Trimethyloxonium modification of single batrachotoxin-activated sodium channels in planar bilayers. Changes in unit conductance and in block by saxitoxin and calcium

Single batrachotoxin-activated sodium channels from rat brain were modified by trimethyloxonium (TMO) after incorporation in planar lipid bilayers. TMO modification eliminated saxitoxin (STX) sensitivity, reduced the single channel conductance by 37%, and reduced calcium block of inward sodium currents. These effects always occurred concomitantly, in an all-or-none fashion. Calcium and STX protected sodium channels from TMO modification with potencies similar to their affinities for block. Calcium inhibited STX binding to rat brain membrane vesicles and relieved toxin block of channels in bilayers, apparently by competing with STX for the toxin binding site. These results suggest that toxins, permeant cations, and blocking cations can interact with a common site on the sodium channel near the extracellular surface. It is likely that permeant cations transiently bind to this superficial site, as the first of several steps in passing inward through the channel.     

Hermaphroditism in icerya zeteki cockerell,and the mechanism of gonial reduction in iceryine coccids (coccoidea: Margarodidae morrison)

In the Panamanian iceryine coccid Icerya zeteki Cockerell (Family Margarodidae Morrison) all females become hermaphroditic early in the first instar; occasional males arise from unfertilized eggs, but self-fertilization is assured by the protandry of the hermaphrodite. In the development of the ovotestis, initiation of the male phase is brought about by haploidization of those germ cells destined for spermatogenesis. In both Icerya zeteki and Icerya purchasi this gonial reduction results from the degeneration and elimination of one genome during prophase. Except for minor variations in the coiling cycle of spermatocytes, the chromosomes (n=2) of I. zeteki correspond closely to those of all other haplo-diploid iceryines known. The present status of the species Icerya zeteki Cockerell is reviewed, and on both taxonomicand cytological grounds is judged to be uncertain.Supported in part by National Science Foundation Grant GB — 1922.     

Sodium periodate stimulation of human lymphocytes : A comparison between normal and chronic lymphocytic leukemia lymphocytes

Lymphocytes from healthy donors and from patients with chronic lymphocytic leukemia (CLL) were stimulated to divide with sodium periodate. The time of maximal response of normal lymphocytes to sodium periodate (NaIO₄) was earlier than that observed to phytohemagglutinin (PHA), but the magnitude was lower. In comparison, CLL lymphocytes responded to NaIO₄ more extensively and earlier than to PHA.     

Therapeutic efficacy of anti‐MMP9 antibody in combination with nab‐paclitaxel‐based chemotherapy in pre‐clinical models of pancreatic cancer

Matrix metalloproteinase 9 (MMP9) is involved in the proteolysis of extracellular proteins and plays a critical role in pancreatic ductal adenocarcinoma (PDAC) progression, invasion and metastasis. The therapeutic potential of an anti‐MMP9 antibody (αMMP9) was evaluated in combination with nab‐paclitaxel (NPT)‐based standard cytotoxic therapy in pre‐clinical models of PDAC. Tumour progression and survival studies were performed in NOD/SCID mice. The mechanistic evaluation involved RNA‐Seq, Luminex, IHC and Immunoblot analyses of tumour samples. Median animal survival compared to controls was significantly increased after 2‐week therapy with NPT (59%), Gem (29%) and NPT+Gem (76%). Addition of αMMP9 antibody exhibited further extension in survival: NPT+αMMP9 (76%), Gem+αMMP9 (47%) and NPT+Gem+αMMP9 (94%). Six‐week maintenance therapy revealed that median animal survival was significantly increased after NPT+Gem (186%) and further improved by the addition of αMMP9 antibody (218%). Qualitative assessment of mice exhibited that αMMP9 therapy led to a reduction in jaundice, bloody ascites and metastatic burden. Anti‐MMP9 antibody increased the levels of tumour‐associated IL‐28 (1.5‐fold) and decreased stromal markers (collagen I, αSMA) and the EMT marker vimentin. Subcutaneous tumours revealed low but detectable levels of MMP9 in all therapy groups but no difference in MMP9 expression. Anti‐MMP9 antibody monotherapy resulted in more gene expression changes in the mouse stroma compared to the human tumour compartment. These findings suggest that anti‐MMP9 antibody can exert specific stroma‐directed effects that could be exploited in combination with currently used cytotoxics to improve clinical PDAC therapy.     

Defining the healthy "core microbiome" of oral microbial communities

Background  

Most studies examining the commensal human oral microbiome are focused on disease or are limited in methodology. In order to diagnose and treat diseases at an early and reversible stage an in-depth definition of health is indispensible. The aim of this study therefore was to define the healthy oral microbiome using recent advances in sequencing technology (454 pyrosequencing).     

Factors influencing the distribution of aquatic plant communities in Irish canals

Terrestrial tardigrades are often found in the lichens and mosses growing on trees and rocks. The assertion that tardigrades in these habitats are very patchy in their distribution has rarely been backed by quantitative sampling. This study assesses spatial variability in tardigrade populations inhabiting small patches (0.1 cm² to over 5 cm²) of moss and lichen on trees and rocks at three sites in the United States of America. Tardigrades were collected from four replicate rocks in the Ouachita Mountains of Arkansas, with 30 lichen patches collected on two adjacent boulders and 20 moss patches on a second pair of boulders. In Fort Myers and in Citrus Springs, Florida, 30 lichen patches per tree were collected from two pairs of trees. The tardigrades in each sample were extracted, mounted, identified, and counted. The variation in tardigrade abundance among lichen or moss patches within rocks or trees was very high; the only consistent pattern was that very small patches usually lacked tardigrades. Tardigrade diversity and abundance also varied greatly within sites when lichens and mosses of the same species from different rocks and trees were compared (in the most extreme case one tree had numerous individuals of two tardigrade species present while the other had almost no tardigrades). The results of this quantitative sampling support the assertion that tardigrades are very patchy in distribution. Given the considerable time investment required for the quantitative processing of tardigrade samples, this high spatial variability in tardigrade diversity and abundance requires that researches testing ecological hypotheses about tardigrade abundance check variability before deciding how many samples to take.     

Substituted indanylacetic acids as PPAR-alpha-gamma activators

A series of oxazole-substituted indanylacetic acids were prepared which show a spectrum of activity as ligands for PPAR nuclear receptor subtypes.