Spatial curvature effects on molecular transport by diffusion

For a substance diffusing on a curved surface, we obtain an explicit relation valid for very small values of the time, between the local concentration, the diffusion coefficient, the intrinsic spatial curvature and the time. We recover the known solution of Fick's law of diffusion in the flat space limit. In the biological context, this result would be useful in understanding the variations in the diffusion rates of integral proteins and other molecules on membranes.Comment: 10 page

Control of cellular automata

We study the problem of master-slave synchronization and control of totalistic cellular automata (CA) by putting a fraction of sites of the slave equal to those of the master and finding the distance between both as a function of this fraction. We present three control strategies that exploit local information about the CA, mainly, the number of nonzero Boolean derivatives. When no local information is used, we speak of synchronization. We find the critical properties of control and discuss the best control strategy compared with synchronization

MicroRNA-125b transforms myeloid cell lines by repressing multiple mRNA

Background: We previously described a t(2;11)(p21;q23) chromosomal translocation found in patients with myelodysplasia or acute myeloid leukemia that leads to over-expression of the microRNA miR-125b, and we showed that transplantation of mice with murine stem/progenitor cells overexpressing miR-125b is able to induce leukemia. In this study, we investigated the mechanism of myeloid transformation by miR-125b. Design and Methods: To investigate the consequences of miR-125b over-expression on myeloid differentiation, apoptosis and proliferation, we used the NB4 and HL60 human promyelocytic cell lines and the 32Dclone3 murine promyelocytic cell line. To test whether miR-125b is able to transform myeloid cells, we used the non-tumorigenic and interleukin-3-dependent 32Dclone3 cell line over-expressing miR-125b, in xenograft experiments in nude mice and in conditions of interleukin-3 deprivation. To identify new miR-125b targets, we compared, by RNA-sequencing, the transcriptome of cell lines that do or do not over-express miR-125b. Results: We showed that miR-125b over-expression blocks apoptosis and myeloid differentiation and enhances proliferation in both species. More importantly, we demonstrated that miR-125b is able to transform the 32Dclone3 cell line by conferring growth independence from interleukin-3; xenograft experiments showed that these cells form tumors in nude mice. Using RNA-sequencing and quantitative real-time polymerase chain reaction experiments, we identified multiple miR-125b targets. We demonstrated that ABTB1, an anti-proliferative factor, is a new direct target of miR-125b and we confirmed that CBFB, a transcription factor involved in hematopoiesis, is also targeted by miR-125b. MiR-125b controls apoptosis by down-regulating genes involved in the p53 pathway including BAK1 and TP53INP1. Conclusions: This study demonstrates that in a myeloid context, miR-125b is an oncomiR able to transform cell lines. miR-125b blocks myeloid differentiation in part by targeting CBFB, blocks apoptosis through down-regulation of multiple genes involved in the p53 pathway, and confers a proliferative advantage to human and mouse myeloid cell lines in part by targeting ABTB1.Leukemia & Lymphoma Society of AmericaNational Institutes of Health (U.S.) (NIH grant DK068348)National Institutes of Health (U.S.) (NIH grant 5P01 HL066105

Symmetric Signaling by an Asymmetric 1 Erythropoietin: 2 Erythropoietin Receptor Complex

Via sites 1 and 2, erythropoietin binds asymmetrically to two identical receptor monomers, although it is unclear how asymmetry affects receptor activation and signaling. Here we report the design and validation of two mutant erythropoietin receptors that probe the role of individual members of the receptor dimer by selectively binding either site 1 or site 2 on erythropoietin. Ba/F3 cells expressing either mutant receptor do not respond to erythropoietin, but cells co-expressing both receptors respond to erythropoietin by proliferation and activation of the JAK2-Stat5 pathway. A truncated receptor with only one cytosolic tyrosine (Y343) is sufficient for signaling in response to erythropoietin, regardless of the monomer on which it is located. Similarly, only one receptor in the dimer needs a juxtamembrane hydrophobic L253 or W258 residue, essential for JAK2 activation. We conclude that despite asymmetry in the ligand-receptor interaction, both sides are competent for signaling, and appear to signal equally.National Institutes of Health (U.S.) (Grant P01 HL32262)Amgen Inc. (Research Grant)National Institutes of Health (U.S.) (Grant GM 065418)United States. Dept. of Energy. Computational Science Graduate Fellowship (DE-FG02-97ER25308)National Institutes of Health (U.S.). Ruth L. Kirschstein National Research Service Award (Postdoctoral Fellowship 5F32HL077036

Corticotropinoma as a Component of Carney Complex.

Known germline gene abnormalities cause one-fifth of the pituitary adenomas in children and adolescents, but, in contrast with other pituitary tumor types, the genetic causes of corticotropinomas are largely unknown. In this study, we report a case of Cushing disease (CD) due to a loss-of-function mutation in PRKAR1A, providing evidence for association of this gene with a corticotropinoma. A 15-year-old male presenting with hypercortisolemia was diagnosed with CD. Remission was achieved after surgical resection of a corticotropin (ACTH)-producing pituitary microadenoma, but recurrence 3 years later prompted reoperation and radiotherapy. Five years after the original diagnosis, the patient developed ACTH-independent Cushing syndrome, and a diagnosis of primary pigmented nodular adrenocortical disease was confirmed. A PRKAR1A mutation (c.671delG, p.G225Afs*16) was detected in a germline DNA sample from the patient, which displayed loss of heterozygosity in the corticotropinoma. No other germline or somatic mutations of interest were found. As corticotropinomas are not a known component of Carney complex (CNC), we performed loss of heterozygosity and messenger RNA stability studies in the patient's tissues, and analyzed the effect of Prkar1a silencing on AtT-20/D16v-F2 mouse corticotropinoma cells. No PRKAR1A defects were found among 97 other pediatric CD patients studied. Our clinical case and experimental data support a role for PRKAR1A in the pathogenesis of a corticotroph cell tumor. This is a molecularly confirmed report of a corticotropinoma presenting in association with CNC. We conclude that germline PRKAR1A mutations are a novel, albeit apparently infrequent, cause of CD

Balancing torques in membrane-mediated interactions: Exact results and numerical illustrations

Torques on interfaces can be described by a divergence-free tensor which is fully encoded in the geometry. This tensor consists of two terms, one originating in the couple of the stress, the other capturing an intrinsic contribution due to curvature. In analogy to the description of forces in terms of a stress tensor, the torque on a particle can be expressed as a line integral along any contour surrounding the particle. Interactions between particles mediated by a fluid membrane are studied within this framework. In particular, torque balance places a strong constraint on the shape of the membrane. Symmetric two-particle configurations admit simple analytical expressions which are valid in the fully nonlinear regime; in particular, the problem may be solved exactly in the case of two membrane-bound parallel cylinders. This apparently simple system provides some flavor of the remarkably subtle nonlinear behavior associated with membrane-mediated interactions.Comment: 16 pages, 10 figures, REVTeX4 style. The Gaussian curvature term was included in the membrane Hamiltonian; section II.B was rephrased to smoothen the flow of presentatio

Pattern formation driven by nematic ordering of assembling biopolymers

The biopolymers actin and microtubules are often in an ongoing assembling/disassembling state far from thermal equilibrium. Above a critical density this leads to spatially periodic patterns, as shown by a scaling argument and in terms of a phenomenological continuum model, that meets also Onsager's statistical theory of the nematic--to--isotropic transition in the absence of reaction kinetics. This pattern forming process depends much on nonlinear effects and a common linear stability analysis of the isotropic distribution of the filaments is often misleading. The wave number of the pattern decreases with the assembling/disassembling rate and there is an uncommon discontinuous transition between the nematic and the periodic state.Comment: 4 pages, 3 figure

A spatial model of autocatalytic reactions

Biological cells with all of their surface structure and complex interior stripped away are essentially vesicles - membranes composed of lipid bilayers which form closed sacs. Vesicles are thought to be relevant as models of primitive protocells, and they could have provided the ideal environment for pre-biotic reactions to occur. In this paper, we investigate the stochastic dynamics of a set of autocatalytic reactions, within a spatially bounded domain, so as to mimic a primordial cell. The discreteness of the constituents of the autocatalytic reactions gives rise to large sustained oscillations, even when the number of constituents is quite large. These oscillations are spatio-temporal in nature, unlike those found in previous studies, which consisted only of temporal oscillations. We speculate that these oscillations may have a role in seeding membrane instabilities which lead to vesicle division. In this way synchronization could be achieved between protocell growth and the reproduction rate of the constituents (the protogenetic material) in simple protocells.Comment: Submitted to Phys. Rev.

A novel mutation in the miR-128b gene reduces miRNA processing and leads to glucocorticoid resistance of MLL-AF4 Acute Lymphocytic Leukemia cells

MLL-AF4 Acute Lymphocytic Leukemia has a poor prognosis, and the mechanisms by which these leukemias develop are not understood despite intensive research based on well-known concepts and methods. MicroRNAs (miRNAs) are a new class of small noncoding RNAs that post-transcriptionally regulate expression of target mRNA transcripts. We recently reported that ectopic expression of miR-128b together with miR-221, two of the miRNAs downregulated in MLL-AF4 ALL, restores glucocorticoid resistance through downregulation of the MLL-AF4 chimeric fusion proteins MLL-AF4 and AF4-MLL that are generated by chromosomal translocation t(4;11). Here we report the identification of new mutations in miR-128b in RS4;11 cells, derived from MLL-AF4 ALL patient. One novel mutation significantly reduces the processing of miR-128b. Finally, this base change occurs in a primary MLL-AF4 ALL sample as an acquired mutation. These results demonstrate that the novel mutation in miR-128b in MLL-AF4 ALL alters the processing of miR-128b and that the resultant downregulation of mature miR-128b contributes to glucocorticoid resistance through the failure to downregulate the fusion oncogenes.National Institutes of Health (U.S.) (NIH Grant R01 DK068348)Netherlands Organization for Scientific ResearchDutch Cancer SocietyJapan Society for the Promotion of Scienc

Michaelis-Menten Relations for Complex Enzymatic Networks

All biological processes are controlled by complex systems of enzymatic chemical reactions. Although the majority of enzymatic networks have very elaborate structures, there are many experimental observations indicating that some turnover rates still follow a simple Michaelis-Menten relation with a hyperbolic dependence on a substrate concentration. The original Michaelis-Menten mechanism has been derived as a steady-state approximation for a single-pathway enzymatic chain. The validity of this mechanism for many complex enzymatic systems is surprising. To determine general conditions when this relation might be observed in experiments, enzymatic networks consisting of coupled parallel pathways are investigated theoretically. It is found that the Michaelis-Menten equation is satisfied for specific relations between chemical rates, and it also corresponds to the situation with no fluxes between parallel pathways. Our results are illustrated for simple models. The importance of the Michaelis-Menten relationship and derived criteria for single-molecule experimental studies of enzymatic processes are discussed.Comment: 10 pages, 4 figure