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Purpose: Identifying clinically relevant comorbidities and their effect on health-related quality of life (HRQoL) outcomes among men with advanced prostate cancer (APC) can inform patient care and improve outcomes; however, this is poorly understood. The aim of this observational study was to examine the prevalence of comorbidities, and the relationship of comorbidity burden to HRQoL and other patient-reported outcomes (PROs) among men with APC. Methods: Participants were 192 men (average age 68.8) with APC (stage III or IV) who completed a psychosocial battery including measures of sociodemographic factors, HRQoL and other PROs, and the Charlson Comorbidity Index (CCI). Hierarchical multiple regression analysis was used to examine the relationships between CCI, HRQOL, and PROs. Results: The vast majority (82%) of participants had at least one comorbidity, with the most common being: hypertension (59%), connective tissue disease or arthritis (31%), diabetes (24%), and problems with kidneys, vision, or another organ (24%). After controlling for covariates, regressions showed that a higher CCI score was significantly associated with worse HRQoL (p < 0.001), lower levels of positive affect (p < 0.05), and higher levels of depression (p < 0.05), fatigue (p < 0.001), pain (p < 0.01), stress (p < 0.01), and cancer-specific distress (p < 0.05). Conclusions: Comorbidities were common among men with APC, and a greater CCI score was associated with detriments in several domains of HRQoL and other PROs. Our findings show the need to address comorbidities in the presence of a cancer diagnosis and subsequent treatment.

Despite life-saving potential, many women struggle to adhere to adjuvant endocrine therapy (AET) for their breast cancer (BCa). Prior research has demonstrated that emotional distress is a barrier to AET adherence. We followed women from a trial to test the long-term effects of two 5-week post-surgical group-based stress management interventions, cognitive behavioral therapy (CBT), and relaxation training versus an attention-matched health education control, on AET adherence. We conducted a long-term follow-up (median = 8 years) of women randomized to CBT, relaxation training, or health education after surgery for stage 0–3 BCa. We measured adherence with the Endocrine Therapy Medication Usage Questionnaire (ETMUQ). First, we established factors on the ETMUQ via confirmatory factor analysis. We then used Bayesian structural equation modeling to regress these factors on study arm, controlling for age and treatments received. Of those who completed long-term follow-up (n = 59, 44.7%), over half (n = 33; 55.9%) reported problems with adherence generally. Women receiving relaxation training (n = 15) had better adherence than those receiving health education (n = 24) on the Forgetfulness/Inconsistency [B(SE) = 0.25(0.14), p = 0.049] and Intentional Nonadherence [B(SE) = 0.31(0.14), p = 0.018] factors of the ETMUQ. Similar results were observed for those receiving relaxation training compared to CBT (n = 20): Forgetfulness/Inconsistency [B(SE) = − 0.47(0.25), p = 0.031]; Intentional Nonadherence [B(SE) = − 0.31(0.15), p = 0.027]. Women receiving relaxation training were less likely to (1) forget to take their AET and (2) intentionally miss doses of AET in the long term compared to women receiving health education or CBT. This is evidence for the need of randomized trials that aim to improve adherence by incorporating theoretically based behavioral change techniques. Trial 2R01-CA-064710 was registered March 26, 2006.

Cognitive behavioral stress management (CBSM) improves quality of life and mitigates stress biology in patients with early-stage cancer, including men with localized prostate cancer. However, treatments for advanced prostate cancer like androgen deprivation therapy (ADT) can lead to significant symptom burden that may be further exacerbated by stress-induced inflammation and cortisol dysregulation. The aim of this study was to examine the effects of CBSM (versus an active health promotion control) on circulating inflammatory markers and cortisol in men with advanced prostate cancer. Methods: Men with stage III or IV prostate cancer (N = 192) who had undergone ADT within the last year were randomized to CBSM or health promotion. Both interventions were 10 weeks, group-based, and delivered online. Venous blood was drawn at baseline, 6 months, and 12 months to measure circulating levels of CRP, IL-6, IL8, IL-10, and TNF-α. Saliva samples were collected at awakening, 30 minutes after awakening, evening, and night for two consecutive days at baseline, 6-months, and 12-months to measure diurnal cortisol slopes. Results: Mixed modeling analyses demonstrated that changes in inflammatory markers and cortisol did not differ by intervention. Men in both CBSM and health promotion showed decreases in IL-10, IL-8, and TNF-α from baseline to 6 months (β=−3.85–5.04, p’s=.004–

The mechanisms underlying memory loss associated with Alzheimer’s disease and related dementias (ADRD) remain unclear, and no effective treatments exist. Fundamental studies have shown that a set of transcriptional regulatory proteins of the nuclear receptor 4a (Nr4a) family serve as molecular switches for long-term memory. Here, we show that Nr4a proteins regulate the transcription of genes encoding chaperones that localize to the endoplasmic reticulum (ER). These chaperones fold and traffic plasticity-related proteins to the cell surface during long-lasting forms of synaptic plasticity and memory. Dysregulation of Nr4a transcription factors and ER chaperones is linked to ADRD, and overexpressing Nr4a1 or the chaperone Hspa5 ameliorates long-term memory deficits in a tau-based mouse model of ADRD, pointing toward innovative therapeutic approaches for treating memory loss. Our findings establish a unique molecular concept underlying long-term memory and provide insights into the mechanistic basis of cognitive deficits in dementia.

BackgroundThere are few if any well-known approaches to reducing avoidable health care utilization and costs in patients with social needs. This study’s objective was to explore the goals, and approaches to organizing and delivering care, of interventions attempting to reduce avoidable resource use by addressing patients’ medical and social needs.MethodsSemi-structured interviews were conducted with study investigators about early interventions in the peer-reviewed literature. A template analysis approach was used to review interview transcripts for common themes and create a final code list. Coder dyads separately coded each interview and resolved any discrepancies.ResultsInterviews were conducted with 15 investigators of interventions that delivered a variety of health services and addressed several individual social needs. Participants frequently described their overall goal as meeting patients’ diverse needs to prevent unnecessary acute care utilization. Reported approaches to addressing medical needs included assistance with receipt of primary care and care coordination across settings. Social needs were described as tightly linked with medical needs; addressing social support and housing were perceived as distinct from addressing other social needs. Participants described their overall approach to meeting patients’ needs in terms of establishing connections, partnership, respect, and being adaptable to patients’ priorities.ConclusionsFindings shed new light on how to simultaneously address medical and social needs. Opportunities for future research include evaluating different approaches to addressing medical needs (primary care versus care coordination), separately evaluating the impacts of housing or social support, and hiring and training procedures to promote trauma-informed, patient-centered care.

Objective: To summarize literature assessing the safety and efficacy of budesonide/formoterol, a low dose inhaled corticosteroid (ICS) and long-acting beta agonist (LABA) used as needed for the treatment of adult patients with mild persistent asthma requiring step 2 therapy compared to low dose inhaled corticosteroid (ICS) plus short-acting beta agonist (SABA) and SABA monotherapy. Data Sources: A literature search of PubMed (1966-October 2020), EMBASE (1973-October 2020) and clinicaltrials.gov was conducted using the following search terms: budesonide, formoterol, as needed, and mild asthma. Study selection and data extraction: Randomized, controlled trials with data describing as needed use of budesonide-formoterol in the treatment of mild, persistent asthma were included. Data synthesis: Current trials demonstrate a reduced risk of exacerbation and an improvement in symptom control in patients receiving budesonide/formoterol as needed when compared to as needed SABA alone. However, when compared to scheduled budesonide maintenance, patients receiving budesonide/formoterol as needed experienced worse symptom control and mixed exacerbation results. Relevance to patient care and clinical practice: This review evaluates the efficacy and safety of budesonide/formoterol as needed for patients with mild asthma. The Global Initiative for Asthma (GINA), a global strategy for asthma management and prevention adopted this change in 2019, and the most recent updated Expert Panel Report 4 of the National Asthma Education and Prevention Program (NAEPP) did not address this area. Conclusions: Based on this review of the literature, further study is needed to determine the place in therapy for budesonide/formoterol as needed in the treatment of mild persistent asthma. Low-dose ICS should remain the standard of therapy in patients with mild asthma requiring Step 2 therapy.

OBJECTIVES: To adapt and test the feasibility, acceptability, and preliminary efficacy of an 8-week resiliency group program for posttreatment lymphoma survivors. DESIGN AND OUTCOMES. This is an exploratory mixed methods study. Phase 1: We conducted qualitative interviews to inform program adaptation. Phase 2: Using a single-arm pilot design, we assessed program feasibility, acceptability, and preliminary efficacy (exploratory outcomes: stress coping, uncertainty intolerance, distress). We also examined the feasibility of collecting hair cortisol samples. RESULTS. Phase 1: Survivors reported feeling socially isolated as they grappled with lingering symptoms that interfered with their return to normalcy. Fears about recurrence triggered bodily hypervigilance. Survivors desired wellness programs that 1) target their whole-body experience, 2) promote social connectedness, and 3) manage fear of recurrence. Phase 2: Thirty-seven survivors enrolled. Participants completed a median of 7/8 sessions, and 76.9% completed ≥6/8 sessions; 65% provided a hair sample. Survivors demonstrated improvements in stress coping (d=.67), uncertainty tolerance (d=.71), and anxiety (d=.41) at program completion. CONCLUSIONS. Findings suggest promising feasibility and efficacy of this program in addressing posttreatment survivorship challenges, particularly fears of uncertainty. A cancer care model that adopts early integration of this program posttreatment has the potential to improve survivors’ emotional, social and physical well-being.

Machine harvest of ‘Brown Snout’ specialty cider apple (Malus ×domestica) has been shown to provide yield and juice quality characteristics similar to that of hand harvest. In this 2-year study, the sensory perception (color, aroma, flavor, mouthfeel, taste, and aftertaste) of ciders produced from machine-harvested and hand-harvested fruit that were ambient stored (56 °F) 0–4 weeks postharvest were compared using a trained panel and electronic tongue (e-tongue). For nearly all sensory attributes evaluated, the trained panelists scored the 2014 machine-harvested samples higher than the 2014 hand-harvested samples. Some of the key sensory differences included a darker color, a more astringent and heated mouthfeel, and a more sour taste of the machine-harvested samples than the hand-harvested samples. Trained panelists perceived no differences due to the harvest method among the 2015 samples for any of the sensory attributes evaluated. The e-tongue demonstrated good discrimination (index value = 95) of 2014 samples, but poor discrimination (index value = −0.5) of 2015 samples, mirroring the year-to-year variation experienced by the trained panelists. Overall, the e-tongue demonstrated a response to metallic and sour that was more associated with the machine-harvested samples and a response to sweet and umami that was more associated with the hand-harvested samples. These results demonstrate that cider made from machine-harvested fruit can have a different sensory profile than cider made from hand-harvested fruit. A consumer tasting panel should be conducted next to provide an indication of market response to the differing sensory profiles, qualifying the impact of harvest method. Results also indicate that ambient storage (56 °F) of fruit up to 4 weeks may not impact cider sensory attributes; however, cider apple growers should avoid ambient storage of machine-harvested fruit given the significant yield losses demonstrated in previous studies. Variation in cider quality due to year of harvest was most likely a result of differences in the hand-harvest technique between the 2 years, specifically more fruit bruising in 2014 than in 2015, demonstrating the importance of harvesting fully mature fruit with a standard protocol so as to supply a consistent raw material to cider producers. The e-tongue produced variable results compared with trained panelists and more development is needed before it can be incorporated into cider sensory evaluation protocol.

Rapid review products are intended to synthesize available evidence in a timely fashion while still meeting the needs of healthcare decision makers. Various methods and products have been applied for rapid evidence syntheses, but no single approach has been uniformly adopted. Methods to gain efficiency and compress the review time period include focusing on a narrow clinical topic and key questions; limiting the literature search; performing single (versus dual) screening of abstracts and full-text articles for relevance; and limiting the analysis and synthesis. In order to maintain the scientific integrity, including transparency, of rapid evidence syntheses, it is imperative that procedures used to streamline standard systematic review methods are prespecified, based on sound review principles and empiric evidence when possible, and provide the end user with an accurate and comprehensive synthesis. The collection of clinical preventive service recommendations maintained by the U.S. Preventive Services Task Force, along with its commitment to rigorous methods development, provide a unique opportunity to refine, implement, and evaluate rapid evidence synthesis methods and add to an emerging evidence base on rapid review methods. This paper summarizes the U.S. Preventive Services Task Force's use of rapid review methodology, its criteria for selecting topics for rapid evidence syntheses, and proposed methods to streamline the review process.

Age-associated cognitive impairments affect an individual’s quality of life and are a growing problem in society. Therefore, therapeutic strategies to treat age-related cognitive decline are needed to enhance the quality of life among the elderly. Activation of the Nr4a family of transcription factors has been closely linked to memory formation and dysregulation of these transcription factors is thought to be associated with age-related cognitive decline. Previously, we have shown that Nr4A transcription can be activated by synthetic bis-indole derived compounds (C-DIM). C-DIM compounds enhance synaptic plasticity and long-term contextual fear memory in young healthy mice. In this study, we show that activation of Nr4a2 by 1,1-bis(3′-Indolyl)-1-(p-chlorophenyl) methane (C-DIM12), enhances long-term spatial memory in young mice and rescues memory deficits in aged mice. These findings suggest that C-DIM activators of Nr4a transcription may be suitable to prevent memory deficits associated with aging.

Many studies have examined relationships of microorganisms to geochemical zones in subseafloor sediment. However, responses to selective pressure and patterns of community succession with sediment depth have rarely been examined. Here we use 16S rDNA sequencing to examine the succession of microbial communities at sites in the Indian Ocean and the Bering Sea. The sediment ranges in depth from 0.16 to 332 m below seafloor and in age from 660 to 1,300,000 years. The majority of subseafloor taxonomic diversity is present in the shallowest depth sampled. The best predictor of sequence presence or absence in the oldest sediment is relative abundance in the near-seafloor sediment. This relationship suggests that perseverance of specific taxa into deep, old sediment is primarily controlled by the taxonomic abundance that existed when the sediment was near the seafloor. The operational taxonomic units that dominate at depth comprise a subset of the local seafloor community at each site, rather than a grown-in group of geographically widespread subseafloor specialists. At both sites, most taxa classified as abundant decrease in relative frequency with increasing sediment depth and age. Comparison of community composition to cell counts at the Bering Sea site indicates that the rise of the few dominant taxa in the deep subseafloor community does not require net replication, but might simply result from lower mortality relative to competing taxa on the long timescale of community burial.

This study reports on the safety and putative probiotic properties of Bacillus amyloliquefaciens B-1895 and Bacillus subtilis KATMIRA1933. According to the bacterial reverse mutation (Ames) test, cell-free supernatants of B. amyloliquefaciens B-1895 and B. subtilis KATMIRA1933 were not mutagenic. The two strains co-aggregated with Escherichia coli and Pseudomonas aeruginosa, and cell-free supernatants inhibited the growth of Streptococcus intermedius and Porphyromonas gingivalis. Endospores of B. amyloliquefaciens B-1895 and B. subtilis KATMIRA1933 were tolerant to 0.3% (w/v) bile salts and survived incubation for 4 h in MRS broth at pH 2.0 to 3.0. The ability of the two strains to produce antimicrobial compounds potentiates their application in health care formulations, personal care products, food and animal feed.

Background CDI is a 2-hit process requiring C. difficile spores and antibiotic-mediated dysbiosis, a low diversity state of the gut microbiome. Recurrent CDI (rCDI) is common and may be related to inadequate antibiotic concentrations (e.g., metronidazole; MET) or persistent dysbiosis (e.g., vancomycin; VAN). SER-262 is an oral investigational microbiome drug rationally designed to reduce rCDI by restoring colonization resistance. Methods SERES-262-001 was a Phase 1b randomized placebo (PBO)-controlled single and multidose study. Subjects with primary CDI (n = 96) were enrolled in 8 cohorts (SER-262: PBO, 5:1). Subjects were dosed after MET (n = 57) or VAN (n = 39) per investigator discretion. Engraftment of SER-262 strains was evaluated using strain-specific molecular probes in fecal samples; microbial diversity was measured via whole metagenomic shotgun sequencing. Endpoints included safety and rCDI rates up to 8 weeks posttreatment and strain engraftment at 1, 4, 8, 12, and 24 weeks. Results SER-262 safety was comparable to PBO. Although overall rCDI rates were similar in SER-262 (n = 80) and PBO (n = 16) subjects (18.8% vs. 12.5%, respectively), in a post-hoc analysis we observed reduced rates of rCDI in the VAN+SER-262 arm compared with MET+SER-262 (6.3 vs. 27.1%, respectively, P = 0.02, Figure 1). Overall, 8 of 12 SER-262 strains showed significant engraftment relative to PBO. However, greater SER-262 strain engraftment was observed in VAN-treated subjects compared with MET-treated subjects (P < 0.001, Figure 2). To better understand the impact of dysbiosis on engraftment, we evaluated baseline microbial diversity by prior antibiotic received and observed that the diversity of Bacteroidetes and Firmicute species was lower in VAN-treated subjects compared with MET-treated subjects (P < 0.001, Figure 3). Conclusion In this first phase 1b study of a fermented microbiome drug in subjects with primary CDI, SER-262 was safe and well-tolerated. The higher efficacy rates of SER-262 in reducing rCDI among VAN-treated subjects may be due to low baseline microbial diversity, which creates an ecologic niche for greater engraftment of dose species. Treatment of C. difficile with VAN, followed by restoration of colonization resistance with SER-262, is a promising 2-pronged therapeutic paradigm to reduce rCDI. Disclosures All authors: No reported disclosures.

Chemical Geology 409 (2015) 28–41 Contents lists available at ScienceDirect Chemical Geology journal homepage: www.elsevier.com/locate/chemgeo Monazite response to ultrahigh-pressure subduction from U–Pb dating by laser ablation split stream Bradley R. Hacker a, ⁎ , Andrew R.C. Kylander-Clark a , Robert Holder a , Torgeir B. Andersen b , Emily M. Peterman c , Emily O. Walsh d , Jonathan K. Munnikhuis e a Earth Science, University California, Santa Barbara, CA 93106-9630, USA University of Oslo, Physics of Geological Processes, PO Box 1048, Blindern, 0316 Oslo, Norway Earth and Oceanographic Science, Bowdoin College, 6800 College Station, Brunswick, ME 04011, USA d Geology, Cornell College, Mount Vernon, IA 52314, USA e Geological Sciences, University of North Carolina, Chapel Hill, Campus Box #3315 Chapel Hill, NC 27599-3315, USA b c a r t i c l e i n f o Article history: Received 5 February 2015 Received in revised form 6 May 2015 Accepted 11 May 2015 Available online 22 May 2015 Editor: K. Mezger Keywords: Monazite Laser ablation Split stream Petrochronology a b s t r a c t To assess the response of monazite during subduction of continental crust to mantle depths, U–Pb isotopic ratios and elemental abundances were measured simultaneously by laser-ablation split-stream inductively-coupled plasma mass spectrometry (LASS) in rocks from the ultrahigh-pressure Western Gneiss Region of the Scandinavian Caledonides. Nearly seventy different samples of quartzofeldspathic basement and overlying metasedimentary rocks were studied. Pre-subduction monazite (chiefly 1.6 Ga and 1.0 Ga) is preserved locally in the structurally lowest, basement rocks because earlier, Precambrian tectonism produced coarse-grained, high-grade rocks that were resistant to further recrystallization in spite of syn-subduction temperatures and pressures of 650–800 °C and 2–3.5 GPa. A few of the monazite in the metasedimentary rocks atop the basement preserve syn-subduction U–Pb dates, but the majority continued to recrystallize during post-subduction exhumation and record a general westward decrease in age related to westward-progressing exhumation. The absence of Precambrian monazite in the metasedimentary rock atop the basement suggests that sedimentation postdated the 1.0–0.9 Ga high-grade metamorphism and was late Proterozoic to early Paleozoic. © 2015 Elsevier B.V. All rights reserved. 1. Introduction The development of techniques to analyze monazite U/Th–Pb dates in situ by electron probe [Suzuki et al., 1991], SIMS [Harrison et al., 1995], and LA-ICP-MS [Kosler et al., 2001] has spurred renewed interest in the petrogenesis of monazite, including understanding neocrystal- lization [Kingsbury et al., 1993], recrystallization [Finger, 1998], compo- sition [Franz et al., 1996], and thermometry [Gratz and Heinrich, 1997; Pyle et al., 2001]. Advances in these complementary tracks of analytical methods and petrologic interpretation have enabled increasing use of monazite as a petrochronometer—i.e., the interpretation of isotopic dates in the context of elemental or complementary isotopic informa- tion collected from the same mineral. One might infer from recent models [Kelsey, 2008] [Yakymchuk and Brown, 2014] that monazite is routinely recrystallized during high- temperature orogenesis and that its U–Pb age records only the final, cooling stage. Here we apply LASS (laser-ablation split-stream inductively-coupled plasma mass spectrometry) [Kylander-Clark et al., 2013] to monazite from the ultrahigh-pressure (UHP) Western Gneiss ⁎ Corresponding author. Tel.: +1 805 893 7952. E-mail address: hacker@geol.ucsb.edu (B.R. Hacker). http://dx.doi.org/10.1016/j.chemgeo.2015.05.008 0009-2541/© 2015 Elsevier B.V. All rights reserved. Region (WGR). Our objective in using in situ, combined U–Pb and trace-element analysis of monazite is to understand the broad-scale metamorphic response of monazite and its host rocks during subduc- tion to, and exhumation from, UHP conditions. The premise behind collecting trace-element and isotopic data simultaneously is that the trace elements provide insight into the petrological context of the isoto- pic dates: depressed heavy rare earth element concentrations may indi- cate that an interpreted U–Pb date coincides with the stability of garnet [Rubatto, 2002], elevated Eu and Sr may indicate HP recrystallization and plagioclase instability [Finger and Krenn, 2007; Holder et al., 2015], and Th and U help understand fluid availability [Hoskin and Schaltegger, 2003] and its potential role in monazite recrystallization [Seydoux-Guillaume et al., 2002]. We show that some monazite sur- vived amphibolite–granulite-facies metamorphism, partial melting, and subduction with its original age intact. 2. Geologic setting The Western Gneiss Region (WGR) of Norway contains one of Earth's largest ultrahigh-pressure terranes (Fig. 1). Like most well-exposed and extensively investigated UHP terranes, the WGR is dominated by quartzofeldspathic gneiss; eclogite and (U)HP

The efficient generation of meshes is an important component in the numerical solution of problems in physics and engineering. Of interest are situations where global mesh quality and a tight coupling to the solution of the physical partial differential equation (PDE) is important. We consider parabolic PDE mesh generation and present a method for the construction of adaptive meshes in two spatial dimensions using stochastic domain decomposition that is suitable for an implementation in a multi- or many-core environment. Methods for mesh generation on periodic domains are also provided. The mesh generator is coupled to a time dependent physical PDE and the system is evolved using an alternating solution procedure. The method uses the stochastic representation of the exact solution of a parabolic linear mesh generator to find the location of an adaptive mesh along the (artificial) subdomain interfaces. The deterministic evaluation of the mesh over each subdomain can then be obtained completely independently using the probabilistically computed solutions as boundary conditions. The parallel performance of this general stochastic domain decomposition approach has previously been shown. We demonstrate the approach numerically for the mesh generation context and compare the mesh obtained with the corresponding single domain mesh using a representative mesh quality measure., 15 pages, 3 figures

Cardiovascular disease can alter the mechanical environment of the vascular system, leading to mechano-adaptive growth and remodeling. Predictive models of arterial mechano-adaptation could improve patient treatments and outcomes in cardiovascular disease. Vessel-scale mechano-adaptation includes remodeling of both the cells and extracellular matrix. Here, we aimed to experimentally measure and characterize a phenomenological mechano-adaptation law for vascular smooth muscle cells (VSMCs) within an artery. To do this, we developed a highly controlled and reproducible system for applying a chronic step-change in strain to individual VSMCs with in vivo like architecture and tracked the temporal cellular stress evolution. We found that a simple linear growth law was able to capture the dynamic stress evolution of VSMCs in response to this mechanical perturbation. These results provide an initial framework for development of clinically relevant models of vascular remodeling that include VSMC adaptation.

The Upper Allochthon of the Scandinavian Caledonides is composed of thrust slices of a variety of metamorphosed volcanic, plutonic, and sedimentary rocks. The rocks are largely interpreted to have been formed in Cambrian to Ordovician oceanic to peri-continental arc environments that were thrust onto Baltica during the Silurian-Devonian Scandian Orogeny. We review the literature on Upper Allochthon igneous rock geochemistry broadly. We also present 87 new analyses of metamorphosed igneous rocks taken from the Surnadal and Moldefjord synforms and the Rissa area in the northern part of the Western Gneiss Region, where highly deformed Upper Allochthon rocks are preserved. Here the Upper Allochthon is dominated by basaltic volcanics and gabbros with sparse intermediate and felsic rocks. Most of the mafic rocks are transitional between MORB- and arc-type compositions in tectonic discriminant diagrams and for REE and multi-element patterns. We present two new discriminant diagrams to illustrate this subtle transitional characteristic. We interpret these volcanics as having been erupted in a mature back-arc basin environment where mantle sources for the magmas were only slightly influenced by the subduction zone component from an adjacent arc. Another set of mafic volcanic rocks, coming only from the Storas and Rissa areas, were extruded in an oceanic arc-type environment. These two geochemical types, back-arc and oceanic-arc, are closely matched by Storen Group ophiolites in the Trondheim Region which are dominated by basaltic volcanics and gabbros and generally lack felsic igneous and sedimentary rocks. Felsic igneous rocks, sedimentary rocks, and calc-alkaline and alkaline volcanics are more abundant in stratigraphically younger units of the Upper Allochthon, including the Lower and Upper Hovin Groups. We correlate the Upper Allochthon igneous rocks in the Moldefjord and Surnadal synforms and the Rissa area with ophiolites of the Storen Group. Early oceanic-arc and back-arc volcanic rocks, followed by more calc-alkaline to alkaline volcanics, are the dominant pattern for ophiolite sequences in the rest of the Upper Allochthon of the Scandinavian Caledonides. We envisage a paleotectonic scenario in which a Late Cambrian to Tremadocian, oceanic-arc system developed above a subduction zone dipping oceanward from a microcontinent that had earlier rifted away from Baltica or possibly Ganderia. The ophiolitic and primitive arc rocks are inferred to have been obducted in Late Tremadocian–Early Floian time upon epicontinental rocks flanking the microcontinent, which was then drifting rapidly across the Iapetus Ocean approaching Laurentia. A new arc and marginal basin developed, following a subduction polarity reversal, with the Dapingian-Darriwilian sedimentary infill being replete with Laurentian faunas, and locally punctuated by calc-alkaline volcanics and dikes, with fringing reefal limestones. The entire volcano-sedimentary assemblage was later affected by Scandian (Silurian–Early Devonian) orogenesis during emplacement of the major nappes onto the Baltoscandian margin.

A new dataset for the high-pressure to ultrahigh-pressure Western Gneiss Region allows the definition of distinct structural and petrological domains. Much of the study area is an E-dipping homocline with E-plunging lineations that exposes progressively deeper, more strongly deformed, more eclogite-rich structural levels westward. Although eclogites crop out across the WGR, Scandian deformation is weak and earlier structures are well preserved in the southeastern half of the study area. The Scandian reworking increases westward, culminating in strong Scandian fabrics with only isolated pockets of older structures; the dominant Scandian deformation was coaxial E–W stretching. The sinistrally sheared More–Trondelag Fault Complex and Nordfjord Mylonitic Shear Zone bound these rocks to the north and south. There was moderate top-E, amphibolite-facies deformation associated with translation of the allochthons over the basement along its eastern edge, and the Nordfjord–Sogn Detachment Zone underwent strong lower amphibolite-facies to greenschist-facies top-W shearing. A northwestward increase in exhumation-related melting is indicated by leucosomes with hornblende, plagioclase, and Scandian sphene. In the western 2/3 of the study area, exhumation-related, amphibolite-facies symplectite formation in quartzofeldspathic gneiss postdated most Scandian deformation; further deformation was restricted to slip along biotite-rich foliation planes and minor local folding. That the Western Gneiss Region quartzofeldspathic gneiss exhibits a strong gradient in degree of deformation, implies that continental crust in general need not undergo pervasive deformation during subduction.

Objective We aimed to create a molecular assay to monitor erythroid (red blood cell [RBC]) engraftment in any patient following allogeneic hematopoietic stem cell transplantation, independent of disease-specific mutations. Materials and Methods We identified 10 common single nucleotide polymorphisms (SNPs), expressed by genes encoding RBC antigens and structural proteins. These SNPs were polymerase chain reaction–amplified from total RNA extracted from peripheral blood, which contains nucleated erythroid progenitors. Mixing studies validated that each SNP can quantitatively measure donor/recipient DNA and RNA. Results We directly genotyped 23 patients who underwent hematopoietic stem cell transplantation and their human leukocyte antigen–matched donors and found a median of three informative SNPs (i.e., discordant between donor and recipient) per pair. By using the informative RBC SNPs to quantify donor-derived RBC transcripts, we compared rates of RBC engraftment in 13 patients with hemoglobinopathies vs donor mononuclear cell (white blood cell [WBC]) engraftment. Consistent with known ineffective erythropoiesis associated with hemoglobinopathies, we detected up to threefold greater RBC-specific compared to overall WBC engraftment in five of eight patients who were mixed chimeras by transplant day 30. The remaining three of eight who received ABH-incompatible grafts, demonstrated at least 0.5-fold lower RBC compared to WBC engraftment that was related to persistence of host-derived anti-isohemagglutinin antibodies. Conclusion This RNA-based assay can be used to monitor RBC-specific engraftment regardless of a patient's specific hemoglobin mutation or even diagnosis. We propose that panels of expressed SNPs informative for other cell lineages can be created to comprehensively assess the impact of novel stem cell–based therapies on lineage-specific engraftment.

The geochemistry of kyanite and orthopyroxene eclogites (7 samples) indicate that they are gabbroic cumulates. Incompatible trace elements in these rocks occur at low concentrations compared to regionally associated eclogites that are compositionally similar to basaltic magmas (11 samples). Eclogites with cumulate protoliths commonly contain 100 ppm Zr, >4 ppm Sm, and >0.4 ppm Lu for basaltic eclogites. Because of low Zr concentrations, igneous and metamorphic zircons are rare or absent in these eclogites. Samarium and Lu concentrations are also low in the kyanite and orthopyroxene eclogites, but they have parent/daughter Sm/Nd ratios of 0.23–0.51 and Lu/Hf ratios of 0.22–0.60, higher than most associated basaltic eclogites at 0.22–0.38 and 0.11–0.18, respectively. These results suggest that kyanite and orthopyroxene eclogites are poor targets for zircon geochronologic work, but are good targets for Sm/Nd and Lu/Hf mineral/whole rock geochronology because of their high parent/daughter ratios.

The Ottfjallet swarm of Late Neoproterozoic mafic dikes, cutting Neoproterozoic sandstones, became a key, 30 years ago, to the tectonics of the Scandian Caledonides. The sandstones were deposited in basins related to opening of lapetus, and intruded by dikes in distal parts of the Baltoscandian margin close to the developing spreading axis. The sandstones and underlying basement rocks were transported, from west of the present Norwegian coast, to as far east as western Sweden during the Silurian-Devonian Scandian Orogeny. The sandstones with dikes make up the Sarv Nappe, up to 2 km thick in Sweden, and the quartzites and amphibolites of the Saetra and equivalent nappes in Norway. These form the upper part of the Middle Allochthon. The lower part of the Middle Allochthon includes Middle Proterozoic basement gneisses and rapakivi granites, containing mafic rocks in some places. The dike-bearing quartzite is a key unit due to contrast with similar rocks lacking dikes at lower tectonic levels derived from inboard parts of Baltica. The Saetra Nappe and equivalents are well constrained on lithotectonic grounds in Norway at Oppdal, Leksdal, and Orkanger. It was also suspected to occur in deep, narrow synclines in the Western Gneiss Region where interlayered feldspathic quartzite and amphibolite are in correct tectonostratigraphic sequence, locally with a total thickness of only 1 to 3 m, and locally with dikes converted to eclogite. To test correlations, 127 samples of mafic rocks were collected from 14 areas west and southwest of Trondheimsfjord into the Western Gneiss region toward Alesund. Samples include mafic rocks in quartzites and others, some clearly dikes, from the underlying 1190 Ma rapakivi granite/augen gneiss of the Risberget Nappe and adjacent basement gneisses. Typical Saetra dikes in the Oppdal quarries, and mafic rocks from other quartzites and related rocks, have La n /Sm n ratios of 1.0 to 1.8, and Nb/La ratios of 0.8 to 1.4 (Oppdal group). Most REE patterns are moderately LREE-enriched with no or very small, mostly negative, Eu anomalies. All have similar multi-element patterns typically with small positive P anomalies, negative Zr-Hf anomalies and an absence of Nb-Ta anomalies, showing that the dikes are unrelated to arcs and have no notable continental crust component. A subset of Saetra, Risberget, and basement dikes is distinguished by higher La n /Sm n ratios of 1.8 to 2.5, but otherwise has very similar characteristics (Ystland Group). These data support correlation of the Saetra Nappe quartzite and dikes into highly deformed parts of the Western Gneiss Region and correlation of nearby dike-rich parts of basement gneiss with the Middle Allochthon. One sample in quartzite at Ura, at an unusual tectonostratigraphic position, has La n /Sm n = 0.7, Nb/La = 0.6, and a multi-element pattern different from Saetra dikes, suggesting it is unrelated to the Ottfjallet dikes. Non-Saetra-like amphibolites also occur in the Risberget Nappe, and have La n /Sm n ratios of 1.4 to 3, all Nb/La ratios

The proteins encoded by the classical HLA class I and class II genes in the major histocompatibility complex (MHC) are highly polymorphic and play an essential role in self/non-self immune recognition. HLA variation is a crucial determinant of transplant rejection and susceptibility to a large number of infectious and autoimmune disease1. Yet identification of causal variants is problematic due to linkage disequilibrium (LD) that extends across multiple HLA and non-HLA genes in the MHC2,3. We therefore set out to characterize the LD patterns between the highly polymorphic HLA genes and background variation by typing the classical HLA genes and >7,500 common single nucleotide polymorphisms (SNPs) and deletion/insertion polymorphisms (DIPs) across four population samples. The analysis provides informative tag SNPs that capture some of the variation in the MHC region and that could be used in initial disease association studies, and provides new insight into the evolutionary dynamics and ancestral origins of the HLA loci and their haplotypes.

Autoimmune, inflammatory, and infectious diseases present a major burden to human health and are frequently associated with loci in the human major histocompatibility complex (MHC). Here, we report a high-resolution (1.9 kb) linkage-disequilibrium (LD) map of a 4.46-Mb fragment containing the MHC in U.S. pedigrees with northern and western European ancestry collected by the Centre d'Etude du Polymorphisme Humain (CEPH) and the first generation of haplotype tag single-nucleotide polymorphisms (tagSNPs) that provide up to a fivefold increase in genotyping efficiency for all future MHC-linked disease-association studies. The data confirm previously identified recombination hotspots in the class II region and allow the prediction of numerous novel hotspots in the class I and class III regions. The region of longest LD maps outside the classic MHC to the extended class I region spanning the MHC-linked olfactory-receptor gene cluster. The extended haplotype homozygosity analysis for recent positive selection shows that all 14 outlying haplotype variants map to a single extended haplotype, which most commonly bears HLA-DRB1*1501. The SNP data, haplotype blocks, and tagSNPs analysis reported here have been entered into a multidimensional Web-based database (GLOVAR), where they can be accessed and viewed in the context of relevant genome annotation. This LD map allowed us to give coordinates for the extremely variable LD structure underlying the MHC.

Cardiac valve formation is a complex process that involves cell signaling events between the myocardial and endocardial layers of the heart across an elaborate extracellular matrix. These signals lead to marked morphogenetic movements and transdifferentiation of the endocardial cells at chamber boundaries. Here we identify the genetic defect in zebrafish jekyll mutants, which are deficient in the initiation of heart valve formation. The jekyll mutation disrupts a homolog of Drosophila Sugarless, a uridine 5′-diphosphate (UDP)–glucose dehydrogenase required for heparan sulfate, chondroitin sulfate, and hyaluronic acid production. The atrioventricular border cells do not differentiate from their neighbors in jekyll mutants, suggesting that Jekyll is required in a cell signaling event that establishes a boundary between the atrium and ventricle.

The association of the major histocompatibility complex (MHC) with SLE is well established yet the causal variants arising from this region remain to be identified, largely due to inadequate study design and the strong linkage disequilibrium demonstrated by genes across this locus. The majority of studies thus far have identified strong association with classical class II alleles, in particular HLA-DRB1*0301 and HLA-DRB1*1501. Additional associations have been reported with class III alleles; specifically, complement C4 null alleles and a tumor necrosis factor promoter SNP (TNF-308G/A). However, the relative effects of these class II and class III variants have not been determined. We have thus used a family-based approach to map association signals across the MHC class II and class III regions in a cohort of 314 complete United Kingdom Caucasian SLE trios by typing tagging SNPs together with classical typing of the HLA-DRB1 locus. Using TDT and conditional regression analyses, we have demonstrated the presence of two distinct and independent association signals in SLE: HLA-DRB1*0301 (nominal p = 4.9 × 10−8, permuted p < 0.0001, OR = 2.3) and the T allele of SNP rs419788 (nominal p = 4.3 × 10−8, permuted p < 0.0001, OR = 2.0) in intron 6 of the class III region gene SKIV2L. Assessment of genotypic risk demonstrates a likely dominant model of inheritance for HLA-DRB1*0301, while rs419788-T confers susceptibility in an additive manner. Furthermore, by comparing transmitted and untransmitted parental chromosomes, we have delimited our class II signal to a 180 kb region encompassing the alleles HLA-DRB1*0301-HLA-DQA1*0501-HLA-DQB1*0201 alone. Our class III signal importantly excludes independent association at the TNF promoter polymorphism, TNF-308G/A, in our SLE cohort and provides a potentially novel locus for future genetic and functional studies., Author Summary Systemic lupus erythematosus (SLE/lupus) is a complex autoimmune disease in which the body's immune system attacks its own tissues, causing inflammation in a variety of different organs such as the skin, joints, and kidneys. The cause of lupus is not known, but genes play a significant role in the predisposition to disease. The major histocompatibility complex (MHC) on Chromosome 6 contains at least 100 different genes that affect the immune system, including the genes with the strongest effect on lupus susceptibility. Despite the importance of the MHC in SLE, the identity of the actual genes in the MHC region that cause SLE has remained elusive. In the present study, we used the latest set of genetic markers present at the MHC in lupus families to identify the actual genes that affect the disease. To our knowledge, we have shown for the first time that two separate groups of genes are involved in SLE. One group of genes alters how the immune system may inappropriately target its own tissues in the disease. How the second set of genes predisposes to SLE is the subject of ongoing study.

The C-C chemokine receptor 5, 32 base-pair deletion (CCR5-Δ32) allele confers strong resistance to infection by the AIDS virus HIV. Previous studies have suggested that CCR5-Δ32 arose within the past 1,000 y and rose to its present high frequency (5%–14%) in Europe as a result of strong positive selection, perhaps by such selective agents as the bubonic plague or smallpox during the Middle Ages. This hypothesis was based on several lines of evidence, including the absence of the allele outside of Europe and long-range linkage disequilibrium at the locus. We reevaluated this evidence with the benefit of much denser genetic maps and extensive control data. We find that the pattern of genetic variation at CCR5-Δ32 does not stand out as exceptional relative to other loci across the genome. Moreover using newer genetic maps, we estimated that the CCR5-Δ32 allele is likely to have arisen more than 5,000 y ago. While such results can not rule out the possibility that some selection may have occurred at C-C chemokine receptor 5 (CCR5), they imply that the pattern of genetic variation seen atCCR5-Δ32 is consistent with neutral evolution. More broadly, the results have general implications for the design of future studies to detect the signs of positive selection in the human genome., Sabeti and colleagues use dense genetic maps to show that the HIV-resistance CCR5-Δ32 allele is more than 5,000 years old and is likely to have been under mainly neutral selection.

Pathogens have played a substantial role in human evolution, with past infections shaping genetic variation at loci influencing immune function. We selected 168 genes known to be involved in the immune response, genotyped common single nucleotide polymorphisms across each gene in three population samples (CEPH Europeans from Utah, Han Chinese from Guangxi, and Yoruba Nigerians from Southwest Nigeria) and searched for evidence of selection based on four tests for non-neutral evolution: minor allele frequency (MAF), derived allele frequency (DAF), Fst versus heterozygosity and extended haplotype homozygosity (EHH). Six of the 168 genes show some evidence for non-neutral evolution in this initial screen, with two showing similar signals in independent data from the International HapMap Project. These analyses identify two loci involved in immune function that are candidates for having been subject to evolutionary selection, and highlight a number of analytical challenges in searching for selection in genome-wide polymorphism data.

To explore the potential value of recently developed high-density linkage mapping methods in the analysis of complex disease we have regenotyped five nuclear families first studied in the 1996 UK multiple sclerosis linkage genome screen, using Applied Biosystems high-density microsatellite linkage mapping set, the Illumina BeadArray linkage mapping panel (version 3) and the Affymetrix GeneChip Human Mapping 10K array. We found that genotyping success, information extraction and genotyping accuracy were improved with all systems. These improvements were particularly marked with the SNP-based methods (Illumina and Affymetrix), with little difference between these. The extent of additional information extracted is considerable, indicating that reanalysis of existing multiplex families using these newer systems would substantially increase power.

Function of the heart begins long before its formation is complete. Analyses in mouse and zebrafish have shown that myocardial function is not required for early steps of organogenesis, such as formation of the heart tube or chamber specification. However, whether myocardial function is required for later steps of cardiac development, such as endocardial cushion (EC) formation, has not been established. Recent technical advances and approaches have provided novel inroads toward the study of organogenesis, allowing us to examine the effects of both genetic and pharmacological perturbations of myocardial function on EC formation in zebrafish. To address whether myocardial function is required for EC formation, we examined silent heart (sih−/−) embryos, which lack a heartbeat due to mutation of cardiac troponin T (tnnt2), and observed that atrioventricular (AV) ECs do not form. Likewise, we determined that cushion formation is blocked in cardiofunk (cfk−/−) embryos, which exhibit cardiac dilation and no early blood flow. In order to further analyze the heart defects in cfk−/− embryos, we positionally cloned cfk and show that it encodes a novel sarcomeric actin expressed in the embryonic myocardium. The Cfks11 variant exhibits a change in a universally conserved residue (R177H). We show that in yeast this mutation negatively affects actin polymerization. Because the lack of cushion formation in sih- and cfk-mutant embryos could be due to reduced myocardial function and/or lack of blood flow, we approached this question pharmacologically and provide evidence that reduction in myocardial function is primarily responsible for the defect in cushion development. Our data demonstrate that early myocardial function is required for later steps of organogenesis and suggest that myocardial function, not endothelial shear stress, is the major epigenetic factor controlling late heart development. Based on these observations, we postulate that defects in cardiac morphogenesis may be secondary to mutations affecting early myocardial function, and that, in humans, mutations affecting embryonic myocardial function may be responsible for structural congenital heart disease., Cardiac anomolies can result from very early defects in heart development. In zebrafish, such defects have been shown to be caused by a new gene called cardiofunk

Numerous studies have clearly indicated a role for the major histocompatibility complex (MHC) in susceptibility to autoimmune diseases. Such studies have focused on the genetic variation of a small number of classical human-leukocyte-antigen (HLA) genes in the region. Although these genes represent good candidates, given their immunological roles, linkage disequilibrium (LD) surrounding these genes has made it difficult to rule out neighboring genes, many with immune function, as influencing disease susceptibility. It is likely that a comprehensive analysis of the patterns of LD and variation, by using a high-density map of single-nucleotide polymorphisms (SNPs), would enable a greater understanding of the nature of the observed associations, as well as lead to the identification of causal variation. We present herein an initial analysis of this region, using 201 SNPs, nine classical HLA loci, two TAP genes, and 18 microsatellites. This analysis suggests that LD and variation in the MHC, aside from the classical HLA loci, are essentially no different from those in the rest of the genome. Furthermore, these data show that multi-SNP haplotypes will likely be a valuable means for refining association signals in this region.

Vertebrate heart development is initiated from bilateral lateral plate mesoderm that expresses the Nkx2.5 and GATA4 transcription factors, but the extracellular signals specifying heart precursor gene expression are not known. We describe here that the secreted signaling factor Fgf8 is expressed in and required for development of the zebrafish heart precursors, particularly during initiation of cardiac gene expression. fgf8 is mutated in acerebellar (ace) mutants, and homozygous mutant embryos do not establish normal circulation, although vessel formation is only mildly affected. In contrast, heart development, in particular of the ventricle, is severely abnormal in acerebellar mutants. Several findings argue that Fgf8 has a direct function in development of cardiac precursor cells: fgf8 is expressed in cardiac precursors and later in the heart ventricle. Fgf8 is required for the earliest stages of nkx2.5 and gata4, but not gata6, expression in cardiac precursors. Cardiac gene expression is restored in acerebellar mutant embryos by injecting fgf8 RNA, or by implanting a Fgf8-coated bead into the heart primordium. Pharmacological inhibition of Fgf signalling during formation of the heart primordium phenocopies the acerebellar heart phenotype, confirming that Fgf signaling is required independently of earlier functions during gastrulation. These findings show that fgf8/acerebellar is required for induction and patterning of myocardial precursors.

We describe the isolation of zebrafish Fgf8 and its expression during gastrulation, somitogenesis, fin bud and early brain development. By demonstrating genetic linkage and by analysing the structure of the Fgf8 gene, we show that acerebellar is a zebrafish Fgf8 mutation that may inactivate Fgf8 function. Homozygous acerebellar embryos lack a cerebellum and the midbrain-hindbrain boundary organizer. Fgf8 function is required to maintain, but not initiate, expression of Pax2.1 and other marker genes in this area. We show that Fgf8 and Pax2.1 are activated in adjacent domains that only later become overlapping, and activation of Fgf8 occurs normally in no isthmus embryos that are mutant for Pax2.1. These findings suggest that multiple signaling pathways are independently activated in the midbrain-hindbrain boundary primordium during gastrulation, and that Fgf8 functions later during somitogenesis to polarize the midbrain. Fgf8 is also expressed in a dorsoventral gradient during gastrulation and ectopically expressed Fgf8 can dorsalize embryos. Nevertheless, acerebellar mutants show only mild dorsoventral patterning defects. Also, in spite of the prominent role suggested for Fgf8 in limb development, the pectoral fins are largely unaffected in the mutants. Fgf8 is therefore required in development of several important signaling centers in the zebrafish embryo, but may be redundant or dispensable for others.

The major histocompatibility complex ( MHC) is one of the most extensively studied regions in the human genome because of the association of variants at this locus with autoimmune, infectious, and inflammatory diseases. However, identification of causal variants within the MHC for the majority of these diseases has remained difficult due to the great variability and extensive linkage disequilibrium ( LD) that exists among alleles throughout this locus, coupled with inadequate study design whereby only a limited subset of about 20 from a total of approximately 250 genes have been studied in small cohorts of predominantly European origin. We have performed a review and pooled analysis of the past 30 years of research on the role of the MHC in six genetically complex disease traits - multiple sclerosis ( MS), type 1 diabetes ( T1D), systemic lupus erythematosus ( SLE), ulcerative colitis ( UC), Crohn's disease ( CD), and rheumatoid arthritis ( RA) - in order to consolidate and evaluate the current literature regarding MHC genetics in these common autoimmune and inflammatory diseases. We corroborate established MHC disease associations and identify predisposing variants that previously have not been appreciated. Furthermore, we find a number of interesting commonalities and differences across diseases that implicate both general and disease- specific pathogenetic mechanisms in autoimmunity.