This paper describes the process and results of a refinement of a framework to characterize modifications to interventions. The original version did not fully capture several aspects of modification ...and adaptation that may be important to document and report. Additionally, the earlier framework did not include a way to differentiate cultural adaptation from adaptations made for other reasons. Reporting additional elements will allow for a more precise understanding of modifications, the process of modifying or adapting, and the relationship between different forms of modification and subsequent health and implementation outcomes.
We employed a multifaceted approach to develop the updated FRAME involving coding documents identified through a literature review, rapid coding of qualitative interviews, and a refinement process informed by multiple stakeholders. The updated FRAME expands upon Stirman et al.'s original framework by adding components of modification to report: (1) when and how in the implementation process the modification was made, (2) whether the modification was planned/proactive (i.e., an adaptation) or unplanned/reactive, (3) who determined that the modification should be made, (4) what is modified, (5) at what level of delivery the modification is made, (6) type or nature of context or content-level modifications, (7) the extent to which the modification is fidelity-consistent, and (8) the reasons for the modification, including (a) the intent or goal of the modification (e.g., to reduce costs) and (b) contextual factors that influenced the decision. Methods of using the framework to assess modifications are outlined, along with their strengths and weaknesses, and considerations for research to validate these measurement strategies.
The updated FRAME includes consideration of when and how modifications occurred, whether it was planned or unplanned, relationship to fidelity, and reasons and goals for modification. This tool that can be used to support research on the timing, nature, goals and reasons for, and impact of modifications to evidence-based interventions.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are relentlessly progressive neurodegenerative disorders with overlapping clinical, genetic and pathological features. ...Cytoplasmic inclusions of fused in sarcoma (FUS) are the hallmark of several forms of FTLD and ALS patients with mutations in the
FUS
gene. FUS is a multifunctional, predominantly nuclear, DNA and RNA binding protein. Here, we report that transgenic mice overexpressing wild-type human FUS develop an aggressive phenotype with an early onset tremor followed by progressive hind limb paralysis and death by 12 weeks in homozygous animals. Large motor neurons were lost from the spinal cord accompanied by neurophysiological evidence of denervation and focal muscle atrophy. Surviving motor neurons in the spinal cord had greatly increased cytoplasmic expression of FUS, with globular and skein-like FUS-positive and ubiquitin-negative inclusions associated with astroglial and microglial reactivity. Cytoplasmic FUS inclusions were also detected in the brain of transgenic mice without apparent neuronal loss and little astroglial or microglial activation. Hemizygous FUS overexpressing mice showed no evidence of a motor phenotype or pathology. These findings recapitulate several pathological features seen in human ALS and FTLD patients, and suggest that overexpression of wild-type FUS in vulnerable neurons may be one of the root causes of disease. Furthermore, these mice will provide a new model to study disease mechanism, and test therapies.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Some veterans face multiple barriers to VA mental healthcare service use. However, there is limited understanding of how veterans' experiences and meaning systems shape their perceptions of barriers ...to VA mental health service use. In 2015, a participatory, mixed-methods project was initiated to elicit veteran-centered barriers to using mental healthcare services among a diverse sample of US rural and urban veterans. We sought to identify veteran-centric barriers to mental healthcare to increase initial engagement and continuation with VA mental healthcare services.
Cultural Domain Analysis, incorporated in a mixed methods approach, generated a cognitive map of veterans' barriers to care. The method involved: 1) free lists of barriers categorized through participant pile sorting; 2) multi-dimensional scaling and cluster analysis for item clusters in spatial dimensions; and 3) participant review, explanation, and interpretation for dimensions of the cultural domain. Item relations were synthesized within and across domain dimensions to contextualize mental health help-seeking behavior.
Participants determined five dimensions of barriers to VA mental healthcare services: concern about what others think; financial, personal, and physical obstacles; confidence in the VA healthcare system; navigating VA benefits and healthcare services; and privacy, security, and abuse of services.
These findings demonstrate the value of participatory methods in eliciting meaningful cultural insight into barriers of mental health utilization informed by military veteran culture. They also reinforce the importance of collaborations between the VA and Department of Defense to address the role of military institutional norms and stigmatizing attitudes in veterans' mental health-seeking behaviors.
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CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The heterogeneous Fenton process has been widely applied though some aspects of this process are still poorly understood. In this study, we simultaneously quantify the adsorption and decomposition of ...formate and H2O2 at pH 4.0 in the presence of freshly formed ferrihydrite and provide new insights into the ferrihydrite-induced heterogeneous Fenton mechanism with the aid of kinetic and reactive-transport modeling. Our results show that the decomposition of H2O2 and formate is controlled by surface-initiated reactions. Adsorbed formate occupies the surface sites otherwise available for reaction with H2O2 and therefore hampers the surface Fenton reactions despite the negligible accumulation of H2O2 on the surface. The minimal impact of methanol (an effective HO• scavenger) on formate oxidation as well as the poor oxidation of fully adsorbed oxalate compared with the ready oxidation of partially adsorbed formate demonstrates that oxidation mainly occurs in the solid–liquid boundary layer, rather than in bulk or on the surface. This is suggested to be due to the diffusion of surface-generated HO•, rather than surface Fe(II), to the boundary layer with the results of kinetic and reactive-transport modeling supporting this conclusion. The new findings are critical to our understanding of the removal behavior of more complex organic target species and to the design of more effective heterogeneous Fenton technologies.
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IJS, KILJ, NUK, PNG, UL, UM
Abstract
The detailed observations of GW170817 proved for the first time directly that neutron star mergers are a major production site of heavy elements. The observations could be fit by a number of ...simulations that qualitatively agree, but can quantitatively differ (e.g., in total r-process mass) by an order of magnitude. We categorize kilonova ejecta into several typical morphologies motivated by numerical simulations, and apply a radiative transfer Monte Carlo code to study how the geometric distribution of the ejecta shapes the emitted radiation. We find major impacts on both spectra and light curves. The peak bolometric luminosity can vary by two orders of magnitude and the timing of its peak by a factor of five. These findings provide the crucial implication that the ejecta masses inferred from observations around the peak brightness are uncertain by at least an order of magnitude. Mixed two-component models with lanthanide-rich ejecta are particularly sensitive to geometric distribution. A subset of mixed models shows very strong viewing angle dependence due to lanthanide “curtaining,” which persists even if the relative mass of lanthanide-rich component is small. The angular dependence is weak in the rest of our models, but different geometric combinations of the two components lead to a highly diverse set of light curves. We identify geometry-dependent P Cygni features in late spectra that directly map out strong lines in the simulated opacity of neodymium, which can help to constrain the ejecta geometry and to directly probe the r-process abundances.
Fluoride ion batteries are potential "next-generation" electrochemical storage devices that offer high energy density. At present, such batteries are limited to operation at high temperatures because ...suitable fluoride ion-conducting electrolytes are known only in the solid state. We report a liquid fluoride ion-conducting electrolyte with high ionic conductivity, wide operating voltage, and robust chemical stability based on dry tetraalkylammonium fluoride salts in ether solvents. Pairing this liquid electrolyte with a copper-lanthanum trifluoride (Cu@LaF
) core-shell cathode, we demonstrate reversible fluorination and defluorination reactions in a fluoride ion electrochemical cell cycled at room temperature. Fluoride ion-mediated electrochemistry offers a pathway toward developing capacities beyond that of lithium ion technology.
Mutations in spastin are the most common cause of hereditary spastic paraplegia (HSP) but the mechanisms by which mutant spastin induces disease are not clear. Spastin functions to regulate ...microtubule organisation, and because of the essential role of microtubules in axonal transport, this has led to the suggestion that defects in axonal transport may underlie at least part of the disease process in HSP. However, as yet there is no direct evidence to support this notion. Here we analysed axonal transport in a novel mouse model of spastin-induced HSP that involves a pathogenic splice site mutation, which leads to a loss of spastin protein. A mutation located within the same splice site has been previously described in HSP. Spastin mice develop gait abnormalities that correlate with phenotypes seen in HSP patients and also axonal swellings containing cytoskeletal proteins, mitochondria and the amyloid precursor protein (APP). Pathological analyses of human HSP cases caused by spastin mutations revealed the presence of similar axonal swellings. To determine whether mutant spastin influenced axonal transport we quantified transport of two cargoes, mitochondria and APP-containing membrane bound organelles, in neurons from mutant spastin and control mice, using time-lapse microscopy. We found that mutant spastin perturbs anterograde transport of both cargoes. In neurons with axonal swellings we found that the mitochondrial axonal transport defects were exacerbated; distal to axonal swellings both anterograde and retrograde transport were severely reduced. These results strongly support a direct role for defective axonal transport in the pathogenesis of HSP because of spastin mutation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
A proline to serine substitution at position 56 in the gene encoding vesicle-associated membrane protein-associated protein B (VAPB) causes some dominantly inherited familial forms of motor neuron ...disease including amyotrophic lateral sclerosis (ALS) type-8. VAPB is an integral endoplasmic reticulum (ER) protein whose amino-terminus projects into the cytosol. Overexpression of ALS mutant VAPBP56S disrupts ER structure but the mechanisms by which it induces disease are not properly understood. Here we show that VAPB interacts with the outer mitochondrial membrane protein, protein tyrosine phosphatase-interacting protein 51 (PTPIP51). ER and mitochondria are both stores for intracellular calcium (Ca(2+)) and Ca(2+) exchange between these organelles occurs at regions of ER that are closely apposed to mitochondria. These are termed mitochondria-associated membranes (MAM). We demonstrate that VAPB is a MAM protein and that loss of either VAPB or PTPIP51 perturbs uptake of Ca(2+) by mitochondria following release from ER stores. Finally, we demonstrate that VAPBP56S has altered binding to PTPIP51 and increases Ca(2+) uptake by mitochondria following release from ER stores. Damage to ER, mitochondria and Ca(2+) homeostasis are all seen in ALS and we discuss the implications of our findings in this context.
Computed structures of core eukaryotic protein complexes Humphreys, Ian R; Pei, Jimin; Baek, Minkyung ...
Science (American Association for the Advancement of Science),
2021-Dec-10, 2021-12-10, 20211210, Volume:
374, Issue:
6573
Journal Article
Peer reviewed
Open access
Protein-protein interactions play critical roles in biology, but the structures of many eukaryotic protein complexes are unknown, and there are likely many interactions not yet identified. We take ...advantage of advances in proteome-wide amino acid coevolution analysis and deep-learning–based structure modeling to systematically identify and build accurate models of core eukaryotic protein complexes within the
proteome. We use a combination of RoseTTAFold and AlphaFold to screen through paired multiple sequence alignments for 8.3 million pairs of yeast proteins, identify 1505 likely to interact, and build structure models for 106 previously unidentified assemblies and 806 that have not been structurally characterized. These complexes, which have as many as five subunits, play roles in almost all key processes in eukaryotic cells and provide broad insights into biological function.
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