C6 pyridinium ceramide influences alternative pre-mRNA splicing by inhibiting protein phosphatase-1

Alternative pre-mRNA processing is a central element of eukaryotic gene regulation. The cell frequently alters the use of alternative exons in response to physiological stimuli. Ceramides are lipid-signaling molecules composed of sphingosine and a fatty acid. Previously, water-insoluble ceramides were shown to change alternative splicing and decrease SR-protein phosphorylation by activating protein phosphatase-1 (PP1). To gain further mechanistical insight into ceramide-mediated alternative splicing, we analyzed the effect of C6 pyridinium ceramide (PyrCer) on alternative splice site selection. PyrCer is a water-soluble ceramide analog that is under investigation as a cancer drug. We found that PyrCer binds to the PP1 catalytic subunit and inhibits the dephosphorylation of several splicing regulatory proteins containing the evolutionarily conserved RVxF PP1-binding motif (including PSF/SFPQ, Tra2-beta1 and SF2/ASF). In contrast to natural ceramides, PyrCer promotes phosphorylation of splicing factors. Exons that are regulated by PyrCer have in common suboptimal splice sites, are unusually short and share two 4-nt motifs, GAAR and CAAG. They are dependent on PSF/SFPQ, whose phosphorylation is regulated by PyrCer. Our results indicate that lipids can influence pre-mRNA processing by regulating the phosphorylation status of specific regulatory factors, which is mediated by protein phosphatase activity.     

Role of endogenous prostaglandins in pregnancy termination by 15-methyl PGF2α

Thirty pregnant women with foetal death in utero received 15-methyl PGF_2α to terminate their pregnancies. Two groups (15 cases each) matched for age, gravidity and age of pregnancy were studied. One group received indomethacin suppositories before and during the PG induction while the second group received the prostaglandin analogue therapy only. The group which received the prostaglandin biosynthesis inhibitor showed a longer induction-termination interval, more PG ampoules were used and the number of failed cases was higher. Thus, the Release of Endogenous prostaglandins seems to play a complementary role in the therapeutic termination of pregnancy.     

Dimensional characteristics of the Filipino dentition

This study concerns odontometric analysis of the Tagalog Filipinos in Manila, Philippines. Mesiodistal and buccolingual dimensions of the permanent dentition, a total of 56 variables, were studied in 100 males and 152 females. Results showed that their absolute tooth size was small. Relative tooth size, however, seemed to reflect their Southeast Asian Mongoloid origin. From univariate analysis, considerable male-female differences were shown in most of the variables studied. When correlation effects among the teeth were held constant through multivariate analysis, male-female distance was found to be small and substantial overlapping of the two multivariate distributions was evident. Only four variables could be shown by stepwise discriminant analysis to contribute significantly to the distance. Even the mandibular canine, as the strongest discriminator, could only account for 16.4% of the total multivariate distance. These contrasting findings for sex dimorphism in a set of teeth taken singly and taken jointly indicate that there are factors other than the teeth themselves that are expected to play important roles in determining overall male-female size differences in the set of teeth, and that these differences may not be as clear-cut as univariate analysis suggests.     

Multimodal Measurements of Single-Molecule Dynamics Using FluoRBT

Single-molecule methods provide direct measurements of macromolecular dynamics, but are limited by the number of degrees of freedom that can be followed at one time. High-resolution rotor bead tracking (RBT) measures DNA torque, twist, and extension, and can be used to characterize the structural dynamics of DNA and diverse nucleoprotein complexes. Here, we extend RBT to enable simultaneous monitoring of additional degrees of freedom. Fluorescence-RBT (FluoRBT) combines magnetic tweezers, infrared evanescent scattering, and single-molecule FRET imaging, providing real-time multiparameter measurements of complex molecular processes. We demonstrate the capabilities of FluoRBT by conducting simultaneous measurements of extension and FRET during opening and closing of a DNA hairpin under tension, and by observing simultaneous changes in FRET and torque during a transition between right-handed B-form and left-handed Z-form DNA under controlled supercoiling. We discover unanticipated continuous changes in FRET with applied torque, and also show how FluoRBT can facilitate high-resolution FRET measurements of molecular states, by using a mechanical signal as an independent temporal reference for aligning and averaging noisy fluorescence data. By combining mechanical measurements of global DNA deformations with FRET measurements of local conformational changes, FluoRBT will enable multidimensional investigations of systems ranging from DNA structures to large macromolecular machines.     

Saitohin, which is nested in the tau locus and confers allele-specific susceptibility to several neurodegenerative diseases, interacts with peroxiredoxin 6

Saitohin is a gene unique to humans and their closest relatives, the function of which is not yet known. Saitohin contains a single polymorphism (Q7R), and its Q and R alleles belong to the H1 and H2 tau haplotype, respectively. The Saitohin Q allele confers susceptibility to several neurodegenerative diseases. To get a handle on Saitohin function, we used it as a bait in a yeast two-hybrid screen. By this assay and subsequent co-immunoprecipitation and glutathione S-transferase pull-down assays, we discovered and confirmed that Saitohin interacts with peroxiredoxin 6, a unique member of that family that is bifunctional and the levels of which increase in Pick disease. The strength of the interaction appeared to be allele-specific, giving the first distinction between the two forms of Saitohin.     

Can some microbes promote host stress and benefit evolutionarily from this strategy?

Microbes can influence host physiology and behavior in many ways. Here we review evidence suggesting that some microbes can contribute to host stress (and other microbes can contribute to increased resilience to stress). We explain how certain microbes, which we call “stress microbes,” can potentially benefit evolutionarily from inducing stress in a host, gaining access to host resources that can help fuel rapid microbial replication by increasing glucose levels in the blood, increasing intestinal permeability, and suppressing the immune system. Other microbes, which we term “resilience microbes,” can potentially benefit from making hosts more resilient to stress. We hypothesize that “stress microbes” use a fast life history strategy involving greater host exploitation while “resilience microbes” use a slow life history strategy characterized by more aligned evolutionary interests with the host. In this paper, we review the evidence that microbes affect host stress and explain the evolutionary pressures that could lead microbes to manipulate host stress, discuss the physiological mechanisms that are known to be involved in both stress and microbial activity, and provide some testable predictions that follow from this hypothesis.