Collagen fibril flow and tissue translocation coupled to fibroblast migration in 3D collagen matrices

In nested collagen matrices, human fibroblasts migrate from cell-containing dermal equivalents into surrounding cell-free outer matrices. Time-lapse microscopy showed that in addition to cell migration, collagen fibril flow occurred in the outer matrix toward the interface with the dermal equivalent. Features of this flow suggested that it depends on the same cell motile machinery that normally results in cell migration. Collagen fibril flow was capable of producing large-scale tissue translocation as shown by closure of a approximately 1-mm gap between paired dermal equivalents in floating, nested collagen matrices. Our findings demonstrate that when fibroblasts interact with collagen matrices, tractional force exerted by the cells can couple to matrix translocation as well as to cell migration.     

Collegiate rowing crew performance varies by morningness-eveningness

During adolescence and early adulthood, most humans are predisposed developmentally, both biologically and socially, toward evening/night activity. The morningness-eveningness (M-E) tendency to be an evening-preferring (E-type) rather than a morning-preferring (M-type) or intermediate/neither (N-type) "chronotype" may affect athletic performance at various times of day. This study evaluated M-E effects on rowing performance of an intact, experienced, university club crew with near-daily early morning (0500-0700 hours) and late afternoon (1630-1800 hours) training schedules. The hypothesis tested was that chronotype would modify circadian effects during morning and afternoon performances. Eight men and eight women (mean age 19.6 +/- 1.5 years) were tested in a randomized, counterbalanced design. A standard qualifying 2000-m ergometer rowing sprint and a nonroutine standing broad jump task were measured during early morning and late afternoon, separated by 3 days of rest. Each subject's chronotype was determined using two standard self-rating M-E scales, resulting in eight E-type (three women/five men), four M-type (two women/two men), and four N-type (three women/one man) subjects. The rowing results show that E-type and N-type subjects did not differ between morning and afternoon rowing performances, whereas M-type subjects rowed significantly faster in the morning. In contrast, the standing broad jump showed no consistent time-of-day or chronotype effect. These findings suggest that basic performance timing in young athletes is determined to some extent by naturally occurring M-E predispositions. Further, modification of time-of-day influences may be possible by routine practice at the same time each day, as was suggested here by the absence of evening superiority in performances. Understanding their personal M-E tendencies could allow young athletes to arrange training schedules at specific times of day to help counteract any natural circadian influences that might work against their performance.     

Lymphocyte-specific compensation for XLF/cernunnos end-joining functions in V(D)J recombination

Mutations in XLF/Cernunnos (XLF) cause lymphocytopenia in humans, and various studies suggest an XLF role in classical nonhomologous end joining (C-NHEJ). We now find that XLF-deficient mouse embryonic fibroblasts are ionizing radiation (IR) sensitive and severely impaired for ability to support V(D)J recombination. Yet mature lymphocyte numbers in XLF-deficient mice are only modestly decreased. Moreover, XLF-deficient pro-B lines, while IR-sensitive, perform V(D)J recombination at nearly wild-type levels. Correspondingly, XLF/p53-double-deficient mice are not markedly prone to the pro-B lymphomas that occur in previously characterized C-NHEJ/p53-deficient mice; however, like other C-NHEJ/p53-deficient mice, they still develop medulloblastomas. Despite nearly normal V(D)J recombination in developing B cells, XLF-deficient mature B cells are moderately defective for immunoglobulin heavy-chain class switch recombination. Together, our results implicate XLF as a C-NHEJ factor but also indicate that developing mouse lymphocytes harbor cell-type-specific factors/pathways that compensate for the absence of XLF function during V(D)J recombination.     

Getting to guanine: mechanism and dynamics of charge separation and charge recombination in DNA revisited.

The mechanism and dynamics of charge separation and charge recombination in synthetic DNA hairpins possessing a stilbenedicarboxamide linker and a single guanine-cytosine base pair have been reinvestigated. The combination of femtosecond broad-band pump probe spectroscopy, nanosecond transient absorption experiments, and picosecond fluorescence decay measurements permits analysis of the formation and decay of the stilbene anion radical. Reversible hole injection resulting in the formation of the stilbene-adenine contact radical ion pair is found to occur on the picosecond time scale. The mechanism for charge separation across two or more base pairs is revised from single step superexchange to a multi-step process: hole injection followed by hole transport and hole trapping. The mechanism of charge recombination remains assigned to a superexchange process.     

The immunobiology of mushrooms

There has been enormous interest in the biologic activity of mushrooms and innumerable claims have been made that mushrooms have beneficial effects on immune function with subsequent implications for inhibition of tumor growth. The majority of these observations are anecdotal and often lack standardization. However, there remains considerable data on both in vitro and in vivo effects that reflect on the potential of mushroom compounds to influence human immunity. A number of these effects are beneficial but, unfortunately, many responses are still characterized based on phenomenology and there is more speculation than substance. With respect to tumor biology, although many neoplastic lesions are immunogenic, tumor antigens frequently are self antigens and induce tolerance and many patients with cancer exhibit suppressed immune responses, including defective antigen presentation. Therefore, if and when mushroom extracts are effective, they more likely function as a result of improved antigen presentation by dendritic cells than by a direct cytopathic effect. In this review we attempt to place these data in perspective, with a particular focus on dendritic cell populations and the ability of mushroom extracts to modulate immunity. There is, at present, no scientific basis for the use of either mushrooms or mushroom extracts in the treatment of human patients but there is significant potential for rigorous research to understand the potential of mushrooms in human disease and thence to focus on appropriate clinical trials to demonstrate effectiveness and/ or potential toxicity.     

Neutral 5-substituted 4-indazolylaminoquinazolines as potent, orally active inhibitors of erbB2 receptor tyrosine kinase

We have identified a new series of C-5 substituted indazolylaminoquinazolines as potent erbB2 kinase inhibitors. The lead compound 22 showed excellent in vitro potency, good physical properties, acceptable oral pharmacokinetics in rat and dog, and low human in vitro clearance. It showed at least equivalent activity dose for dose compared to lapatinib in various erbB2- or EGFR-driven xenograft models after chronic oral administration.     

Synthesis and biological activity of novel peptide mimetics as melanocortin receptor agonists

A series of novel peptidomimetic analogs was prepared containing cyclohexyl, phenyl, or heterocyclic groups to ostensibly orient the guanidine or mimic of an arginine in a putative melanocortin receptor ligand pharmacophore. Some binding affinity at the melanocortin receptors MC(3) and MC(4) was noted. In silico docking also indicated that the relative positions of the hydrogen-bonding sites and hydrophobic regions of the compounds are reasonably well matched to the receptor-binding site. This may present a lead entry into a selective series of MC(4)R agonists.     

Diet composition in San Francisco Estuary striped bass: does trophic adaptability have its limits?

Trophic adaptability is a term used to describe feeding flexibility in fishes. Though a useful conceptual starting point, fishes often face constraints on their ability to switch prey that could limit feeding success even when prey switching is observed. We compared striped bass diet compositions summarized from previously published studies in California’s Sacramento-San Joaquin Delta during two time periods (1963–1964 and 2001–2003), which allowed us to evaluate trophic adaptability in San Francisco Estuary striped bass at multiple time scales, ranging from intra-annual to multidecadal. The Delta is the landward region of the San Francisco Estuary; over time between the study periods, the Delta underwent substantial changes in potential prey availability for striped bass. We found evidence for trophic adaptability in San Francisco Estuary (SFE) striped bass at all temporal scales examined. Despite this ability to adapt to changes in prey availability, the relative abundance and carrying capacity of young striped bass have declined. This decline has previously been associated with substantial declines in their dominant historical prey—mysid shrimp. Our results, coupled with these previous findings, indicate that trophic adaptability may have limited usefulness as a conceptual model to predict foraging success when other food web constraints are not considered. We speculate that this is particularly true in highly invaded ecosystems like the San Francisco Estuary because invading species often introduce substantial and permanent changes into food webs, decreasing the likelihood that a predator will find prey assemblages that fully replace historical prey assemblages.