2,180 research outputs found
Modeling the dynamics of glacial cycles
This article is concerned with the dynamics of glacial cycles observed in the geological record of the Pleistocene Epoch. It focuses on a conceptual model proposed by Maasch and Saltzman [J. Geophys. Res.,95, D2 (1990), pp. 1955-1963], which is based on physical arguments and emphasizes the role of atmospheric CO2 in the generation and persistence of periodic orbits (limit cycles). The model consists of three ordinary differential equations with four parameters for the anomalies of the total global ice mass, the atmospheric CO2 concentration, and the volume of the North Atlantic Deep Water (NADW). In this article, it is shown that a simplified two-dimensional symmetric version displays many of the essential features of the full model, including equilibrium states, limit cycles, their basic bifurcations, and a Bogdanov-Takens point that serves as an organizing center for the local and global dynamics. Also, symmetry breaking splits the Bogdanov-Takens point into two, with different local dynamics in their neighborhoods
Generation and Characterization of Mice Carrying a Conditional Allele of the Wwox Tumor Suppressor Gene
WWOX, the gene that spans the second most common human chromosomal fragile site, FRA16D, is inactivated in multiple human cancers and behaves as a suppressor of tumor growth. Since we are interested in understanding WWOX function in both normal and cancer tissues we generated mice harboring a conditional Wwox allele by flanking Exon 1 of the Wwox gene with LoxP sites. Wwox knockout (KO) mice were developed by breeding with transgenic mice carrying the Cre-recombinase gene under the control of the adenovirus EIIA promoter. We found that Wwox KO mice suffered from severe metabolic defect(s) resulting in growth retardation and all mice died by 3 wk of age. All Wwox KO mice displayed significant hypocapnia suggesting a state of metabolic acidosis. This finding and the known high expression of Wwox in kidney tubules suggest a role for Wwox in acid/base balance. Importantly, Wwox KO mice displayed histopathological and hematological signs of impaired hematopoeisis, leukopenia, and splenic atrophy. Impaired hematopoeisis can also be a contributing factor to metabolic acidosis and death. Hypoglycemia and hypocalcemia was also observed affecting the KO mice. In addition, bone metabolic defects were evident in Wwox KO mice. Bones were smaller and thinner having reduced bone volume as a consequence of a defect in mineralization. No evidence of spontaneous neoplasia was observed in Wwox KO mice. We have generated a new mouse model to inactivate the Wwox tumor suppressor gene conditionally. This will greatly facilitate the functional analysis of Wwox in adult mice and will allow investigating neoplastic transformation in specific target tissues
Inhibition of activin/nodal signalling is necessary for pancreatic differentiation of human pluripotent stem cells
Peer reviewedPublisher PD
Preclinical activity and determinants of response of the GPRC5DxCD3 bispecific antibody talquetamab in multiple myeloma.
Cell surface expression levels of GPRC5D, an orphan G protein-coupled receptor, are significantly higher on multiple myeloma (MM) cells, compared with normal plasma cells or other immune cells, which renders it a promising target for immunotherapeutic strategies. The novel GPRC5D-targeting T-cell redirecting bispecific antibody, talquetamab, effectively kills GPRC5D+ MM cell lines in the presence of T cells from both healthy donors or heavily pretreated MM patients. In addition, talquetamab has potent anti-MM activity in bone marrow (BM) samples from 45 patients, including those with high-risk cytogenetic aberrations. There was no difference in talquetamab-mediated killing of MM cells from newly diagnosed, daratumumab-naïve relapsed/refractory (median of 3 prior therapies), and daratumumab-refractory (median of 6 prior therapies) MM patients. Tumor cell lysis was accompanied by T-cell activation and degranulation, as well as production of pro-inflammatory cytokines. High levels of GPRC5D and high effector:target ratio were associated with improved talquetamab-mediated lysis of MM cells, whereas an increased proportion of T cells expressing PD-1 or HLA-DR, and elevated regulatory T-cell (Treg) counts were associated with suboptimal killing. In cell line experiments, addition of Tregs to effector cells decreased MM cell lysis. Direct contact with bone marrow stromal cells also impaired the efficacy of talquetamab. Combination therapy with daratumumab or pomalidomide enhanced talquetamab-mediated lysis of primary MM cells in an additive fashion. In conclusion, we show that the GPRC5D-targeting T-cell redirecting bispecific antibody talquetamab is a promising novel antimyeloma agent. These results provide the preclinical rationale for ongoing studies with talquetamab in relapsed/refractory MM
Field evidence for the upwind velocity shift at the crest of low dunes
Wind topographically forced by hills and sand dunes accelerates on the upwind
(stoss) slopes and reduces on the downwind (lee) slopes. This secondary wind
regime, however, possesses a subtle effect, reported here for the first time
from field measurements of near-surface wind velocity over a low dune: the wind
velocity close to the surface reaches its maximum upwind of the crest. Our
field-measured data show that this upwind phase shift of velocity with respect
to topography is found to be in quantitative agreement with the prediction of
hydrodynamical linear analysis for turbulent flows with first order closures.
This effect, together with sand transport spatial relaxation, is at the origin
of the mechanisms of dune initiation, instability and growth.Comment: 13 pages, 6 figures. Version accepted for publication in
Boundary-Layer Meteorolog
Non-abelian Action for Multiple Five-Branes with Self-Dual Tensors
We construct an action for non-abelian 2-form in 6-dimensions. Our action
consists of a non-abelian generalization of the abelian action of Perry and
Schwarz for a single five-brane. It admits a self-duality equation on the field
strength as the equation of motion. It has a modified 6d Lorentz symmetry. On
dimensional reduction on a circle, our action gives the standard 5d Yang-Mills
action plus higher order corrections. Based on these properties, we propose
that our theory describes the gauge sector of multiple M5-branes in flat space.Comment: LaTeX, 26 pages. v2: improved discussion of Lorentz symmetry. ref
added. v3: add comments in the discussion section on the inclusion of scalar
fields and supersymmetry; title changed to a more suitable one; version
published in JHE
Questionnaire survey of working relationships between nurses and doctors in University Teaching Hospitals in Southern Nigeria
BACKGROUND: Smooth working relationships between nurses and doctors are necessary for efficient health care delivery. However, previous studies have shown that this is often absent with negative impact on the quality of health care delivery. In 2002, we studied factors that affect nurse-doctor working relationships in University Teaching Hospitals (UTH) in Southern Nigeria in order to characterize it and identify managerial and training needs that might be used to improve it. METHOD: Questionnaire survey of doctors and nurses working in four UTH in Southern Nigeria was done in 2002. The setting and subjects were selected by random sampling procedures. Information on factors in domains of work, union activities, personnel and hospital management were studied using closed and open-ended questionnaires. RESULTS: Nurse-doctor working relationships were statistically significantly affected by poor after-work social interaction, staff shortages, activist unionism, disregard for one's profession, and hospital management and government policies. In general, nurses had better opinion of doctors' work than doctors had about nurses' work. CONCLUSION: Working relationships between doctors and nurses need to be improved through improved training and better working conditions, creation of better working environment, use of alternative methods of conflict resolution and balanced hospital management and government policies. This will improve the retention of staff, job satisfaction and efficiency of health care delivery in Nigeria
Capturing the essence of folding and functions of biomolecules using Coarse-Grained Models
The distances over which biological molecules and their complexes can
function range from a few nanometres, in the case of folded structures, to
millimetres, for example during chromosome organization. Describing phenomena
that cover such diverse length, and also time scales, requires models that
capture the underlying physics for the particular length scale of interest.
Theoretical ideas, in particular, concepts from polymer physics, have guided
the development of coarse-grained models to study folding of DNA, RNA, and
proteins. More recently, such models and their variants have been applied to
the functions of biological nanomachines. Simulations using coarse-grained
models are now poised to address a wide range of problems in biology.Comment: 37 pages, 8 figure
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