The importance of the Musgrave Province in continental reconstructions of Proterozoic Australia is only beginning to be appreciated. The Mesoproterozoic Musgrave Province sits in a geographically ...central location within Australia and is bounded by older and more isotopically evolved regions including the Gawler Craton of South Australia and Arunta Region of the Northern Territory. Understanding the crustal growth and deformation mechanisms involved in the formation of the Musgrave Province, and also the nature of the basement that separates these tectonic elements, allows for greater insight into defining the timing and processes responsible for the amalgamation of Proterozoic Australia. The ca. 1.60-1.54 Ga Musgravian Gneiss preserves geochemical and isotopic signatures related to ongoing arc-magmatism in an active margin between the North Australian and South Australian Cratons (NAC and SAC). Characteristic geochemical patterns of the Musgravian Gneiss include negative anomalies in Nb, Ti, and Y, and are accompanied by steep LREE patterns. Also characteristic of the Musgravian Gneiss is its juvenile Nd isotopic composition (ɛNd1.55 values from -1.2 to +0.9). The juvenile isotopic signature of the Musgravian Gneiss separates it from the bounding comparitively isotopically evolved terranes of the Arunta Region and Gawler Craton. The geochemical and isotopic signatures of these early Mesoproterozoic felsic rocks have similarities with island arc systems involving residual Ti-bearing minerals and garnet. Circa 1.40 Ga metasedimentary rocks of the eastern Musgrave Province also record vital evidence for determining Australia.s location and fit within a global plate reconstruction context during the late Mesoproterozoic. U-Pb detrital zircon and Sm-Nd isotopic data from these metasedimentary rocks suggests a component of derivation from sources outside of the presently exposed Australian crust. Best fit matches come from rocks originating from eastern Laurentia. Detrital zircon ages range from Palaeoproterozoic to late Mesoproterozoic, constraining the maximum depositional age of the metasediments to approximately 1.40 Ga, similar to that of the Belt Supergroup in western Laurentia. The 1.49-1.36 Ga detrital zircons in the Musgrave metasediments are interpreted to have been derived from the voluminous A-type suites of Laurentia, as this time period represents a “magmatic gap” in Australia, with an extreme paucity of sources this age recognized. The metasedimentary rocks exhibit a range of Nd isotopic signatures, with ɛNd(1.4 Ga) values ranging from -5.1 to 0.9, inconsistent with complete derivation from Australian sources, which are more isotopically evolved. The isotopically juvenile ca. 1.60-1.54 Ga Musgravian Gneiss is also an excellent candidate for the source of the abundant ca. 1.6-1.54 Ga detrital zircons within the lower sequences of the Belt Supergroup. If these interpretations are correct, they support a palaeogeographic reconstruction involving proximity of Australia and Laurentia during the pre-Rodinia Mesoproterozoic. This also increases the prospectivity of the eastern Musgrave Province to host a metamorphised equivalent of the massive Pb-Zn-Ag Sullivan deposit. The geochemical and isotopic signatures recorded in mafic-ultramafic rocks can divulge important information regarding the state of the sub continental lithospheric mantle (SCLM). The voluminous cumulate mafic-ultramafic rocks of the ca. 1.08 Ga Giles Complex record geochemical and Nd-Sr isotopic compositions consistent with an enriched parental magma. Traverses across three layered intrusions, the Kalka, Ewarara, and Gosse Pile were geochemically and isotopically analysed. Whole rock samples display variably depleted to enriched LREE patterns when normalised to chondrite ((La/Sm)N = 0.43-4.72). Clinopyroxene separates display similar depleted to enriched LREE patterns ((La/Sm)N = 0.37-7.33) relative to a chondritic source. The cumulate rocks display isotopically evolved signatures (ɛNd ~-1.0 to .5.0 and ɛSr ~19.0 to 85.0). Using simple bulk mixing and AFC equations, the Nd-Sr data of the more radiogenic samples can be modelled by addition of ~10% average Musgrave crust to a primitive picritic source, without need for an enriched mantle signature. Shallow decompressional melting of an asthenospheric plume source beneath thinned Musgravian lithosphere is envisaged as a source for the parental picritic magma. A model involving early crustal contamination within feeder zones is favoured, and consequently explorers looking for Ni-Cu-Co sulphides should concentrate on locating these feeder zones. Few absolute age constraints exist for the timing of the intracratonic Petermann Orogeny of the Musgrave Province. The Petermann Orogeny is responsible for much of the lithospheric architecture we see today within the Musgrave Province, uplifting and exhuming large parts along crustal scale E-W trending fault/shear systems. Isotopic and geochemical analysis of a suite of stratigraphic units within the Neoproterozoic to Cambrian Officer Basin to the immediate south indicate the development of a foreland architecture at ca. 600 Ma. An excursion in ɛNd values towards increasingly less negative values at this time is interpreted as representing a large influx of Musgrave derived sediments. Understanding the nature of the basement separating the SAC from the NAC and WAC is vital in constructing models of the amalgamation of Proterozoic Australia. This region is poorly understood as it is overlain by the thick sedimentary cover of the Officer Basin. However, the Coompana Block is one place where basement is shallow enough to be intersected in drillcore. The previously geochronologically, geochemically, and isotopically uncharacterised granitic gneiss of the Coompana Block represents an important period of within-plate magmatism during a time of relative magmatic quiescence in the Australian Proterozoic. U-Pb LA-ICPMS dating of magmatic zircons provides an age of ca. 1.50 Ga, interpreted as the crystallisation age of the granite protolith. The samples have distinctive A-type chemistry characterised by high contents of Zr, Nb, Y, Ga, LREE with low Mg#, Sr, CaO and HREE. ɛNd values are high with respect to surrounding exposed crust of the Musgrave Province and Gawler Craton, and range from +1.2 to +3.3 at 1.5 Ga. The tectonic environment into which the granite was emplaced is also unclear, however one possibility is emplacement within an extensional environment represented by interlayered basalts and arenaceous sediments of the Coompana Block. Regardless, the granitic gneiss intersected in Mallabie 1 represents magmatic activity during the “Australian magmatic gap” of ca. 1.52-1.35 Ga, and is a possible source for detrital ca. 1.50 zircons found within sedimentary rocks of Tasmania and Antarctica, and metasedimentary rocks of the eastern Musgrave Province.
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Thesis(PhD)-- University of Adelaide, School of Earth and Environmental Sciences, 2006
Children may be at higher risk for swimming-associated illness following exposure to fecally-contaminated recreational waters. We analyzed a pooled data set of over 80,000 beachgoers from 13 beach ...sites across the United States to compare risks associated with the fecal indicator bacteria Enterococcus spp. (measured by colony forming units, CFU and quantitative polymerase chain reaction cell equivalents, qPCR CE) for different age groups across different exposures, sites and health endpoints.
Sites were categorized according to the predominant type of fecal contamination (human or non-human). Swimming exposures of varying intensity were considered according to degree of contact and time spent in the water. Health endpoints included gastrointestinal and respiratory symptoms and skin rashes. Logistic regression models were used to analyze the risk of illness as a function of fecal contamination in water as measured by Enterococcus spp. among the exposed groups. Non-swimmers (those who did not enter the water) were excluded from the models to reduce bias and facilitate comparison across groups.
Gastrointestinal symptoms were the most sensitive health endpoint and strongest associations were observed with Enterococcus qPCR CE at sites impacted by human fecal contamination. Under several exposure scenarios, associations between illness and Enterococcus spp. levels were significantly higher among children compared to adolescents and adults. Respiratory symptoms were also associated with Enterococcus spp. exposures among young children at sites affected by human fecal sources, although small sample sizes resulted in imprecise estimates for these associations.
Under many exposure scenarios, children were at higher risk of illness associated with exposure to fecal contamination as measured by the indicator bacteria Enterococcus spp. The source of fecal contamination and the intensity of swimming exposure were also important factors affecting the association between Enterococcus spp. and swimming-associated illness.
Zinc (Zn) is an essential metal that vertebrates sequester from pathogens to protect against infection. Investigating the opportunistic pathogen Acinetobacter baumannii’s response to Zn starvation, ...we identified a putative Zn metallochaperone, ZigA, which binds Zn and is required for bacterial growth under Zn-limiting conditions and for disseminated infection in mice. ZigA is encoded adjacent to the histidine (His) utilization (Hut) system. The His ammonia-lyase HutH binds Zn very tightly only in the presence of high His and makes Zn bioavailable through His catabolism. The released Zn enables A. baumannii to combat host-imposed Zn starvation. These results demonstrate that A. baumannii employs several mechanisms to ensure bioavailability of Zn during infection, with ZigA functioning predominately during Zn starvation, but HutH operating in both Zn-deplete and -replete conditions to mobilize a labile His-Zn pool.
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•A. baumannii responds to Zn starvation by upregulating a Zn metallochaperone ZigA•ZigA is a Zn-binding GTPase that impacts intracellular histidine levels in low Zn•The histidine ammonia-lyase HutH is activated by Zn, potentially obtained from ZigA•Histidine is a labile Zn pool mobilized during low Zn via histidine degradation by HutH
Zinc (Zn) is an essential metal that vertebrates sequester from pathogens to protect against infection. Nairn et al. show that the nosocomial opportunistic pathogen A. baumannii’s response to Zn starvation involves both the upregulation of a Zn-binding metallochaperone and by mobilization of a labile histidine-bound Zn pool via histidine degradation.
The X‐linked filaminopathies represent a diverse group of clinical conditions, all caused by variants in the gene FLNA. FLNA encodes the widely expressed actin binding protein, filamin A that has ...multiple roles during embryonic development including cell migration, mechanical sensing, and cell signaling. In this review, we discuss the 10 distinct X‐linked filaminopathy conditions that between them affect almost all organ systems, including the brain, skeleton, heart, and skin, highlighting the critical role of this protein in human development. We review each of the phenotypes and discuss their pathogenesis, where known. Assigning pathogenicity to variants in FLNA can prove difficult, especially for missense variants and small indels, in‐part because of the X‐linked nature of the phenotypes, the overlap of phenotypic features between conditions, and poor understanding of the function of certain protein domains. We outline here approaches to characterize phenotypes, highlight hotspot regions within FLNA commonly mutated in these conditions, and approaches to resolving some variants of uncertain significance.
The location of causative variants leading to the filaminopathies A are mapped onto FLNA protein monomers. Variants leading to ‘loss‐of‐function’ disorders (left monomer) and ‘gain‐of‐function’ disorders (right monomer) can clearly be seen to cluster. ‘Hotspot’ regions are marked with larger symbols. PH: periventricular heterotopia, CIPX: congenital intestinal pseudo‐obstruction, IMT: isolated macrothrombocytopenia, FCMPD: familial cardiac myxomatous polyvalvular dystrophy, OPD: otopalatodigital syndrome, FMD: frontometaphyseal dysplasia, CKCO: condition comprising contractures, keloid, cardiac defects and optic anomalies, MNS: Melnick‐Needles syndrome, DCD: digitocutaneous dysplasia, ABD: actin‐binding domain, CHD: calponin homology domain, H: hinge.
Patients with major depression show reductions in striatal and paleostriatal volumes. The functional integrity and connectivity of these regions are also shown to change with antidepressant response. ...Electroconvulsive therapy (ECT) is a robust and rapidly acting treatment for severe depression. However, whether morphological changes in the dorsal and ventral striatum/pallidum relate to or predict therapeutic response to ECT is unknown. Using structural MRI, we assessed cross-sectional effects of diagnosis and longitudinal effects of ECT for volume and surface-based shape metrics of the caudate, putamen, pallidum, and nucleus accumbens in 53 depressed patients (mean age: 44.1 years, 13.8 SD; 52% female) and 33 healthy controls (mean age: 39.3 years, 12.4 SD; 57% female). Patients were assessed before ECT, after their second ECT, and after completing an ECT treatment index. Controls were evaluated at two time points. Support vector machines determined whether morphometric measures at baseline predicted ECT-related clinical response. Patients showed smaller baseline accumbens and pallidal volumes than controls (P<0.05). Increases in left putamen volume (P<0.03) occurred with ECT. Global increases in accumbens volume and local changes in pallidum and caudate volume occurred in patients defined as treatment responders. Morphometric changes were absent across time in controls. Baseline volume and shape metrics predicted overall response to ECT with up to 89% accuracy. Results support that ECT elicits structural plasticity in the dorsal and ventral striatum/pallidum. The morphometry of these structures, forming key components of limbic-cortical-striatal-pallidal-thalamic circuitry involved in mood and emotional regulation, may determine patients likely to benefit from treatment.
Interleukin (IL)-1R3 is the co-receptor in three signaling pathways that involve six cytokines of the IL-1 family (IL-1α, IL-1β, IL-33, IL-36α, IL-36β and IL-36γ). In many diseases, multiple ...cytokines contribute to disease pathogenesis. For example, in asthma, both IL-33 and IL-1 are of major importance, as are IL-36 and IL-1 in psoriasis. We developed a blocking monoclonal antibody (mAb) to human IL-1R3 (MAB-hR3) and demonstrate here that this antibody specifically inhibits signaling via IL-1, IL-33 and IL-36 in vitro. Also, in three distinct in vivo models of disease (crystal-induced peritonitis, allergic airway inflammation and psoriasis), we found that targeting IL-1R3 with a single mAb to mouse IL-1R3 (MAB-mR3) significantly attenuated heterogeneous cytokine-driven inflammation and disease severity. We conclude that in diseases driven by multiple cytokines, a single antagonistic agent such as a mAb to IL-1R3 is a therapeutic option with considerable translational benefit.
Depression symptom heterogeneity limits the identifiability of treatment‐response biomarkers. Whether improvement along dimensions of depressive symptoms relates to separable neural networks remains ...poorly understood. We build on work describing three latent symptom dimensions within the 17‐item Hamilton Depression Rating Scale (HDRS) and use data‐driven methods to relate multivariate patterns of patient clinical, demographic, and brain structural changes over electroconvulsive therapy (ECT) to dimensional changes in depressive symptoms. We included 110 ECT patients from Global ECT‐MRI Research Collaboration (GEMRIC) sites who underwent structural MRI and HDRS assessments before and after treatment. Cross validated random forest regression models predicted change along symptom dimensions. HDRS symptoms clustered into dimensions of somatic disturbances (SoD), core mood and anhedonia (CMA), and insomnia. The coefficient of determination between predicted and actual changes were 22%, 39%, and 39% (all p < .01) for SoD, CMA, and insomnia, respectively. CMA and insomnia change were predicted more accurately than HDRS‐6 and HDRS‐17 changes (p < .05). Pretreatment symptoms, body‐mass index, and age were important predictors. Important imaging predictors included the right transverse temporal gyrus and left frontal pole for the SoD dimension; right transverse temporal gyrus and right rostral middle frontal gyrus for the CMA dimension; and right superior parietal lobule and left accumbens for the insomnia dimension. Our findings support that recovery along depressive symptom dimensions is predicted more accurately than HDRS total scores and are related to unique and overlapping patterns of clinical and demographic data and volumetric changes in brain regions related to depression and near ECT electrodes.
Depression symptom heterogeneity limits the identifiability of treatment‐response biomarkers. We developed machine learning models to predict symptom change along latent dimensions of depression following treatment with electroconvulsive therapy in a large, multisite cohort using a combination of neuroimaging, clinical, and demographic predictors. Recovery along homogenous latent symptom dimensions was predicted more accurately than change along standard, more heterogeneous total score measures.
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