Thermotolerance in S. cerevisiae as a model to study extracellular vesicle biology.

The budding yeast Saccharomyces cerevisiae is a proven model organism for elucidating conserved eukaryotic biology, but to date its extracellular vesicle (EV) biology is understudied. Here, we show yeast transmit information through the extracellular medium that increases survival when confronted with heat stress and demonstrate the EV-enriched samples mediate this thermotolerance transfer. These samples contain vesicle-like particles that are exosome-sized and disrupting exosome biogenesis by targeting endosomal sorting complexes required for transport (ESCRT) machinery inhibits thermotolerance transfer. We find that Bro1, the yeast ortholog of the human exosome biomarker ALIX, is present in EV samples, and use Bro1 tagged with green fluorescent protein (GFP) to track EV release and uptake by endocytosis. Proteomics analysis reveals that heat shock protein 70 (HSP70) family proteins are enriched in EV samples that provide thermotolerance. We confirm the presence of the HSP70 ortholog stress-seventy subunit A2 (Ssa2) in EV samples and find that mutant yeast cells lacking SSA2 produce EVs but they fail to transfer thermotolerance. We conclude that Ssa2 within exosomes shared between yeast cells contributes to thermotolerance. Through this work, we advance Saccharomyces cerevisiae as an emerging model organism for elucidating molecular details of eukaryotic EV biology and establish a role for exosomes in heat stress and proteostasis that seems to be evolutionarily conserved.

The plan formulation method: An empirically validated and clinically useful procedure applied to a clinical case of a patient with a severe personality disorder.

The plan formulation method (PFM) is an empirically validated procedure for identifying a patient's goals for therapy, what is hindering the patient from attaining those goals, and how the patient is likely to work in therapy. In this paper, we employ the PFM to analyze the initial psychotherapy sessions of Geena, a 30-year-old outpatient with borderline personality disorder and relational and substance abuse problems. Employing the PFM, we identify a family of pathogenic beliefs (e.g., that she is unlovable and unworthy; that her parents will be hurt if she has satisfying intimate relationships) that Geena sought to disprove in her therapy and explain how she worked with the therapist to do so. We illustrate how the PFM can help the therapist identify what information and what types of interventions will be helpful for a given patient.

An examination of energy efficiency retrofit scheme applications by low-income households in Ireland.

This paper studies the determinants of why low-income households in Ireland abandon energy efficiency retrofit applications using administrative data from a targeted energy efficiency grant. By applying for the scheme, the applicants overcome any financial barriers for undertaking retrofits and demonstrate their willingness to improve the energy efficiency of their dwellings. Hence this study contributes to the scarce literature on non-financial barriers preventing low-income households from undertaking energy efficiency retrofits. Contrary to previous findings, we find that the higher the number of retrofits to be implemented, the lower the probability of households abandoning their applications. We also find that planning to undertake retrofits such as ventilation, which can significantly improve the health and safety standards of the dwelling, is associated with a higher probability of abandonment. Both findings indicate the presence of key behavioural and informational barriers which prevent low-income households from fully comprehending the purpose or benefits of proposed energy efficient retrofits. Our findings also suggest that higher grant expenditure on dwellings with poor pre-works energy efficiency rating and on retrofits such as attic insulation and heating system upgrades may have the highest energy efficiency improvements per unit of expenditure. Within the constraints of limited budgets for retrofit grant supports, this research can inform the redesign of grant schemes to achieve the greatest aggregate improvements in residential building energy efficiency.

Dietary Polyphenol and Methylsulfonylmethane Supplementation Improves Immune, DAMP Signaling, and Inflammatory Responses During Recovery From All-Out Running Efforts.

Nutritional ingredients with defined mechanisms of action can be useful in the recovery of the body from the physical demands of a habitual training plan. The purpose of this study was to determine the effect of dietary supplementation with optimized curcumin, pomegranate ellagitannins, and MSM (R + MSM) on immune-associated mRNA during early recovery (i.e., up to 8 h post-exercise) following all-out running efforts (5-km, 10-km, and 21.1-km). Subjects (N = 14) were randomized to either a supplement (R + MSM) or a control group using an open label design. The study was completed over a period of 31-day prior to a scheduled half-marathon race. Venous blood samples were collected into PAXgene tubes at baseline, subsequent samples were collected at 2, 4, and 8 h after each running effort. A 574-plex mRNA Immunology Array (NanoString) was measured for each sample and ROSALIND® Advanced Analysis Software was used to examined changes in 31 annotated immune response pathways and specific mRNA changes. The greatest change in immune pathways occurred at 2 h (GSS > 3) followed by 4 h (GSS 2-3) and 8 h (GSS 1-2). R + MSM was associated with an increase in innate immunity (CAMP, LTF, TIRAP, CR1, IL1R1, CXCR1, PDCDILG2, and GNLY) and a blunted/smaller increase in damage-associated molecular pattern (DAMP) signaling/inflammation (TLR4, TLR5, S100A8, S100A9, and IFP35). We also found changes in immune-associated mRNA that have not been previously linked to exercise recovery (SOCS1, SOCS2, MME, CECAM6, MX1, IL-1R2, KLRD1, KLRK1, and LAMP3). Collectively these results demonstrate that supplementation with a combination of optimized curcumin, pomegranate ellagitannins, and methylsulfonylmethane resulted in changes that may improve biological recovery from all-out running efforts.

Household attributes associated with peak period domestic appliance loads.

Household appliances represent substantial electricity load within the residential sector, particularly during the electricity system's period of peak evening load. While there is broad understanding of the factors that systematically impact on aggregate residential loads, much less is known about appliance loads. A research priority is understanding how socio-demographic, dwelling, and appliance factors are associated with the timing and scale of appliance loads. Using data from Ireland the analysis finds that the number of household occupants; number of appliances; and daytime occupancy of the home are closely associated with appliance loads but varies depending on the time of day. No association is found between appliance uses and building tenure, type or age; or socio-demographic variables such as income, age or education. The empirical findings have relevance for modelling residential electricity loads, and for design of measures to shift residential loads away from the evening peak period.

Dimensions of childhood trauma and their direct and indirect links to PTSD, impaired control over drinking, and alcohol-related-problems.

INTRODUCTION: Post-Traumatic Stress Disorder (PTSD) develops after experiencing events that evoke fear, helplessness, or horror. The Hyperarousablity Hypothesis suggests that those with PTSD may drink more to dampen physiological reactivity. We examined the direct and indirect relationships between childhood trauma (e.g., physical-neglect, emotional-abuse, physical-abuse, sexual-abuse) versus an emotionally-supportive-family on PTSD, impaired control over drinking (IC), alcohol-use, and alcohol-related-problems. IC reflects consuming more alcohol than one originally intended. METHODS: We fit a multiple-group SEM to data on 835 participants. Mediational analyses were conducted by using the (K = 20,000) bootstrap technique with confidence intervals. RESULTS: Physical-neglect was directly linked to more IC among both genders. Emotional abuse was also found to be directly linked to more PTSD among both genders. Furthermore, PTSD was directly linked to more impaired control over alcohol use (IC) among both genders. Mediational analyses showed that physical-neglect was indirectly linked to more alcohol-related-problems through increased IC. Having an emotionally supportive family was directly linked to fewer PTSD symptoms among women. For both genders, emotional abuse was indirectly linked to more alcohol-related-problems through more PTSD symptoms, impaired control over alcohol use difficulties, and in turn, more alcohol-use. Sexual abuse was indirectly linked to increased alcohol-related- problems through increased PTSD symptoms and more IC, and in turn, more alcohol-use among men. CONCLUSIONS: Recalled childhood trauma (sexual and emotional abuse) may contribute to PTSD symptoms and dysregulated drinking. In conclusion, our data suggest that reducing PTSD symptoms may assist individuals in regaining control over their drinking.

Plan-compatible termination in psychotherapy: Perspectives from control-mastery theory.

Termination processes in psychotherapy vary widely across patients, therapists, and therapies. While general guidelines on termination can inform ethical and responsible termination practices, termination decisions and processes are likely optimized using a case-specific approach. Control-mastery theory (CMT) provides a framework for considering the unique ways individual patients work in psychotherapy and can be applied to help therapists understand and facilitate optimal terminations. The present article provides a brief overview of CMT and outlines perspectives regarding the decision-making and discussion of psychotherapy termination, the processing of termination, and the final session of therapy. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Radiological manifestations of COVID-19: key points for the physician.

The emergence of the SARS-CoV-2 virus at the end of 2019 has led to unprecedented demand on healthcare systems around the world. Healthcare workers, including doctors, have found themselves having to work in unfamiliar environments in the effort to control this pandemic. This article gives the hospital physician an overview of the radiological manifestations of COVID-19 disease, to improve knowledge and increase familiarity when reviewing radiographic images.

Residential stock data and dataset on energy efficiency characteristics of residential building fabrics in Ireland.

These data support the research article "Improving energy savings from a residential retrofit policy: a new model to inform better retrofit decisions" - (Mac Uidhir et al., 2019) [1]. This article presents 3 data sources which are utilised in conjunction with a detailed energy system model of the residential sector to explore policy pathways for residential retrofitting. Data is collected from the Central Statistics Office (CSO) and the Sustainable Energy Authority of Ireland (SEAI). The first SEAI dataset is compiled for Ireland in compliance with the EU Energy Performance of Buildings Directive (EPBD) [2]. Data is collected using the Dwelling Energy Assessment Procedure (DEAP) [3]. DEAP is used to produce energy performance certificates known as Building Energy Ratings (BER). A BER indicates a buildings energy performance across a 15-point energy efficiency scale, rated alphabetically from A1 to G, in units of kWh/m2 year. A BER is required for new buildings and the rent or sale of existing dwellings - therefore the database has consistently grown in size since its inception in 2006. The BER database contains 735,906 records of individual dwellings. The database includes detailed building fabric information across a range of different building types, year of construction, Main/Secondary space/water heating fuels, heating system efficiency, ventilation method and structure type (Insulated concrete form, Masonry, Timber or Steel Frame). The second SEAI dataset (PWBER) contains aggregated pre and post BER information for a sample of 112,007 dwellings retrofitted during the period 2010-2015; this database contains mean energy efficiency improvement (kWh/m2 year) for a range of retrofit combinations as they apply to nine distinct building archetypes. The third CSO dataset is compiled from census data, representing the frequency of building types by year of construction.

Incidence and evolution of imaging changes on cone-beam CT during and after radical radiotherapy for non-small cell lung cancer.

BACKGROUND AND PURPOSE: Cone beam CT (CBCT) is used to improve accuracy of radical radiotherapy by adjusting treatment to the observed imaging changes. To ensure appropriate adjustment, image interpretation should precede any changes to treatment delivery. This study provides the methodology for image interpretation and the frequency and evolution of the changes in patients undergoing radical radiotherapy for localised and locally advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: From December 2012 to December 2014, 250 patients with localised and locally advanced NSCLC had 2462 chest CBCT scans during the course of fractionated radical radiotherapy (RT) (3-5 daily CBCTs in the first week followed by at least weekly imaging, mean 9.5 per patient, range 1-21). All CBCT images were reviewed describing changes and their evolution using diagnostic imaging definitions and validated by an independent chest radiologist. RESULTS: During radical RT for NSCLC 328 imaging changes were identified on CBCT in 180 (72%) patients; 104 (32%) had reduction and 41 (13%) increase in tumour size; 48 (15%) had changes in consolidations contiguous to the primary lesion, 26 (8%) non-contiguous consolidations, 43 (13%) changes in tumour cavitation, 36 (11%) pleural effusion and 30 (9%) changes in atelectasis. In 105 patients imaging changes were noted in continuity with the treated tumour of which only 41 (39%) represented tumour enlargement; others included new or enlarging adjacent consolidation (34%), and new or enlarging atelectasis (19%). The changes evolved during treatment. CONCLUSION: Imaging changes on CBCT include real and apparent changes in tumour size and parenchymal changes which evolve during treatment. Correct image interpretation, particularly when occurring adjacent to the tumour, is essential prior to adjustment to treatment delivery.

Evaluating temporal controls on greenhouse gas (GHG) fluxes in an Arctic tundra environment: An entropy-based approach.

There is significant spatial and temporal variability associated with greenhouse gas (GHG) fluxes in high-latitude Arctic tundra environments. The objectives of this study are to investigate temporal variability in CO2 and CH4 fluxes at Barrow, AK and to determine the factors causing this variability using a novel entropy-based classification scheme. In particular, we analyzed which geomorphic, soil, vegetation and climatic properties most explained the variability in GHG fluxes (opaque chamber measurements) during the growing season over three successive years. Results indicate that multi-year variability in CO2 fluxes was primarily associated with soil temperature variability as well as vegetation dynamics during the early and late growing season. Temporal variability in CH4 fluxes was primarily associated with changes in vegetation during the growing season and its interactions with primary controls like seasonal thaw. Polygonal ground features, which are common to Arctic regions, also demonstrated significant multi-year variability in GHG fluxes. Our results can be used to prioritize field sampling strategies, with an emphasis on measurements collected at locations and times that explain the most variability in GHG fluxes. For example, we found that sampling primary environmental controls at the centers of high centered polygons in the month of September (when freeze-back period begins) can provide significant constraints on GHG flux variability - a requirement for accurately predicting future changes to GHG fluxes. Overall, entropy results document the impact of changing environmental conditions (e.g., warming, growing season length) on GHG fluxes, thus providing clues concerning the manner in which ecosystem properties may be shifted regionally in a future climate.

Adding Resistance Training to the Standard of Care for Inpatient Substance Abuse Treatment in Men With Human Immunodeficiency Virus Improves Skeletal Muscle Health Without Altering Cytokine Concentrations.

Vingren, JL, Curtis, JH, Levitt, DE, Duplanty, AA, Lee, EC, McFarlin, BK, and Hill, DW. Adding resistance training to the standard of care for inpatient substance abuse treatment in men with human immunodeficiency virus improves skeletal muscle health without altering cytokine concentrations. J Strength Cond Res 32(1): 76-82, 2018-Substance abuse and human immunodeficiency virus (HIV) infection can independently lead to myopathy and related inflammatory alterations; importantly, these effects seem to be additive. Resistance training (RT) can improve muscle health in people living with HIV (PLWH), but the efficacy of this intervention has not been examined for PLWH recovering from substance abuse. The purpose of this study was to determine the effect of RT on muscle health markers (mass, strength, and power) and basal circulating biomarkers for men living with HIV undergoing substance abuse treatment. Men living with HIV undergoing 60-day inpatient substance abuse treatment completed either RT (3×/wk) or no exercise training (control) for 6 weeks. Muscle mass, strength, and power, and fasting circulating cytokines (interferon γ, tumor necrosis factor-α, interleukin (IL)-1ß, IL-2, IL-4, IL-6, and IL-10), vascular cellular adhesion molecule-1, and cortisol were measured before (PRE) and after (POST) the 6-week period. Both groups received the standard of care for HIV and substance abuse treatment determined by the inpatient facility. Muscle mass, strength, and power increased (p ≤ 0.05) from PRE to POST for RT but were unchanged for control. No differences were found for circulating biomarkers. Adding RT to the standard of care for substance abuse treatment improved aspects of muscle health (mass, strength, and power) in men living with HIV. These improvements are associated with a lower risk of a number of health conditions. Therefore, practitioners should consider implementing RT interventions as part of substance abuse treatment programs in this population to help manage long-term health.

Recreational boating site choice and the impact of water quality.

This paper examines whether water quality has an effect on recreational boating activity. The analysis is based on survey data collected by face-to-face interviews with recreational visitors to 10 waterway sites across Ireland. We model the respondent's choice decision to travel to a specific site for the purposes of beginning their recreational boating activity. Water quality data is from European Union Water Framework Directive monitoring stations. Across recreational sites, which have generally high water quality levels within our sample, we find that boaters favour sites with better water quality; as indicated by biological oxygen demand and phosphates metrics. We also find that for each additional 10 km distance from respondents' homes the probability that a site is visited declines by up to 10%. Preferences for other site attributes, such as boat slipways, parking and toilet facilities, were counter to expectation but reflects the fact that all boat users do not necessarily access or need all facilities provided.

Pictorial review: the pearls and pitfalls of the radiological manifestations of gallstone ileus.

We present a pictorial review of a range of typical and atypical cases of gallstone ileus (GI), across a wide range of imaging modalities. GI is a complication of gallstone disease causing mechanical intestinal obstruction due to impaction of gallstone in the gastrointestinal tract. The spectrum of presentation can vary enormously, and we highlight the importance of accurate imaging diagnosis of GI especially early use of computed tomography. This will lead to timely and appropriate surgical intervention with the potential avoidance of unnecessary outcomes. The ambition of pictorial synopsis is to make the radiologists to be more vigilant to the common and more obscure imaging findings of GI.

Use of advanced imaging techniques during visits to emergency departments--implications, costs, patient benefits/risks.

25 years ago, on a Friday evening at 9 pm, the emergency department (ED) was full of patients with a wide range of clinical problems. Their investigations included plain radiographs, but no other imaging was included until the next working day. At present, many patients are receiving advanced imaging such as ultrasound, CT and MRI, often delivered out of hours--an obvious advance for patients or sometimes an unnecessary development? In this article, we will consider how to assess patient benefits and whether increased use of advanced imaging is an overall advance for patients. We will address the general implications for healthcare services which come with greater use of advanced imaging. We will then address the effect of advanced imaging on individual fictional ED patients with a variety of complaints.

The Association Between Heroin Inhalation and Early Onset Emphysema.

BACKGROUND: Inhalation/smoking has become the most common method of recreational opiate consumption in the United Kingdom and other countries. Although some heroin smokers appear to develop COPD, little is known about the association. METHODS: We present data from a cohort of 73 heroin smokers with clinician-diagnosed and spirometrically confirmed COPD, seen within our clinical service, where symptoms developed before the age of 40 years. RESULTS: The whole group mean age at diagnosis was 41 years, subjects had smoked heroin for 14 years, and mean FEV1 was 1.08 L (31.5% predicted), with mean FEV1/FVC of 0.4. No subject was found to have severe α1-antitrypsin deficiency. Forty-four subjects had either a high-resolution CT (HRCT) scan (32) or measurement of lung diffusion (12). Overall HRCT scan emphysema score averaged across the upper, middle, and lower part of the lung was 2.3 (5%-25% emphysema), with 47% subjects having an upper lobe emphysema score ≥ 3 (25%-50% emphysema). Median diffusing capacity of the lung for carbon monoxide was 48% of predicted value. CONCLUSIONS: Recreational smoking of heroin appears to lead to early onset COPD with a predominant emphysema phenotype. This message is important to both clinicians and the public, and targeted screening and education of this high-risk population may be justified.

A retrospective observational study of leucoreductive strategies to manage patients with acute myeloid leukaemia presenting with hyperleucocytosis.

Acute myeloid leukaemia (AML) patients with hyperleucocytosis have higher early mortality, lower complete remission (CR) and overall survival (OS). Whether different pre-induction leucoreduction strategies can improve outcome is unknown. A single centre retrospective cohort study was conducted on AML patients with a white blood cell count (WBC) >100 × 10(9) /l between 1987 and 1997, and on all AML patients between 1998 and 2006, to determine (a) the effect of four different leucoreductive strategies (leukapheresis, hydroxycarbamide, leukapheresis and hydroxycarbamide or no pre-induction leucoreduction) on early (day 28) mortality, CR, and OS; and (b) whether a high presenting WBC remains a negative predictor of OS in patients surviving induction (first 28 d). In the 1998-2006 cohort (n = 702), higher WBC was associated with higher early mortality and lower OS but its effects were greatly diminished in patients who survived the first 28 d (Hazard Ratio 1·094 vs. 1·002). A WBC of 34·1 × 10(9) /l had the highest sensitivity (75·6%) and specificity (67·4%) for early mortality. None of the four leucoreduction strategies differed significantly in early mortality, CR, or OS in patients with WBC>100 × 10(9) /l (n = 166). The number of leucostatic signs was a significant predictor of early mortality (P < 0·0001) and OS (P = 0·0007). The results suggest that AML patients with hyperleucocytosis should be induced, if eligible, without pre-induction leucoreduction.

Sphingosine kinase 1 regulates measles virus replication.

Measles virus (MV) manipulates host factors to facilitate virus replication. Sphingosine kinase (SK) is an enzyme catalyzing the formation of sphingosine 1-phosphate and modulates multiple cellular processes including the host defense system. Here, we determined the role of SK1 in MV replication. Overexpression of SK1 enhanced MV replication. In contrast, inhibition of SK impaired viral protein expression and infectious virus production from cells expressing MV receptor, SLAM or Nectin-4. The inhibition of virus replication was observed when the cells were infected by vaccine strain or wild type MV or V/C gene-deficient MV. Importantly, SK inhibition suppressed MV-induced activation of NF-κB. The inhibitors specific to NF-κB signal pathway repressed the synthesis of MV proteins, revealing the importance of NF-κB activation for efficient MV replication. Therefore, SK inhibition restricts MV replication and modulates the NF-κB signal pathway, demonstrating that SK is a cellular factor critical for MV replication.

The TRPM8 channel forms a complex with the 5-HT(1B) receptor and phospholipase D that amplifies its reversal of pain hypersensitivity.

Effective relief from chronic hypersensitive pain states remains an unmet need. Here we report the discovery that the TRPM8 ion channel, co-operating with the 5-HT(1B) receptor (5-HT(1B)R) in a subset of sensory afferents, exerts an influence at the spinal cord level to suppress central hypersensitivity in pain processing throughout the central nervous system. Using cell line models, ex vivo rat neural tissue and in vivo pain models, we assessed functional Ca(2+) fluorometric responses, protein:protein interactions, immuno-localisation and reflex pain behaviours, with pharmacological and molecular interventions. We report 5-HT(1B)R expression in many TRPM8-containing afferents and direct interaction of these proteins in a novel multi-protein signalling complex, which includes phospholipase D1 (PLD1). We provide evidence that the 5-HT(1B)R activates PLD1 to subsequently activate PIP 5-kinase and generate PIP2, an allosteric enhancer of TRPM8, achieving a several-fold increase in potency of TRPM8 activation. The enhanced activation responses of synaptoneurosomes prepared from spinal cord and cortical regions of animals with a chronic inflammatory pain state are inhibited by TRPM8 activators that were applied in vivo topically to the skin, an effect potentiated by co-administered 5-HT(1B)R agonists and attenuated by 5-HT(1B)R antagonists, while 5-HT(1B)R agents alone had no detectable effect. Corresponding results are seen when assessing reflex behaviours in inflammatory and neuropathic pain models. Control experiments with alternative receptor/TRP channel combinations reveal no such synergy. Identification of this novel receptor/effector/channel complex and its impact on nociceptive processing give new insights into possible strategies for enhanced analgesia in chronic pain.