Ubiquitination by the anaphase-promoting complex drives spindle checkpoint inactivation

Eukaryotic cells rely on a surveillance mechanism known as the spindle checkpoint to ensure accurate chromosome segregation. The spindle checkpoint prevents sister chromatids from separating until all kinetochores achieve bipolar attachments to the mitotic spindle. Checkpoint proteins tightly inhibit the anaphase-promoting complex (APC), a ubiquitin ligase required for chromosome segregation and progression to anaphase. Unattached kinetochores promote the binding of checkpoint proteins Mad2 and BubR1 to the APC-activator Cdc20, rendering it unable to activate APC. Once all kinetochores are properly attached, however, cells inactivate the checkpoint within minutes, allowing for the rapid and synchronous segregation of chromosomes. How cells switch from strong APC inhibition before kinetochore attachment to rapid APC activation once attachment is complete remains a mystery. Here we show that checkpoint inactivation is an energy-consuming process involving APC-dependent multi-ubiquitination. Multi-ubiquitination by APC leads to the dissociation of Mad2 and BubR1 from Cdc20, a process that is reversed by a Cdc20-directed de-ubiquitinating enzyme. The mutual regulation between checkpoint proteins and APC leaves the cell poised for rapid checkpoint inactivation and ensures that chromosome segregation promptly follows the completion of kinetochore attachment. In addition, our results suggest a mechanistic basis for how cancer cells can have a compromised spindle checkpoint without corresponding mutations in checkpoint genes.     

The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity

The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens.     

A new genus and two new species of Parastenocarididae (Copepoda: Harpacticoida) from southeastern India

Indocaris gen. nov. with two new species, Indocaris imbricata sp. nov. and Indocaris inopinata sp. nov., and also for the already known Indocaris tirupatiensis (Ranga Reddy 2011a) comb. nov. – all from the groundwaters in peninsular India. The highly diagnostic synapomorphy of the new genus is a composite character associated with the male leg 4 basis: five or six prominent, imbricate, enlarged, petal-like spinules, arranged as a semi-whorl at the insertion of the endopod and increasing in size from internal to external. Another distinctive feature of the same appendage is that its one-segmented endopod is dilated or bulbous in the proximal half, produced distally into an incurved spiniform or horn-like structure about as long as the corresponding first exopodal segment, and ornamented with three or four fine spinules on the subproximal outer margin. The three species also share a unique constellation of other salient morphologic features, which along with the phylogenetic position of Indocaris gen. nov. within the family Parastenocarididae are discussed. Indocaris gen. nov. has closest phylogenetic affinity with the Neotropical Remaneicari Jakobi, 1972. A short note on the ecology and biogeography of the parastenocaridid species of the Indian subcontinent is provided besides a key for their identification.     

Ontogenic development of peptide hormones in the mammalian fetal pancreas

The ontogeny of insulin, glucagon, PP and somatostatin in the mammalian fetal pancreas has been examined in recent years largely by immunocytochemistry and in some instances by radioimmunoassay. Complete ontogenic data are available only for the rat, human, pig and sheep. Figure 3 compares the time of appearance of the endocrine cell-types within the fetal pancreas when the periods of gestation of the four species are converted to a uniform scale. The striking ontogenic difference in the rat probably reflects the immaturity of the rodent fetus at birth compared with the human, pig and sheep. In the fetal pancreas, differences in cell number of glucagon and PP cells in the dorsal and ventral lobes become apparent from an early gestational period. Factors responsible for the functional and structural maturation of the fetal pancreatic endocrine cells and the processes involved in pancreatic organogenesis are poorly understood. Studies in these areas would have clinical implications since it may be possible in the future to employ agents for selective replication of fetal beta-cells for transplantation in patients with Type I diabetes, bearing in mind that such cells must have the capacity to respond to normal stimuli and repressors when transplanted. The presence of the other islet cell-types may be obligatory for these appropriate responses. This would require a more complete knowledge of those factors which produce the normal selectivity of the four hormonal cell-types.     

Dominant lethal mutations induced by14C in mice

Summary The mutagenic potential of 1.0 Ci¹⁴C was evaluated in Swiss albino male mice by the dominant lethal assay. A significant increase in post-implantation loss was seen, the maximum being in the 3rd week after treatment.Authors express their thanks to University Grants Commission, New Delhi, for financial assistance.     

Ontogenic development of peptide hormones in the mammalian fetal pancreas

Summary The ontogeny of insulin, glucagon, PP and somatostatin in the mammalian fetal pancreas has been examined in recent years largely by immunocytochemistry and in some instances by radioimmunoassay. Complete ontogenic data are available only for the rat, human pig and sheep. Figure 3 compares the time of appearance of the endocrine cell-types within the fetal pancreas when the periods of gestation of the four species are converted to a uniform scale. The striking ontogenic difference in the rat probably reflects the immaturity of the rodent fetus at birth compared with the human, pig and sheep. In the fetal pancreas, differences in cell number of glucagon and PP cells in the dorsal and ventral lobes become apparent from an early gestational period. Factors responsible for the functional and structural maturation of the fetal pancreatic endocrine cells and the processes involved in pancreatic organogenesis are poorly understood. Studies in these areas would have clinical implications since it may be possible in the future to employ agents for selective replication of fetal -cells for transplantation in patients with Type I diabetes, bearing in mind that such cells must have the capacity to respond to normal stimuli and repressors when transplanted. The presence of the other islet cell-types may be obligatory for these appropriate responses. This would require a more complete knowledge of those factors which produce the normal selectivity of the four hormonal cell-types.     

Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia.

To ascertain the role of cyclin-dependent kinase 4 (Cdk4) in vivo, we have targeted the mouse Cdk4 locus by homologous recombination to generate two strains of mice, one that lacks Cdk4 expression and one that expresses a Cdk4 molecule with an activating mutation. Embryonic fibroblasts proliferate normally in the absence of Cdk4 but have a delayed S phase on re-entry into the cell cycle. Moreover, mice devoid of Cdk4 are viable, but small in size and infertile. These mice also develop insulin-deficient diabetes due to a reduction in beta-islet pancreatic cells. In contrast, mice expressing a mutant Cdk4 that cannot bind the cell-cycle inhibitor P16INK4a display pancreatic hyperplasia due to abnormal proliferation of beta-islet cells. These results establish Cdk4 as an essential regulator of specific cell types.     

Revision of Indian species of Baeus Haliday (Hymenoptera: Platygastroidea: Scelionidae)

ABSTRACT

Baeus senus Kozlov and Lê from Vietnam and B. primitus Rajmohana from India are the only two species of the genus known from the Oriental region. Thirty eight new species of Baeus are here described from India: B. acuminatus sp. n., B. agniparvathus sp. n., B. airavata sp. n., B. arachnophagus sp. n., B. bagheera sp. n., B. bharathiae sp. n., B. chakora sp. n., B. chitrasena sp. n., B. ciprianii sp. n., B. densipilosus sp. n., B. flaviscapus sp. n., B. gajakarna sp. n., B. giganteus sp. n., B. himalayanus sp. n., B. krishnareddyi sp. n., B. krumbiegeli sp. n., B. kubera sp. n., B. longiabdominalis sp. n., B. mahanetra sp. n., B. mareecha sp. n., B. menaka sp. n., B. nbairus sp. n., B. nicobarensis sp. n., B. pygmaeus sp. n., B. rachanae sp. n., B. rambha sp. n., B. ravana sp. n., B. reticulatus sp. n., B. sreedeviae sp. n., B. striatus sp. n., B. takshaka sp. n., B. tejaswii sp. n., B. tilottama sp. n., B. tripurasundari sp. n., B. tumburu sp. n., B. urvashi sp. n., B. vichitra sp. n. and B. xanthoclavatus sp. n. A key to the Indian species of Baeus is provided along with illustrations.

http://www.zoobank.org/urn:lsid:zoobank.org:pub:878C5BFB-C2CB-4163-A08B-C761B4C6F087