A response to Yu et al. "A forward-backward fragment assembling algorithm for the identification of genomic amplification and deletion breakpoints using high-density single nucleotide polymorphism (SNP) array", BMC Bioinformatics 2007, 8: 145

<p>Abstract</p> <p>Background</p> <p>Yu et al. (BMC Bioinformatics 2007,8: 145+) have recently compared the performance of several methods for the detection of genomic amplification and deletion breakpoints using data from high-density single nucleotide polymorphism arrays. One of the methods compared is our non-homogenous Hidden Markov Model approach. Our approach uses Markov Chain Monte Carlo for inference, but Yu et al. ran the sampler for a severely insufficient number of iterations for a Markov Chain Monte Carlo-based method. Moreover, they did not use the appropriate reference level for the non-altered state.</p> <p>Methods</p> <p>We rerun the analysis in Yu et al. using appropriate settings for both the Markov Chain Monte Carlo iterations and the reference level. Additionally, to show how easy it is to obtain answers to additional specific questions, we have added a new analysis targeted specifically to the detection of breakpoints.</p> <p>Results</p> <p>The reanalysis shows that the performance of our method is comparable to that of the other methods analyzed. In addition, we can provide probabilities of a given spot being a breakpoint, something unique among the methods examined.</p> <p>Conclusion</p> <p>Markov Chain Monte Carlo methods require using a sufficient number of iterations before they can be assumed to yield samples from the distribution of interest. Running our method with too small a number of iterations cannot be representative of its performance. Moreover, our analysis shows how our original approach can be easily adapted to answer specific additional questions (e.g., identify edges).</p

p120-catenin prevents multinucleation through control of MKLP1-dependent RhoA activity during cytokinesis.

Spatiotemporal activation of RhoA and actomyosin contraction underpins cellular adhesion and division. Loss of cell-cell adhesion and chromosomal instability are cardinal events that drive tumour progression. Here, we show that p120-catenin (p120) not only controls cell-cell adhesion, but also acts as a critical regulator of cytokinesis. We find that p120 regulates actomyosin contractility through concomitant binding to RhoA and the centralspindlin component MKLP1, independent of cadherin association. In anaphase, p120 is enriched at the cleavage furrow where it binds MKLP1 to spatially control RhoA GTPase cycling. Binding of p120 to MKLP1 during cytokinesis depends on the N-terminal coiled-coil domain of p120 isoform 1A. Importantly, clinical data show that loss of p120 expression is a common event in breast cancer that strongly correlates with multinucleation and adverse patient survival. In summary, our study identifies p120 loss as a driver event of chromosomal instability in cancer

Criteria for effective zero-deforestation commitments

Zero-deforestation commitments are a type of voluntary sustainability initiative that companies adopt to signal their intention to reduce or eliminate deforestation associated with commodities that they produce, trade, and/or sell. Because each company defines its own zero-deforestation commitment goals and implementation mechanisms, commitment content varies widely. This creates challenges for the assessment of commitment implementation or effectiveness. Here, we develop criteria to assess the potential effectiveness of zero-deforestation commitments at reducing deforestation within a company supply chain, regionally, and globally. We apply these criteria to evaluate 52 zero-deforestation commitments made by companies identified by Forest 500 as having high deforestation risk. While our assessment indicates that existing commitments converge with several criteria for effectiveness, they fall short in a few key ways. First, they cover just a small share of the global market for deforestation-risk commodities, which means that their global impact is likely to be small. Second, biome-wide implementation is only achieved in the Brazilian Amazon. Outside this region, implementation occurs mainly through certification programs, which are not adopted by all producers and lack third-party near-real time deforestation monitoring. Additionally, around half of all commitments include zero-net deforestation targets and future implementation deadlines, both of which are design elements that may reduce effectiveness. Zero-net targets allow promises of future reforestation to compensate for current forest loss, while future implementation deadlines allow for preemptive clearing. To increase the likelihood that commitments will lead to reduced deforestation across all scales, more companies should adopt zero-gross deforestation targets with immediate implementation deadlines and clear sanction-based implementation mechanisms in biomes with high risk of forest to commodity conversion.ISSN:0959-3780ISSN:1872-949

Limitations and potentials of dual-purpose cow herds in Central Coastal Veracruz, Mexico

Feed chemical and kinetic composition and animal performance information was used to evaluate productivity limitations and potentials of dual-purpose member herds of the Genesis farmer organization of central coastal Veracruz, Mexico. The Cornell Net Carbohydrate and Protein System model (Version 6.0) was systematically applied to specific groups of cows in structured simulations to establish probable input–output relationships for typical management, and to estimate probable outcomes from alternative management based on forage-based dietary improvements. Key herd vulnerabilities were pinpointed: chronic energy deficits among dry cows of all ages in late gestation and impeded growth for immature cows. Regardless of the forage season of calving, most cows, if not all, incur energy deficits in the final trimester of gestation; thus reducing the pool of tissue energy and constraining milking performance. Under typical management, cows are smaller and underweight for their age, which limits feed intake capacity, milk production and the probability of early postpartum return to ovarian cyclicity. The substitution of good-quality harvested forage for grazing increased predicted yields by about one-third over typical scenarios for underweight cows. When diets from first parturition properly supported growth and tissue repletion, milk production in second and third lactations was predicted to improve about 60%. Judiciously supplemented diets based on good quality grass and legume forages from first calving were predicted to further increase productivity by about 80% across a three-lactation cow lifetime. These dual-purpose herd owners have large incentives to increase sales income by implementing nutritional strategies like those considered in this study

Revised calibration of the mbt-cbt paleotemperature proxy based on branched tetraether membrane lipids in surface soils

The MBT-CBT proxy for the reconstruction of paleotemperatures and past soil pH is based on the distribution of branched glycerol dialkyl glycerol tetraether (brGDGT) membrane lipids. The Methylation of Branched Tetraether (MBT) and the Cyclisation of Branched Tetraether (CBT) indices were developed to quantify these distributions, and significant empirical relations between these indices and annual mean air temperature (MAT) and/or soil pH were found in a large data set of soils. In this study, we extended this soil dataset to 278 globally distributed surface soils. Of these soils, 26% contains all nine brGDGTs, while in 63% of the soils the seven most common brGDGTs were detected, and the latter were selected for calibration purposes. This resulted in new transfer functions for the reconstruction of pH based on the CBT index: pH = 7.90-1.97 x CBT (r(2) = 0.70; RMSE = 0.8; n = 176), as well as for MAT based on the CBT index and methylation index based on the seven most abundant GDGTs (defined as MBT'): MAT = 0.81-5.67 x CBT + 31.0 x MBT' (r(2) = 0.59; RMSE = 5.0 degrees C; n = 176). The new transfer function for MAT has a substantially lower correlation coefficient than the original equation (r(2) = 0.77). To investigate possible improvement of the correlation, we used our extended global surface soil dataset to statistically derive the indices that best describe the relations of brGDGT composition with MAT and soil pH. These new indices, however, resulted in only a relatively minor increase in correlation coefficients, while they cannot be explained straightforwardly by physiological mechanisms. The large scatter in the calibration cannot be fully explained by local factors or by seasonality, but MAT for soils from arid regions are generally substantially (up to 20 degrees C) underestimated, suggesting that absolute brGDGT-based temperature records for these areas should be interpreted with caution.<br>The applicability of the new MBT'-CBT calibration function was tested using previously published MBT-CBT-derived paleotemperature records covering the last deglaciation in Central Africa and East Asia, the Eocene-Oligocene boundary and the Paleocene-Eocene thermal maximum. The results show that trends remain similar in all records, but that absolute temperature estimates and the amplitude of temperature changes are lower for most records, and generally in better agreement with independent proxy data

Human recombinant anti-thyroperoxidase autoantibodies: in vitro cytotoxic activity on papillary thyroid cancer expressing TPO

International audienceBACKGROUND: Thyroid cancers are difficult to treat due to their limited responsiveness to chemo- and radiotherapy. There is thus a great interest in and a need for alternative therapeutic approaches. RESULTS: We studied the cytotoxic activity of anti-thyroperoxidase autoantibodies (anti-TPO aAbs, expressed in baculovirus/insect cell (B4) and CHO cells (B4') or purified from patients' sera) against a papillary thyroid cancer (NPA) cell line. Anti-TPO aAbs from patients' sera led to a partial destruction of NPA cell line by complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) and exhibited an anti-proliferative activity. Comparison of the cytotoxic activity of anti-TPO aAbs shows that B4' induced an anti-proliferative effect and a better ADCC than B4, but a lower one than anti-TPO aAbs from patients' sera. Antibody-dependent cell-mediated cytotoxicity was increased when human peripheral blood mononuclear cells were used as effector cells, suggesting that FcgammaRs, CD64, CD32 and CD16 are involved. Indeed, anti-TPO aAbs from patients' sera, but not B4 and B4', exhibited CDC activity. CONCLUSIONS: These data indicate that anti-TPO aAbs display moderate ADCC and anti-proliferative activities on NPA cells; IgG glycosylation appears to be important for cytotoxic activity and ADCC efficiency depends on FcgammaR-bearing cells. Finally, recombinant human anti-TPO aAbs cannot yet be considered as an optimal tool for the development of a novel therapeutic approach for thyroid cancer

Single Cell Clonotypic and Transcriptional Evolution of Multiple Myeloma Precursor Disease

Multiple myeloma remains an incurable disease, and the cellular and molecular evolution from precursor conditions, including monoclonal gammopathy of undetermined significance and smoldering multiple myeloma, is incompletely understood. Here, we combine single-cell RNA and B cell receptor sequencing from fifty-two patients with myeloma precursors in comparison with myeloma and normal donors. Our comprehensive analysis reveals early genomic drivers of malignant transformation, distinct transcriptional features, and divergent clonal expansion in hyperdiploid versus non-hyperdiploid samples. Additionally, we observe intra-patient heterogeneity with potential therapeutic implications and identify distinct patterns of evolution from myeloma precursor disease to myeloma. We also demonstrate distinctive characteristics of the microenvironment associated with specific genomic changes in myeloma cells. These findings add to our knowledge about myeloma precursor disease progression, providing valuable insights into patient risk stratification, biomarker discovery, and possible clinical applications

Interplay between Structure and Dynamics in Chitosan Films Investigated with Solid-State NMR, Dynamic Mechanical Analysis, and X-ray Diffraction

Modern solid-state NMR techniques, combined with X-ray diffraction, revealed the molecular origin of the difference in mechanical properties of self-associated chitosan films. Films cast from acidic aqueous solutions were compared before and after neutralization, and the role of the counterion (acetate vs Cl⁻) was investigated. There is a competition between local structure and long-range order. Hydrogen bonding gives good mechanical strength to neutralized films, which lack long-range organization. The long-range structure is better defined in films cast from acidic solutions in which strong electrostatic interactions cause rotational distortion around the chitosan chains. Plasticization by acetate counterions enhances long-range molecular organization and film flexibility. In contrast, Cl⁻ counterions act as a defect and impair the long-range organization by immobilizing hydration water. Molecular motion and proton exchange are restricted, resulting in brittle films despite the high moisture content

Repeated PTZ Treatment at 25-Day Intervals Leads to a Highly Efficient Accumulation of Doublecortin in the Dorsal Hippocampus of Rats

BACKGROUND: Neurogenesis persists throughout life in the adult mammalian brain. Because neurogenesis can only be assessed in postmortem tissue, its functional significance remains undetermined, and identifying an in vivo correlate of neurogenesis has become an important goal. By studying pentylenetetrazole-induced brain stimulation in a rat model of kindling we accidentally discovered that 25±1 days periodic stimulation of Sprague-Dawley rats led to a highly efficient increase in seizure susceptibility. METHODOLOGY/PRINCIPAL FINDINGS: By EEG, RT-PCR, western blotting and immunohistochemistry, we show that repeated convulsive seizures with a periodicity of 25±1 days led to an enrichment of newly generated neurons, that were BrdU-positive in the dentate gyrus at day 25±1 post-seizure. At the same time, there was a massive increase in the number of neurons expressing the migratory marker, doublecortin, at the boundary between the granule cell layer and the polymorphic layer in the dorsal hippocampus. Some of these migrating neurons were also positive for NeuN, a marker for adult neurons. CONCLUSION/SIGNIFICANCE: Our results suggest that the increased susceptibility to seizure at day 25±1 post-treatment is coincident with a critical time required for newborn neurons to differentiate and integrate into the existing hippocampal network, and outlines the importance of the dorsal hippocampus for seizure-related neurogenesis. This model can be used as an in vivo correlate of neurogenesis to study basic questions related to neurogenesis and to the neurogenic mechanisms that contribute to the development of epilepsy