Central spindle robustness by PRC1-centralspindlin interaction

Mitotic apparatus (MA) plays central roles in cell division for both mitosis and cytokinesis. It achieves these mechanical tasks by changing its morphology under the control of cell cycle machinery. This relies on dynamic polymerization and depolymerization cycles of microtubules and their assembly into higher order structures such as bundles involving various microtubule regulators. A dramatic remodeling of the MA occurs at the metaphase to anaphase transition (Fig. 1). Before this, 2 spindle poles are connected both by interpolar microtubules and by kinetochore microtubules attaching the unsegregated chromatids. After anaphase onset, the link via kinetochore microtubules and chromosomes disappears due to loss of chromosome cohesion. As a consequence, the interpolar microtubules, which have now developed into a more prominent structure termed the central spindle, become the sole mechanical link between the 2 poles (Fig. 1, case i). Metaphase-anaphase transition also promotes the growth of astral microtubules. Dynein anchored at the cell cortex interacts with the astral microtubules and generates mechanical forces (cortical pulling forces) that pull spindle poles toward the cell cortex.1 Grill SW, et al. Nature 2001; 409(6820):630-3; PMID:11214323; http://dx.doi.org/10.1038/35054572 [CrossRef], [PubMed], [Web of Science ®] In some cell types such as the C. elegans embryos, cortical pulling force is the major driving force for chromosome separation via elongation of the pole-to-pole distance (anaphase B). In this situation, the central spindle is dispensable for chromosome segregation; it rather works as a brake against the cortical pulling force. Indeed, in C. elegans embryos, chromosome separation is accelerated when the central spindle is severed by laser manipulation or by genetic perturbation.2 Saunders AM, et al. Curr Biol 2007; 17(12):R453-4; PMID:17580072; http://dx.doi.org/10.1016/j.cub.2007.05.001 [CrossRef], [PubMed], [Web of Science ®] So, why does a cell form the central spindle? Well, this is because it has an important role in cytokinesis

Optimization of Analytic Window Functions

Analytic functions represent the state-of-the-art way of performing complex data analysis within a single SQL statement. In particular, an important class of analytic functions that has been frequently used in commercial systems to support OLAP and decision support applications is the class of window functions. A window function returns for each input tuple a value derived from applying a function over a window of neighboring tuples. However, existing window function evaluation approaches are based on a naive sorting scheme. In this paper, we study the problem of optimizing the evaluation of window functions. We propose several efficient techniques, and identify optimization opportunities that allow us to optimize the evaluation of a set of window functions. We have integrated our scheme into PostgreSQL. Our comprehensive experimental study on the TPC-DS datasets as well as synthetic datasets and queries demonstrate significant speedup over existing approaches.Comment: VLDB201

Direct interaction between centralspindlin and PRC1 reinforces mechanical resilience of the central spindle

During animal cell division, the central spindle, an anti-parallel microtubule bundle structure formed between segregating chromosomes during anaphase, cooperates with astral microtubules to position the cleavage furrow. Because the central spindle is the only structure linking the two halves of the mitotic spindle, it is under mechanical tension from dynein-generated cortical pulling forces, which determine spindle positioning and drive chromosome segregation through spindle elongation. The central spindle should be flexible enough for efficient chromosome segregation while maintaining its structural integrity for reliable cytokinesis. How the cell balances these potentially conflicting requirements is poorly understood. Here, we demonstrate that the central spindle in C. elegans embryos has a resilient mechanism for recovery from perturbations by excess tension derived from cortical pulling forces. This mechanism involves the direct interaction of two different types of conserved microtubule bundlers that are crucial for central spindle formation, PRC1 and centralspindlin

Programmable DNA-mediated multitasking processor

Because of DNA appealing features as perfect material, including minuscule size, defined structural repeat and rigidity, programmable DNA-mediated processing is a promising computing paradigm, which employs DNAs as information storing and processing substrates to tackle the computational problems. The massive parallelism of DNA hybridization exhibits transcendent potential to improve multitasking capabilities and yield a tremendous speed-up over the conventional electronic processors with stepwise signal cascade. As an example of multitasking capability, we present an in vitro programmable DNA-mediated optimal route planning processor as a functional unit embedded in contemporary navigation systems. The novel programmable DNA-mediated processor has several advantages over the existing silicon-mediated methods, such as conducting massive data storage and simultaneous processing via much fewer materials than conventional silicon devices

CYK-4 functions independently of its centralspindlin partner ZEN-4 to cellularize oocytes in germline syncytia

International audienceThroughout metazoans, germ cells undergo incomplete cytokinesis to form syncytia connected by intercellular bridges. Gamete formation ultimately requires bridge closure, yet how bridges are reactivated to close is not known. The most conserved bridge component is centralspindlin, a complex of the Rho family GTPase-activating protein (GAP) CYK-4/MgcRacGAP and the microtubule motor ZEN-4/kinesin-6. Here, we show that oocyte production by the syncytial Caenorhabditis elegans germline requires CYK-4 but not ZEN-4, which contrasts with cytokinesis, where both are essential. Longitudinal imaging after conditional inactivation revealed that CYK-4 activity is important for oocyte cellularization, but not for the cytokinesis-like events that generate syncytial compartments. CYK-4's lipid-binding C1 domain and the GTPase-binding interface of its GAP domain were both required to target CYK-4 to intercellular bridges and to cellularize oocytes. These results suggest that the conserved C1-GAP region of CYK-4 constitutes a targeting module required for closure of intercellular bridges in germline syncytia

A randomized control trial comparing peginterferon-α-2a versus observation after stopping tyrosine kinase inhibitor in chronic myeloid leukemia with deep molecular response for at least two years

Background: There is much advancement in treatment of chronic myeloid leukemia (CML) since the approval of first tyrosine kinase inhibitor (TKI), imatinib, by US FDA in 2001. One of them is definitely the concept of stopping TKI, starting at the CML patients who have achieved deep molecular response (MR) of MR4.5 for a reasonable long period of at least two years, pioneered by the researchers from French and Australia. Meanwhile, interferon, the standard treatment of CML before the era of TKI, showed that interferon-responded patients may indeed retain the response once interferon was withdrawn via interferon-induced immunity towards the leukemic clone. This is further supported by stop trial in Japan, in which after stopping TKI, interferon was given for 2 years and it showed a higher drug-free rate compared to stop trial from French and Australia. Hence, it is logical to postulate the use of interferon after TKI was stopped when patients have attained deep MR for more than two years will increase the percentage of patients remain TKI-free on follow-up. Materials and Methods: This is a multi-center randomized controlled trial. Adult CML patients, diagnosed in chronic phase, treated with ongoing TKI for at least 3 years without previous history of TKI failure and have achieved stable deep MR on International Scale for ≥2 years with at least 2 readings of MR4.5 (including the latest before study entry), were randomized into 2 arms: (1) peginterferon-α-2a, subcutaneous weekly, starting at 180 mcg, or (2) observation. Disease is monitored by PCR (centralized in Ampang Hospital) at monthly for the first year, 2 monthly for the second year and 3 monthly for the third year. Relapse is defined as either (i) one reading of loss of major MR, i.e. reading of >0.1% IS and confirmed by second analysis taken 1 month later if the first analysis point reading is ≤1% IS, or (ii) positivity of BCR-ABL1 transcripts, as confirmed by a second analysis point, indicating the increase (at least 1 log) in relation to the first analysis point at two successive assessments. Quality of Life is assessed using EORTC QLO-C30. Results: At the time of writing, total of 8 patients were randomized, 5 into peginterferon arm, 3 into observation arm, all were on imatinib, M:F = 4:4, Malay: Chinese:Indian = 3:4:1, median age 49.5 (range 25-58), median follow-up 4 months (range 1-6) and none of them relapse. Two patients developed imatinib withdrawal syndrome, both female on observation arm, one was mild and resolved after 2 months but one was severe and needed termination after 2 months and restarted on imatinib. Two patients in peginterferon arm developed mild hepatitis with liver enzymes <2x of ULN. Four patients were able to tolerate peginterferon-α-2a at the dose of 180 mcg weekly, while one patient needed dose reduction to 90 mcg weekly. Quality of life score comparing two months after stopping TKI and baseline will be presented in the conference later. Conclusion: No conclusive date can be drawn so far because sample size is small and follow-up is short. Nonetheless, this trial provides Malaysian CML a platform to stop TKI safely

Ancestral roles of the Fam20C family of secreted protein kinases revealed in C. elegans.

Fam20C is a secreted protein kinase mutated in Raine syndrome, a human skeletal disorder. In vertebrates, bone and enamel proteins are major Fam20C substrates. However, Fam20 kinases are conserved in invertebrates lacking bone and enamel, suggesting other ancestral functions. We show that FAMK-1, the Caenorhabditis elegans Fam20C orthologue, contributes to fertility, embryogenesis, and development. These functions are not fulfilled when FAMK-1 is retained in the early secretory pathway. During embryogenesis, FAMK-1 maintains intercellular partitions and prevents multinucleation; notably, temperature elevation or lowering cortical stiffness reduces requirement for FAMK-1 in these contexts. FAMK-1 is expressed in multiple adult tissues that undergo repeated mechanical strain, and selective expression in the spermatheca restores fertility. Informatic, biochemical, and functional analysis implicate lectins as FAMK-1 substrates. These findings suggest that FAMK-1 phosphorylation of substrates, including lectins, in the late secretory pathway is important in embryonic and tissue contexts where cells are subjected to mechanical strain