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Ssn3, also known as Cdk8, is a member of the four protein Cdk8 submodule within the multi-subunit Mediator complex involved in the co-regulation of transcription. In Candida albicans, the loss of Ssn3 kinase activity affects multiple phenotypes including cellular morphology, metabolism, nutrient acquisition, immune cell interactions, and drug resistance. In these studies, we generated a strain in which Ssn3 was replaced with a functional variant of Ssn3 that can be rapidly and selectively inhibited by the ATP analog 3-MB-PP1. Consistent with ssn3 null mutant and kinase dead phenotypes, inhibition of Ssn3 kinase activity promoted hypha formation. Furthermore, the increased expression of hypha-specific genes was the strongest transcriptional signal upon inhibition of Ssn3 in transcriptomics analyses. Rapid inactivation of Ssn3 was used for phosphoproteomic studies performed to identify Ssn3 kinase substrates associated with filamentation potential. Both previously validated and novel Ssn3 targets were identified. Protein phosphorylation sites that were reduced specifically upon Ssn3 inhibition included two sites in Flo8 which is a transcription factor known to positively regulate C. albicans morphology. Mutation of the two Flo8 phosphosites (threonine 589 and serine 620) was sufficient to increase Flo8-HA levels and Flo8 dependent transcriptional and morphological changes, suggesting that Ssn3 kinase activity negatively regulates Flo8.Under embedded conditions, when ssn3Δ/Δ and efg1Δ/Δ mutants were hyperfilamentous, FLO8 was essential for hypha formation. Previous work has also shown that loss of Ssn3 activity leads to increased alkalinization of medium with amino acids. Here, we show that the ssn3Δ/Δ medium alkalinization phenotype, which is dependent on STP2, a transcription factor involved in amino acid utilization, also requires FLO8 and EFG1. Together, these data show that Ssn3 activity can modulate Flo8 and its direct and indirect interactions in different ways, and underscores the potential importance of considering Ssn3 function in the control of transcription factor activities., Author summary In Candida albicans, Ssn3 kinase activity co-regulates the transcription of numerous genes involved in hyphal growth, metabolism and nutrient acquisition, immune cell interactions, and drug resistance. Using a strain in which Ssn3 could be rapidly and selectively inhibited, we identified both known and novel Ssn3 targets. We identified two phosphosites in Flo8, a regulator of morphology and virulence, that were shown to negatively regulate Flo8 levels and activity. The data and tools presented here will enable a better understanding of how Ssn3 impacts transcriptional and post-transcriptional regulation in order to coordinate processes during physiological and morphological transitions as well as during steady state growth.

Long‐term variability of middle atmosphere temperature (T) and zonal wind (U) is investigated using a three‐member ensemble of historical simulations of NCAR's Whole Atmospheric Community Climate Model latest version 6 (WACCM6) for 1850–2014 (165 years). The model reproduces the climatological features of T and U. The contributions of Quasi Biennial Oscillation (QBO) at 10 and 30 hPa, solar cycle (SC), El Niño‐Southern Oscillation (ENSO), ozone depleting substances (ODS), carbon dioxide (CO2), and stratospheric sulfate aerosol (volcanic eruptions) to change in monthly zonal mean T and U are analyzed using multiple linear regression. The signal due to CO2 increase dominates as a predictor of the net multidecadal global annual mean temperature change at all levels in the middle atmosphere. Contributions from ODS also affect the net multidecadal global mean temperature trend in the stratosphere. Because of similarities in the time evolution of the emissions of CO2 and ODS, the analysis of existing model output cannot accurately separate the attributions of cooling to these two dominant forcing processes. On shorter time scales, solar flux variations are the largest source of variability in the mesosphere while volcanic eruptions are the largest in the stratosphere. In the stratosphere and mesosphere, both QBO and ENSO can significantly impact zonal mean temperature and zonal‐mean zonal wind depending on latitudes, but their impact on the multidecadal global mean temperature trend is very small.

Long‐term variability and tendencies in migrating diurnal tide (DW1) are investigated for the first time using a three‐member ensemble of historical simulations by NCAR's Whole Atmosphere Community Climate Model, latest Version 6 (WACCM6) for 1850–2014 (165 years). The model reproduces the climatological features of the tide in temperature (T), zonal wind (U), and meridional wind (V). The amplitudes peak in the upper mesosphere and lower thermosphere (above ~0.001 hPa) at the equator for T (~10 K) and over 20–30°N and S latitudes for U (~15 m/s) and V (~25 m/s). The contributions of solar cycle (SC), quasi biennial oscillation (QBO) at 10 and 30 hPa, El Niño–Southern Oscillation (ENSO), ozone depleting substances (ODS), carbon dioxide (CO2), and stratospheric sulfate aerosols (volcanic eruptions) to change in annual mean amplitudes are analyzed using multiple linear regression. The tidal amplitudes in three components show a long‐term increase in the upper stratosphere (0.95–10.7 hPa) and the upper mesosphere (0.0001–0.01 hPa), predominantly due to increasing CO2 with a smaller contribution from the trend in ENSO. Interestingly, the global mean tidal amplitude in T decreases sharply after 1950–1960 until 1995 and then increases in association with changes in ODSs. The seasonal differences in tidal responses to the above indices can be as large as the overall signals. All the responses are stronger in the upper mesosphere; however, there is also a pronounced negative response of temperature tide to ODSs over middle to high latitudes around the stratopause (~1 hPa) during all seasons.

The Whole Atmosphere Community Climate Model version 6 (WACCM6) is a major update of the whole atmosphere modeling capability in the Community Earth System Model (CESM), featuring enhanced physical, chemical and aerosol parameterizations. This work describes WACCM6 and some of the important features of the model. WACCM6 can reproduce many modes of variability and trends in the middle atmosphere, including the Quasi‐Biennial Oscillation, Stratospheric Sudden Warmings and the evolution of Southern Hemisphere springtime ozone depletion over the 20th century. WACCM6 can also reproduce the climate and temperature trends of the 20th century throughout the atmospheric column. The representation of the climate has improved in WACCM6, relative to WACCM4. In addition, there are improvements in high latitude climate variability at the surface and sea ice extent in WACCM6 over the lower top version of the model (CAM6) that come from the extended vertical domain and expanded aerosol chemistry in WACCM6, highlighting the importance of the stratosphere and tropospheric chemistry for high latitude climate variability.

Sasha E Parets,1 Anna K Knight,2 Alicia K Smith,1,2 1Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA; 2Genetics and Molecular Biology Program, Emory University, Atlanta, GA, USA Abstract: Preterm birth (PTB

© 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society Objectives: To determine the prevalence and outcomes of breathlessness in older Americans. Setting: Community-dwelling older adults. Participants: Individuals aged 70 and older in the nationally representative Health and Retirement Study (2008, follow-up through 2012) (N = 3,671; mean age 78). Measurements: Breathlessness was assessed by asking the question, “How often do you become short of breath while awake?” Responses of often or sometimes were considered to represent a level of breathlessness sufficient to warrant clinical attention. The prevalence of breathlessness is described overall and in subpopulations, then rates of associated symptoms, well-being, and health services use of participants who were breathless are compared with rates of those who were not. The risk of decline in activities of daily living (ADLs) and death through 2012 was estimated by creating a multivariable Cox proportional hazards model, adjusting for age, sex, race and ethnicity, and education. Results: Twenty-five percent of participants reported breathlessness. The prevalence of breathlessness was higher in certain subpopulations: chronic lung disease (63%), multimorbidity (≥2 chronic conditions) (45%), current smokers (38%), heart disease (36%), obesity (body mass index ≥30.0 kg/m2) (33%), and education less than high school (32%). Breathlessness was associated with higher rates of depression, anxiety, and severe fatigue; lower ratings of well-being; and higher rates of clinic and emergency department visits and hospitalizations (all P

© 2015 The Author(s) BACKGROUND: As our society ages, improving medical care for an older population will be crucial. Discrimination in healthcare may contribute to substandard experiences with the healthcare system, increasing the burden of poor health in

Rising use of advance directives has made surrogate decision making both easier and harder. In many cases, these directives help guide decision making for patients who have lost decision-making capacity. In some cases, however, directives may conflict with what physicians or surrogates view as what is in the patient's best interest. These conflicts can place substantial emotional and moral burdens on physicians and surrogates, and there is little practical guidance for how to address them. We propose a 5-question framework for untangling the conflict between advance directives and best interests of a patient with a surrogate decision maker: (1) Is the clinical situation an emergency? (2) In view of the patient's values and goals, how likely is it that the benefits of the intervention will outweigh the burdens? (3) How well does the advance directive fit the situation at hand? (4) How much leeway did the patient provide the surrogate for overriding the advance directive? (5) How well does the surrogate represent the patient's best interests? We use 2 clinical cases with contrasting outcomes to demonstrate how this framework can help resolve common dilemmas.

Objectives To determine whether advance care planning influences quality of end-of-life care. Design In this observational cohort study, Medicare data and survey data from the Health and Retirement Study (HRS) were combined to determine whether advance care planning was associated with quality metrics. Setting The nationally representative HRS. Participants Four thousand three hundred ninety-nine decedent subjects (mean age 82.6 at death, 55% women). Measurements Advance care planning (ACP) was defined as having an advance directive (AD), durable power of attorney (DPOA) or having discussed preferences for end-of-life care with a next of kin. Outcomes included previously reported quality metrics observed during the last month of life (rates of hospital admission, in-hospital death, >14 days in the hospital, intensive care unit admission, >1 emergency department visit, hospice admission, and length of hospice ≤3 days). Results Seventy-six percent of subjects engaged in ACP. Ninety-two percent of ADs stated a preference to prioritize comfort. After adjustment, subjects who engaged in ACP were less likely to die in a hospital (adjusted relative risk (aRR) = 0.87, 95% confidence interval (CI) = 0.80-0.94), more likely to be enrolled in hospice (aRR = 1.68, 95% CI = 1.43-1.97), and less likely to receive hospice for 3 days or less before death (aRR = 0.88, 95% CI = 0.85-0.91). Having an AD, a DPOA or an ACP discussion were each independently associated with a significant increase in hospice use (P