Inhibiting spinal cord-specific hsp90 isoforms reveals a novel strategy to improve the therapeutic index of opioid treatment.

Opioids are the gold standard for the treatment of chronic pain but are limited by adverse side effects. In our earlier work, we showed that Heat shock protein 90 (Hsp90) has a crucial role in regulating opioid signaling in spinal cord; Hsp90 inhibition in spinal cord enhances opioid anti-nociception. Building on these findings, we injected the non-selective Hsp90 inhibitor KU-32 by the intrathecal route into male and female CD-1 mice, showing that morphine anti-nociceptive potency was boosted by 1.

Selection forces underlying aneuploidy patterns in cancer.

Aneuploidy, the presence of an aberrant number of chromosomes, has been associated with tumorigenesis for over a century. More recently, advances in karyotyping techniques have revealed its high prevalence in cancer: About 90% of solid tumors and 50-70% of hematopoietic cancers exhibit chromosome gains or losses. When analyzed at the level of specific chromosomes, there are strong patterns that are observed in cancer karyotypes both pan-cancer and for specific cancer types.

Adaptation to spindle assembly checkpoint inhibition through the selection of specific aneuploidies.

Both the presence of an abnormal complement of chromosomes (aneuploidy) and an increased frequency of chromosome missegregation (chromosomal instability) are hallmarks of cancer. Analyses of cancer genome data have identified certain aneuploidy patterns in tumors; however, the bases behind their selection are largely unexplored. By establishing time-resolved long-term adaptation protocols, we found that human cells adapt to persistent spindle assembly checkpoint (SAC) inhibition by acquiring specific chromosome arm gains and losses.

Adaptation to high rates of chromosomal instability and aneuploidy through multiple pathways in budding yeast.

Both an increased frequency of chromosome missegregation (chromosomal instability, CIN) and the presence of an abnormal complement of chromosomes (aneuploidy) are hallmarks of cancer. To better understand how cells are able to adapt to high levels of chromosomal instability, we previously examined yeast cells that were deleted of the gene BIR1, a member of the chromosomal passenger complex (CPC). We found bir1Δ cells quickly adapted by acquiring specific combinations of beneficial aneuploidies.

Aurora B activity is promoted by cooperation between discrete localization sites in budding yeast.

Chromosome biorientation is promoted by the four-member chromosomal passenger complex (CPC) through phosphorylation of incorrect kinetochore-microtubule attachments. During chromosome alignment, the CPC localizes to the inner centromere, the inner kinetochore, and spindle microtubules. Here we show that a small domain of the CPC subunit INCENP/Sli15 is required to target the complex to all three of these locations in budding yeast.

Bisphenol A Exposure Induces Sensory Processing Deficits in Larval Zebrafish during Neurodevelopment.

Because of their development, relatively simple nervous system, translucency, and availability of tools to investigate neural function, larval zebrafish are an exceptional model for understanding neurodevelopmental disorders and the consequences of environmental toxins. Furthermore, early in development, zebrafish larvae easily absorb chemicals from water, a significant advantage over methods required to expose developing organisms to chemical agents Bisphenol A (BPA) and BPA analogs are ubiquitous environmental toxins with known molecular consequences. All humans have measurable quantities of BPA in their bodies.

Phylogenetic relationships and chloroplast capture in the Amelanchier-Malacomeles-Peraphyllum clade (Maleae, Rosaceae): Evidence from chloroplast genome and nuclear ribosomal DNA data using genome skimming.

The Amelanchier-Malacomeles-Peraphyllum (AMP) clade consists of ca. 26 species distributed in North and Central America, Europe, Asia, and northwestern Africa. While molecular and morphological data strongly support this clade, relationships of its genera are uncertain.

Genetic interactions between specific chromosome copy number alterations dictate complex aneuploidy patterns.

Cells that contain an abnormal number of chromosomes are called aneuploid. High rates of aneuploidy in cancer are correlated with an increased frequency of chromosome missegregation, termed chromosomal instability (CIN). Both high levels of aneuploidy and CIN are associated with cancers that are resistant to treatment.

An overview of extant conifer evolution from the perspective of the fossil record.

Premise Of The Study: Conifers are an important living seed plant lineage with an extensive fossil record spanning more than 300 million years. The group therefore provides an excellent opportunity to explore congruence and conflict between dated molecular phylogenies and the fossil record.

Methods: We surveyed the current state of knowledge in conifer phylogenetics to present a new time-calibrated molecular tree that samples ~90% of extant species diversity.

Cdc73 suppresses genome instability by mediating telomere homeostasis.

Defects in the genes encoding the Paf1 complex can cause increased genome instability. Loss of Paf1, Cdc73, and Ctr9, but not Rtf1 or Leo1, caused increased accumulation of gross chromosomal rearrangements (GCRs). Combining the cdc73Δ mutation with individual deletions of 43 other genes, including TEL1 and YKU80, which are involved in telomere maintenance, resulted in synergistic increases in GCR rates.

An engineered minimal chromosomal passenger complex reveals a role for INCENP/Sli15 spindle association in chromosome biorientation.

The four-subunit chromosomal passenger complex (CPC), whose enzymatic subunit is Aurora B kinase, promotes chromosome biorientation by detaching incorrect kinetochore-microtubule attachments. In this study, we use a combination of truncations and artificial dimerization in budding yeast to define the minimal CPC elements essential for its biorientation function. We engineered a minimal CPC comprised of the dimerized last third of the kinase-activating Sli15/INCENP scaffold and the catalytic subunit Ipl1/Aurora B.

Understanding diploid diversity: A first step in unraveling polyploid, apomictic complexity in Amelanchier.

Premise Of The Study: Delimitation of Amelanchier species is difficult because of polyploidy and gametophytic apomixis. A first step in unraveling this species problem is understanding the diversity of the diploids that contributed genomes to polyploid apomicts. This research helps clarify challenging species-delimitation problems attending polyploid, apomictic complexity.

Comparison of drug release from poly(lactide-co-glycolide) microspheres and novel fibre formulations.

Intraperitoneal cisplatin delivery has recently been shown to benefit ovarian cancer patients. Cisplatin-containing poly(lactide-co-glycolide) (PLGA) microspheres have been proposed for cisplatin delivery. The drug loading of cisplatin containing microspheres produced elsewhere is 3-10%w.

The CENP-A N-tail confers epigenetic stability to centromeres via the CENP-T branch of the CCAN in fission yeast.

In most eukaryotes, centromeres are defined epigenetically by presence of the histone H3 variant CENP-A [1-3]. CENP-A-containing chromatin recruits the constitutive centromere-associated network (CCAN) of proteins, which in turn directs assembly of the outer kinetochore to form microtubule attachments and ensure chromosome segregation fidelity [4-6]. Whereas the mechanisms that load CENP-A at centromeres are being elucidated, the functions of its divergent N-terminal tail remain enigmatic [7-12].

Effects of apomixis and polyploidy on diversification and geographic distribution in Amelanchier (Rosaceae).

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Premise Of The Study: Amelanchier polyploid apomicts differ from sexual diploids in their more complex diversification, greater species problems, and geographic distribution. To understand these differences, we investigated the occurrence of polyploidy and frequency of apomixis. This research helps clarify species delimitation in an evolutionarily complex genus.

PCNA and Msh2-Msh6 activate an Mlh1-Pms1 endonuclease pathway required for Exo1-independent mismatch repair.

Genetic evidence has implicated multiple pathways in eukaryotic DNA mismatch repair (MMR) downstream of mispair recognition and Mlh1-Pms1 recruitment, including Exonuclease 1 (Exo1)-dependent and -independent pathways. We identified 14 mutations in POL30, which encodes PCNA in Saccharomyces cerevisiae, specific to Exo1-independent MMR. The mutations identified affected amino acids at three distinct sites on the PCNA structure.

Mlh2 is an accessory factor for DNA mismatch repair in Saccharomyces cerevisiae.

In Saccharomyces cerevisiae, the essential mismatch repair (MMR) endonuclease Mlh1-Pms1 forms foci promoted by Msh2-Msh6 or Msh2-Msh3 in response to mispaired bases. Here we analyzed the Mlh1-Mlh2 complex, whose role in MMR has been unclear. Mlh1-Mlh2 formed foci that often colocalized with and had a longer lifetime than Mlh1-Pms1 foci.

Dominant mutations in S. cerevisiae PMS1 identify the Mlh1-Pms1 endonuclease active site and an exonuclease 1-independent mismatch repair pathway.

Lynch syndrome (hereditary nonpolypsis colorectal cancer or HNPCC) is a common cancer predisposition syndrome. Predisposition to cancer in this syndrome results from increased accumulation of mutations due to defective mismatch repair (MMR) caused by a mutation in one of the mismatch repair genes MLH1, MSH2, MSH6 or PMS2/scPMS1. To better understand the function of Mlh1-Pms1 in MMR, we used Saccharomyces cerevisiae to identify six pms1 mutations (pms1-G683E, pms1-C817R, pms1-C848S, pms1-H850R, pms1-H703A and pms1-E707A) that were weakly dominant in wild-type cells, which surprisingly caused a strong MMR defect when present on low copy plasmids in an exo1Δ mutant.

Tension sensing by Aurora B kinase is independent of survivin-based centromere localization.

Accurate segregation of the replicated genome requires chromosome biorientation on the spindle. Biorientation is ensured by Aurora B kinase (Ipl1), a member of the four-subunit chromosomal passenger complex (CPC). Localization of the CPC to the inner centromere is central to the current model for how tension ensures chromosome biorientation: kinetochore-spindle attachments that are not under tension remain close to the inner centromere and are destabilized by Aurora B phosphorylation, whereas kinetochores under tension are pulled away from the influence of Aurora B, stabilizing their microtubule attachments.

What the hec is up with mouse oocyte meiosis?

In this issue of Developmental Cell, Gui and Homer (2013) report that the proper execution of meiosis I in mouse oocytes requires the stabilization of cyclin B2 by the kinetochore protein Hec1, revealing unanticipated functions for both proteins.

Objective assessment of nanoparticle disposition in mammalian skin after topical exposure.

The use of nanoparticles as formulation components of topical drug delivery systems for the skin has been widely investigated in the literature. Because of the conflicting conclusions resulting from these studies concerning the ultimate disposition of the nanoparticles employed, the research presented in this paper has been designed to evaluate objectively the fate of such structures when administered to mammalian skin. Confocal microscopy images of skin exposed to nanoparticles have therefore been assessed by quantitative statistical analysis.

Visualization of eukaryotic DNA mismatch repair reveals distinct recognition and repair intermediates.

DNA mismatch repair (MMR) increases replication fidelity by eliminating mispaired bases resulting from replication errors. In Saccharomyces cerevisiae, mispairs are primarily detected by the Msh2-Msh6 complex and corrected following recruitment of the Mlh1-Pms1 complex. Here, we visualized functional fluorescent versions of Msh2-Msh6 and Mlh1-Pms1 in living cells.

In vivo visualization of type II plasmid segregation: bacterial actin filaments pushing plasmids.

Type II par operons harness polymerization of the dynamically unstable actin-like protein ParM to segregate low-copy plasmids in rod-shaped bacteria. In this study, we use time-lapse fluorescence microscopy to follow plasmid dynamics and ParM assembly in Escherichia coli. Plasmids lacking a par operon undergo confined diffusion with a diffusion constant of 5 x 10(-5) microm(2)/s and a confinement radius of 0.

Reconstitution of DNA segregation driven by assembly of a prokaryotic actin homolog.

Multiple unrelated polymer systems have evolved to partition DNA molecules between daughter cells at division. To better understand polymer-driven DNA segregation, we reconstituted the three-component segregation system of the R1 plasmid from purified components. We found that the ParR/parC complex can construct a simple bipolar spindle by binding the ends of ParM filaments, inhibiting dynamic instability, and acting as a ratchet permitting incorporation of new monomers and riding on the elongating filament ends.

Nuclear ribosomal DNA internal transcribed spacer 1 (ITS1) in Picea (Pinaceae): sequence divergence and structure.

The nrDNA ITS1 of Picea is 2747-3271 bp, the longest known of all plants. We obtained 24 cloned ITS1 sequences from six individuals of Picea glehnii, Picea mariana, Picea orientalis, and Picea rubens. Mean sequence divergence within these individuals (0.