Antarctic ice sheet sensitivity to atmospheric CO2 variations in the early to mid-Miocene.

Geological records from the Antarctic margin offer direct evidence of environmental variability at high southern latitudes and provide insight regarding ice sheet sensitivity to past climate change. The early to mid-Miocene (23-14 Mya) is a compelling interval to study as global temperatures and atmospheric CO2 concentrations were similar to those projected for coming centuries. Importantly, this time interval includes the Miocene Climatic Optimum, a period of global warmth during which average surface temperatures were 3-4 °C higher than today. Miocene sediments in the ANDRILL-2A drill core from the Western Ross Sea, Antarctica, indicate that the Antarctic ice sheet (AIS) was highly variable through this key time interval. A multiproxy dataset derived from the core identifies four distinct environmental motifs based on changes in sedimentary facies, fossil assemblages, geochemistry, and paleotemperature. Four major disconformities in the drill core coincide with regional seismic discontinuities and reflect transient expansion of grounded ice across the Ross Sea. They correlate with major positive shifts in benthic oxygen isotope records and generally coincide with intervals when atmospheric CO2 concentrations were at or below preindustrial levels (∼280 ppm). Five intervals reflect ice sheet minima and air temperatures warm enough for substantial ice mass loss during episodes of high (∼500 ppm) atmospheric CO2 These new drill core data and associated ice sheet modeling experiments indicate that polar climate and the AIS were highly sensitive to relatively small changes in atmospheric CO2 during the early to mid-Miocene.

Sepsis and Septic Shock in the Equine Neonate.

Sepsis and septic shock represent a major cause of morbidity and mortality in equine neonates and in all species. Early recognition of the condition is important, but definitive examination and laboratory variables to predict equine neonatal sepsis are lacking. Early and aggressive treatment should include broad-spectrum antimicrobial coverage, source control, and hemodynamic support. Field practitioners and intensive care clinicians work together in the management of this condition because the recognition and initial treatment should begin as early as possible.

Diagnostic test accuracy of artificial intelligence in screening for referable diabetic retinopathy in real-world settings: A systematic review and meta-analysis.

Retrospective studies on artificial intelligence (AI) in screening for diabetic retinopathy (DR) have shown promising results in addressing the mismatch between the capacity to implement DR screening and increasing DR incidence. This review sought to evaluate the diagnostic test accuracy (DTA) of AI in screening for referable diabetic retinopathy (RDR) in real-world settings. We searched CENTRAL, PubMed, CINAHL, Scopus, and Web of Science on 9 February 2023. We included prospective DTA studies assessing AI against trained human graders (HGs) in screening for RDR in patients with diabetes. Two reviewers independently extracted data and assessed methodological quality against QUADAS-2 criteria. We used the hierarchical summary receiver operating characteristics (HSROC) model to pool estimates of sensitivity and specificity and, forest plots and SROC plots to visually examine heterogeneity in accuracy estimates. From our initial search results of 3899 studies, we included 15 studies comprising 17 datasets. Meta-analyses revealed a sensitivity of 95.33% (95%CI: 90.60-100%) and specificity of 92.01% (95%CI: 87.61-96.42%) for patient-level analysis (10 datasets, N = 45,785) while, for the eye-level analysis, sensitivity was 91.24% (95%CI: 79.15-100%) and specificity, 93.90% (95%CI: 90.63-97.16%) (7 datasets, N = 15,390). Subgroup analyses did not provide variations in the diagnostic accuracy of country classification and DR classification criteria. However, a moderate increase was observed in diagnostic accuracy in the primary-level healthcare settings: sensitivity of 99.35% (95%CI: 96.85-100%), specificity of 93.72% (95%CI: 88.83-98.61%) and, a minimal decrease in the tertiary-level healthcare settings: sensitivity of 94.71% (95%CI: 89.00-100%), specificity of 90.88% (95%CI: 83.22-98.53%). Sensitivity analyses did not show any variations in studies that included diabetic macular edema in the RDR definition, nor studies with ≥3 HGs. This review provides evidence, for the first time from prospective studies, for the effectiveness of AI in screening for RDR in real-world settings. The results may serve to strengthen existing guidelines to improve current practices.

Mercury evidence from southern Pangea terrestrial sections for end-Permian global volcanic effects.

The latest Permian mass extinction (LPME) was triggered by magmatism of the Siberian Traps Large Igneous Province (STLIP), which left an extensive record of sedimentary Hg anomalies at Northern Hemisphere and tropical sites. Here, we present Hg records from terrestrial sites in southern Pangea, nearly antipodal to contemporaneous STLIP activity, providing insights into the global distribution of volcanogenic Hg during this event and its environmental processing. These profiles (two from Karoo Basin, South Africa; two from Sydney Basin, Australia) exhibit significant Hg enrichments within the uppermost Permian extinction interval as well as positive Δ199Hg excursions (to ~0.3‰), providing evidence of long-distance atmospheric transfer of volcanogenic Hg. These results demonstrate the far-reaching effects of the Siberian Traps as well as refine stratigraphic placement of the LPME interval in the Karoo Basin at a temporal resolution of ~105 years based on global isochronism of volcanogenic Hg anomalies.

Lethal microbial blooms delayed freshwater ecosystem recovery following the end-Permian extinction.

Harmful algal and bacterial blooms linked to deforestation, soil loss and global warming are increasingly frequent in lakes and rivers. We demonstrate that climate changes and deforestation can drive recurrent microbial blooms, inhibiting the recovery of freshwater ecosystems for hundreds of millennia. From the stratigraphic successions of the Sydney Basin, Australia, our fossil, sedimentary and geochemical data reveal bloom events following forest ecosystem collapse during the most severe mass extinction in Earth's history, the end-Permian event (EPE; c. 252.2 Ma). Microbial communities proliferated in lowland fresh and brackish waterbodies, with algal concentrations typical of modern blooms. These initiated before any trace of post-extinction recovery vegetation but recurred episodically for >100 kyrs. During the following 3 Myrs, algae and bacteria thrived within short-lived, poorly-oxygenated, and likely toxic lakes and rivers. Comparisons to global deep-time records indicate that microbial blooms are persistent freshwater ecological stressors during warming-driven extinction events.

Inflamed Odontogenic Cyst with Actinomyces Colonization: Management of an Atypical Case in a 16-Year-Old Patient.

Inflammatory odontogenic cysts, if not treated, may lead to progression of osteolytic activity, potential paresthesia, and loss of teeth. A 16-year-old female patient was referred by a pediatric dentist for asymptomatic abnormal radiolucency found interproximally to the mandibular left first and second premolars. Radiographic, clinical, and pathologic analyses led to a diagnosis of an inflamed odontogenic cyst (type K09.0) with Actinomyces colonization. The cyst was treated by periodontal regenerative therapy and resulted in successful osseous regeneration. This was a rare case because of the patient's age, the location of the lesion, its association with vital teeth, and its presentation.

Age and pattern of the southern high-latitude continental end-Permian extinction constrained by multiproxy analysis.

Past studies of the end-Permian extinction (EPE), the largest biotic crisis of the Phanerozoic, have not resolved the timing of events in southern high-latitudes. Here we use palynology coupled with high-precision CA-ID-TIMS dating of euhedral zircons from continental sequences of the Sydney Basin, Australia, to show that the collapse of the austral Permian Glossopteris flora occurred prior to 252.3 Ma (~370 kyrs before the main marine extinction). Weathering proxies indicate that floristic changes occurred during a brief climate perturbation in a regional alluvial landscape that otherwise experienced insubstantial change in fluvial style, insignificant reorganization of the depositional surface, and no abrupt aridification. Palaeoclimate modelling suggests a moderate shift to warmer summer temperatures and amplified seasonality in temperature across the EPE, and warmer and wetter conditions for all seasons into the Early Triassic. The terrestrial EPE and a succeeding peak in Ni concentration in the Sydney Basin correlate, respectively, to the onset of the primary extrusive and intrusive phases of the Siberian Traps Large Igneous Province.

Activation of ATP-binding cassette transporter A1 transcription by chromatin remodeling complex.

OBJECTIVE: Liver X receptor (LXR) regulates the transcription of ATP-binding cassette transporter A1 (ABCA1) by binding to the DR-4 promoter element as a heterodimer with retinoid X receptor (RXR). The role of chromatin remodeling complex in LXR or ABCA1 activation has not been established previously. In this study, we investigated the activation of ABCA1 by brahma-related gene 1 (BRG-1) and brahma, members of the SWI/SNF (mating type switching/sucrose nonfermenting) chromatin remodeling complex. METHODS AND RESULTS: Overexpression of wild-type BRG-1 in SW-13 cells, but not a catalytically inactive mutant, increased ABCA1 mRNA levels determined by RT-PCR. These effects were enhanced by LXR and RXR agonists. In 293T (epithelial kidney cell line) and Hep3B (hepatocyte cell line) cells, small interfering RNA against BRG-1/brm also affected ABCA1 mRNA levels. Synergistic activation of ABCA1 was obtained after coexpressing BRG-1 and SRC-1, a coactivator of LXR. Luciferase assays showed that this activation of ABCA1 was dependent on the promoter DR-4 element. Coimmunoprecipitation and chromatin immunoprecipitation studies indicated that the mechanism of BRG-1-mediated activation of ABCA1 involved interaction of LXR/RXR with BRG-1 and binding of this complex to ABCA1 promoter. CONCLUSIONS: Catalytic subunits of SWI/SNF chromatin remodeling complex, BRG-1 and brahma, play significant roles in enhancing LXR/RXR-mediated transcription of ABCA1 via the promoter DR-4 element.

Relationship between cholesterol trafficking and signaling in rafts and caveolae.

Caveolae and lipid rafts are two distinct populations of free cholesterol, sphingolipid (FC/SPH)-rich cell surface microdomains. They differ in stability, shape, and the presence or absence of caveolin (present in caveolae) or GPI-anchored proteins (enriched in lipid rafts). In primary cells, caveolae and rafts support the assembly of different signaling complexes, though signal transduction from both is strongly dependent on the presence of FC. It was initially thought that FC promoted the formation of inactive reservoirs of signaling proteins. Recent data supports the concept of a more dynamic role for FC in caveolae and probably, also lipid rafts. It is more likely that the FC content of these domains is actively modulated as protein complexes are formed and, following signal transduction, disassembled. In transformed cell lines with few caveolae, little caveolin and a preponderance of rafts, complexes normally assembled on caveolae may function in rafts, albeit with altered kinetics. However, caveolae and lipid rafts appear not to be interconvertible. The presence of non-caveolar pools of caveolin in recycling endosomes (RE), the trans-Golgi network (TGN) and in mobile chaperone complexes is now recognized. A role in the uptake of microorganisms by cells ascribed to caveolae now seems more likely to be mediated by cell surface rafts.

Role of p160 coactivator complex in the activation of liver X receptor.

OBJECTIVE: Liver X receptor (LXR) is a member of a nuclear receptor family regulating the expression of several key proteins involved in lipid metabolism and inflammation. In contrast to several other nuclear receptors, very little is known about the coactivators needed for the agonist-mediated transactivation by LXR. In this study, we have investigated the role of p160 coactivator complex in the regulation of ATP-binding transporter A1 (ABCA1), a clinically important gene transcriptionally upregulated by LXR/RXR (retinoid X receptor) heterodimer. METHODS AND RESULTS: Overexpression of LXRalpha, SRC-1, and p300, either alone or in combination, increased the luciferase activity driven by the wild-type ABCA1 promoter. The same coactivators bound to the ABCA1 promoter on oxysterol induction in chromatin immunoprecipitation assays. To the contrary, CARM-1 and P/CAF had no effect on ABCA1 transactivation, nor do they bind the promoter. When the DR-4 element was mutated from the ABCA1 promoter, only p300 was able to activate ABCA1 transcription in a ligand-independent manner. CONCLUSIONS: The p160 coactivator complex members SRC-1 and p300, but not CARM-1 and P/CAF, coactivate LXR-mediated transcription of ABCA1 gene. In addition, p300 activates ABCA1 transcription independently of DR-4 element and LXR/RXR.

The use of World War II chest radiograph in the identification of a missing-in-action U.S. Marine.

A World War II mass grave was recovered in 1999 by a U.S. Army team and yielded 20 complete skeletons. A case study involving the identification of one of these individuals is presented in this article. The thought processes and problems that presented themselves to the forensic anthropologist and odontologist are detailed. Methods used to establish identity are described. This case demonstrates how standard operating procedures used by a forensic anthropologist and odontologist can narrow the field of possible individuals associated with remains, and with extra information--in this case, a military radiograph taken in 1941--can ultimately establish the identity of a decedent. The authors learned that some medical records, which at first glance appear to be excess or irrelevant, may contain the item required to be certain that a case is strong in support of a recommended identification.

Nutrient canals of the alveolar process as an anatomic feature for dental identifications.

Nutrient canals are anatomic structures of the alveolar bone through which neurovascular elements transit to supply teeth and supporting structures. A dental identification using a nutrient canal of the mandibular alveolar process as the most compelling anatomic feature for antemortem-postmortem radiographic comparison is described. Nutrient canals as a potential marker for clinical disease is also discussed.

A minimally destructive technique for sampling dentin powder for mitochondrial DNA testing.

The purpose of this paper is to present the horizontal sectioning technique used by odontologists at the Central Identification Laboratory to sample dentin for mtDNA analysis. From the perspective of DNA testing, anthropologists and odontologists at the Central Identification Laboratory work with ancient remains. In many instances, the lack of comprehensive antemortem records, the potential for fragmentation and commingling, and environmental exposure makes the use of traditional forensic identification techniques difficult or impossible. Teeth are highly resistant to environmental degradation and are an excellent source of mitochondrial DNA (mtDNA). This technique is simple, quick, and relatively conservative, allowing for preservation of the majority of the external portion of the tooth structure.

Bone morphogenetic protein-1 (BMP-1) cleaves human proapolipoprotein A1 and regulates its activation for lipid binding.

Apolipoprotein A1 (apo A1), the major protein of high-density lipoprotein, is secreted as a proprotein and then cleaved by an uncharacterized metalloproteinase. Here this enzyme is identified as C-terminal procollagen endoproteinase/bone morphogenetic protein-1 (BMP-1). Studies with recombinant BMP-1, BMP-1 antibody, and BMP-1 siRNA establish this proteinase as the major or only apo A1-converting activity secreted by human liver-derived (HepG2) cells and CHO cells stably expressing human apo A1. BMP-1 stimulates the conversion of newly secreted proapo A1 to its phospholipid- (PL-) binding form. In this way it promotes formation of functional HDL and reverse cholesterol transport, while inhibiting filtration and clearance of uncleaved proprotein. Alpha2-macroglobulin, a protease inhibitor secreted as part of the innate immune response, inhibits BMP-1 activity and blocks the maturation of proapo A1. The decrease in circulating apo A1 levels that is characteristic of the response to inflammation and infection may be mediated, at least in part, via BMP-1 by this novel mechanism.

CO2-forced climate and vegetation instability during Late Paleozoic deglaciation.

The late Paleozoic deglaciation is the vegetated Earth's only recorded icehouse-to-greenhouse transition, yet the climate dynamics remain enigmatic. By using the stable isotopic compositions of soil-formed minerals, fossil-plant matter, and shallow-water brachiopods, we estimated atmospheric partial pressure of carbon dioxide (pCO2) and tropical marine surface temperatures during this climate transition. Comparison to southern Gondwanan glacial records documents covariance between inferred shifts in pCO2, temperature, and ice volume consistent with greenhouse gas forcing of climate. Major restructuring of paleotropical flora in western Euramerica occurred in step with climate and pCO2 shifts, illustrating the biotic impact associated with past CO2-forced turnover to a permanent ice-free world.

Mechanism of prebeta-HDL formation and activation.

The mechanism of formation of functional high-density lipoprotein (HDL) from secreted lipid-free apolipoprotein A1 (apo A1) was determined using human liver-derived (HepG2) cells, human intestine-derived (CaCO2) cells, and CHO cells stably expressing full-length human apo A1 (CHO-A1 cells). In each cell line, a significant proportion of secreted apo A1 had a Stokes radius of 2.6 nm and was inactive in binding phospholipids (PL) or free cholesterol (FC). Extracellularly, in a reaction dependent on membrane transporter ABCA1, prealpha-migrating 2.6 nm apo A1 was converted to a prebeta-migrating product that was able to bind PL. Both forms were reactive with mAb55201, a monoclonal antibody specific for native plasma lipid-poor (prebeta1) HDL [Nakamura, Y., et al. (2004) Biochemistry 43, 14311-14318]. The physical properties of precursor and product apo A1 suggested that both are monomers, with Stokes radii of 2.6 and 3.6 nm, respectively, consistent with the absence of intermolecular cross-linking of apo A1 in lipid-poor HDL, reported previously. Product but not precursor apo A1 promoted reverse cholesterol transport (RCT) from human aortic smooth muscle cells. These studies suggest an important contribution of secreted lipid-free apo A1 to HDL formation.

Preparation and biochemical evaluation of fluorenone-containing lipid analogs.

Syntheses are described of fatty acid analogs 5 and 6, and cholesterol (2) analogs 7 and 8 containing fluorenone groups, which are both photoactivable and fluorescent. The potential of the analogs of 2 as biochemical research tools has been demonstrated by the findings that 7 and 8 can replace 2 in apolipoprotein A-I-induced cellular efflux of 2 and that fluorescence is easily visible at the surface of smooth muscle cells equilibrated with 8.

Mechanism of platelet-derived growth factor-dependent caveolin-1 phosphorylation: relationship to sterol binding and the role of serine-80.

In human vascular smooth muscle cells, inhibitors of protein kinase C activity reduced serine phosphorylation of caveolin-1 and increased sterol binding by this protein. This was measured after immunoprecipitation of caveolin-1 from cells labeled with tritiated cholesterol or the photoactivable cholesterol analogue FCBP [Fielding et al. (2002) Biochemistry 41, 4929-4937]. At the same time cellular sterol efflux was inhibited. Mutagenesis within a caveolin-1 central domain (residues 80-104) suggested a major role for serine-80 in mediating both of these effects. To perturb sterol binding, platelet-derived growth factor was added to the cells, leading to a transient loss of caveolin-1-associated sterol. Under these conditions, sterol efflux was stimulated, and caveolin-1 phosphorylation at tyrosine(14), assayed with a selective antibody, was substantially increased above baseline levels. These changes were also blocked by inhibitors of protein kinase C activity. Selective inhibitors of the platelet-derived growth factor receptor and downstream kinases were used to show that loss of sterol from caveolin-1 preceded tyrosine phosphorylation, but relipidation was dependent on phosphotyrosine hydrolysis.

Regulation of ATP-binding cassette transporter A1 transcription by thyroid hormone receptor.

Transcriptional regulation of the ATP-binding cassette transporter (ABCA1) gene is complex. It involves multiple transcription start sites and the binding of several different transcription factors to the ABCA1 promoter region. Cholesterol- and oxysterol-mediated up-regulation of ABCA1 transcription includes the binding of the liver X receptor and retinoid X receptor (LXR/RXR) heterodimer to the DR-4 element of the ABCA1 promoter. In this study we show that another nuclear hormone receptor, thyroid hormone receptor (TR), can suppress ABCA1 transcription. Electrophoretic mobility shift assays using both purified proteins and isolated nuclear extracts from primary human fibroblasts and 293T cells demonstrate that the TR/RXR heterodimer is able to bind to the DR-4 element of the ABCA1 promoter. This binding is also demonstrated in vivo by chromatin immunoprecipitation studies. Luciferase assays from 293T cells transfected with TRbeta or LXRalpha expression plasmids show that TR, together with its ligand T3, suppresses ABCA1 transcriptional activity, even in the presence of LXR-activating oxysterols. Finally, competition between TR/RXR and LXR/RXR heterodimers to suppress or activate ABCA1 transcription is shown to be dynamic and dependent on the amount of nuclear receptor present in the cells. These data identify a novel regulatory mechanism for ABCA1 and suggest new strategies to modify its expression.