Inhibition of prostaglandin-degrading enzyme 15-PGDH rejuvenates aged muscle mass and strength.

Treatments are lacking for sarcopenia, a debilitating age-related skeletal muscle wasting syndrome. We identifed increased amounts of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the prostaglandin E2 (PGE2)-degrading enzyme, as a hallmark of aged tissues, including skeletal muscle. The consequent reduction in PGE2 signaling contributed to muscle atrophy in aged mice and results from 15-PGDH-expressing myofibers and interstitial cells, such as macrophages, within muscle. Overexpression of 15-PGDH in young muscles induced atrophy. Inhibition of 15-PGDH, by targeted genetic depletion or a small-molecule inhibitor, increased aged muscle mass, strength, and exercise performance. These benefits arise from a physiological increase in PGE2 concentrations, which augmented mitochondrial function and autophagy and decreased transforming growth factor-ß signaling and activity of ubiquitin-proteasome pathways. Thus, PGE2 signaling ameliorates muscle atrophy and rejuvenates muscle function, and 15-PGDH may be a suitable therapeutic target for countering sarcopenia.

Cognitive Bias Under Adverse and Rewarding Conditions: A Systematic Review of Rodent Studies.

Background: Cognitive bias refers to emotional influences on cognition and provides a cognitive measure of negativity- or positivity-bias through assessment of the behavioral responses to ambiguous stimuli. Thus, under negative conditions an animal is more likely to judge ambiguous stimuli as negative, and under positive conditions as positive. The transfer of past experiences to novel but similar situations is highly adaptive, as it allows the animal to anticipate on the most likely outcome of the ambiguous cues. Methods: We conducted a systematic review to summarize the current state of evidence on cognitive bias in rodents under adverse and rewarding or supportive conditions. Results: In total 20 studies were identified, in which auditory, spatial, tactile, or visual tasks were used. Stressed rodents generally made fewer positive responses than their non-stressed conspecifics. Housing enrichment made rodents more positive in anticipation of ambiguous cues. Ethanol seeking rats generalized the ambiguous cues to sucrose and less to ethanol if sucrose was available. Amphetamine, fluoxetine, and ketamine shifted the bias toward positivity, while reboxetine elevated negative bias. Conclusion: The auditory tasks have been most extensively validated, followed by the tactile and spatial tasks, and finally the visual tasks. The tactile and spatial tasks use latency as readout, which is sensitive to confounding factors. It is yet uncertain whether spatial tasks measure cognitive bias. Across all tasks, with some exceptions, rodents exposed to stress show less positivity-bias when exposed to ambiguous cues, whereas rodents exposed to rewarding substances or treated with antidepressant drugs are biased toward reward. Considering the methodological heterogeneity and risk of bias, the present data should be interpreted with caution.

Host TIMP-1 overexpression confers resistance to experimental brain metastasis of a fibrosarcoma cell line.

Within the tumor-stromal microenvironment a disrupted balance between matrix metalloproteinases (MMPs) and their inhibitors compromises the integrity of the extracellular matrix and promotes malignancy. Tissue inhibitors of metalloproteinases (TIMPs) have been linked to tumor suppression in studies of genetically altered tissue culture cells and in analyses of clinical specimens in situ. We generated transgenic mice as a model system to test the relationship between TIMP-1 levels in a host organ and susceptibility to experimentally targeted metastasis. Ectopically overexpressed TIMP-1 in the brain resulted in a tissue microenvironment with elevated protein levels of this natural MMP inhibitor. Metastatic challenge provided by lacZ-tagged fibrosarcoma cells permitted high-resolution analysis of metastatic load and pattern. We found that elevated host TIMP-1 imposed resistance to experimental metastasis of fibrosarcoma: In TIMP-1 overexpressing mice, brain metastases were significantly reduced by 75% compared to wild-type littermates. Our findings demonstrate that ectopic TIMP-1 expression efficiently exerts a suppressive effect on metastasizing tumor cells.

Clinical aspects of a successful embryo cryopreservation programme from IVF cycles in Singapore General Hospital.

An analysis in November 1991 showed a successful cryopreservation programme between May 1989 and October 1991 in Singapore General Hospital. This programme has resulted in 9.1% more pregnancies in addition to those from conventional in-vitro fertilisation (IVF) methods, increasing pregnancy rates during the same period, from 27.8% per IVF cycle to 36.9% per cycle. The current policy is to transfer 3 fresh embryos in the IVF cycle and freeze the remainder using a modified Testart's method. Clinical factors that influence the success rate include the number of embryos transferred, stage of development of embryos and genital tract infections. Age of patient and grade of embryos did not seem to have affected pregnancy rates. Patients with anovulatory cycles enjoy similar pregnancy rates using a regulated cycle regime for frozen-thawed embryo transfer.

Effects of navigation speed on motion sickness caused by an immersive virtual environment.

This study investigated the effects of navigation speed on the level of motion sickness during and after a 30-min head-steered virtual environment. Root-mean-squares for 8 speeds in the fore-and-aft axis were 3, 4, 6, 8, 10, 24, 30, and 59 m/s. Participants were 96 Chinese men. Both the nausea and vection ratings increased significantly with speeds increasing from 3 m/s to 10 m/s. At speeds exceeding 10 m/s, the ratings stabilized. Navigation speeds were found to significantly affect the onset times of vection and nausea but did not affect their rates of increase with duration of exposure. For the various Simulator Sickness Questionnaire scores, navigation speed had a significant influence on only the oculomotor subscore. Actual or potential applications of this research include the prediction of sickness associated with simulation tours in a virtual environment at different navigation speeds.

Chromosomes of oocytes failing in-vitro fertilization.

Of 263 oocytes that failed to fertilize after in-vitro fertilization and were sent for cytogenetic investigation, 179 (68.1%) were analysable. More than 72.0% were normal metaphase II haploids (23,X). Hyperhaploidy, hypohaploidy and complex cases made up a total aneuploidy rate of 12.3%, while 10.1% were diploid. In addition, there were five oocytes with structural aberrations and eight yielded chromatids only. The total chromosome aberration rate was 29.1%. No significant difference was found between the aneuploidy rate and maternal age. Here we present photographic evidence of oocytes with extra whole chromosomes and extra single chromatids. We suggest that both predivision and nondisjunction contribute to the formation of trisomy in man.

Laboratory production of ammonium and ferric sulfate aerosols.

Since sulfate aerosol particles are an environmental factor of possible concern, laboratory studies are being conducted to determine their health effects. It is important in such studies that aerosols be controlled and monitored. Submicron sulfate aerosols at high (greater than 80%) and low (30-40%) relative humidities were generated and characterized in support of animal inhalation experiments. Aqueous solutions of ammonium sulfate and ferric sulfate were aerosolized with a compressed air nebulizer, dried, discharged and passed into an aerosol chamber. Aerosol characterization was performed using cascade impactors, electron microscopy, filter samples and an electrical mobility analyzer. Parameters measured included particle size distribution and mass concentration. Instruments used for sizing the aerosols were compared. The electrical mobility analyzer provided useful information on the time stability of the particle size and the mass concentration, but agreement between this instrument and electron microscopy or cascade impaction was poor.

MMP inhibitors augment fibroblast adhesion through stabilization of focal adhesion contacts and up-regulation of cadherin function.

Increased pericellular proteolysis due to an imbalance between MMPs (matrix metalloproteinases) and TIMPs (tissue inhibitors of metalloproteinases) promotes early stages of tumorigenesis. We have reported that TIMP-1 down-regulation confers tumorigenicity on immortal Swiss 3T3 fibroblasts. In pursuit of the mechanism involved in this transformation, we asked whether MMP inhibitors modulate contact inhibition and cell adhesion, because the dysregulation of these events is essential for cellular transformation. Using both genetic and biochemical means, we demonstrate that MMP inhibitors regulate fibroblast cell adhesion. TIMP-1 down-regulated cells formed dense, multilayered colonies, suggesting a loss of contact inhibition. Recombinant TIMP-1 and synthetic MMP inhibitors (MMPi) restored normal cell contact and density of these cells in a dose-dependent manner. Consequently, the effect of MMPi on both cell-extracellular matrix (ECM) and cell-cell adhesion were investigated. Upon MMPi treatment, p125(FAK) was redistributed, together with vinculin, to points of cell-ECM contact. Furthermore, phosphorylation of p125(FAK) was restored to levels similar to that of wild type. In parallel, MMPi treatment increased cadherin levels and stabilized cadherin-mediated cell-cell contacts. Moreover, enhanced cadherin function was evident as increased calcium-dependent cell-cell aggregation and co-localization of cadherin and beta-catenin at the cell membrane. We also obtained independent evidence of altered cadherin function using timp-1(-/-) mouse embryonic fibroblasts. Our data provide provocative evidence that increased pericellular proteolysis impacts cell adhesion systems to offset normal contact inhibition, with subsequent effects on cell transformation and tumorigenesis.

Cellular turnover and extracellular matrix remodeling in female reproductive tissues: functions of metalloproteinases and their inhibitors.

Female reproductive tissues possess a unique ability to accommodate a remarkable amount of cell turnover and extracellular matrix (ECM) remodeling following puberty. Cellular structures within ovary, uterus, and mammary tissue not only change cyclically in response to ovarian hormones but also undergo differentiation during pregnancy, and eventually revert to that resembling the pre-pregnant stage. Cell proliferation, apoptosis, invasion, and differentiation are integral cellular processes that are precisely regulated in reproductive tissues, but become dysregulated in pathologies such as cancer. Explicit reorganization of ECM and basement membranes is also critical to preserve the form and function of these tissues. Here we review the evidence that coordinated spatiotemporal expression patterns of matrix metalloproteinase (MMP) genes and their tissue inhibitors (TIMPs) are important in cell and ECM turnover of the ovary, uterus, and mammary tissues. We discuss how perturbation in these gene families may impact the biology of these reproductive tissues and the factors implicated in the control of MMP and TIMP gene expression. The observed trends in MMP and TIMP expression involved in ovarian and mammary carcinomas are also presented.

Transgenic TIMP-1 inhibits simian virus 40 T antigen-induced hepatocarcinogenesis by impairment of hepatocellular proliferation and tumor angiogenesis.

Tissue inhibitors of metalloproteinases (TIMP) block proteolytic degradation of extracellular matrix and consequently impede tumor invasion and metastasis. In addition, we have previously reported that hepatic TIMP-1 modulation alters the susceptibility of the liver to oncogene (simian virus 40 T-antigen; TAg)-induced tumorigenesis in a double-transgenic mouse model. To identify the cellular processes by which TIMP-1 inhibits hepatocarcinogenesis, we examined the effects of TIMP-1 on four specific events that are important during tumorigenesis: hepatocellular proliferation, apoptosis, the stromal characteristics of the liver, and tumor vascularization. Transgenic mice with elevated or reduced hepatic TIMP-1 expression were bred independently with TAg transgenics. Liver tissue from littermates were analyzed by in situ hybridization with TIMP-1 cDNA probes; gelatin enzymography; immunohistochemistry for proliferating cell nuclear antigen, von Willebrand factor, and collagen type IV; reticulin histochemistry; and collagens type III and IV, laminin, fibronectin, and CD31 immunoblotting. We demonstrate that TIMP-1 overexpression significantly inhibited the proliferation of hepatocytes in TAg mice but did not affect their apoptotic index, the hepatic parenchymal architecture, or extracellular matrix composition, including collagens type III and IV, laminin, and fibronectin. Moreover, the hepatocellular carcinomas formed in TIMP-1-overexpressing mice had significantly reduced tumor vascularization; conversely, tumor vascularization was significantly increased in TIMP-1-reduced livers. These data indicate that TIMP-1 inhibits TAg-induced hepatocarcinogenesis by altering hepatocellular proliferation and tumor vascularization, without any effect on hepatocyte apoptosis and stromal composition. To our knowledge, this is the first in vivo demonstration that genetic modulation of TIMP-1 inhibits cellular proliferation and angiogenesis during hepatocarcinogenesis. This potentially extends the use of matrix metalloproteinase inhibitors in cancer beyond control of invasion and metastasis.