ABSTRACT
The Perseverance rover landed in Jezero crater, Mars, to investigate ancient lake and river deposits. We report observations of the crater floor, below the crater's sedimentary delta, finding that the floor consists of igneous rocks altered by water. The lowest exposed unit, informally named Séítah, is a coarsely crystalline olivine-rich rock, which accumulated at the base of a magma body. Magnesium-iron carbonates along grain boundaries indicate reactions with carbon dioxide-rich water under water-poor conditions. Overlying Séítah is a unit informally named Máaz, which we interpret as lava flows or the chemical complement to Séítah in a layered igneous body. Voids in these rocks contain sulfates and perchlorates, likely introduced by later near-surface brine evaporation. Core samples of these rocks have been stored aboard Perseverance for potential return to Earth.
ABSTRACT
Geological evidence shows that ancient Mars had large volumes of liquid water. Models of past hydrogen escape to space, calibrated with observations of the current escape rate, cannot explain the present-day deuterium-to-hydrogen isotope ratio (D/H). We simulated volcanic degassing, atmospheric escape, and crustal hydration on Mars, incorporating observational constraints from spacecraft, rovers, and meteorites. We found that ancient water volumes equivalent to a 100 to 1500 meter global layer are simultaneously compatible with the geological evidence, loss rate estimates, and D/H measurements. In our model, the volume of water participating in the hydrological cycle decreased by 40 to 95% over the Noachian period (~3.7 billion to 4.1 billion years ago), reaching present-day values by ~3.0 billion years ago. Between 30 and 99% of martian water was sequestered through crustal hydration, demonstrating that irreversible chemical weathering can increase the aridity of terrestrial planets.
ABSTRACT
Microfibril-associated glycoprotein-1 (MAGP1) is an extracellular matrix protein that interacts with fibrillin and is involved in regulating the bioavailability of signaling molecules such as TGFß. Mice with germline MAGP1 deficiency (Mfap2-/-) develop increased adiposity, hyperglycemia, insulin resistance, bone marrow adipose tissue expansion, reduced cancellous bone mass, cortical bone thinning and bone fragility. The goal of this study was to assess whether the Mfap2-/- bone phenotypes were due to loss of MAGP1 locally or secondary to a change in whole body physiology (metabolic dysfunction). To do this, mice with conditional deletion of MAGP1 in the limb skeleton were generated by crossing MAGP1-flox mice (Mfap2lox/lox) with Prx1-Cre mice. Mfap2Prx-/- mice did not show any changes in peripheral adiposity, hyperglycemia or insulin sensitivity, but did have increased bone length and cancellous bone loss that was comparable to the germline Mfap2-/- knockout. Unlike the germline knockout, marrow adiposity, cortical bone thickness and bone strength in Mfap2Prx-/- mice were normal. These findings implicate systemic metabolic dysfunction in the development of bone fragility in germline Mfap2-/- mice. An unexpected finding of this study was the detection of MAGP1 protein in the Mfap2Prx-/- hematopoietic bone marrow, despite the absence of MAGP1 protein in osseous bone matrix and absent Mfap2 transcript expression at both sites. This suggests MAGP1 from a secondary site may accumulate in the bone marrow, but not be incorporated into the bone matrix, during times of regional MAGP1 depletion.
Subject(s)
Bone and Bones/pathology , Contractile Proteins/deficiency , Extracellular Matrix Proteins/deficiency , Homeodomain Proteins/metabolism , Metabolic Diseases/genetics , Adipocytes/metabolism , Animals , Bone Marrow/metabolism , Bone and Bones/metabolism , Disease Models, Animal , Germ-Line Mutation , Homeodomain Proteins/genetics , Metabolic Diseases/metabolism , Mice , RNA Splicing Factors , Signal TransductionABSTRACT
Asthma is a common respiratory disease affecting â¼300 million people worldwide. Airway inflammation is thought to contribute to asthma pathogenesis, but the direct relationship between inflammation and airway hyperresponsiveness (AHR) remains unclear. This study investigates the role of inflammation in a steroid-insensitive, severe allergic airway disease model and in severe asthmatics stratified by inflammatory profile. First, we used the T-helper (T(H))-17 cells adoptive transfer mouse model of asthma to induce pulmonary inflammation, which was lessened by tumor necrosis factor (TNF)-α neutralization or neutrophil depletion. Although decreased airspace inflammation following TNFα neutralization and neutrophil depletion rescued lung compliance, neither intervention improved AHR to methacholine, and tissue inflammation remained elevated when compared with control. Further, sputum samples were collected and analyzed from 41 severe asthmatics. In severe asthmatics with elevated levels of sputum neutrophils, but low levels of eosinophils, increased inflammatory markers did not correlate with worsened lung function. This subset of asthmatics also had significantly higher levels of T(H)17-related cytokines in their sputum compared with severe asthmatics with other inflammatory phenotypes. Overall, this work suggests that lung compliance may be linked with cellular inflammation in the airspace, whereas T-cell-driven AHR may be associated with tissue inflammation and other pulmonary factors.
Subject(s)
Asthma/complications , Inflammation/complications , Lung/physiology , Adolescent , Adult , Age of Onset , Aged , Aged, 80 and over , Animals , Asthma/immunology , Asthma/physiopathology , Bronchial Hyperreactivity/immunology , Bronchoconstrictor Agents/pharmacology , Child , Cytokines/immunology , Female , Humans , Lung/drug effects , Lung/pathology , Male , Methacholine Chloride/pharmacology , Mice , Mice, Transgenic , Middle Aged , Severity of Illness Index , Sputum/immunologyABSTRACT
Inhibitory deficits contribute to cognitive decline in the aging brain. Separating subcomponents of response inhibition may help to resolve contradictions in the existing literature. A total of 49 healthy participants underwent functional magnetic resonance imaging (fMRI) while performing a Go/no-go-, a Simon-, and a Stop-signal task. Regression analyses were conducted to identify correlations of age and activation patterns. Imaging results revealed a differential effect of age on subcomponents of response inhibition. In a simple Go/no-go task (no spatial discrimination), aging was associated with increased activation of the core inhibitory network and parietal areas. In the Simon task, which required spatial discrimination, increased activation in additional inhibitory control regions was present. However, in the Stop-signal task, the most demanding of the three tasks, aging was associated with decreased activation. This suggests that older adults increasingly recruit the inhibitory network and, with increasing load, additional inhibitory regions. However, if inhibitory load exceeds compensatory capacity, performance declines in concert with decreasing activation. Thus, the present findings may refine current theories of cognitive aging.
Subject(s)
Aging/physiology , Aging/psychology , Brain/pathology , Brain/physiopathology , Cognition Disorders/etiology , Cognition Disorders/psychology , Inhibition, Psychological , Adult , Aged , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Neuropsychological Tests , Reaction Time , Young AdultABSTRACT
Leptin influences bone formation centrally through the hypothalamus and peripherally by acting on osteoblasts or their precursors. However, neither mechanism explains the divergent, gender-specific correlation between leptin and bone mineral density in humans. Although leptin is a potent regulator of pro-inflammatory immune responses, a potential role for leptin as an osteoimmunologic intermediate in bone metabolism has not been tested. Mice with myeloid-specific ablation of the long-form leptin receptor (ObRb) were generated using mice expressing cre-recombinase from the lysoszyme M promoter. At 12 weeks of age, the conditional knockout mice did not display any appreciable phenotype. However, at 52 weeks 2 changes were noted. First, there was a mild increase in liver inflammation. Second, a gender-specific, divergent bone phenotype was observed. Female mice displayed a consistent trend toward decreased trabecular bone parameters including reductions in bone volume fraction, trabecular number, and bone mineral content as well as a significant increase in marrow adipogenesis. Conversely, male mice lacked trabecular changes, but had statistically significant increases in cortical bone volume, thickness, and bone mineral density with equivalent total cortical volume. Since the year 2000, over 25 studies on more than 10,000 patients have sought to determine the correlation between leptin and bone mineral density. The results revealed a gender-specific correlation similar to that observed in our LysM transgenic animals. We hypothesize and show new evidence that regulation of myeloid lineage cells by leptin may facilitate their actions as an osteoimmunologic intermediate and contribute to leptin-regulated bone formation and metabolism in a gender-specific manner.
Subject(s)
Bone and Bones/metabolism , Cell Lineage , Leptin/metabolism , Myeloid Cells/cytology , Myeloid Cells/metabolism , Animals , Bone and Bones/diagnostic imaging , Female , Femur/diagnostic imaging , Femur/metabolism , Integrases/metabolism , Male , Mice , Mice, Knockout , Muramidase , Receptors, Leptin/deficiency , Receptors, Leptin/metabolism , X-Ray MicrotomographyABSTRACT
Osteonecrosis of the jaw (ONJ), a side-effect of bisphosphonate therapy, is characterized by exposed bone that fails to heal within eight weeks. Healing time of oral epithelial wounds is decreased in the presence of amino-bisphosphonates; however, the mechanism remains unknown. We examined human tissue from individuals with ONJ and non-bisphosphonate-treated control individuals to identify changes in oral epithelium and connective tissue. Oral and intravenous bisphosphonate-treated ONJ sites had reduced numbers of basal epithelial progenitor cells, as demonstrated by a 13.8±1.1% and 31.9±5.8% reduction of p63 expression, respectively. No significant differences in proliferation rates, vessel density, or macrophage number were noted. In vitro treatment of clonal and primary oral keratinocytes with zoledronic acid (ZA) inhibited p63, and expression was rescued by the addition of mevalonate pathway intermediates. In addition, both ZA treatment and p63 shRNA knock-down impaired formation of 3D Ex Vivo Produced Oral Mucosa Equivalents (EVPOME) and closure of an in vitro scratch assay. Analysis of our data suggests that bisphosphonate treatment may delay oral epithelial healing by interfering with p63-positive progenitor cells in the basal layer of the oral epithelium in a mevalonate-pathway-dependent manner. This delay in healing may increase the likelihood of osteonecrosis developing in already-compromised bone.
Subject(s)
Adult Stem Cells/drug effects , Bone Density Conservation Agents/adverse effects , Diphosphonates/adverse effects , Imidazoles/adverse effects , Jaw Diseases/genetics , Keratinocytes/drug effects , Membrane Proteins/genetics , Osteonecrosis/genetics , Analysis of Variance , Case-Control Studies , Cell Line, Transformed , Gene Expression/drug effects , Gene Knockdown Techniques , Humans , Jaw Diseases/chemically induced , Keratinocytes/metabolism , Membrane Proteins/biosynthesis , Mevalonic Acid/metabolism , Osteonecrosis/chemically induced , RNA, Small Interfering , Tissue Culture Techniques , Wound Healing/drug effects , Wound Healing/genetics , Zoledronic AcidABSTRACT
Gene therapy is defined as the treatment of disease by transfer of genetic material into cells. This review will explore methods available for gene transfer as well as current and potential applications for craniofacial regeneration, with emphasis on future development and design. Though non-viral gene delivery methods are limited by low gene transfer efficiency, they benefit from relative safety, low immunogenicity, ease of manufacture, and lack of DNA insert size limitation. In contrast, viral vectors are nature's gene delivery machines that can be optimized to allow for tissue-specific targeting, site-specific chromosomal integration, and efficient long-term infection of dividing and non-dividing cells. In contrast to traditional replacement gene therapy, craniofacial regeneration seeks to use genetic vectors as supplemental building blocks for tissue growth and repair. Synergistic combination of viral gene therapy with craniofacial tissue engineering will significantly enhance our ability to repair and replace tissues in vivo.
Subject(s)
Bone Regeneration/genetics , Facial Bones/physiology , Gene Transfer Techniques , Genetic Therapy/methods , Genetic Vectors , Animals , Carcinoma, Squamous Cell/therapy , Head and Neck Neoplasms/therapy , Humans , Skin Transplantation/methods , Tissue Engineering , VirusesABSTRACT
More than 85% of the global population requires repair or replacement of a craniofacial structure. These defects range from simple tooth decay to radical oncologic craniofacial resection. Regeneration of oral and craniofacial tissues presents a formidable challenge that requires synthesis of basic science, clinical science and engineering technology. Identification of appropriate scaffolds, cell sources and spatial and temporal signals (the tissue engineering triad) is necessary to optimize development of a single tissue, hybrid organ or interface. Furthermore, combining the understanding of the interactions between molecules of the extracellular matrix and attached cells with an understanding of the gene expression needed to induce differentiation and tissue growth will provide the design basis for translating basic science into rationally developed components of this tissue engineering triad. Dental tissue engineers are interested in regeneration of teeth, oral mucosa, salivary glands, bone and periodontium. Many of these oral structures are hybrid tissues. For example, engineering the periodontium requires growth of alveolar bone, cementum and the periodontal ligament. Recapitulation of biological development of hybrid tissues and interfaces presents a challenge that exceeds that of engineering just a single tissue. Advances made in dental interface engineering will allow these tissues to serve as model systems for engineering other tissues or organs of the body. This review will begin by covering basic tissue engineering principles and strategic design of functional biomaterials. We will then explore the impact of biomaterials design on the status of craniofacial tissue engineering and current challenges and opportunities in dental tissue engineering.
Subject(s)
Mouth/surgery , Tissue Engineering/methods , Animals , Biocompatible Materials/therapeutic use , Bone Regeneration , Dermatologic Surgical Procedures , Humans , Mouth Mucosa/surgery , Temporomandibular Joint/surgery , Tissue Scaffolds , Tooth/surgeryABSTRACT
Dental pulp stem cells (DPSCs) are a unique precursor population isolated from postnatal human dental pulp and have the ability to regenerate a reparative dentin-like complex. Canonical Wnt signaling plays a critical role in tooth development and stem cell self-renewal through beta-catenin. In this study, the regulation of odontoblast-like differentiation of DPSCs by canonical Wnt signaling was examined. DPSCs were stably transduced with canonical Wnt-1 or the active form of beta-catenin, with retrovirus-mediated infection. Northern blot analysis found that Wnt-1 strongly induced the expression of matricellular protein osteopontin, and modestly enhanced the expression of type I collagen in DPSCs. Unexpectedly, Wnt-1 inhibited alkaline phosphatase (ALP) activity and the formation of mineralized nodules in DPSCs. Moreover, over-expression of beta-catenin was also sufficient to suppress the differentiation and mineralization of DPSCs. In conclusion, our results suggest that canonical Wnt signaling negatively regulates the odontoblast-like differentiation of DPSCs.
Subject(s)
Dental Pulp/cytology , Stem Cells/physiology , Wnt1 Protein/physiology , beta Catenin/physiology , Alkaline Phosphatase/antagonists & inhibitors , Anthraquinones , Blotting, Northern , Blotting, Western , Calcification, Physiologic/physiology , Cell Differentiation/physiology , Cells, Cultured , Collagen Type I/analysis , Coloring Agents , Dental Pulp/physiology , Genetic Vectors/genetics , Humans , Odontoblasts/physiology , Osteopontin/analysis , Polymerase Chain Reaction , Retroviridae/genetics , Signal Transduction/physiology , Transduction, GeneticABSTRACT
OBJECTIVE: To investigate changes in the composition of articular cartilage matrix during the development of experimental osteoarthritis (OA), collagen type II, collagen type I, and the noncollagenous proteins fibronectin and tenascin were studied in normal and osteoarthritic cartilage of rabbits. METHODS: OA of the knee joint was induced by a medial meniscectomy and section of the medial collateral ligament and anterior cruciate ligament. Frozen sections of rabbit normal and OA cartilage were stained with monoclonal antibodies against collagen type II, collagen type I, fibronectin, and tenascin. RESULTS: Collagen II manifested a decreased interterritorial staining and seemed to increase territorially in the deeper zones of the OA cartilage. Collagen I was found in normal cartilage as a thin layer covering the surface and also in OA fibrillated cartilage. Fibronectin was present in normal and OA cartilage. Whereas a layer covered the normal cartilage, a thicker layer was observed in OA cartilage. In addition, changes in fibronectin distribution from the pericellular to the interterritorial matrix were observed. Tenascin was also found in normal cartilage matrix, particularly in the territorial and interterritorial matrix of the deeper zones. It showed an increased staining intensity in fibrillated cartilage, in the pericellular matrix of the upper chondrocytes, and on the surface lining in OA cartilage. CONCLUSION: Collagen type II deposition seems to increase in the deeper cartilage zones during the osteoarthritic process, as a sign of tissue repair response. Collagen type I, fibronectin, and tenascin show enhanced deposition in the upper, fibrillated osteoarthritic cartilage, suggesting a common mediator controlled pathway.
Subject(s)
Cartilage, Articular/metabolism , Collagen/metabolism , Fibronectins/metabolism , Osteoarthritis/metabolism , Tenascin/metabolism , Animals , Female , Hindlimb/pathology , Immunohistochemistry , Joints/pathology , Protein Isoforms/metabolism , RabbitsSubject(s)
Abortion, Induced/methods , Dinoprostone/analogs & derivatives , Mifepristone/therapeutic use , Phloroglucinol/pharmacology , Uterine Contraction/drug effects , Abortifacient Agents, Nonsteroidal/therapeutic use , Adult , Dinoprostone/therapeutic use , Drug Therapy, Combination , Female , Humans , Parity , Phloroglucinol/therapeutic use , PregnancyABSTRACT
PIP: 45 women undergoing 1st trimester abortions induced by RU-486 were divided into 3 groups for a double-blind randomized vs. placebo trail of analgesia following sulprostone administration. 600 mg of RU-486 was administered orally 36-48 hours before admission to the hospital. After admission, 10 women received 600 mg of acetaminophen, 14 received 80 mg of dipropyline, and 14 received a placebo. 500 mcg of sulprostone was injected about 30 minutes later. The study excluded method failures, expulsions occurring before hospital admission, deviations from the protocol, and delays to expulsion greater than 8 hours. There was no significant difference between the 3 groups in maximal pain, but the placebo group appeared to experience less discomfort than the other two. The delay to expulsion was significantly longer in the acetaminophen group than in the other two. The relatively lower amount of pain in the placebo group was probably due to the reduced proportion of nulliparas in it compared to the other 2 groups. 6 women in the acetaminophen group, 9 in the dipropyline group, and only 5 in the placebo group were nulliparas. Comparing nulliparas with mothers within groups, the maximal pain was significantly less intense among mothers than among nulliparas in the placebo group and to a lesser extent in the dipropyline group but not in the acetaminophen group. Based on these results it is recommended that a systematic study be made of analgesia for RU-486 and sulprostone-induced abortions. An antispasmodic effect on the cervical fibers should be sought more than analgesia per se.^ieng