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Author(s): T. D. Jones (corresponding author) [1]; D. R. Davies [1]; I. H. Campbell [1]; G. Iaffaldano [2]; G. Yaxley [1]; S. C. Kramer [3]; C. R. Wilson [4, 5] [...]

The basic equations used to study the fluid diffusion in porous media have been set by Fick and Darcy in the mid of the XIXth century but some data on the flow of fluids in rocks exhibit properties which may not be interpreted with the classical theory of propagation of pressure and fluids in porous media (Bell and Nur, 1978; Roeloffs, 1988). Concerning the fluids and the flow, some fluids carry solid particles which may obstruct some of the pores diminishing their size or even closing them, some others may chemically and physically react with the medium enlarging the pores; so permeability changes during time and the flow occurs as if the medium had a memory. In this paper we show, with experimental data, that the permeability of sand layers may decrease due to rearrangement of the grains and consequent compaction as shown qualitatively by Elias and Hajash (Elias and Hajash, 1992). We also provide a memory model for diffusion of fluids in porous media which fits well the flux rate observed in five laboratory experiments of diffusion of water in sand. Finally we show that the flux rate variations observed during the experiments are compatible with the compaction of sand, due to the amount of fluid which went through the grains locally, and therefore with the reduction of porosity. [ABSTRACT FROM AUTHOR]

Presents comments on the study "Experimental and Theoretical Memory Diffusion of Water in Sand," by G. Iaffaldano et al. Quality of experiments with automatic device to be used in flux measurements; Need for the modification of theoretic equations used to resolve flux variations.

Tectonic plate motions drive the earthquake cycle, as they result in the slow accrual and sudden release of energy along plate boundaries. Steadiness of plate motions over the earthquake cycle is a central tenet of the plate tectonics theory and has long been a main pillar in models of earthquake genesis, or of plate-margins seismic potential inferred from slip-deficit estimates. The advent of geodesy in the geosciences and the availability of multi-year-long series of position measurements permit tracking the motions of tectonic plates from before to after the time of significant seismic events that occur along their margins. Here, we present evidence that large earthquakes are capable of modifying the motions of entire microplates. We use high precision Global Navigation Satellite System (GNSS) position time-series covering the periods 2001-2004 and 2014-2017 to demonstrate that, contrary to the tenet above, the South China microplate motion changed after the 2008 M W 7.9 Great Wenchuan earthquake. The GNSS data and associated uncertainties indicate a plate motion slowdown of up to 20% that is beyond the possible impact of data noise and is thus tectonically meaningful. We use quantitative models of torque balance to show that generating this kinematic change requires a force upon the South China microplate compatible with that imparted by the Great Wenchuan earthquake of 2008. The existence of a kinematic signal linked to the earthquake cycle that impacts an entire microplate might offer an additional, novel perspective to assessing the hazards of earthquake-prone tectonic regions., (© 2024. The Author(s).)

Over million years, convergence between the Nazca and South America tectonic plates results in Andean orogeny. Over decades/centuries, it fuels the earthquake cycle of the Andean megathrust. It is well recognised that, over the geologically-long term of million years, Andean orogeny feeds back onto plate convergence rates, generating temporal changes documented throughout the Neogene. In contrast, no feedback mechanism operated over the geologically-short term by the earthquake cycle is currently contemplated. In fact, it is commonly assumed that the rates of contemporary convergence, which are accurately measured via geodesy, remain steady during the megathrust earthquake cycle. Here we investigate whether the contemporary Nazca/South America plate motion varies over year-/decade-long periods in response to megathrust stress variations associated with the earthquake cycle. We focus on the decade preceding the three largest and most recent [Formula: see text] earthquakes (2010 [Formula: see text] Maule, 2014 [Formula: see text] Iquique, 2015 [Formula: see text] Illapel), and find slowdowns of both Nazca and South America whole-plate motions that exceed the impact of data uncertainty or noise. We show that the torque variations required upon Nazca and South America to generate the slowdowns are consistent with that arising from the buildup of interseismic stress preceding the earthquakes., (© 2023. The Author(s).)

The Andean cordillera was constructed during compressive tectonic events, whose causes and controls remain unclear. Exploring a possible link to plate convergence has been impeded by the coarse temporal resolution of existing plate kinematic models. Here we show that the Neogene evolution of the Andean margin is primarily related to changes in convergence as observed in new high-resolution plate reconstructions. Building on a compilation of plate finite rotations spanning the last 30 million years and using noise-mitigation techniques, we predict several short-term convergence changes that were unresolved in previous models. These changes are related to main tectono-magmatic events and require forces that are compatible with a range of geodynamic processes. These results allow to revise models of ongoing subduction orogeny at its type locality, emphasizing the role of upper plate deformation in the balance between kinematic energy associated with plate motion and gravitational potential energy stored in orogenic crustal roots., (© 2022. The Author(s).)

The directed differentiation of patient-derived induced pluripotent stem cells into cell-type specific neurons has inspired the development of therapeutic discovery for neurodegenerative diseases. Many forms of ataxia result from degeneration of cerebellar Purkinje cells, but thus far it has not been possible to efficiently generate Purkinje neuron (PN) progenitors from human or mouse pluripotent stem cells, let alone to develop a methodology for in vivo transplantation in the adult cerebellum. Here, we present a protocol to obtain an expandable population of cerebellar neuron progenitors from mouse embryonic stem cells. Our protocol is characterized by applying factors that promote proliferation of cerebellar progenitors. Cerebellar progenitors isolated in culture from cell aggregates contained a stable subpopulation of PN progenitors that could be expanded for up to 6 passages. When transplanted into the adult cerebellum of either wild-type mice or a strain lacking Purkinje cells (L7cre-ERCC1 knockout), GFP-labeled progenitors differentiated in vivo to establish a population of calbindin-positive cells in the molecular layer with dendritic trees typical of mature PNs. We conclude that this protocol may be useful for the generation and maturation of PNs, highlighting the potential for development of a regenerative medicine approach to the treatment of cerebellar neurodegenerative diseases.

Bone marrow (BM) has long been considered a potential stem cell source for cardiac repair due to its abundance and accessibility. Although previous investigations have generated cardiomyocytes from BM, yields have been low, and far less than produced from ES or induced pluripotent stem cells (iPSCs). Since differentiation of pluripotent cells is difficult to control, we investigated whether BM cardiac competency could be enhanced without making cells pluripotent. From screens of various molecules that have been shown to assist iPSC production or maintain the ES cell phenotype, we identified the G9a histone methyltransferase inhibitor BIX01294 as a potential reprogramming agent for converting BM cells to a cardiac-competent phenotype. BM cells exposed to BIX01294 displayed significantly elevated expression of brachyury, Mesp1, and islet1, which are genes associated with embryonic cardiac progenitors. In contrast, BIX01294 treatment minimally affected ectodermal, endodermal, and pluripotency gene expression by BM cells. Expression of cardiac-associated genes Nkx2.5, GATA4, Hand1, Hand2, Tbx5, myocardin, and titin was enhanced 114, 76, 276, 46, 635, 123, and 5-fold in response to the cardiogenic stimulator Wnt11 when BM cells were pretreated with BIX01294. Immunofluorescent analysis demonstrated that BIX01294 exposure allowed for the subsequent display of various muscle proteins within the cells. The effect of BIX01294 on the BM cell phenotype and differentiation potential corresponded to an overall decrease in methylation of histone H3 at lysine9, which is the primary target of G9a histone methyltransferase. In summary, these data suggest that BIX01294 inhibition of chromatin methylation reprograms BM cells to a cardiac-competent progenitor phenotype.

Rationale: Embryonic and fetal myocardial growth is characterized by a dramatic increase in myocyte number, but whether the expansion of the myocyte compartment is dictated by activation and commitment of resident cardiac stem cells (CSCs), division of immature myocytes or both is currently unknown., Objective: In this study, we tested whether prenatal cardiac development is controlled by activation and differentiation of CSCs and whether division of c-kit-positive CSCs in the mouse heart is triggered by spontaneous Ca(2+) oscillations., Methods and Results: We report that embryonic-fetal c-kit-positive CSCs are self-renewing, clonogenic and multipotent in vitro and in vivo. The growth and commitment of c-kit-positive CSCs is responsible for the generation of the myocyte progeny of the developing heart. The close correspondence between values computed by mathematical modeling and direct measurements of myocyte number at E9, E14, E19 and 1 day after birth strongly suggests that the organogenesis of the embryonic heart is dependent on a hierarchical model of cell differentiation regulated by resident CSCs. The growth promoting effects of c-kit-positive CSCs are triggered by spontaneous oscillations in intracellular Ca(2+), mediated by IP3 receptor activation, which condition asymmetrical stem cell division and myocyte lineage specification., Conclusions: Myocyte formation derived from CSC differentiation is the major determinant of cardiac growth during development. Division of c-kit-positive CSCs in the mouse is promoted by spontaneous Ca(2+) spikes, which dictate the pattern of stem cell replication and the generation of a myocyte progeny at all phases of prenatal life and up to one day after birth.

Understanding lithospheric plate motions is of paramount importance to geodynamicists. Much effort is going into kinematic reconstructions featuring progressively finer temporal resolution. However, the challenge of precisely identifying ocean-floor magnetic lineations, and uncertainties in geomagnetic reversal timescales result in substantial finite-rotations noise. Unless some type of temporal smoothing is applied, the scenario arising at the native temporal resolution is puzzling, as plate motions vary erratically and significantly over short periods (<1 Myr). This undermines our ability to make geodynamic inferences, as the rates at which forces need to be built upon plates to explain these kinematics far exceed the most optimistic estimates. Here we show that the largest kinematic changes reconstructed across the Atlantic, Indian and South Pacific ridges arise from data noise. We overcome this limitation using a trans-dimensional hierarchical Bayesian framework. We find that plate-motion changes occur on timescales no shorter than a few million years, yielding simpler kinematic patterns and more plausible dynamics.

This study examined transgenic mice whose expression of a β-galactosidase (lacZ) reporter is driven by a GATA6 gene enhancer. Previous investigations established that transcription of the transgene was associated with precardiac mesoderm and primary heart tube myocardium, which decreased progressively, so that its expression was no longer observed within ventricular myocardium by midgestation. Expression of this reporter in the adult was investigated for insights into myocyte homeostasis and cardiovascular biology. Morphometric analysis determined that <1% of myocytes, often found in small clusters, express this GATA6-associated reporter in the adult heart. LacZ expression was also found in the ascending aorta. Myocardial expression of the transgene was not associated with a proliferative phenotype or new myocyte formation, as lacZ-positive myocytes neither labeled with cell division markers nor following 5-bromodeoxyuridine pulse-chase experimentation. Despite exhibiting normal adherens junctions, these myocytes appeared to exhibit decreased connexin 43 gap junctions. Treatment with the gap junctional blocker heptanol both in vivo and in culture elevated myocardial β-galactosidase activity, suggesting that deficient gap junctional communication underlies expression of the transgenic reporter. LacZ expression within the myocardium was also enhanced in response to cryoinjury and isoproterenol-induced hypertrophy. These results reveal a previously uncharacterized phenotypic heterogeneity in the myocardium and suggest that decreased gap junctional coupling leads to induction of a signaling pathway that utilizes a unique GATA6 enhancer. Upregulation of lacZ reporter gene expression following cardiac injury indicates this transgenic mouse may serve as a model for examining the transition of the heart from healthy to pathological states.

Objective: The vascular competence of human-derived hematopoietic progenitors for postnatal vascularization is still poorly characterized. It is unclear whether, in the absence of ischemia, hematopoietic progenitors participate in neovascularization and whether they play a role in new blood vessel formation by incorporating into developing vessels or by a paracrine action., Methods and Results: In the present study, human cord blood-derived CD34(+) (hCD34(+)) cells were transplanted into pre- and postgastrulation zebrafish embryos and in an adult vascular regeneration model induced by caudal fin amputation. When injected before gastrulation, hCD34(+) cells cosegregated with the presumptive zebrafish hemangioblasts, characterized by Scl and Gata2 expression, in the anterior and posterior lateral mesoderm and were involved in early development of the embryonic vasculature. These morphogenetic events occurred without apparent lineage reprogramming, as shown by CD45 expression. When transplanted postgastrulation, hCD34(+) cells were recruited into developing vessels, where they exhibited a potent paracrine proangiogenic action. Finally, hCD34(+) cells rescued vascular defects induced by Vegf-c in vivo targeting and enhanced vascular repair in the zebrafish fin amputation model., Conclusions: These results indicate an unexpected developmental ability of human-derived hematopoietic progenitors and support the hypothesis of an evolutionary conservation of molecular pathways involved in endothelial progenitor differentiation in vivo.

Background: Mental disorders are frequent in hemodialysis (HD) patients. Depression and anxiety along with physical co-morbidity affect quality of life (QOL). Uremia is associated with inflammation and release of cytokines by lymphomonocytes. Inflammatory cytokines are relevant in depression. The aim of this study was to assess the psychological alterations and QOL in HD patients, and to correlate them with pattern of cytokine production., Patients: 30 HD patients and 20 subjects with CKD Stage I-II K-DOQI. Psychometric tests were administered: 1) Hospital Anxiety and Depression Scale (HADS) composed of an anxiety subscale (HADS-A) and a depression subscale (HADS-D); 2) Kidney Disease Quality of Life (KDQOL) modified, including a cognitive function subscale (KDQOL-CF). Whole blood samples collected at beginning of HD session were diluted with RPMI/heparin and incubated for 24 h in presence of lipopolysaccharide (LPS). IL-1Gamma, IL-6, TNF-alpha and IL-10 were assayed on supernatants and results were normalized per number of lymphomonocytes (ng/106 cells)., Results: A depressive mood was more frequent in HD patients (50%) than controls (20%, p < 0.0001). No difference for anxiety (HD = 43%, controls = 45%) was observed. QOL score was significantly lower in HD than controls (p = 0.006) and correlated inversely with HADS total, HADS-A and HADS-D (p < 0.0001). Albumin, Kt/V and phosphate were comparable in patients with or without anxiety or depression. Cytokine production was significantly higher in HD patients than controls (IL-1beta p = 0.05; IL-6 p = 0.010; TNF-alpha p < 0.0001; IL-10, p = 0.0019). HD patients with the HADS-A positive for anxiety showed higher IL-6 production (p = 0.026), while IL-1beta levels were not associated with symptoms of depression. KDQOL-CF correlated inversely with levels of IL-6, TNF-alpha and IL-10., Conclusions: HD patients have symptoms of depression and anxiety that negatively affect QOL. These symptoms are independent of the efficiency of dialysis and nutritional status. On the contrary, IL-6 is linked to the presence of psychological discomfort in these patients.

Brief maternal separations of neonatal animals can exert long-lasting effects on the reactivity of the neuroendocrine system. The aim of the present study was to investigate whether manipulations of the mother-infant interaction could affect susceptibility to immune-mediated diseases, such experimental autoimmune encephalomyelitis (EAE), and whether this effect would be mediated by changes in leptin which has been shown to regulate disease susceptibility and severity at adulthood. Given the different gender susceptibility to EAE previously described, we tested also whether early experiences could differentially affect the two genders. To this purpose, female and male C56BL/6 mice were subjected to handling (15 min daily) postnatally, from day 2 until day 14. All subjects were weaned at 21 days. At 7 weeks of age mice were immunized with MOG(35-55) to actively induce EAE. We thus determined the effect of neonatal handling on plasma concentrations of testosterone in male mice and leptin in both genders at different times post EAE induction. Our results show that early experiences influence susceptibility to EAE in a gender-specific manner, early manipulations resulting in an enhancement of sex-related differences in susceptibility. These effects were associated with changes in the testosterone profile of male subjects. Changes in leptin levels during the preclinical stage of EAE may predict a more severe disease course.

The possibility that adult bone marrow cells (BMCs) retain a remarkable degree of developmental plasticity and acquire the cardiomyocyte lineage after infarction has been challenged, and the notion of BMC transdifferentiation has been questioned. The center of the controversy is the lack of unequivocal evidence in favor of myocardial regeneration by the injection of BMCs in the infarcted heart. Because of the interest in cell-based therapy for heart failure, several approaches including gene reporter assay, genetic tagging, cell genotyping, PCR-based detection of donor genes, and direct immunofluorescence with quantum dots were used to prove or disprove BMC transdifferentiation. Our results indicate that BMCs engraft, survive, and grow within the spared myocardium after infarction by forming junctional complexes with resident myocytes. BMCs and myocytes express at their interface connexin 43 and N-cadherin, and this interaction may be critical for BMCs to adopt the cardiomyogenic fate. With time, a large number of myocytes and coronary vessels are generated. Myocytes show a diploid DNA content and carry, at most, two sex chromosomes. Old and new myocytes show synchronicity in calcium transients, providing strong evidence in favor of the functional coupling of these two cell populations. Thus, BMCs transdifferentiate and acquire the cardiomyogenic and vascular phenotypes restoring the infarcted heart. Together, our studies reveal that locally delivered BMCs generate de novo myocardium composed of integrated cardiomyocytes and coronary vessels. This process occurs independently of cell fusion and ameliorates structurally and functionally the outcome of the heart after infarction.