Hodgesjohansson7134

Cell survival in response to stress is determined by the coordination of various signaling pathways. The kinase p38α is activated by many stresses, but the intensity and duration of the signal depends on the stimuli. HDAC inhibitor How different p38α-activation dynamics may impact cell life/death decisions is unclear. Here, we show that the p38α-signaling output in response to stress is modulated by the expression levels of the downstream kinase MK2. We demonstrate that p38α forms a complex with MK2 in nonstimulated mammalian cells. Upon pathway activation, p38α phosphorylates MK2, the complex dissociates, and MK2 is degraded. Interestingly, transient p38α activation allows MK2 reexpression, reassembly of the p38α-MK2 complex, and cell survival. In contrast, sustained p38α activation induced by severe stress interferes with p38α-MK2 interaction, resulting in irreversible MK2 loss and cell death. MK2 degradation is mediated by the E3 ubiquitin ligase MDM2, and we identify four lysine residues in MK2 that are directly ubiquitinated by MDM2. Expression of an MK2 mutant that cannot be ubiquitinated by MDM2 enhances the survival of stressed cells. Our results indicate that MK2 reexpression and binding to p38α is critical for cell viability in response to stress and illustrate how particular p38α-activation patterns induced by different signals shape the stress-induced cell fate.CD8+ T cells are inherently cross-reactive and recognize numerous peptide antigens in the context of a given major histocompatibility complex class I (MHCI) molecule via the clonotypically expressed T cell receptor (TCR). The lineally expressed coreceptor CD8 interacts coordinately with MHCI at a distinct and largely invariant site to slow the TCR/peptide-MHCI (pMHCI) dissociation rate and enhance antigen sensitivity. However, this biological effect is not necessarily uniform, and theoretical models suggest that antigen sensitivity can be modulated in a differential manner by CD8. We used two intrinsically controlled systems to determine how the relationship between the TCR/pMHCI interaction and the pMHCI/CD8 interaction affects the functional sensitivity of antigen recognition. Our data show that modulation of the pMHCI/CD8 interaction can reorder the agonist hierarchy of peptide ligands across a spectrum of affinities for the TCR.Cellular respiration is powered by membrane-bound redox enzymes that convert chemical energy into an electrochemical proton gradient and drive the energy metabolism. By combining large-scale classical and quantum mechanical simulations with cryo-electron microscopy data, we resolve here molecular details of conformational changes linked to proton pumping in the mammalian complex I. Our data suggest that complex I deactivation blocks water-mediated proton transfer between a membrane-bound quinone site and proton-pumping modules, decoupling the energy-transduction machinery. We identify a putative gating region at the interface between membrane domain subunits ND1 and ND3/ND4L/ND6 that modulates the proton transfer by conformational changes in transmembrane helices and bulky residues. The region is perturbed by mutations linked to human mitochondrial disorders and is suggested to also undergo conformational changes during catalysis of simpler complex I variants that lack the "active"-to-"deactive" transition. Our findings suggest that conformational changes in transmembrane helices modulate the proton transfer dynamics by wetting/dewetting transitions and provide important functional insight into the mammalian respiratory complex I.Nutrient acquisition is crucial for oceanic microbes, and competitive solutions to solve this challenge have evolved among a range of unicellular protists. However, solitary solutions are not the only approach found in natural populations. A diverse array of oceanic protists form temporary or even long-lasting attachments to other protists and marine aggregates. Do these planktonic consortia provide benefits to their members? Here, we use empirical and modeling approaches to evaluate whether the relationship between a large centric diatom, Coscinodiscus wailesii, and a ciliate epibiont, Pseudovorticella coscinodisci, provides nutrient flux benefits to the host diatom. We find that fluid flows generated by ciliary beating can increase nutrient flux to a diatom cell surface four to 10 times that of a still cell without ciliate epibionts. This cosmopolitan species of diatom does not form consortia in all environments but frequently joins such consortia in nutrient-depleted waters. Our results demonstrate that symbiotic consortia provide a cooperative alternative of comparable or greater magnitude to sinking for enhancement of nutrient acquisition in challenging environments.

Suboptimal symptom control in patients with life-limiting illnesses is a major issue. A clinical decision support system (CDSS) that combines a patient-reported symptom assessment scale (SAS) and guideline-based individualised recommendations has the potential to improve symptom management. However, lacking end-user acceptance often prevents CDSS use in daily practice.We aimed to evaluate the acceptability and feasibility of a palliative care CDSS according to its targeted end-users.

Six focus groups with different groups of stakeholders were conducted (1) patient representatives; (2) community nurses; (3) hospital nurses; (4) general practitioners; (5) hospital physicians and (6) palliative care specialists. Audiotapes were transcribed verbatim and thematically analysed.

Fifty-one stakeholders (6-12 per focus group) participated. Six themes were discussed effect, validity, continuity, practical usability, implementation and additional features. All participants expected a CDSS to improve symptom manageing a patient-reported SAS, lacking care continuity and unclear indications for use.Although dopamine is known to play a prominent role in mediating the abuse-related effects of cocaine, the specific roles of dopamine receptor subtypes are not fully understood. Whereas the effects of drugs acting at dopamine D2-like receptors (D2R) have been characterized, less is known about dopamine D1-like receptors (D1R). The present experiments examined the effect of drugs with varying intrinsic efficacy at D1R on the relative reinforcing strength of cocaine in male cynomolgus monkeys. Use of socially housed monkeys permitted the assessment of whether social status influenced the behavioral effects of D1R-acting drugs. The high-efficacy D1R agonist SKF 81297, low-efficacy D1R agonist SKF 38393 and D1R antagonist SCH 23390 were administered acutely to monkeys self-administering cocaine under a food-cocaine choice procedure in which a cocaine choice dose-effect curve was determined daily. To assess selectivity of behavioral effects on cocaine choice, effects of doses that did not disrupt responding (indicresent study in nonhuman primates found that cocaine choice was decreased only by a low-efficacy D1R agonist, and this effect was dependent on the social status of the monkey.

Various carotenoids in circulation, including isomers, may have different influences on cancer risk.

We conducted a nested case-control study including 343 incident prostate cancer cases and 640 controls individually matched on age, race, study site, and time of blood collection. Carotenoids investigated were carotene, cryptoxanthin, lycopene, dihydrolycopene, lutein, anhydrolutein, and zeaxanthin, including α versus β configurations and

versus

isomers. General linear model and conditional logistic regression were applied to evaluate associations for prostate cancer risk, with adjustment for potential confounders. We conducted additional analyses with further stratification by race, multivitamin use, and smoking status.

Case-control differences were found in carotenoid subtype levels, although not all reached the multiple comparison adjusted threshold for significance. Plasma lycopene [OR

= 0.51; 95% confidence interval (CI), 0.29-0.87;



= 0.014], dihydrolycopene (OR

= 0.37; 95% CI, 0.18-d isomers into consideration.

Patients with cancer are recommended to follow cancer prevention guidelines due to inadequate evidence for specific recommendations for cancer survivors.

We examined whether diet and lifestyle scores measuring adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention guidelines were associated with colorectal cancer-specific and overall mortality among 1,491 patients with colorectal cancer in two prospective cohorts. Cox proportional hazards regression models were used to calculate the multivariable-adjusted HRs and 95% confidence intervals (CI).

During a median follow-up of 7.92 years, there were 641 deaths (179 colorectal cancer-specific deaths). Patients in the highest quartile of the post-diagnostic WCRF/AICR lifestyle score including diet, body mass index (BMI), and physical activity had a 24% lower risk (HR = 0.76, 95% CI 0.49-1.18) of colorectal cancer-specific mortality and a 37% lower risk (HR = 0.63, 95% CI 0.50-0.78) of overall mortans after diagnosis. Future studies on cancer survivors will continue to contribute to evidence-based diet and lifestyle recommendations for patients with cancer.

Cancer ranks as the second leading cause of death among children ages 1 to 14 years in the United States. Previous research finds that strong cohort selection

against males precedes a reduction in live-born males considered frail. We examine whether such cohort selection

may similarly affect the frequency of childhood cancers among male live births.

We examined 1,368 childhood cancers among males born in Sweden over 144 months, from January 1990 to December 2001, and followed to age 15 in the Swedish Cancer Registry. We retrieved the count of male twins by birth month from the Swedish Birth Registry. We applied autoregressive, integrated, moving average time-series methods to identify and control for temporal patterns in monthly childhood cancers and to evaluate robustness of results.

Fewer childhood cancers occur among monthly male birth cohorts with elevated selection

(i.e., a low count of live-born male twins). This association appears in the concurrent month (coef = 0.04; 95% CI, 0.001-0.079) as well as in the following month in which most births from the twin's conception cohort are "scheduled" to be born (coef = 0.055; 95% CI, 0.017-0.094).

Elevated cohort selection

may reduce the number of frail male gestations that would otherwise have survived to birth and received a cancer diagnosis during childhood.

This novel result warrants further investigation of prenatal exposures, including those at the population level, that may induce cohort selection

for some cancer types but not others.

This novel result warrants further investigation of prenatal exposures, including those at the population level, that may induce cohort selection in utero for some cancer types but not others.

Socio-economic inequalities in colon cancer survival exist in high-income countries, but the reasons are unclear. We assessed the mediating effects of stage at diagnosis, comorbidities, and treatment (surgery and intravenous chemotherapy) on survival from colon cancer.

We identified 2,203 people aged 15 to 79 years with first primary colon cancer diagnosed in Victoria, Australia, between 2008 and 2011. Colon cancer cases were identified through the Victorian Cancer Registry (VCR), and clinical information was obtained from hospital records. Deaths till December 31, 2016 (

= 807), were identified from Victorian and national death registries. Socio-economic disadvantage was based on residential address at diagnosis. For stage III disease, we decomposed its total effect into direct and indirect effects using interventional mediation analysis.

Socio-economic inequalities in colon cancer survival were not explained by stage and were greater for men than women. For men with stage III disease, there were 161 [95% confidence interval (CI), 67-256] additional deaths per 1,000 cases in the 5 years following diagnosis for the most disadvantaged compared with the least disadvantaged.