The Glen Torridon (GT) region within Gale crater, Mars, occurs in contact with the southern side of Vera Rubin ridge (VRR), a well-defined geomorphic feature that is comparatively resistant to ...erosion. Prior to detailed ground-based investigation of GT, its geologic relationship with VRR was unknown. Distinct lithologic subunits within the Jura member (Murray formation), which forms the upper part of VRR, made it possible to be also identified within GT. This indicates that the strata pass across the geomorphic divide between regions. Furthermore, the cross-bedded lower part of the overlying Knockfarril Hill member (Carolyn Shoemaker formation) also occurs within both VRR and GT. Correlation of both units demonstrates that the strata form a continuous stratigraphic succession regardless of large-scale geomorphic expression. The lithologic change from mudstone (Jura member) to cross-bedded sandstone (Knockfarril Hill member) heralds a significant shift in paleoenvironment from lacustrine to fluvial. The upper part of the Knockfarril Hill member consists of interbedded mudstone and sandstone that transitions to the overlying finely laminated mudstone of the Glasgow member, and a return to lacustrine deposition. In GT, the Stimson formation unconformably overlies the Glasgow member, where it demarks the southern boundary of GT. Contacts for each stratigraphic unit were defined and transferred to a high-resolution image base to make a geologic map and cross sections perpendicular to the NE strike. Stratal dips cannot exceed 2° NW to retain the positions of stratigraphic units in the locations they are exposed throughout GT.
Background. In human immunodeficiency virus (HIV)–infected patients, fluconazole prophylaxis is associated with reductions in the rate of fungal infection. However, concerns exist with regard to the ...use of fluconazole prophylaxis and the risk of development of fluconazole treatment—refractory infections. Methods. We performed a randomized, open-label trial that compared oral fluconazole given continuously (200 mg 3 times weekly; the “continuous fluconazole arm”) with fluconazole that was provided only for episodes of orophayngeal candidiasis (OPC) or esophageal candidiasis (EC) (the “episodic fluconazole arm”) in HIV-infected persons with CD4+ T cell counts of <150 cells/mm3 and a history of OPC. The primary study end point was the time to development of fluconazole-refractory OPC or EC, which was defined as lack of response to 200 mg fluconazole given daily for 14 or 21 days, respectively. Results. A total of 413 subjects were randomized to receive continuous fluconazole, and 416 were randomized to receive episodic fluconazole. After 42 months, 17 subjects (4.1%) in the continuous fluconazole arm developed fluconazole-refractory OPC or EC infections, compared with 18 subjects (4.3%) in the episodic fluconazole arm, with no difference between treatment arms with regard to the time to development of a fluconazole-refractory infection within 24 months (P = .88, by log-rank test) or before the end of the study (P = .97, by the log-rank test). Continuous fluconazole therapy was associated with fewer cases of OPC or EC (0.29 vs. 1.08 episodes per patient-year; P < .0001) and fewer invasive fungal infections (15 vs. 28 episodes; P = .04, by χ2 test), but not with improved survival, compared with episodic fluconazole therapy. Conclusion. Continuous fluconazole therapy is not associated with significant risk of fluconazole-refractory OPC or EC, compared with episodic fluconazole therapy, in HIV-infected patients with access to active antiretroviral therapy.
The organization and sorting of regulatory information for transcription, replication and repair depends on components of nuclear architecture. It is necessary, therefore, to understand cellular ...processes within the context of intranuclear microenvironments that mediate the focal assembly of the machinery for transcription, replication and repair and which facilitate the orchestration of these essential processes. Here, we discuss how nuclear anatomy supports the temporal and spatial coordination of regulatory protein recruitment for combinatorial control.
Achieving optimal exclusive breastfeeding (EBF) remains a challenge. Because intention is a precursor of practice, we examined factors associated with EBF intention during pregnancy in two rural ...sub-districts of Kishoreganj district, Bangladesh. We studied 2,400 pregnant women in their third trimester (26–32 weeks gestation). We assessed knowledge (6 items, scale range 0–6), attitudes (15 items, scale range 15–75) and self-efficacy (6 items, scale range 6–30) by interview using a standardized questionnaire. 83.9 % of pregnant women reported EBF intention. Mean breastfeeding knowledge was 3.5 (SD 1.3), mean attitude was 55.8 (SD 8.1) and mean self-efficacy was 25.6 (SD 3.4). Knowledge was associated with EBF intention (OR 2.47, 95 % CI 1.74, 3.51), attitudes toward EBF (OR 1.68, 95 % CI 1.31, 2.16) and self-efficacy (OR 1.72, 95 % CI 1.23, 2.40) were independently associated with EBF intention in the model in which all three constructs were entered simultaneously. Receipt of breastfeeding counseling during pregnancy and being literate were each associated with EBF knowledge and EBF intention (all
p
< 0.05). Increasing maternal knowledge, positive attitudes, and self-efficacy regarding EBF were associated with prenatal EBF intention. These results reinforce the importance of appropriate counseling to increase EBF prevalence .
The osteolytic bone destruction associated with breast cancer skeletal metastases represents a serious and incurable clinical condition. However, the molecular mechanisms regulating tumor cell ...expression of factors involved in the generation of osteolytic disease remain elusive. We demonstrated recently that breast cancer cells express the Runx2 transcription factor, essential for bone formation and a regulator of skeletal homeostasis. Our experimental results demonstrate that perturbation of Runx2 regulatory function in tumor cells abolishes their ability to form osteolytic lesions in vivo. In vitro, we show that breast cancer cells inhibit osteoblast differentiation while concurrently enhancing osteoclast differentiation in marrow stromal cell cultures. Disruption of Runx2 activity abrogates both of these cancer cell-mediated effects on bone cells. These results demonstrate that Runx2 expression in breast cancer cells provides a molecular phenotype that enables the interactions between tumor cells and the bone microenvironment that lead to osteolytic disease.
Background The pathophysiology of adhesion formation after abdominal and pelvic surgery is still largely unknown. The aim of the study was to investigate the role of macrophage polarization and the ...effect of peroxisome proliferator-activated receptor (PPAR) gamma stimulation on adhesion formation in an animal model. Methods Peritoneal adhesion formation was induced by the creation of ischaemic buttons within the peritoneal wall and the formation of a colonic anastomosis in wild-type, interleukin (IL) 10-deficient (IL-10-/-), IL-4-deficient (IL-4-/-) and CD11b-Cre/PPARgammafl/fl mice. Adhesions were assessed at regular intervals, and cell preparations were isolated from ischaemic buttons and normal peritoneum. These samples were analysed for macrophage differentiation and its markers, and expression of cytokines by quantitative PCR, fluorescence microscopy, arginase activity and pathological examination. Some animals underwent pioglitazone (PPAR-gamma agonist) or vehicle treatment to inhibit adhesion formation. Anastomotic healing was evaluated by bursting pressure measurement and collagen gene expression. Results Macrophage M2 marker expression and arginase activity were raised in buttons without adhesions compared with buttons with adhesions. IL-4-/- and IL-10-/- mice were not affected, whereas CD11b-Cre/PPARgammafl/fl mice showed decreased arginase activity and increased adhesion formation. Perioperative pioglitazone treatment increased arginase activity and decreased adhesion formation in wild-type but not CD11b-Cre/PPARgammafl/fl mice. Pioglitazone had no effect on anastomotic healing. Conclusion Endogenous macrophage-specific PPAR-gamma signalling affected arginase activity and macrophage polarization, and counter-regulated peritoneal adhesion manifestation. Pharmacological PPAR-gamma agonism induced a shift towards macrophage M2 polarization and ameliorated adhesion formation in a macrophage-dependent manner. Surgical relevance Postoperative adhesion formation is frequently seen after abdominal surgery and occurs in response to peritoneal trauma. The pathogenesis is still unknown but includes an imbalance in fibrinolysis, collagen production and inflammatory mechanisms. Little is known about the role of macrophages during adhesion formation. In an experimental model, macrophage M2 marker expression was associated with reduced peritoneal adhesion formation and involved PPAR-gamma-mediated arginase activity. Macrophage-specific PPAR-gamma deficiency resulted in reduced arginase activity and aggravated adhesion formation. Pioglitazone, a PPAR-gamma agonist, induced M2 polarization and reduced postoperative adhesion formation without compromising anastomotic healing in mice. Pioglitazone ameliorated postoperative adhesion formation without compromising intestinal wound healing. Therefore, perioperative PPAR-gamma agonism might be a promising strategy for prevention of adhesion formation after abdominal surgery. It's all about macrophages
Postmitotic gene expression requires restoration of nuclear organization and assembly of regulatory complexes. The hematopoietic and osteogenic Runx (Cbfa/AML) transcription factors are punctately ...organized in the interphase nucleus and provide a model for understanding the subnuclear organization of tissue-specific regulatory proteins after mitosis. Here we have used quantitative in situ immunofluorescence microscopy and quantitative image analysis to show that Runx factors undergo progressive changes in cellular localization during mitosis while retaining a punctate distribution. In comparison, the acetyl transferase p300 and acetylated histone H4 remain localized with DNA throughout mitosis while the RNA processing factor SC35 is excluded from mitotic chromatin. Subnuclear organization of Runx foci is completely restored in telophase, and Runx proteins are equally partitioned into progeny nuclei. In contrast, subnuclear organization of SC35 is restored subsequent to telophase. Our results show a sequential reorganization of Runx and its coregulatory proteins that precedes restoration of RNA processing speckles. Thus, mitotic partitioning and spatiotemporal reorganization of regulatory proteins together render progeny cells equivalently competent to support phenotypic gene expression.
The HLA system shows the most extensive polymorphism in the human genome. Allelic and haplotypic frequencies of HLA genes vary dramatically across human populations. Due to a complex history of ...migration, populations in Latin America show a broad variety of admixture proportions, usually varying not only between countries, but also within countries. Knowledge of HLA allele and haplotype frequencies is essential for medical fields such as transplantation, but also serves as a means to assess genetic diversity and ancestry in human populations. Here, we have determined high‐resolution HLA‐A, ‐B, ‐C, and ‐DRB1 allele and haplotype frequencies in a sample of 713 healthy subjects from three Mestizo populations, one population of African descent, and Amerindians of five different groups from Costa Rica and Nicaragua and compared their profiles to a large set of indigenous populations from Iberia, Sub‐Saharan Africa, and the Americas. Our results show a great degree of allelic and haplotypic diversity within and across these populations, with most extended haplotypes being private. Mestizo populations show alleles and haplotypes of putative European, Amerindian, and Sub‐Saharan African origin, albeit with differential proportions. Despite some degree of gene flow, Amerindians and Afro‐descendants show great similarity to other Amerindian and West African populations, respectively. This is the first comprehensive study reporting high‐resolution HLA diversity in Central America, and its results will shed light into the genetic history of this region while also supporting the development of medical programs for organ and stem cell transplantation.
Osterix is a bone-related transcription factor that functions genetically downstream of Runx2, which controls both growth and differentiation in osteoblasts. Here we assessed the biological function ...of Osterix in mesenchymal cells that are not normally committed to the osteogenic lineage. Stably transfected NIH3T3 fibroblasts that express exogenous Osterix were examined for their ability to convert into osteoblastic cells by analyzing gene expression profiles of bone phenotype related markers, as well as by measuring bone nodule formation and cell proliferation. Forced expression of Osterix stimulates osteopontin gene expression but not the expression or activity of other bone-related markers, including collagen type I, alkaline phosphatase, osteocalcin, or osteonectin. Moreover, cells stably expressing Osterix do not induce bone nodule formation. Strikingly, both polyclonal and monoclonal cells expressing Osterix exhibit enhanced proliferation. Collectively, these results indicate that Osterix is insufficient to establish osteogenic lineage commitment, perhaps due to the ability of Osterix to promote cell growth. We propose that regulatory pathways operating upstream of or in parallel with Osterix are required for osteogenic conversion of uncommitted mesenchymal cells.
An elevated apolipoprotein B-apolipoprotein A-I (apo B-apo A-I) ratio is a risk factor for future coronary artery disease (CAD). It is not known whether this ratio is better than traditional lipid ...values for risk assessment and prediction and whether it adds predictive value to the Framingham risk score.
To evaluate whether the apo B-apo A-I ratio is associated with future CAD events independent of traditional lipid measurements and the Framingham risk score and to evaluate the ability of this ratio to predict occurrence of future CAD.
Prospective, nested case-control study.
Norfolk, United Kingdom.
Apparently healthy men and women (45 to 79 years of age) in the European Prospective Investigation into Cancer and Nutrition-Norfolk. Cases (n = 869) were persons who developed fatal or nonfatal CAD. Controls (n = 1511) were persons without CAD who were matched for age, sex, and enrollment period.
Total cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, apolipoprotein, and C-reactive protein levels were measured directly. Low-density lipoprotein (LDL) cholesterol values were calculated by using the Friedewald formula.
The apo B-apo A-I ratio was associated with future CAD events, independent of traditional lipid values (adjusted odds ratio, 1.85 95% CI, 1.15 to 2.98), including the total cholesterol-HDL cholesterol ratio, and independent of the Framingham risk score (adjusted odds ratio, 1.77 CI, 1.31 to 2.39). However, it did no better than lipid values at discriminating between CAD cases and controls (area under the receiver-operating characteristic curve, 0.670 for total cholesterol-HDL cholesterol ratio vs. 0.673 for apo B-apo A-I ratio P = 0.38) and added little to the predictive value of the Framingham risk score (area under the receiver-operating characteristic curve, 0.594 for Framingham risk score alone vs. 0.613 for Framingham risk score plus apo B-apo A-I ratio P < 0.001). In addition, it incorrectly classified 41.1% of cases and 50.4% of controls.
No participant was taking lipid-lowering medication, and diabetes was uncommon.
The apo B-apo A-I ratio is independently associated with, but adds little to, existing measures for CAD risk assessment and discrimination in the general population. Other characteristics of the test, such as the ability to perform it on nonfasting samples, may still make it useful in some settings.
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