The development of the Silurian trilobite Aulacopleura koninckii reconstructed by applying inferred growth and segmentation dynamics: A case study in paleo-evo-devo

Fossilized growth series provide rare glimpses into the development of ancient organisms, illustrating descriptively how size and shape changed through ontogeny. Occasionally fossil preservation is such that it is feasible to test alternative possibilities about how ancient development was regulated. Here we apply inferred developmental parameters pertaining to size, shape, and segmentation in the abundant and well-preserved 429 Myr old trilobite Aulacopleura koninckii that we have investigated previously to reconstruct the post-embryonic ontogeny of this ancient arthropod. Our published morphometric analyses associated with model testing have shown that: specification of the adult number of trunk segments (polymorphic in this species) was determined precociously in ontogeny; that growth regulation was targeted (i.e., compensatory), such that each developmental stage exhibited comparable variance in size and shape; and that growth gradients operating along the main body axis, both during juvenile and adult ontogeny, resulted from a form of growth control based on positional specification. While such developmental features are common among extant organisms, our results represent the oldest evidence for them within Metazoa. Herein, the novel reconstruction of the development of Aulacopleura koninckii permits visualization of patterns of relative and absolute growth and segmentation as never before possible for a fossilized arthropod ontogeny. By conducting morphometric analysis of appropriate data sets it is thus possible to move beyond descriptive ontogenetic studies and to address questions of high interest for evolutionary developmental biology using data from fossils, which can help elucidate both how developmental processes themselves evolve and how they affect the evolution of organismal body patterning. By extending similar analyses to other cases of exceptional preservation of fossilized ontogeny, we can anticipate beginning to realize the research program of “paleo-evo-devo.

Functional Interactions of Alcohol-sensitive Sites in the \u3cem\u3eN\u3c/em\u3e-Methyl-d-aspartate Receptor M3 and M4 Domains

The N-methyl-d-aspartate receptor is an important mediator of the behavioral effects of ethanol in the central nervous system. Previous studies have demonstrated sites in the third and fourth membrane-associated (M) domains of the N-methyl-d-aspartate receptor NR2A subunit that influence alcohol sensitivity and ion channel gating. We investigated whether two of these sites, Phe-637 in M3 and Met-823 in M4, interactively regulate the ethanol sensitivity of the receptor by testing dual substitution mutants at these positions. A majority of the mutations decreased steady-state glutamate EC50 values and maximal steady-state to peak current ratios (Iss/Ip), whereas only two mutations altered peak glutamate EC50 values. Steady-state glutamate EC50 values were correlated with maximal glutamate Iss/Ip values, suggesting that changes in glutamate potency were attributable to changes in desensitization. In addition, there was a significant interaction between the substituents at positions 637 and 823 with respect to glutamate potency and desensitization. IC50 values for ethanol among the mutants varied over the approximate range 100–325 mm. The sites in M3 and M4 significantly interacted in regulating ethanol sensitivity, although this was apparently dependent upon the presence of methionine in position 823. Molecular dynamics simulations of the NR2A subunit revealed possible binding sites for ethanol near both positions in the M domains. Consistent with this finding, the sum of the molecular volumes of the substituents at the two positions was not correlated with ethanol IC50 values. Thus, there is a functional interaction between Phe-637 and Met-823 with respect to glutamate potency, desensitization, and ethanol sensitivity, but the two positions do not appear to form a unitary site of alcohol action

The Signature of Primordial Grain Growth in the Polarized Light of the AU Mic Debris Disk

We have used the Hubble Space Telescope/ACS coronagraph to make polarization maps of the AU Mic debris disk. The fractional linear polarization rises monotonically from about 0.05 to 0.4 between 20 and 80 AU. The polarization is perpendicular to the disk, indicating that the scattered light originates from micron sized grains in an optically thin disk. Disk models, which simultaneously fit the surface brightness and polarization, show that the inner disk (< 40-50 AU) is depleted of micron-sized dust by a factor of more than 300, which means that the disk is collision dominated. The grains have high maximum linear polarization and strong forward scattering. Spherical grains composed of conventional materials cannot reproduce these optical properties. A Mie/Maxwell-Garnett analysis implicates highly porous (91-94%) particles. In the inner Solar System, porous particles form in cometary dust, where the sublimation of ices leaves a "bird's nest" of refractory organic and silicate material. In AU Mic, the grain porosity may be primordial, because the dust "birth ring" lies beyond the ice sublimation point. The observed porosities span the range of values implied by laboratory studies of particle coagulation by ballistic cluster-cluster aggregation. To avoid compactification, the upper size limit for the parent bodies is in the decimeter range, in agreement with theoretical predictions based on collisional lifetime arguments. Consequently, AU Mic may exhibit the signature of the primordial agglomeration process whereby interstellar grains first assembled to form macroscopic objects.Comment: 12 pages, 8 figures, ApJ, in pres

Suppliers\u27 Quality Practices in Six Countries and Regions: China, Taiwan, India, Korea, Mexico, and Costa Rica

In this paper we report suppliers’ quality practices in six countries — China, Taiwan, India, Korea, Mexico and Costa Rica. The practices include suppliers’ education, technical assistances, involvement in product development and long-term relationships. India, China, Korea and Taiwan are four major countries in Asia that have shown substantial economic growth over the years. Mexico is a member of NAFTA. Cost Rica is a growing country in Central America. Differences in terms of quality results are explored as well. In general, supplier quality practices are related to the overall quality management practices. Supplier quality practices affect the internal and external quality results. However, the length of quality experience in the organizations turns out to be a discriminating factor for choosing particular supplier quality practices. The implication of these results confirms that supplier quality practices are important practices for both internal and external quality results

Advanced gynecologic malignancies treated with a combination of the VEGF inhibitor bevacizumab and the mTOR inhibitor temsirolimus.

BackgroundBevacizumab and temsirolimus are active agents in gynecologic tumors. Temsirolimus attenuates upregulation of HIF-1α levels, a resistance mechanism for antiangiogenics, and targets the PI3-kinase/AKT/mTOR axis, commonly aberrant in these tumors.Patients and methodsWe analyzed safety and responses in 41 patients with gynecologic cancers treated as part of a Phase I study of bevacizumab and temsirolimus.ResultsMedian age of the 41 women was 60 years (range, 33-80 years); median number of prior systemic therapies was 4 (1-11). Grade 3 or 4 treatment-related toxicities included: thrombocytopenia (10%), mucositis (2%), hypertension (2%), hypercholesterolemia (2%), fatigue (7%), elevated aspartate aminotransferase (2%), and neutropenia (2%). Twenty-nine patients (71%) experienced no treatment-related toxicity greater than grade 2. Full FDA-approved doses of both drugs (bevacizumab 15mg/kg IV Q3weeks and temsirolimus 25mg IV weekly) were administered without dose-limiting toxicity. Eight patients (20%) achieved stable disease (SD) &gt; 6 months and 7 patients (17%), a partial response (PR) [total = 15/41 patients (37%)]. Eight of 13 patients (62%) with high-grade serous histology (ovarian or primary peritoneal) achieved SD &gt; 6 months/PR.ConclusionBevacizumab and temsirolimus was well tolerated. Thirty-seven percent of heavily-pretreated patients achieved SD &gt; 6 months/PR, suggesting that this combination warrants further study

Dual EGFR inhibition in combination with anti-VEGF treatment in colorectal cancer.

Preclinical studies demonstrate that epidermal growth factor receptor (EGFR) signals through both kinase-dependent and independent pathways and that combining a small-molecule EGFR inhibitor, EGFR antibody, and/or anti-angiogenic agent is synergistic. We conducted a dose-escalation, phase I study combining erlotinib, cetuximab, and bevacizumab. The subset of patients with metastatic colorectal cancer was analyzed for safety and antitumor activity. Forty-one patients with heavily pretreated metastatic colorectal cancer received treatment on a range of dose levels. The most common treatment-related grade ≥2 adverse events were rash (68%), hypomagnesemia (37%), and fatigue (15%). Thirty of 34 patients (88%) treated at the full FDA-approved doses of all three drugs tolerated treatment without drug-related dose-limiting effects. Eleven patients (27%) achieved stable disease (SD) ≥6 months and three (7%) achieved a partial response (PR) (total SD&gt;6 months/PR= 14 (34%)). Of the 14 patients with SD≥6 months/PR, eight (57%) had received prior sequential bevacizumab and cetuximab, two (5%) had received bevacizumab and cetuximab concurrently, and four (29%) had received prior bevacizumab but not cetuximab or erlotinib (though three had received prior panitumumab). The combination of bevacizumab, cetuximab, and erlotinib was well tolerated and demonstrated antitumor activity in heavily pretreated patients with metastatic colorectal cancer

Dual EGFR inhibition in combination with anti-VEGF treatment: a phase I clinical trial in non-small cell lung cancer.

BackgroundPreclinical data indicate EGFR signals through both kinase-dependent and independent pathways and that combining a small-molecule EGFR inhibitor, EGFR antibody, and/or anti-angiogenic agent is synergistic in animal models.MethodsWe conducted a dose-escalation, phase I study combining erlotinib, cetuximab, and bevacizumab. The subset of patients with non-small cell lung cancer (NSCLC) was analyzed for safety and response.ResultsThirty-four patients with NSCLC (median four prior therapies) received treatment on a range of dose levels. The most common treatment-related grade ≥2 adverse events were rash (n=14, 41%), hypomagnesemia (n=9, 27%), and fatigue (n=5, 15%). Seven patients (21%) achieved stable disease (SD) ≥6 months, two achieved a partial response (PR) (6%), and two achieved an unconfirmed partial response (uPR) (6%) (total=32%). We observed SD≥6 months/PR/uPR in patients who had received prior erlotinib and/or bevacizumab, those with brain metastases, smokers, and patients treated at lower dose levels. Five of 16 patients (31%) with wild-type EGFR experienced SD≥6 months or uPR. Correlation between grade of rash and rate of SD≥6 months/PR was observed (p less than 0.01).ConclusionThe combination of erlotinib, cetuximab, and bevacizumab was well-tolerated and demonstrated antitumor activity in heavily pretreated patients with NSCLC

Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death.

The altered metabolism of cancer can render cells dependent on the availability of metabolic substrates for viability. Investigating the signaling mechanisms underlying cell death in cells dependent upon glucose for survival, we demonstrate that glucose withdrawal rapidly induces supra-physiological levels of phospho-tyrosine signaling, even in cells expressing constitutively active tyrosine kinases. Using unbiased mass spectrometry-based phospho-proteomics, we show that glucose withdrawal initiates a unique signature of phospho-tyrosine activation that is associated with focal adhesions. Building upon this observation, we demonstrate that glucose withdrawal activates a positive feedback loop involving generation of reactive oxygen species (ROS) by NADPH oxidase and mitochondria, inhibition of protein tyrosine phosphatases by oxidation, and increased tyrosine kinase signaling. In cells dependent on glucose for survival, glucose withdrawal-induced ROS generation and tyrosine kinase signaling synergize to amplify ROS levels, ultimately resulting in ROS-mediated cell death. Taken together, these findings illustrate the systems-level cross-talk between metabolism and signaling in the maintenance of cancer cell homeostasis