Dissociation of biological catch-bond by periodic perturbation

The analysis of the P-selectin/PSGL-1 catch-slip bond that is periodically driven by a detaching force predicts that in the frequency range on the order of 1 s(-1) the bond lifetime undergoes significant changes with respect to both frequency and amplitude of the force. The result indicates how variations in the heart rate could have a substantial effect on leukocyte and lymphoid cell transport and adhesion to endothelial cells and platelets during inflammatory processes.     

Cellular basis for response diversity in the olfactory periphery

An emerging idea in olfaction is that temporal coding of odor specificity can be intrinsic to the primary olfactory receptor neurons (ORNs). As a first step towards understanding whether lobster ORNs are capable of generating odor-specific temporal activity and what mechanisms underlie any such heterogeneity in discharge pattern, we characterized different patterns of activity in lobster ORNs individually and ensemble using patch-clamp recording and calcium imaging. We demonstrate that lobster ORNs show tonic excitation, tonic inhibition, phaso-tonic excitation, and bursting, and that these patterns are faithfully reflected in the calcium signal. We then demonstrate that the various dynamic patterns of response are inherent in the cells, and that this inherent heterogeneity is largely determined by heterogeneity in the underlying intrinsic conductances.     

A corpus of full-text journal articles is a robust evaluation tool for revealing differences in performance of biomedical natural language processing tools

ABSTRACT: BACKGROUND: We introduce the linguistic annotation of a corpus of 97 full-text biomedical publications, known as the Colorado Richly Annotated Full Text (CRAFT) corpus. We further assess the performance of existing tools for performing sentence splitting, tokenization, syntactic parsing, and named entity recognition on this corpus. RESULTS: Many biomedical natural language processing systems demonstrated large differences between their previously published results and their performance on the CRAFT corpus when tested with the publicly available models or rule sets. Trainable systems differed widely with respect to their ability to build high-performing models based on this data. CONCLUSIONS: The finding that some systems were able to train high-performing models based on this corpus is additional evidence, beyond high inter-annotator agreement, that the quality of the CRAFT corpus is high. The overall poor performance of various systems indicates that considerable work needs to be done to enable natural language processing systems to work well when the input is full-text journal articles. The CRAFT corpus provides avaluable resource to the biomedical natural language processing community for evaluation and training of new models for biomedical full text publications.     

Polymorphism of canonical and noncanonical <Emphasis Type="Italic">gypsy</Emphasis> sequences in different species of <Emphasis Type="Italic">Drosophila </Emphasis><Emphasis Type="Italic">melanogaster</Emphasis> subgroup: possible evolutionary relations

Mobile genetic elements constitute a substantial part of eukaryotic genome and play an important role in its organization and functioning. Co-evolution of retrotransposons and their hosts resulted in the establishment of control systems employing mechanisms of RNA interference that seem to be impossible to evade. However, “active” copies of endogenous retrovirus gypsy escape cellular control in some cases, while its evolutionary elder “inactive” variants do not. To clarify the evolutionary relationship between “active” and “inactive” gypsy we combined two approaches: the analysis of gypsy sequences, isolated from G32 Drosophila melanogaster strain and from different Drosophila species of the melanogaster subgroup, as well as the study of databases, available on the Internet. No signs of “intermediate” (between “active” and “inactive”) gypsy form were found in GenBank, and four full-size G32 gypsy copies demonstrated a convergence that presumably involves gene conversion. No “active” gypsy were revealed among PCR generated gypsy ORF3 sequences from the various Drosophila species indicating that “active” gypsy appeared in some population of D. melanogaster and then started to spread out. Analysis of sequences flanking gypsy variants in G32 revealed their predominantly heterochromatic location. Discrepancy between the structure of actual gypsy sites in G32 and corresponding sequences in database might indicate significant inter-strain heterochromatin diversity. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

The spinocerebellar ataxia 12 gene product and protein phosphatase 2A regulatory subunit Bbeta2 antagonizes neuronal survival by promoting mitochondrial fission

The neurodegenerative disorder spinocerebellar ataxia 12 (SCA12) is caused by CAG repeat expansion in the non-coding region of the PPP2R2B gene. PPP2R2B encodes Bbeta1 and Bbeta2, alternatively spliced and neuron-specific regulatory subunits of the protein phosphatase 2A (PP2A) holoenzyme. We show here that in PC12 cells and hippocampal neurons, cell stressors induced a rapid translocation of PP2A/Bbeta2 to mitochondria to promote apoptosis. Conversely, silencing of PP2A/Bbeta2 protected hippocampal neurons against free radical-mediated, excitotoxic, and ischemic insults. Evidence is accumulating that the mitochondrial fission/fusion equilibrium is an important determinant of cell survival. Accordingly, we found that Bbeta2 expression induces mitochondrial fragmentation, whereas Bbeta2 silencing or inhibition resulted in mitochondrial elongation. Based on epistasis experiments involving Bcl2 and core components of the mitochondrial fission machinery (Fis1 and dynamin-related protein 1), mitochondrial fragmentation occurs upstream of apoptosis and is both necessary and sufficient for hippocampal neuron death. Our data provide the first example of a proapoptotic phosphatase that predisposes to neuronal death by promoting mitochondrial division and point to a possible imbalance of the mitochondrial morphogenetic equilibrium in the pathogenesis of SCA12.     

Exhaustive computational identification of pathogen sequences far-distant from background genomes: Identification and experimental verification of human-blind dengue PCR primers

We recently developed novel algorithms for exhaustive identification of all nucleotide subsequences present in a pathogen genome which differ by at least a chosen number of mismatches from the sequences of host/background organisms. This type of exhaustive computational analysis will be useful in reducing false positives and cross-reactivity in PCR and hybridization assays. We present the first experimental test of the method by showing that the subsequences identified when used as 18-mer PCR primers can detect the presence of dengue virus (DENV) even in the presence of a large excess of complex human genomic DNA. From our computations, 715 serotype-specific primer pairs were identified for three different DENV serotypes in which each primer sequence lies at least two mismatches from the nearest human sequence. DNA clones of representative strains of DENV-1, DENV-2, and DENV-4 viruses were subjected to real-time PCR testing using eight primer pairs each. Efficiencies were uniformly very high (mean+/-S.D.=99.6+/-3%), and amplification of human DNA was never observed within 35 cycles, even at a 5.5-fold molar excess of human DNA. Exhaustive primer/probe screening can potentially produce more selective and sensitive diagnostic assays for pathogens, especially in the presence of complex backgrounds.     

Reinvestigation of the O-antigens of Yersinia pseudotuberculosis: revision of the O2c and confirmation of the O3 antigen structures

Structures of the O-antigens of Yersinia pseudotuberculosis O2c and O3 were reinvestigated by NMR spectroscopy, including 2D (1)H,(1)H COSY, TOCSY, ROESY, (1)H,(13)C HSQC, and HMBC experiments. The following revised structure of the O2c tetrasaccharide repeating unit was established, which differs from the structure proposed earlier in the glycosylation pattern of the mannose residue at the branching point: where Abe stands for 3,6-dideoxy-d-xylo-hexose. The structure of the Y. pseudotuberculosis O3 antigen reported earlier was confirmed.     

Structure of the O-specific polysaccharide of the lipopolysaccharide of Rahnella aquatilis 95 U003

The O-polysaccharide of Rahnella aquatilis 95 U003 was obtained by mild acid degradation of the lipopolysaccharide and studied by sugar and methylation analyses, Smith degradation and (1)H and (13)C NMR spectroscopy, including 2D (1)H,(1)H COSY, TOCSY, ROESY, H-detected (1)H,(13)C HSQC and HMQC-TOCSY experiments. The O-polysaccharide was found to have a branched hexasaccharide repeating unit of the following structure: