SWISS MADE: Standardized WithIn Class Sum of Squares to Evaluate Methodologies and Dataset Elements

Contemporary high dimensional biological assays, such as mRNA expression microarrays, regularly involve multiple data processing steps, such as experimental processing, computational processing, sample selection, or feature selection (i.e. gene selection), prior to deriving any biological conclusions. These steps can dramatically change the interpretation of an experiment. Evaluation of processing steps has received limited attention in the literature. It is not straightforward to evaluate different processing methods and investigators are often unsure of the best method. We present a simple statistical tool, Standardized WithIn class Sum of Squares (SWISS), that allows investigators to compare alternate data processing methods, such as different experimental methods, normalizations, or technologies, on a dataset in terms of how well they cluster a priori biological classes. SWISS uses Euclidean distance to determine which method does a better job of clustering the data elements based on a priori classifications. We apply SWISS to three different gene expression applications. The first application uses four different datasets to compare different experimental methods, normalizations, and gene sets. The second application, using data from the MicroArray Quality Control (MAQC) project, compares different microarray platforms. The third application compares different technologies: a single Agilent two-color microarray versus one lane of RNA-Seq. These applications give an indication of the variety of problems that SWISS can be helpful in solving. The SWISS analysis of one-color versus two-color microarrays provides investigators who use two-color arrays the opportunity to review their results in light of a single-channel analysis, with all of the associated benefits offered by this design. Analysis of the MACQ data shows differential intersite reproducibility by array platform. SWISS also shows that one lane of RNA-Seq clusters data by biological phenotypes as well as a single Agilent two-color microarray.     

The sea lamprey Petromyzon marinus genome reveals the early origin of several chemosensory receptor families in the vertebrate lineage

Background  

In gnathostomes, chemosensory receptors (CR) expressed in olfactory epithelia are encoded by evolutionarily dynamic gene families encoding odorant receptors (OR), trace amine-associated receptors (TAAR), V1Rs and V2Rs. A limited number of OR-like sequences have been found in invertebrate chordate genomes. Whether these gene families arose in basal or advanced vertebrates has not been resolved because these families have not been examined systematically in agnathan genomes.     

Mosquito species composition and Plasmodium vivax infection rates on Baengnyeong-do (island), Republic of Korea

Vivax malaria is a significant military and civilian health threat in the north of the Republic of Korea (ROK). The island of Baengnyeong-do is the westernmost point of the ROK and is located close to the southwestern coast of the Democratic People's Republic of Korea (DPRK). Mosquitoes were collected using a black light trap on Baengnyeong-do, and Anopheles spp. were assayed by PCR, to identify the species, and screened for sporozoites of Plasmodium vivax. Of a subsample of 257 mosquitoes, Anopheles lesteri was the most frequently collected (49.8%), followed by Anopheles sinensis (22.6%), Anopheles pullus (18.7%), Anopheles kleini (7.8%), and Anopheles belenrae (1.2%). The overall sporozoite rate was 3.1%, with the highest rates observed in An. kleini (15.0%), An. sinensis (5.2%), and An. lesteri (1.6%). No sporozoite positive An. pullus or An. belenrae were observed. The results extend our knowledge of the distribution and potential role in malaria transmission of An. kleini, An. lesteri, and An. sinensis, for an area previously considered to be at a low risk for contracting vivax malaria.     

Structural studies of several clinically important oncology drugs in complex with human serum albumin

Background

Serum albumin is a major pharmacokinetic effector of drugs. To gain further insight into albumin binding chemistry, the crystal structures of six oncology agents were determined in complex with human serum albumin at resolutions of 2.8 to 2.0 Å: camptothecin, 9-amino-camptothecin, etoposide, teniposide, bicalutamide and idarubicin.

Methods

Protein crystal growth and low temperature X-ray crystallography

Results

These large, complex drugs are all bound within the subdomain IB binding region which can be described as a hydrophobic groove formed by α-helices h7, h8 and h9 covered by the extended polypeptide L1. L1 creates a binding cavity with two access sites, one between loop L1 and α-helices h7 and h8 (distal site: IB_d) and the other between L1 and α-helix h9 (proximal site: IB_p). Camptothecin (2.4 Å) and 9 amino camptothecin (2.0 Å) are clearly bound as the open lactone form (IB_p). Idarubicin (2.8 Å) binds in a DNA like dimer complex via an intermolecular π stacking arrangement in IB_d. Bicalutamide (2.4 Å) is bound in a folded intramolecular π stacking arrangement between two aromatic rings in IB_d similar to idarubicin. Teniposide (2.7 Å) and etoposide (2.7 Å), despite small chemical differences, are bound in two distinctly different sites at or near IB. Teniposide is internalized via primarily hydrophobic interactions and spans through both openings (IB_p-d). Etoposide is bound between the exterior of IB and IIA and exhibits an extensive hydrogen bonding network.

Conclusions

Subdomain IB is a major binding site for complex heterocyclic molecules.

General significance

The structures have important implications for drug design and development. This article is part of a Special Issue entitled Serum Albumin.     

Swarming Characteristics of Proteus mirabilis Under Anaerobic and Aerobic Conditions

Nutrients have a pronounced effect on the growth and swarming behaviour of Proteus mirabilis 7002. Iron, zinc, amino acids, and dioxygen are important for rapid growth and normal swarming. Anaerobically grown cultures of P. mirabilis 7002 were unable to swarm on anaerobically maintained rich nutrient agar. Upon exposure to aerobic conditions, P. mirabilis 7002 resumed swarming behaviour. Scanning electron microscopy was used to demonstrate the presence of community organization and mature rafts during normal swarming. These results support the importance of dioxygen and redox status in cell differentiation.     

Synthesis and dopamine transporter affinity of chiral 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(2-hydroxypropyl)piperazines as potential cocaine abuse therapeutic agents

A series of optically pure phenyl-and non-phenyl-substituted 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(2-hydroxypropyl)piperazines was synthesized and their binding affinity for dopamine transporter (DAT) was investigated. The analogues with a hydroxyl group in the S configuration were more selective for the DAT over the serotonin transporter (SERT) than the corresponding R enantiomers. Compound (+)-11 showed high affinity and selectivity for DAT over the SERT and, therefore, is a potential candidate for the development of a long-acting cocaine abuse therapeutic agent.     

Fertility potential: a comparison of intra-abdominal and intracanalicular testes by age groups in children.

We compared a group of intra-abdominal (IA) with intracanalicular (IC) testes of the same age in order to see if there were differences in the fertility potential of the testes in these two locations. We also wished to determine at what age, if any, differences became apparent. Semithin (1 microm thick) sections of 54 IA and 103 IC testes between the ages of 3 months and 5 years were evaluated and the spermatic index (SI) calculated for each. The two groups were compared using mathematical models to describe the relationship between age and SI. Models of both IA and IC testes show a sharp decline in the SI during the first 1.8 years of life and remain near zero thereafter. The models are statistically indistinguishable, suggesting there is no detectable difference in the fertility potential of IA and IC testes up to 5 years. The SI appears to reach a critically low value in both groups between 8 and 9 months of age, suggesting that surgical intervention would be appropriate before this time.     

Disability and <Emphasis Type="Italic">Depression</Emphasis>

Here, Ann Cvetkovich, interviewed by Abby Wilkerson, brings Cvetkovich’s influential cultural studies analysis of depression explicitly into conversation with disability studies. Cvetkovich understands “feeling bad” (a term she prefers to “depression”) as a defining affective state under neoliberalism. Drawing on a distinctive historical/cultural archive, she challenges the atomism of the neoliberal medical model that frames depression and affective distress more generally as the result of faulty brain chemistry—individual organisms gone awry. Instead, she traces these common experiences to sociopolitical phenomena ranging from current neoliberal demands for productivity as exemplified in university life, to histories of colonization, slavery, and displacement. The conversation considers the value of disability frameworks for understanding mental health diagnoses and the intersections of social institutions, bodily practices, and everyday affective life.