G protein-coupled receptors (GPCRs) mediate diverse signaling in part through interaction with arrestins, whose binding promotes receptor internalization and signaling through G protein-independent ...pathways. High-affinity arrestin binding requires receptor phosphorylation, often at the receptor’s C-terminal tail. Here, we report an X-ray free electron laser (XFEL) crystal structure of the rhodopsin-arrestin complex, in which the phosphorylated C terminus of rhodopsin forms an extended intermolecular β sheet with the N-terminal β strands of arrestin. Phosphorylation was detected at rhodopsin C-terminal tail residues T336 and S338. These two phospho-residues, together with E341, form an extensive network of electrostatic interactions with three positively charged pockets in arrestin in a mode that resembles binding of the phosphorylated vasopressin-2 receptor tail to β-arrestin-1. Based on these observations, we derived and validated a set of phosphorylation codes that serve as a common mechanism for phosphorylation-dependent recruitment of arrestins by GPCRs.
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•A rhodopsin-arrestin complex structure with phosphorylated rhodopsin C terminus•Structural mechanism for recognition of phosphorylated rhodopsin by visual arrestin•Phosphorylation codes are a common mechanism of arrestin recruitment by GPCRs
A crystal structure of a fully engaged rhodopsin-arrestin complex identifies phosphorylation codes as a common mechanism of arrestin recruitment by GPCRs.
Summary Background The phase 3 trial of the RTS,S/AS01 malaria vaccine candidate showed modest efficacy of the vaccine against Plasmodium falciparum malaria, but was not powered to assess mortality ...endpoints. Impact projections and cost-effectiveness estimates for longer timeframes than the trial follow-up and across a range of settings are needed to inform policy recommendations. We aimed to assess the public health impact and cost-effectiveness of routine use of the RTS,S/AS01 vaccine in African settings. Methods We compared four malaria transmission models and their predictions to assess vaccine cost-effectiveness and impact. We used trial data for follow-up of 32 months or longer to parameterise vaccine protection in the group aged 5–17 months. Estimates of cases, deaths, and disability-adjusted life-years (DALYs) averted were calculated over a 15 year time horizon for a range of levels of Plasmodium falciparum parasite prevalence in 2–10 year olds ( Pf PR2–10 ; range 3–65%). We considered two vaccine schedules: three doses at ages 6, 7·5, and 9 months (three-dose schedule, 90% coverage) and including a fourth dose at age 27 months (four-dose schedule, 72% coverage). We estimated cost-effectiveness in the presence of existing malaria interventions for vaccine prices of US$2–10 per dose. Findings In regions with a Pf PR2–10 of 10–65%, RTS,S/AS01 is predicted to avert a median of 93 940 (range 20 490–126 540) clinical cases and 394 (127–708) deaths for the three-dose schedule, or 116 480 (31 450–160 410) clinical cases and 484 (189–859) deaths for the four-dose schedule, per 100 000 fully vaccinated children. A positive impact is also predicted at a Pf PR2–10 of 5–10%, but there is little impact at a prevalence of lower than 3%. At $5 per dose and a Pf PR2–10 of 10–65%, we estimated a median incremental cost-effectiveness ratio compared with current interventions of $30 (range 18–211) per clinical case averted and $80 (44–279) per DALY averted for the three-dose schedule, and of $25 (16–222) and $87 (48–244), respectively, for the four-dose schedule. Higher ICERs were estimated at low Pf PR2–10 levels. Interpretation We predict a significant public health impact and high cost-effectiveness of the RTS,S/AS01 vaccine across a wide range of settings. Decisions about implementation will need to consider levels of malaria burden, the cost-effectiveness and coverage of other malaria interventions, health priorities, financing, and the capacity of the health system to deliver the vaccine. Funding PATH Malaria Vaccine Initiative; Bill & Melinda Gates Foundation; Global Good Fund; Medical Research Council; UK Department for International Development; GAVI, the Vaccine Alliance; WHO.
BACKGROUND: Insulin resistance is associated with elevated plasma triacylglycerol, low HDL concentrations, elevated postprandial lipemia, and a predominance of small, dense LDLs (sdLDLs). It has been ...hypothesized that the dietary ratio of n-6 to n-3 (n-6:n-3) polyunsaturated fatty acids (PUFAs) may have favorable effects on these risk factors by increasing insulin sensitivity. OBJECTIVE: The objective was to measure changes in insulin sensitivity, lipoprotein size, and postprandial lipemia after a 6-mo alteration in n-6:n-3. DESIGN: In a randomized, parallel design in 258 subjects aged 45-70 y, we compared 4 diets providing 6% of energy as PUFAs with an n-6:n-3 between 5:1 and 3:1 with a control diet that had an n-6:n-3 of 10:1. The diets were enriched in α-linolenic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), or both. Insulin sensitivity was assessed with the homeostatic model assessment of insulin resistance and the revised quantitative insulin sensitivity test. RESULTS: Dietary intervention did not influence insulin sensitivity or postprandial lipase activities. Fasting and postprandial triacylglycerol concentrations were lower, and the proportion of sdLDLs decreased (by 12.7%; 95% CI: -22.9%, 2.4%), with an n-6:n-3 of almost equal to3:1, which was achieved by the addition of long-chain n-3 PUFAs (EPA and DHA). CONCLUSIONS: Decreasing the n-6:n-3 does not influence insulin sensitivity or lipase activities in older subjects. The reduction in plasma triacylglycerol after an increased intake of n-3 long-chain PUFAs results in favorable changes in LDL size.
•Emotion dysregulation may confer risk for poor stress responding.•We examined pre-pandemic emotion regulation in predicting stress in early pandemic.•Global emotion regulation difficulties predicted ...greater COVID-19 acute stress.•Reappraisal and suppression were not uniquely predictive of COVID-19 acute stress.•Suppression negatively related to COVID-19 acute stress when reappraisal was high.
Preliminary prospective research suggests emotion dysregulation may confer vulnerability to poor stress responses. The present prospective study extends this research by examining both specific emotion regulation strategies and global emotion regulation difficulties in the context of acute stress following onset of the COVID-19 global pandemic in 119 young adults. As part of a larger study, emotion regulation was assessed prior to pandemic onset (January 2019 – February 2020) using two standard measures (Emotion Regulation Questionnaire, ERQ, Gross & John, 2003; Difficulties in Emotion Regulation Scale, DERS, Gratz & Roemer, 2004). A self-report assessment of acute stress was conducted 2−3½ weeks after the COVID-19 pandemic declaration. Results demonstrated cognitive reappraisal and expressive suppression (i.e., ERQ) were not individually predictive of acute stress; however, there was a significant interaction of suppression by reappraisal. Simple effects indicated suppression was negatively associated with acute stress only when reappraisal levels were high. Greater global emotion regulation difficulties (i.e., DERS), particularly nonacceptance of emotions and limited access to emotion regulation strategies, significantly predicted greater acute stress. These results provide further evidence of the temporal relationship between emotion dysregulation and stress reactions, and also suggest the expected effects of emotion regulation strategies may differ across contexts.
Purpose To systematically review the literature to identify all studies reporting outcomes of arthroscopically repaired isolated subscapularis tears, to (1) report outcomes across all repair ...techniques, (2) compare outcomes by arthroscopic technique, and (3) highlight the frequency and management of associated long head of biceps pathology, and the influence of these concomitant procedures on outcomes following arthroscopic subscapularis repair. Methods A systematic literature review was conducted using the MEDLINE, Embase, and Scopus databases with the following term: (“isolated repair” AND “arthroscopic subscapularis tear”). Only studies evaluating the techniques and outcomes of isolated subscapularis repair were included. Data were extracted, including patient characteristics, surgical technique, and outcomes. Descriptive analysis was provided for the available literature. Results Eight studies were included in this review. Uniformly, improvements in patient-reported outcome scores were substantial after arthroscopic subscapularis repair. Constant Total scores improved in each individual study from preoperative to postoperative (range, Δ18.8-Δ49.8 points), as did Strength (range, Δ1.3-Δ13.7 points), Pain (range, Δ7.6-Δ8.9 points), Range of Motion (range, Δ7.3-Δ13.3 points), and Activities of Daily Living (range, Δ8.7-Δ10.2 points) subscores. Significant improvements were seen in most individual studies for belly-press (Δ21.6 N or Δ1.9 out of 5) and lift-off strength (Δ24.3 N or Δ1.7-Δ1.9 out of 5), range of motion in forward flexion (29.1°-37.0°), external rotation (10.3°-16.0°), and internal rotation. Complications were relatively infrequent overall, with 5 studies reporting no complications, and the remaining 3 studies with rerupture rates between 4.8% and 11.8%. Studies that used only double-row repair reported fewer complications (0% vs 5%-10%) and better outcome scores than single-row repair, similar to those studies that uniformly performed biceps tenodesis compared with no biceps intervention. Conclusions This descriptive study highlights that arthroscopic subscapularis repair appears to be a reasonable option for the treatment of isolated tears of the subscapularis to obtain successful functional and patient-reported clinical outcomes. Its findings also pose the question of whether future prospective, comparative studies will find double-row surgical fixation and concomitant biceps tenodesis surgery to be superior to single-row fixation and leaving the biceps alone. Level of Evidence Level IV, systematic review of Level IV studies.
Monkeypox is a viral zoonotic disease endemic in Central and West Africa. In May 2022, dozens of non-endemic countries reported hundreds of monkeypox cases, most with no epidemiological link to ...Africa. We identified two lineages of monkeypox virus (MPXV) among two 2021 and seven 2022 US monkeypox cases: the major 2022 outbreak variant called B.1 and a minor contemporaneously sampled variant called A.2. Analyses of mutations among these two variants revealed an extreme preference for GA-to-AA mutations indicative of human APOBEC3 cytosine deaminase activity among Clade IIb MPXV (previously West African, Nigeria) sampled since 2017. Such mutations were not enriched within other MPXV clades. These findings suggest that APOBEC3 editing may be a recurrent and a dominant driver of MPXV evolution within the current outbreak.
analysis of a community food waste stream Griffin, Mary; Sobal, Jeffery; Lyson, Thomas A
Agriculture and human values,
03/2009, Letnik:
26, Številka:
1-2
Journal Article
Recenzirano
Food waste comprises a significant portion of the waste stream in industrialized countries, contributing to ecological damages and nutritional losses. Guided by a systems approach, this study ...quantified food waste in one U.S. County in 1998-1999. Publications and personal interviews were used to quantify waste from food production, processing, distribution, and consumption. Approximately 10,205 tons of food waste was generated annually in this community food system. Of all food waste, production waste comprised 20%, processing 1%, distribution 19%, and 60% of food waste was generated by consumers. Less than one-third (28%) of total food waste was recovered via composting (25%) and food donations (3%), and over 7,000 tons (72%) were landfilled. More than 8.8 billion kilocalories of food were wasted, enough to feed county residents for 1.5 months. This case study offers an example of procedures to quantify and compare food waste across a whole community food system.
Epstein-Barr virus (EBV) is a human herpesvirus that persists as a largely subclinical infection in the vast majority of adults worldwide. Recent evidence indicates that an important component of the ...persistence strategy involves active interference with the MHC class I antigen processing pathway during the lytic replication cycle. We have now identified a novel role for the lytic cycle gene, BILF1, which encodes a glycoprotein with the properties of a constitutive signaling G-protein-coupled receptor (GPCR). BILF1 reduced the levels of MHC class I at the cell surface and inhibited CD8(+) T cell recognition of endogenous target antigens. The underlying mechanism involves physical association of BILF1 with MHC class I molecules, an increased turnover from the cell surface, and enhanced degradation via lysosomal proteases. The BILF1 protein of the closely related CeHV15 gamma(1)-herpesvirus of the Rhesus Old World primate (80% amino acid sequence identity) downregulated surface MHC class I similarly to EBV BILF1. Amongst the human herpesviruses, the GPCR encoded by the ORF74 of the KSHV gamma(2)-herpesvirus is most closely related to EBV BILF1 (15% amino acid sequence identity) but did not affect levels of surface MHC class I. An engineered mutant of BILF1 that was unable to activate G protein signaling pathways retained the ability to downregulate MHC class I, indicating that the immune-modulating and GPCR-signaling properties are two distinct functions of BILF1. These findings extend our understanding of the normal biology of an important human pathogen. The discovery of a third EBV lytic cycle gene that cooperates to interfere with MHC class I antigen processing underscores the importance of the need for EBV to be able to evade CD8(+) T cell responses during the lytic replication cycle, at a time when such a large number of potential viral targets are expressed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
For external irradiation, the variability in organ dose estimation found between computational phantom generations arises particularly from the differences in organ positioning. This work represents ...the first effort to quantify the differences in organ depth below the body surface between a stylized and voxel phantom series. Herein, the revised Oak Ridge National Laboratory stylized phantom series and the University of Florida/National Cancer Institute voxel phantom series were compared. Both series include whole-body models of the newborn; the 1-, 5-, 10-, and 15-year-old; and the adult human. Organ depths from eight different directions applicable to external irradiation geometries were computed: antero-posterior, postero-anterior, left and right lateral, rotational, isotropic, cranial and caudal directions. Organ depths in the stylized phantoms were computed using a ray-tracing technique available through Monte Carlo radiation transport simulations in MCNP6. Organ depths in the voxel phantom were found using phantom matrix manipulation. Resultant organ depths for both series were plotted as distributions; available are twenty-four organs and two bone tissue distributions for each of six phantom ages and in each of the eight directional geometries. Quantitative data descriptors (e.g. mean and median depths) were also tabulated. For demonstration purposes, a literature review of relevant stylized versus voxel comparison works was performed to explore where the quantification of organ depth differences can provide further insight or evidence to study conclusions. The entire dataset of organ depth distributions and their data descriptors can be found in online supplementary files.
G-protein-coupled receptors (GPCRs) signal primarily through G proteins or arrestins. Arrestin binding to GPCRs blocks G protein interaction and redirects signalling to numerous G-protein-independent ...pathways. Here we report the crystal structure of a constitutively active form of human rhodopsin bound to a pre-activated form of the mouse visual arrestin, determined by serial femtosecond X-ray laser crystallography. Together with extensive biochemical and mutagenesis data, the structure reveals an overall architecture of the rhodopsin-arrestin assembly in which rhodopsin uses distinct structural elements, including transmembrane helix 7 and helix 8, to recruit arrestin. Correspondingly, arrestin adopts the pre-activated conformation, with a ∼20° rotation between the amino and carboxy domains, which opens up a cleft in arrestin to accommodate a short helix formed by the second intracellular loop of rhodopsin. This structure provides a basis for understanding GPCR-mediated arrestin-biased signalling and demonstrates the power of X-ray lasers for advancing the frontiers of structural biology.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
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