Road to Ruin: Targeting Proteins for Degradation in the Endoplasmic Reticulum

Some nascent proteins that fold within the endoplasmic reticulum (ER) never reach their native state. Misfolded proteins are removed from the folding machinery, dislocated from the ER into the cytosol, and degraded in a series of pathways collectively referred to as ER-associated degradation (ERAD). Distinct ERAD pathways centered on different E3 ubiquitin ligases survey the range of potential substrates. We now know many of the components of the ERAD machinery and pathways used to detect substrates and target them for degradation. Much less is known about the features used to identify terminally misfolded conformations and the broader role of these pathways in regulating protein half-lives.National Institutes of Health (U.S.

Lateral drill holes decrease strength of the femur: An observational study using finite element and experimental analyses

BACKGROUND: Internal fixation of femoral fractures requires drilling holes through the cortical bone of the shaft of the femur. Intramedullary suction reduces the fat emboli produced by reaming and nailing femoral fractures but requires four suction portals to be drilled into the femoral shaft. This work investigated the effect of these additional holes on the strength of the femur. METHODS: Finite element analysis (FEA) was used to calculate compression, tension and load limits which were then compared to the results from mechanical testing. Models of intact femora and fractured femora internally fixed with intramedullary nailing were generated. In addition, four suction portals, lateral, anterior and posterior, were modelled. Stresses were used to calculate safety factors and predict fatigue. Physical testing on synthetic femora was carried out on a universal mechanical testing machine. RESULTS: The FEA model for stresses generated during walking showed tensile stresses in the lateral femur and compression stresses in the medial femur with a maximum sheer stress through the neck of the femur. The lateral suction portals produced tensile stresses up to over 300% greater than in the femur without suction portals. The anterior and posterior portals did not significantly increase stresses. The lateral suction portals had a safety factor of 0.7, while the anterior and posterior posts had safety factors of 2.4 times walking loads. Synthetic bone subjected to cyclical loading and load to failure showed similar results. On mechanical testing, all constructs failed at the neck of the femur. CONCLUSIONS: The anterior suction portals produced minimal increases in stress to loading so are the preferred site should a femur require such drill holes for suction or internal fixation

Assessment of suitable referral, effectiveness and long-term outcomes of standard vs intensive pain management programmes for people with chronic pain

Background: Chronic pain is a leading cause of disability, often requiring multidisciplinary management. 2021 NICE guidance has questioned the quality of the evidence surrounding the efficacy of pain management programmes (PMPs), with only minor benefit demonstrated in psychological and physical outcomes. There is need for further high-quality evidence for the efficacy of PMPs for a range of chronic pain conditions and to identify barriers to successful management of chronic pain. Objective: This service evaluation utilised routinely collected outcome data of 508 PMP attendees to investigate change in pain- and patient-related outcomes across two distinct PMPs; a standard and an intensive PMP, and establish their longer-term efficacy and appropriateness for patients with differing degrees of need. Results: More people with chronic widespread pain, fibromyalgia, and osteoarthritis were referred to the intensive PMP (reflecting greater disability and distress in these conditions). Those referred to the intensive PMP demonstrated greater distress (such as more severe depression and anxiety), lower pain acceptance and poorer physical function. Improvements were observed in all outcomes across both PMPs (including physical function, pain catastrophising and pain acceptance). Depression and disability demonstrated clinically meaningful improvements in the intensive PMP, and pain severity showed clinically meaningful improvement in both PMPs. However, depression severity, disability, pain severity, and pain interference significantly deteriorated at 6-month follow-up for those on the intensive PMP, with pain severity increasing to a clinically meaningful degree (by more than 10%), though these outcomes remained better than at baseline. Conclusion: This evaluation identified that people with chronic pain most at risk of deterioration in physical and psychological wellbeing after completing a PMP require early identification to mitigate such deterioration. Established and emerging PMPs need to be tailored to the needs of this group, particularly at follow-up to reduce risks of pain severity increasing, alongside establishing/reinforcing safeguards against deterioration post-PMP

Evidence-based implementation practices applied to the intensive treatment of eating disorders: Summary of research and illustration of principles using a case example

Implementation of evidence‐based practices (EBPs) in intensive treatment settings poses a major challenge in the field of psychology. This is particularly true for eating disorder (ED) treatment, where multidisciplinary care is provided to a severe and complex patient population; almost no data exist concerning best practices in these settings. We summarize the research on EBP implementation science organized by existing frameworks and illustrate how these practices may be applied using a case example. We describe the recent successful implementation of EBPs in a community‐based intensive ED treatment network, which recently adapted and implemented transdiagnostic, empirically supported treatment for emotional disorders across its system of residential and day‐hospital programs. The research summary, implementation frameworks, and case example may inform future efforts to implement evidence‐based practice in intensive treatment settings.Published versio

Estimating extragalactic Faraday rotation

(abridged) Observations of Faraday rotation for extragalactic sources probe magnetic fields both inside and outside the Milky Way. Building on our earlier estimate of the Galactic contribution, we set out to estimate the extragalactic contributions. We discuss the problems involved; in particular, we point out that taking the difference between the observed values and the Galactic foreground reconstruction is not a good estimate for the extragalactic contributions. We point out a degeneracy between the contributions to the observed values due to extragalactic magnetic fields and observational noise and comment on the dangers of over-interpreting an estimate without taking into account its uncertainty information. To overcome these difficulties, we develop an extended reconstruction algorithm based on the assumption that the observational uncertainties are accurately described for a subset of the data, which can overcome the degeneracy with the extragalactic contributions. We present a probabilistic derivation of the algorithm and demonstrate its performance using a simulation, yielding a high quality reconstruction of the Galactic Faraday rotation foreground, a precise estimate of the typical extragalactic contribution, and a well-defined probabilistic description of the extragalactic contribution for each data point. We then apply this reconstruction technique to a catalog of Faraday rotation observations. We vary our assumptions about the data, showing that the dispersion of extragalactic contributions to observed Faraday depths is most likely lower than 7 rad/m^2, in agreement with earlier results, and that the extragalactic contribution to an individual data point is poorly constrained by the data in most cases.Comment: 20 + 6 pages, 19 figures; minor changes after bug-fix; version accepted for publication by A&A; results are available at http://www.mpa-garching.mpg.de/ift/faraday

Self-Regulation of Emotion, Functional Impairment, and Comorbidity Among Children With AD/HD

Objective: This study investigated the role of self-regulation of emotion in relation to functional impairment and comorbidity among children with and without AD/HD. Method: A total of 358 probands and their siblings participated in the study, with 74% of the sample participants affected by AD/HD. Parent-rated levels of emotional lability served as a marker for self-regulation of emotion. Results: Nearly half of the children affected by AD/HD displayed significantly elevated levels of emotional lability versus 15% of those without this disorder. Children with AD/HD also displayed significantly higher rates of functional impairment, comorbidity, and treatment service utilization. Emotional lability partially mediated the association between AD/HD status and these outcomes. Conclusion: Findings lent support to the notion that deficits in the self-regulation of emotion are evident in a substantial number of children with AD/HD and that these deficits play an important role in determining functional impairment and comorbidity outcomes

VO: Vaccine Ontology

Vaccine research, as well as the development, testing, clinical trials, and commercial uses of vaccines involve complex processes with various biological data that include gene and protein expression, analysis of molecular and cellular interactions, study of tissue and whole body responses, and extensive epidemiological modeling. Although many data resources are available to meet different aspects of vaccine needs, it remains a challenge how we are to standardize vaccine annotation, integrate data about varied vaccine types and resources, and support advanced vaccine data analysis and inference. To address these problems, the community-based Vaccine Ontology (VO) has been developed through collaboration with vaccine researchers and many national and international centers and programs, including the National Center for Biomedical Ontology (NCBO), the Infectious Disease Ontology (IDO) Initiative, and the Ontology for Biomedical Investigations (OBI). VO utilizes the Basic Formal Ontology (BFO) as the top ontology and the Relation Ontology (RO) for definition of term relationships. VO is represented in the Web Ontology Language (OWL) and edited using the Protégé-OWL. Currently VO contains more than 2000 terms and relationships. VO emphasizes on classification of vaccines and vaccine components, vaccine quality and phenotypes, and host immune response to vaccines. These reflect different aspects of vaccine composition and biology and can thus be used to model individual vaccines. More than 200 licensed vaccines and many vaccine candidates in research or clinical trials have been modeled in VO. VO is being used for vaccine literature mining through collaboration with the National Center for Integrative Biomedical Informatics (NCIBI). Multiple VO applications will be presented

Impact of recently upwelled water on productivity investigated using in situ and incubation-based methods in Monterey Bay

Author Posting. © American Geophysical Union, 2017. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research: Oceans 122 (2017): 1901–1926, doi:10.1002/2016JC012306.Photosynthetic conversion of inline image to organic carbon and the transport of this carbon from the surface to the deep ocean is an important regulator of atmospheric inline image. To understand the controls on carbon fluxes in a productive region impacted by upwelling, we measured biological productivity via multiple methods during a cruise in Monterey Bay, California. We quantified net community production and gross primary production from measurements of inline image/Ar and inline image triple isotopes ( inline image), respectively. We simultaneously conducted incubations measuring the uptake of 14C, inline image, and inline image, and nitrification, and deployed sediment traps. At the start of the cruise (Phase 1) the carbon cycle was at steady state and the estimated net community production was 35(10) and 35(8) mmol C m−2 d−1 from inline image/Ar and 15N incubations, respectively, a remarkably good agreement. During Phase 1, net primary production was 96(27) mmol C m−2 d−1 from C uptake, and gross primary production was 209(17) mmol C m−2 d−1 from inline image. Later in the cruise (Phase 2), recently upwelled water with higher nutrient concentrations entered the study area, causing 14C and inline image uptake to increase substantially. Continuous inline image/Ar measurements revealed submesoscale variability in water mass structure and likely productivity in Phase 2 that was not evident from the incubations. These data demonstrate that inline image/Ar and inline image incubation-based NCP estimates can give equivalent results in an N-limited, coastal system, when the nonsteady state inline image fluxes are negligible or can be quantified.Funding for this work was provided by NSF awards OCE-1060840 to R.H.R. Stanley, OCE-1129644 to D.P. Nicholson, OCE-1357042 to F.P. Chavez, NASA award NNX14AI06G to M.R. Fewings, the David and Lucile Packard Foundation through their generous annual donation to the Monterey Bay Aquarium Research Institute, an Ocean Ventures Fund award from the WHOI Academic Programs Office to CC Manning, and graduate scholarships from NSERC and CMOS to CC Manning.2017-09-1