes instead of sensory processing. To further explain our findings and uncover plausible neural mechanisms, we simulated our experiments with a cortical network model and tested alternative mechanisms for how reward could exert its influence. We found that our experimental observations are more compatible with reward-dependent input to the output layer of the decision circuit. Together, our results suggest that, during a temporal judgment task, reward exerts its influence via changing later stages of decision-making (i.e., response bias) rather than early sensory processing (i.e., perceptual bias).

Background: Anaplastic multiple myeloma (AMM) is a very rare but distinct subtype of multiple myeloma (MM) with an extremely poor prognosis. Due to its rarity, AMM lacks detailed descriptions and clear definitions. Moreover, there is no consensus on the treatment and evidence suggests that AMM responds poorly to several novel therapies. We conducted a literature review and retrospective case series to determine clinical characteristics, pathological features, and outcomes of AMM. Case Presentation: Published case reports and case series of AMM since 1983 were systematically extracted and reviewed. A total of 52 patients with AMM were reported in the PUBMED since 1983, including 26 males (50%) and 26 females (50%). The age ranged from 29 years old to 85 years old, with a mean age of 57.02 years old. Most of the patients presented with bone pain (23, 44.2%), fatigue (18, 34.6%), plasmacytoma (18, 34.6%) and weight loss (7, 13.5%). The median survival of the patients was 4 months. To investigate the outcomes of patients with AMM in the current era of treatment, a series of 14 patients with AMM diagnosed at our institute between December 2012 and July 2021was retrospectively analyzed. Our retrospective case series consisted of 12 males (85.7%) and 2 females (14.3%), with a mean age of 59 years old. Most of our AMM patients displayed bone lytic lesions as a common manifestation. The common cytogenetic abnormality was 1q amplification. All patients received standard combination chemotherapy consisting of proteasome inhibitors and/or immunomodulatory agents, and half of the patients underwent autologous hematopoietic stem cell transplantation. The median progression-free survival (PFS) and overall survival (OS) for our 14 AMM patients were 0.84 years and 1.52 years, respectively, which was significantly worse than the regular MM patients treated at our institute from 2003-2013 who had a PFS of 2.28 years and OS of 4.92 years. Conclusions: AMM is a very rare, morphologically distinct variant of MM. It has adverse cytogenetics and an aggressive course. It is often resistant to standard chemotherapy and presents with an extremely low survival rate.

The critical cellular transitions that govern human pancreas development are largely unknown. We performed large-scale single-cell RNA-sequencing (scRNA-Seq) to interrogate human fetal pancreas development from 8-20 weeks post conception. We identified 103 distinct cell types, including four novel endocrine progenitor subtypes displaying unique transcriptional features and differentiation potency. Integration with single-nucleus Assay for Transposase Accessible Chromatin Sequencing (snATAC-Seq) identified candidate regulators of human endocrine cell fate and revealed development-specific regulatory annotation at diabetes risk loci. Comparison of in vitro stem cell-derived and endogenous endocrine cells predicted aberrant genetic programs leading to the generation of off-target cells. Finally, knock-out studies revealed that the gene FEV regulates human endocrine differentiation. This work establishes a roadmap of human pancreatic development, highlights previously unappreciated cellular diversity and lineage dynamics, and provides a blueprint for understanding pancreatic disease and physiology, as well as generating human stem cell-derived islet cells in vitro for regenerative medicine purposes.

Nonmelanoma skin cancer is the most common malignancy and immunosuppression is a key risk factor. Despite the promising data demonstrating the efficacy of immune checkpoint inhibition in the treatment of cutaneous squamous cell carcinoma (cSCC), most immunosuppressed patients are not included in immunotherapy trials due to the risk for toxicity and the lack of data regarding cSCC immune landscape in immunosuppressed patients. To characterize the specific alterations accounting for a diminished antitumor immune response in immunosuppressed patients, we used multispectral imaging on cSCC pathology specimens from immunosuppressed patients with age and stage matched immunocompetent controls. We show that densities of CD68+ cells are diminished in immunosuppressed patients. Moreover, using an organ transplant recipient cohort from two cancer centers, we found significantly lower effector T-cells densities as compared with controls. Overall, density of CD68+ and CD8+LAG3+ cells were predictors of disease-specific and disease-free survival. These findings provide insight into the patterns of immune infiltrating cells in patients with different types of immunosuppression; leading us to conjecture that different immune based therapeutic approaches may be needed to treat immunosuppressed cSCC patients.

Simple Summary Multiple myeloma is the second most common hematologic malignancy in the United States. Eventually, all myeloma patients will relapse and develop resistance to currently available agents. There is an unmet medical need to identify novel therapeutic targets. PIM kinases play an important role in myeloma pathogenesis and disease relapse. We herein provided a comprehensive review on the roles of PIM kinases in myeloma cell survival and proliferation and in the bone marrow microenvironment that supports myeloma growth. The development and testing of novel PIM kinase inhibitors were summarized. Finally, the preclinical studies of the combinatorial effects of PIM kinase inhibitors and other anti-myeloma agents were presented. Abstract Multiple myeloma (MM) remains an incurable disease and novel therapeutic agents/approaches are urgently needed. The PIM (Proviral insertion in murine malignancies) serine/threonine kinases have 3 isoforms: PIM1, PIM2, and PIM3. PIM kinases are engaged with an expansive scope of biological activities including cell growth, apoptosis, drug resistance, and immune response. An assortment of molecules and pathways that are critical to myeloma tumorigenesis has been recognized as the downstream targets of PIM kinases. The inhibition of PIM kinases has become an emerging scientific interest for the treatment of multiple myeloma and several PIM kinase inhibitors, such as SGI-1776, AZD1208, and PIM447 (formerly LGH447), have been developed and are under different phases of clinical trials. Current research has been focused on the development of a new generation of potent PIM kinase inhibitors with appropriate pharmacological profiles reasonable for human malignancy treatment. Combination therapy of PIM kinase inhibitors with chemotherapeutic appears to create an additive cytotoxic impact in cancer cells. Notwithstanding, the mechanisms by which PIM kinases modulate the immune microenvironment and synergize with the immunomodulatory agents such as lenalidomide have not been deliberately depicted. This review provides a comprehensive overview of the PIM kinase pathways and the current research status of the development of PIM kinase inhibitors for the treatment of MM. Additionally, the combinatorial effects of the PIM kinase inhibitors with other targeted agents and the promising strategies to exploit PIM as a therapeutic target in malignancy are highlighted.

Background: There is conflicting evidence regarding prevalence and incidence of atherosclerotic cardiovascular disease (ASCVD) in patients with liver cirrhosis. The risk factors associated with ASCVD within this group of patients have not been investigated previously. Methods and Results: This is a retrospective longitudinal study utilizing the Veterans Affairs (VA) Greater Los Angeles Electronic Medical Record of 623 patients with diagnosis of liver disease. We investigated the incidence of ASCVD events and risk factors associated with ASCVD in these patients. We observed an increase in prevalence of ASCVD events in patients with cirrhosis compared to liver disease patients without cirrhosis (19.12% vs 2.46%). Although the cirrhosis group patients were older but, in our Cox-regression model, after adjusting for traditional ASCVD risk factors especially age, cirrhosis remained a major risk factor for ASCVD events with a hazard ratio (HR) of 5.73 (CI: 2.74-12.72). In the subgroup analysis of cirrhosis group, transferrin saturation greater or equal to 40% had 4.27 times higher risk of ASCVD events than lower transferrin saturation. Conclusion: We propose that the liver damage and subsequent decrease in hepcidin production in patients with cirrhosis would cause a major increase in Non-Transferrin-Bound Iron (NTBI) in circulation. Circula-ting NTBI promotes endothelial dysfunction, produces reactive oxygen species (ROS), and exposes important biomolecules, like low density lipoprotein (LDL), to oxidative stress to facilitate atherosclerosis. Accordingly, these epidemiological results provide evidence for further translational investigations to identify factors to mitigate the development of ASCVD.

Context effects have been explained by either low-level neural adjustments or high-level cognitive processes but not their combination. It is currently unclear how these processes interact to shape individuals’ responses to context. Here, we used a large cohort of human subjects in experiments involving choice between two or three gambles in order to study the dependence of context effects on neural adaptation and individuals’ risk attitudes. Our experiments did not provide any evidence that neural adaptation on long timescales (~100 trials) contributes to context effects. Using post-hoc analyses we identified two groups of subjects with distinct patterns of responses to decoys, both of which depended on individuals’ risk aversion. Subjects in the first group exhibited strong, consistent decoy effects and became more risk averse due to decoy presentation. In contrast, subjects in the second group did not show consistent decoy effects and became more risk seeking. The degree of change in risk aversion due to decoy presentation was positively correlated with the original degrees of risk aversion. To explain these results and reveal underlying neural mechanisms, we developed new models incorporating both low- and high-level processes and used these models to fit individuals’ choice behavior. We found that observed distinct patterns of decoy effects can be explained by a combination of adjustments in neural representations and competitive weighting of reward attributes, both of which depend on risk aversion but in opposite directions. Altogether, our results demonstrate how a combination of low- and high-level processes shapes choice behavior in more naturalistic settings, modulates overall risk preference, and explains distinct behavioral phenotypes., Author summary A large body of experimental work has illustrated that the introduction of a new, and often irrelevant, option can influence preference among the existing options, a phenomenon referred to as context or decoy effects. For example, introducing a new option that is worse than one of the two existing options in all its attributes but better than the alternative option in some attributes (and thus should not ever be selected) can increase the preference for the former option. Context effects have been explained by high-level cognitive processes—such as comparisons and competitions between attributes—or low-level adjustments of neural representations. However, it is unclear how these processes interact to shape individuals’ responses to context. Here, we show that both high-level cognitive processes and low-level neural adjustments shift risk preference during choice between multiple risky options but in opposite directions. Moreover, we demonstrate that combinations of these processes can account for distinct patterns of context effects in human subjects.

Context effects have been explained by either high-level cognitive processes or low-level neural adjustments but not their combination. It is currently unclear how these processes interact to shape individuals’ responses to context. Here, we used a large cohort of human subjects in experiments involving choice between two or three gambles in order to study the dependence of context effects on neural adaptation and individuals’ risk attitudes. We found no evidence that neural adaptation on long timescales (~100 trials) contributes to context effects. However, we identified two groups of subjects with distinct patterns of responses to decoys, both of which depended on individuals’ risk aversion. Subjects in the first group exhibited strong, consistent decoy effects and became more risk averse due to decoy presentation. In contrast, subjects in the second group did not show consistent decoy effects and became more risk seeking. The degree of change in risk aversion due to decoy presentation was positively correlated with the initial degrees of risk aversion. To explain these results and reveal underlying neural mechanisms, we developed a new model that incorporates both low- and high-level processes to fit individuals’ choice behavior. We found that observed decoy effects can be explained by a combination of adjustments in neural representations and competitive weighting of reward attributes, both of which depend on risk aversion but in opposite directions. Altogether, our results demonstrate how a combination of low- and high-level processes shapes multi-attribute choice, modulates overall risk preference, and explains distinct behavioral phenotypes.Significance statementA large body of experimental work has illustrated that the introduction of a new, and often irrelevant, option can influence preference among the existing options, a phenomenon referred to as context or decoy effects. Although context effects have been explained by high-level cognitive processes—such as comparisons and competitions between attributes—or low-level adjustments of neural representations, it is unclear how these processes interact to shape individuals’ responses to context. Here, we show that both high-level cognitive processes and low-level neural adjustments shift risk preference during choice between multiple options but in opposite directions. Moreover, we demonstrate that a combination of these processes can account for distinct patterns of context effects in human subjects.

Perceptual decision making is influenced by reward expected from alternative options or actions, but the underlying neural mechanisms are currently unknown. More specifically, it is debated whether reward effects are mediated through changes in sensory processing and/or later stages of decision making. To address this question, we conducted two experiments in which human subjects made saccades to what they perceived to be the first or second of two visually identical but asynchronously presented targets, while we manipulated expected reward from correct and incorrect responses on each trial. We found that unequal reward caused similar shifts in target selection (reward bias) between the two experiments. Moreover, observed reward biases were independent of the individual’s sensitivity to sensory signals. These findings suggest that the observed reward effects were determined heuristically via modulation of decision-making processes instead of sensory processing and thus, are more compatible with response bias rather than perceptual bias. To further explain our findings and uncover plausible neural mechanisms, we simulated our experiments with a cortical network model and tested alternative mechanisms for how reward could exert its influence. We found that our observations are more compatible with reward-dependent input to the output layer of the decision circuit. Together, our results suggest that during a temporal judgment task, the influence of reward information on perceptual choice is more compatible with changing later stages of decision making rather than early sensory processing.

Decisions we face in real life are inherently risky and can result in one of many possible outcomes. However, most of what we know about choice under risk is based on studies that use options with only two possible outcomes (simple gambles), so it remains unclear how the brain constructs reward values for more complex risky options faced in real life. To address this question, we combined experimental and modeling approaches to examine choice between pairs of simple gambles and pairs of three-outcome gambles in male and female human subjects. We found that subjects evaluated individual outcomes of three-outcome gambles by multiplying functions of reward magnitude and probability. To construct the overall value of each gamble, however, most subjects differentially weighted possible outcomes based on either reward magnitude or probability. These results reveal a novel dissociation between how reward information is processed when evaluating complex gambles: valuation of each outcome is based on a combination of reward information whereas weighting of possible outcomes mainly relies on a single piece of reward information. We show that differential weighting of possible outcomes enabled subjects to make decisions more easily and quickly. Together, our findings reveal a plausible mechanism for how salience, in terms of possible reward magnitude or probability, can influence the construction of subjective values for complex gambles. They also point to separable neural mechanisms for how reward value controls choice and attention in order to allow for more adaptive decision making under risk. SIGNIFICANCE STATEMENT Real-life decisions are inherently risky and can result in one of many possible outcomes, but how does the brain integrate information from all these outcomes to make decisions? To address this question, we examined choice between pairs of gambles with multiple outcomes using various computational models. We found that subjects evaluated individual outcomes by multiplying functions of reward magnitude and probability. To construct the overall value of each gamble, however, they differentially weighted possible outcomes based on either reward magnitude or probability. By doing so, they were able to make decisions more easily and quickly. Our findings illustrate how salience, in terms of possible reward magnitude or probability, can influence the construction of subjective values for more adaptive choice.

NASA is continuing to develop high-power Hall thrusters in the range of 20 to 100 kW for future cargo and manned missions. The cathodes for these thrusters will be required to produce discharge currents in the 50 to 300 A range with lifetimes in excess of 10 kh. A prototype high-current hollow cathode with a 2-cm-diam lanthanum hexaboride (LaB6) insert was previously developed for these applications. The original design featured a graphite cathode tube to interface with the LaB6 insert and an AL2O3 insulated sheath heater capable of heating the higher temperature emitter to ignition temperatures. A new version of this cathode has been designed and built that uses a refractory metal cathode tube and features a robust design similar to the small LaB6 cathode used for the H6 Hall thruster. The new cathode has been successfully tested at steady-state discharge currents from 25 to 300 A. This cathode is intended to be used in an 80 kW nested Hall thruster being built at the University of Michigan at discharge ...

Studies of the hollow-cathode discharge have shown the existence of energetic ions at high-discharge currents that are likely responsible for the high erosion rates observed on the cathode keeper electrode. This work examines the effect of neutral gas injection in the discharge plume of a 250 A lanthanum hexaboride hollow cathode on the production of energetic ions to determine the conditions that yield cathode operation and life. Two different gas injector types are used to deliver neutral gas into the discharge plume and a retarding-potential analyzer is used for ion energy measurements. The flow splits between the cathode internal and external flows, and the number and locations of the external gas injection sites are examined as a function of the discharge current. It is found that increasing discharge current increases the energetic ion production at any given flow rate or injection location. External gas injection reduces energetic ion production for constant cathode flow, with collimated gas-jet in...

Type II phosphatidylinositol 4-kinase IIalpha (PI4KIIalpha) is the dominant phosphatidylinositol kinase activity measured in mammalian cells and has important functions in intracellular vesicular trafficking. Recently PI4KIIalpha has been shown to have important roles in neuronal survival and tumorigenesis. This study focuses on the relationship between membrane cholesterol levels, phosphatidylinositol 4-phosphate (PI4P) synthesis, and PI4KIIalpha mobility. Enzyme kinetic measurements, sterol substitution studies, and membrane fragmentation analyses all revealed that cholesterol regulates PI4KIIalpha activity indirectly through effects on membrane structure. In particular, we found that cholesterol levels determined the distribution of PI4KIIalpha to biophysically distinct membrane domains. Imaging studies on cells expressing enhanced green fluorescent protein (eGFP)-tagged PI4KIIalpha demonstrated that cholesterol depletion resulted in morphological changes to the juxtanuclear membrane pool of the enzyme. Lateral membrane diffusion of eGFP-PI4KIIalpha was assessed by fluorescence recovery after photobleaching (FRAP) experiments, which revealed the existence of both mobile and immobile pools of the enzyme. Sterol depletion decreased the size of the mobile pool of PI4KIIalpha. Further measurements revealed that the reduction in the mobile fraction of PI4KIIalpha correlated with a loss of trans-Golgi network (TGN) membrane connectivity. We conclude that cholesterol modulates PI4P synthesis through effects on membrane organization and enzyme diffusion.

The role of ACTH in stimulating or inhibiting growth of adrenal cells has been a subject of some controversy. Reports that ACTH may stimulate ERK/MAPK in Y1 cells have suggested a role for cAMP in this process. In attempting to extend this work, the ACTH responses in the human H295R cell line have been studied. This cell line makes only a very modest cAMP response to ACTH, yet the ERK1/2 response is highly reproducible and immediate but not prolonged. It is minimally reduced by the protein kinase A inhibitor, H89, but unaffected by protein kinase C and calcium inhibitors. Inhibition of epidermal growth factor receptor or other tyrosine kinase receptor transactivation was without effect, as was inhibition of c-Src activity or c-Src phosphorylation. The most effective inhibitor of this pathway was dansylcadaverine, an inhibitor of receptor internalization. These findings imply that ACTH-induced ERK1/2 activation in H295R cells is dependent on a mechanism distinct from that by which most G protein-coupled receptors activate ERK1/2 but that nevertheless seems to depend on receptor internalization.

The effect of short-term exercise (15 min step-exercise) on serum brain-derived neurotrophic factor (BDNF) levels was evaluated in healthy human subjects. Results showed a short-term, significant increase in serum BDNF levels after exercise. Intra-individual differences in serum BDNF levels were remarkably small on the rest day and also when compared to rest values on the day of the exercise test. Inter-individual differences, on the other hand, were larger by comparison. The result of this study supports the need for larger sample size in studies on BDNF changes in psychiatric disorders or psychiatric drug effects.

Cholesterol has important functions in the organization of membrane structure and this may be mediated via the formation of cholesterol-rich, liquid-ordered membrane microdomains often referred to as lipid rafts. Methyl-beta-cyclodextrin (cyclodextrin) is commonly used in cell biology studies to extract cholesterol and therefore disrupt lipid rafts. However, in this study we reassessed this experimental strategy and investigated the effects of cyclodextrin on the physical properties of sonicated and carbonate-treated intracellular membrane vesicles isolated from Cos-7 fibroblasts. We treated these membranes, which mainly originate from thetrans-Golgi network and endosomes, with cyclodextrin and measured the effects on their equilibrium buoyant density, protein content, represented by the palmitoylated protein phosphatidylinositol 4-kinase type IIα, and cholesterol. Despite the reduction in mass stemming from cholesterol removal, the vesicles became denser, indicating a possible large volumetric decrease, and this was confirmed by measurements of hydrodynamic vesicle size. Subsequent mathematical analyses demonstrated that only half of this change in membrane size was attributable to cholesterol loss. Hence, the non-selective desorption properties of cyclodextrin are also involved in membrane size and density changes. These findings may have implications for preceding studies that interpreted cyclodextrin-induced changes to membrane biochemistry in the context of lipid raft disruption without taking into account our finding that cyclodextrin treatment also reduces membrane size.

Please accept this letter as a thank you for enrolling and supporting me for my placement in the On-Line Research Summer Co-Op at the Foundation for Student Science and Technology. It has been an incredible month and I want to express my gratitude to you and the foundation for allowing me to pursue such an opportunity.

Over the past century, NGOs have been rapidly growing in numbers have become increasingly involved in such health crises as HIV/Aids and Ebola around the world. Many organizations have also been founded to recognize and support oppressed groups in certain countries, one of the most important of these being women. It is undeniable that women of developing nations have been greatly affected by the rise of NGOs, and the ensuing phenomenon of NGO-isation, from increased opportunities for activism, to unsustainable dependencies on nutritional supplements,. This article presents a background of both NGOs and the plight of women in developing nations, as well as attempting to draw a relationship between these two stakeholders in our global society. This article also presents evidence to support the hypotheses that NGOs allow women to become more politically and socially active through government-neutral involvement, but also hinder their health and job prospects by failing to employ local workers and using short-term solutions instead of sustainable ones. Major analysis is conducted on these topics and attempts to determine the correlation between NGOs and their involvement with women in impoverished communities. The article concludes with final comments from the author about their overall experience and thoughts on the issue.Au cours du précédent siècle, les ONG sont rapidement augmentés en nombre et en implication dans plusieurs pays en développement en conséquence de plusieurs crises de santé telles que VIH / SIDA et Ebola. Plusieurs organisations ont aussi été créés pour donner reconnaissance à certaines groupes dans des pays oppressifs, un des plus importants parmi ces groupes étant les femmes. Il est indéniable que les femmes des pays en développement ont été aidés considérablement par la montée des ONG et le phénomène qui s'ensuit d'ONG-isation. Cet article présente un contexte d'à la fois les ONG et la situation des femmes dans les pays en développement et décrit une proposition de recherche pour tenter de déterminer la relation entre ces deux très importantes parties intéressées dans notre société globale. Cette proposition de recherche décrit ses objectives, buts et hypothèses qui concernent divers aspects de la vie d'une femme et ensuite ça décrit pourquoi ceci est un problème important et comment les données vont être obtenues. L'article conclut avec des commentaires finales de l'auteur à propos de leur expérience générale et leurs pensées concernant le problème.

Purpose: To evaluate the influence of gender on baseline characteristics and 1-year clinical outcomes in patients with non-valvular atrial fibrillation (AF). Methods: In the ongoing, international registry GARFIELD, a total of 12,458 prospective patients were enrolled at 739 randomly selected sites in 30 countries between March 2010 and January 2013. Results: Compared with men, women with AF were more likely to be older and have a history of hypertension or venous thromboembolism, but less likely to have a history of vascular disease. Use of antithrombotic therapy was similar in the two groups. At 1-year follow-up, the hazard ratio for women versus men, adjusted for age group, use of vitamin K antagonist, Factor Xa inhibitor, direct thrombin inhibitor, and antiplatelet, congestive cardiac failure, hypertension, diabetes, stroke/transient ischaemic attack, and vascular disease, was 0.815 (95% confidence interval, 0.695-0.957) for the incidence of all-cause mortality, 1.414 (1.053-1.899) for the incidence of stroke/systemic embolism (SE), and 1.024 (0.714-1.470) for the incidence of major bleeding. Conclusion: These findings suggest that women with non-valvular AF have a lower mortality rate despite a higher stroke/SE rate compared with men.

NASA is continuing to develop high power Hall thrusters in the range of 20 to 100 kW for future cargo and manned-missions. The cathodes for these thrusters will be required to produce discharge currents in the 50 to likely over 300 A range with lifetimes in excess of 10 khrs. A prototype high current hollow cathode with a 2-cm-dia lanthanum hexaboride (LaB 6 ) insert was previously developed for these applications. The original design featured a graphite cathode tube to interface with the LaB 6 insert and an Al 2 O 3 insulated sheath heater capable of heating the higher temperature emitter to ignition temperatures. A new version of this cathode has been designed and built that uses a refractory metal cathode tube and features a robust design similar to the small LaB 6 cathode used for the H6 Hall thruster. The cathode has been successfully tested at steady-state discharge currents from 25 A to 300 A. This cathode is intended to be used in the X3/80 80-kW Nested Hall thruster being built at the University of Michigan at discharge currents over 250 A.

Cholesterol is an abundant lipid of the trans-Golgi network (TGN) and of certain endosomal membranes where cholesterol-rich microdomains are important in the organization and compartmentalization of vesicular trafficking. Here we describe the development of a rapid method to isolate a cholesterol-rich endomembrane fraction. We show that widely used subcellular fractionation techniques incompletely separate cholesterol-rich membranes, such as the TGN, from organelles, such as late endosomes and lysosomes. To address this issue, we devised a new subcellular fractionation scheme involving two rounds of velocity centrifugation, membrane sonication, and discontinuous sucrose density gradient centrifugation. This strategy resulted in the isolation of a cholesterol and GM1 glycosphingolipid-enriched membrane fraction that was completely cleared of plasma membrane, endoplasmic reticulum, and mitochondria. This buoyant fraction was enriched for the TGN and recycling endosome proteins Rab11 and syntaxin-6, and it was well resolved from cis-Golgi and early and late endosomal membranes. We demonstrate that this technique can give useful insights into the compartmentation of phosphoinositide synthesis, and it facilitates the isolation of cholesterol-rich membranes from a population of TGN-trafficking vesicles.