Characterization of β-amyloid peptide precursor processing by the yeast Yap3 and Mkc7 proteases

AbstractTwo proteases, denoted β- and γ-secretase, process the β-amyloid peptide precursor (APP) to yield the Aβ peptides involved in Alzheimer's disease. A third protein, α-secretase, cleaves APP near the middle of the Aβ sequence and thus prevents Aβ formation. These enzymes have defied identification. Because of its similarity to the systems of mammalian cells the yeast secretory system has provided important clues for finding mammalian processing enzymes. When expressed in Saccharomyces cerevisiae APP is processed by enzymes that possess the specificity of the α-secretases of multicellular organisms. APP processing by α-secretases occurred in sec1 and sec7 mutants, in which transport to the cell surface or to the vacuole is blocked, but not in sec17 or sec18 mutants, in which transport from the endoplasmic reticulum to the Golgi is blocked. Neutralization of the vacuole by NH4Cl did not block α-secretase action. The time course of processing of a pro-α-factor leader-APP chimera showed that processing by Kex2 protease, a Golgi protease that removes the leader, preceded processing by α-secretase. Deletions of the genes encoding the GPI-linked aspartyl proteases Yap3 and Mkc7 decreased α-secretase activity by 56 and 29%, respectively; whereas, the double deletion decreased the activity by 86%. An altered form of APP-695, in which glutamine replaced Lys-612 at the cleavage site, is cleaved by Yap3 at 5% the rate of the wild-type APP. Mkc7 protease cleaved APP (K612Q) at about 20% the rate of wild-type APP. The simplest interpretation of these results is that Yap3 and Mkc7 proteases are α-secretases which act on APP in the late Golgi. They suggest that GPI-linked aspartyl proteases should be investigated as candidate secretases in mammalian tissues

A Simplified Approach to Operational InSAR Monitoring of Volcano Deformation in Low- and Middle-Income Countries: Case Study of Rabaul Caldera, Papua New Guinea

The primary goal of operational volcano monitoring is the timely identification of volcanic unrest. This provides critical information to decision makers tasked with mitigating the societal impacts of volcanic eruptions. Volcano deformation is recognized as a key indicator of unrest at many active volcanoes and can be used to provide insight into the depth and geometry of the magma source. Interferometric Synthetic Aperture Radar (InSAR) is a remote sensing technique that has detected deformation at many volcanoes globally, but most often with hindsight. To date, the use of InSAR for operational volcano monitoring has been limited to a few cases and only in high income countries. Yet a vast number of active volcanoes are located in low- and middle-income countries (LMICs), where resources for operational monitoring are constrained. In these countries, InSAR could provide deformation monitoring at many active volcanoes, including those that have no existing ground monitoring infrastructure. Several barriers combine to make uptake of InSAR into operational volcano monitoring difficult in most countries, but particularly in resource-constrained environments. To overcome some of these limiting factors, we propose a simplified processing chain to better incorporate InSAR and Global Navigation Satellite Systems (GNSS) data into the decision-making process at volcano observatories. To combine the InSAR and GNSS data we use a joint modelling procedure that infers volume changes of a spherical source beneath the volcano. The benefits of our approach for operational use include that the algorithm is computationally lightweight and can be run quickly on a standard desktop or laptop PC. This enables a volcano observatory to interpret geodetic data in a timely fashion, and use the information as part of frequent reporting procedures. To demonstrate our approach we combine ALOS-PALSAR InSAR data and continuous GNSS data from the Rabaul Caldera, Papua New Guinea between 2007 and 2011. Joint inversion of the two datasets indicates volume loss of ~1 × 107 m3 (deflation) occurring between February 2008 and November 2009, followed by volume gain of ~2.5 × 106 m3 (inflation) until February 2011 in a magma body situated ~1.5 km beneath the caldera

Influence of Combinatorial Histone Modifications on Antibody and Effector Protein Recognition

SummaryIncreasing evidence suggests that histone posttranslational modifications (PTMs) function in a combinatorial fashion to regulate the diverse activities associated with chromatin. Yet how these patterns of histone PTMs influence the adapter proteins known to bind them is poorly understood. In addition, how histone-specific antibodies are influenced by these same patterns of PTMs is largely unknown. Here we examine the binding properties of histone-specific antibodies and histone-interacting proteins using peptide arrays containing a library of combinatorially modified histone peptides. We find that modification-specific antibodies are more promiscuous in their PTM recognition than expected and are highly influenced by neighboring PTMs. Furthermore, we find that the binding of histone-interaction domains from BPTF, CHD1, and RAG2 to H3 lysine 4 trimethylation is also influenced by combinatorial PTMs. These results provide further support for the histone code hypothesis and raise specific concerns with the quality of the currently available modification-specific histone antibodies

Spectral and Timing Properties of IGR J17091-3624 in the Rising Hard State During its 2016 Outburst

We present a spectral and timing study of the NuSTAR and Swift observations of the black hole candidate IGR J17091-3624 in the hard state during its outburst in 2016. Disk reflection is detected in each of the NuSTAR spectra taken in three epochs. Fitting with relativistic reflection models reveals that the accretion disk is truncated during all epochs with $R_{\rm in}>10~r_{\rm g}$, with the data favoring a low disk inclination of $\sim 30^{\circ}-40^{\circ}$. The steepening of the continuum spectra between epochs is accompanied by a decrease in the high energy cut-off: the electron temperature $kT_{\rm e}$ drops from $\sim 64$ keV to $\sim 26$ keV, changing systematically with the source flux. We detect type-C QPOs in the power spectra with frequency varying between 0.131 Hz and 0.327 Hz. In addition, a secondary peak is found in the power spectra centered at about 2.3 times the QPO frequency during all three epochs. The nature of this secondary frequency is uncertain, however a non-harmonic origin is favored. We investigate the evolution of the timing and spectral properties during the rising phase of the outburst and discuss their physical implications.Comment: 11 pages, 9 figures, accepted by Ap

Proceedings from a Forum and Consultation on the Church as Partner in Community Economic Development.

Funding for this forum and consultation was provided in part by the Emma B. Howe Foundation, Minneapolis, MN; by the Joyce Foundation, Chicago, IL; and by the Center for Urban and Regional Affairs, University of Minnesota

Capturing the value of peer support : measuring recovery-oriented services

Purpose: The purpose of this paper is to examine the gap between recovery-oriented processes and clinical outcomes in peer support, an exemplar of recovery-oriented services, and offer suggestions for bridging this gap. Design/methodology/approach: This viewpoint is a brief review of literature on peer support services and gaps in outcome measurement towards building an evidence base for recovery-oriented services. Findings: Clinical outcomes like hospitalizations or symptoms remain a focus of research, practice and policy in recovery-oriented services and contribute to a mixed evidence base for peer support services, in which recovery-oriented outcomes like empowerment, self-efficacy and hopefulness have more evidentiary support. One approach is to identify the theoretical underpinnings of peer support services and the corresponding change mechanisms in models that would make these recovery-oriented outcomes mediators or process outcomes. A better starting point is to consider which outcomes are valued by the people who use services and develop an evaluation approach according to those stated goals. User driven measurement approaches and more participatory types of research can improve both the quality and impact of health and mental health services. Originality/value: This viewpoint provides a brief review of peer support services and the challenges of outcome measurement in establishing an evidence base and recommends user driven measurement as a starting point in evaluation of recovery-oriented services

Acceptance and commitment therapy for symptom interference in metastatic breast cancer patients: a pilot randomized trial

PURPOSE: Breast cancer is the leading cause of cancer mortality in women worldwide. With medical advances, metastatic breast cancer (MBC) patients often live for years with many symptoms that interfere with activities. However, there is a paucity of efficacious interventions to address symptom-related suffering and functional interference. Thus, this study examined the feasibility and preliminary efficacy of telephone-based acceptance and commitment therapy (ACT) for symptom interference with functioning in MBC patients. METHODS: Symptomatic MBC patients (N = 47) were randomly assigned to six telephone sessions of ACT or six telephone sessions of education/support. Patients completed measures of symptom interference and measures assessing the severity of pain, fatigue, sleep disturbance, depressive symptoms, and anxiety. RESULTS: The eligibility screening rate (64%) and high retention (83% at 8 weeks post-baseline) demonstrated feasibility. When examining within-group change, ACT participants showed decreases in symptom interference (i.e., fatigue interference and sleep-related impairment; Cohen's d range = - 0.23 to - 0.31) at 8 and 12 weeks post-baseline, whereas education/support participants showed minimal change in these outcomes (d range = - 0.03 to 0.07). Additionally, at 12 weeks post-baseline, ACT participants showed moderate decreases in fatigue and sleep disturbance (both ds = - 0.43), whereas education/support participants showed small decreases in these outcomes (ds = - 0.24 and - 0.18 for fatigue and sleep disturbance, respectively). Both the ACT and education/support groups showed reductions in depressive symptoms (ds = - 0.27 and - 0.28) at 12 weeks post-baseline. Group differences in all outcomes were not statistically significant. CONCLUSIONS: ACT shows feasibility and promise in improving fatigue and sleep-related outcomes in MBC patients and warrants further investigation

Predicting fear of breast cancer recurrence and self-efficacy in survivors by age at diagnosis

PURPOSE/OBJECTIVES: To determine the effect that age at diagnosis has on fear of breast cancer recurrence and to identify the predictors of fear of recurrence using self-efficacy as a mediator. DESIGN: Cross-sectional survey. SETTING: Two university cancer centers and one cooperative group in the midwestern United States. SAMPLE: 1,128 long-term survivors. METHODS: Survivors were eligible if they were aged 18-45 years (younger group) or 55-70 years (older group) at cancer diagnosis, had received chemotherapy, and were three to eight years postdiagnosis. Fear of recurrence was compared between younger and older groups. Multiple regression analyses were used to test variables' prediction of fear of recurrence and breast cancer survivor self-efficacy, as well as breast cancer survivor self-efficacy mediation effects. MAIN RESEARCH VARIABLES: Fear of recurrence, breast cancer survivor self-efficacy, and age at diagnosis. FINDINGS: Survivors diagnosed at a younger age had significantly higher fear of recurrence, as well as health, role, womanhood, death, and parenting worries. Perceived risk of recurrence, trait anxiety, and breast cancer reminders explained significant variance in fear of recurrence and breast cancer survivor self-efficacy. Breast cancer survivor self-efficacy partially mediated the effects of variables on fear of recurrence. CONCLUSIONS: The findings suggest that breast cancer survivor self-efficacy may have a protective effect for survivors who are younger at diagnosis and have higher perceived risk of recurrence, higher trait anxiety, and more breast cancer reminders. Oncology nurses already use the skills required to support self-efficacy. Additional research is needed to define and test breast cancer survivor self-efficacy interventions. IMPLICATIONS FOR NURSING: Oncology nurses are in a key role to assess fear of recurrence and provide self-efficacy interventions to reduce it in breast cancer survivors. Strategies to efficiently address fear of recurrence to reduce psychological distress in survivorship follow-up care are warranted

Pain management practices surrounding lumbar punctures in children: A survey of Canadian emergency physicians.

OBJECTIVES: Lumbar punctures (LPs) are painful for children, and analgesia is recommended by academic societies. However, less than one-third of pediatric emergency physicians (EPs) adhere to recommendations. We assessed the willingness to provide analgesia among pediatric and general EPs and explored patient and provider-specific barriers. METHODS: We surveyed physicians in the Pediatric Emergency Research Canada (PERC) or Canadian Association of Emergency Physicians (CAEP) databases from May 1 to August 1, 2016, regarding hypothetical scenarios for a 3-week-old infant, a 3-year-old child, and a 16-year-old child requiring an LP. The primary outcome was the willingness to provide analgesia. Secondary outcomes included the type of analgesia, reasons for withholding analgesia, and their perceived competence performing LPs. RESULTS: For a 3-week old infant, 123/144 (85.4%) pediatric EPs and 231/262 (88.2%) general EPs reported a willingness to provide analgesia. In contrast, the willingness to provide analgesia was almost universal for a 16-year-old (144/144 [100%] of pediatric EPs and 261/262 [99.6%] of general EPs) and a 3-year-old (142/144 [98.6%] of pediatric EPs and 256/262 [97.7%] of general EPs). For an infant, the most common barrier cited by pediatric EPs was the perception that it produced additional discomfort (13/21, 61.9%). The same reason was cited by general EPs (12/31, 38.7%), along with unfamiliarity surrounding analgesic options (13/31, 41.9%). CONCLUSION: Compared to a preschool child and adolescent, the willingness to provide analgesia for an LP in a young infant is suboptimal among pediatric and general EPs. Misconceptions and the lack of awareness of analgesic options should be targets for practice-changing strategies