Distribution and Abundance of Submerged Aquatic Vegetation in 1984 and 1985

Communities of submerged aquatic vegetation (SA V) are an integral part of the Chesapeake Bay ecosystem. They provide an important habitat for many species, either as a food source or as protection from predators, i.e., as a nursery. By reducing currents and baffling waves, they allow for deposition of suspended material. In addition, they bind sediments with their roots and rhizomes to prevent erosion of the underlying material. They are important in nutrient cycling through both the absorption and release of nitrogen and phosphorus.https://scholarworks.wm.edu/vimsbooks/1165/thumbnail.jp

Huntington’s disease age at motor onset is modified by the tandem hexamer repeat in TCERG1

Huntington’s disease is caused by an expanded CAG tract in HTT. The length of the CAG tract accounts for over half the variance in age at onset of disease, and is influenced by other genetic factors, mostly implicating the DNA maintenance machinery. We examined a single nucleotide variant, rs79727797, on chromosome 5 in the TCERG1 gene, previously reported to be associated with Huntington’s disease and a quasi-tandem repeat (QTR) hexamer in exon 4 of TCERG1 with a central pure repeat. We developed a method for calling perfect and imperfect repeats from exome-sequencing data, and tested association between the QTR in TCERG1 and residual age at motor onset (after correcting for the effects of CAG length in the HTT gene) in 610 individuals with Huntington’s disease via regression analysis. We found a significant association between age at onset and the sum of the repeat lengths from both alleles of the QTR (p = 2.1 × 10−9), with each added repeat hexamer reducing age at onset by one year (95% confidence interval [0.7, 1.4]). This association explained that previously observed with rs79727797. The association with age at onset in the genome-wide association study is due to a QTR hexamer in TCERG1, translated to a glutamine/alanine tract in the protein. We could not distinguish whether this was due to cis-effects of the hexamer repeat on gene expression or of the encoded glutamine/alanine tract in the protein. These results motivate further study of the mechanisms by which TCERG1 modifies onset of HD

An Intermittent Live Cell Imaging Screen for siRNA Enhancers and Suppressors of a Kinesin-5 Inhibitor

Kinesin-5 (also known as Eg5, KSP and Kif11) is required for assembly of a bipolar mitotic spindle. Small molecule inhibitors of Kinesin-5, developed as potential anti-cancer drugs, arrest cell in mitosis and promote apoptosis of cancer cells. We performed a genome-wide siRNA screen for enhancers and suppressors of a Kinesin-5 inhibitor in human cells to elucidate cellular responses, and thus identify factors that might predict drug sensitivity in cancers. Because the drug's actions play out over several days, we developed an intermittent imaging screen. Live HeLa cells expressing GFP-tagged histone H2B were imaged at 0, 24 and 48 hours after drug addition, and images were analyzed using open-source software that incorporates machine learning. This screen effectively identified siRNAs that caused increased mitotic arrest at low drug concentrations (enhancers), and vice versa (suppressors), and we report siRNAs that caused both effects. We then classified the effect of siRNAs for 15 genes where 3 or 4 out of 4 siRNA oligos tested were suppressors as assessed by time lapse imaging, and by testing for suppression of mitotic arrest in taxol and nocodazole. This identified 4 phenotypic classes of drug suppressors, which included known and novel genes. Our methodology should be applicable to other screens, and the suppressor and enhancer genes we identified may open new lines of research into mitosis and checkpoint biology

Search for Nucleon Decays induced by GUT Magnetic Monopoles with the MACRO Experiment

The interaction of a Grand Unification Magnetic Monopole with a nucleon can lead to a barion-number violating process in which the nucleon decays into a lepton and one or more mesons (catalysis of nucleon decay). In this paper we report an experimental study of the effects of a catalysis process in the MACRO detector. Using a dedicated analysis we obtain new magnetic monopole (MM) flux upper limits at the level of $\sim 3\cdot 10^{-16} cm^{-2} s^{-1} sr^{-1}$ for $1.1\cdot 10^{-4} \le |\beta| \le 5\cdot 10^{-3}$, based on the search for catalysis events in the MACRO data. We also analyze the dependence of the MM flux limit on the catalysis cross section.Comment: 12 pages, Latex, 10 figures and 2 Table

Huntington's disease pathogenesis: two sequential components

Historically, Huntington’s disease (HD; OMIM #143100) has played an important role in the enormous advances in human genetics seen over the past four decades. This familial neurodegenerative disorder involves variable onset followed by consistent worsening of characteristic abnormal movements along with cognitive decline and psychiatric disturbances. HD was the first autosomal disease for which the genetic defect was assigned to a position on the human chromosomes using only genetic linkage analysis with common DNA polymorphisms. This discovery set off a multitude of similar studies in other diseases, while the HD gene, later renamed HTT, and its vicinity in chromosome 4p16.3 then acted as a proving ground for development of technologies to clone and sequence genes based upon their genomic location, with the growing momentum of such advances fueling the Human Genome Project. The identification of the HD gene has not yet led to an effective treatment, but continued human genetic analysis of genotype-phenotype relationships in large HD subject populations, first at the HTT locus and subsequently genome-wide, has provided insights into pathogenesis that divide the course of the disease into two sequential, mechanistically distinct components

A Lentivirus-Mediated Genetic Screen Identifies Dihydrofolate Reductase (DHFR) as a Modulator of β-Catenin/GSK3 Signaling

The multi-protein β-catenin destruction complex tightly regulates β-catenin protein levels by shuttling β-catenin to the proteasome. Glycogen synthase kinase 3β (GSK3β), a key serine/threonine kinase in the destruction complex, is responsible for several phosphorylation events that mark β-catenin for ubiquitination and subsequent degradation. Because modulation of both β-catenin and GSK3β activity may have important implications for treating disease, a complete understanding of the mechanisms that regulate the β-catenin/GSK3β interaction is warranted. We screened an arrayed lentivirus library expressing small hairpin RNAs (shRNAs) targeting 5,201 human druggable genes for silencing events that activate a β-catenin pathway reporter (BAR) in synergy with 6-bromoindirubin-3′oxime (BIO), a specific inhibitor of GSK3β. Top screen hits included shRNAs targeting dihydrofolate reductase (DHFR), the target of the anti-inflammatory compound methotrexate. Exposure of cells to BIO plus methotrexate resulted in potent synergistic activation of BAR activity, reduction of β-catenin phosphorylation at GSK3-specific sites, and accumulation of nuclear β-catenin. Furthermore, the observed synergy correlated with inhibitory phosphorylation of GSK3β and was neutralized upon inhibition of phosphatidyl inositol 3-kinase (PI3K). Linking these observations to inflammation, we also observed synergistic inhibition of lipopolysaccharide (LPS)-induced production of pro-inflammatory cytokines (TNFα, IL-6, and IL-12), and increased production of the anti-inflammatory cytokine IL-10 in peripheral blood mononuclear cells exposed to GSK3 inhibitors and methotrexate. Our data establish DHFR as a novel modulator of β-catenin and GSK3 signaling and raise several implications for clinical use of combined methotrexate and GSK3 inhibitors as treatment for inflammatory disease

Circulating β-endorphin, adrenocorticotrophic hormone and cortisol levels of stallions before and after short road transport: stress effect of different distances

<p>Abstract</p> <p>Background</p> <p>Since transport evokes physiological adjustments that include endocrine responses, the objective of this study was to examine the responses of circulating β-endorphin, adrenocorticotrophic hormone (ACTH) and cortisol levels to transport stress in stallions.</p> <p>Methods</p> <p>Forty-two healthy Thoroughbred and crossbred stallions were studied before and after road transport over distances of 100, 200 and 300 km. Blood samples were collected from the jugular vein: first in a single box immediately before loading (pre-samples), then immediately after transport and unloading on arrival at the breeding stations (post-samples).</p> <p>Results</p> <p>An increase in circulating β-endorphin levels after transport of 100 km (<it>P </it>< 0.01), compared to basal values was observed. Circulating ACTH levels showed significant increases after transport of 100 km (<it>P </it>< 0.001) and 200 km (<it>P </it>< 0.001). Circulating cortisol levels showed significant increases after road transport over distances of 100, 200 and 300 km (<it>P </it>< 0.001). An effect of transport on β-endorphin, ACTH and cortisol variations was therefore evident for the different distances studied. No significant differences (<it>P </it>> 0.05) between horses of different ages and different breeds were observed for β-endorphin, ACTH and cortisol levels.</p> <p>Conclusion</p> <p>The results obtained for short term transportation of stallions showed a very strong reaction of the adrenocortical system. The lack of response of β-endorphin after transport of 200–300 km and of ACTH after transport of 300 km seems to suggest a soothing effect of negative feedback of ACTH and cortisol levels.</p

A Yersinia Effector with Enhanced Inhibitory Activity on the NF-κB Pathway Activates the NLRP3/ASC/Caspase-1 Inflammasome in Macrophages

A type III secretion system (T3SS) in pathogenic Yersinia species functions to translocate Yop effectors, which modulate cytokine production and regulate cell death in macrophages. Distinct pathways of T3SS-dependent cell death and caspase-1 activation occur in Yersinia-infected macrophages. One pathway of cell death and caspase-1 activation in macrophages requires the effector YopJ. YopJ is an acetyltransferase that inactivates MAPK kinases and IKKβ to cause TLR4-dependent apoptosis in naïve macrophages. A YopJ isoform in Y. pestis KIM (YopJKIM) has two amino acid substitutions, F177L and K206E, not present in YopJ proteins of Y. pseudotuberculosis and Y. pestis CO92. As compared to other YopJ isoforms, YopJKIM causes increased apoptosis, caspase-1 activation, and secretion of IL-1β in Yersinia-infected macrophages. The molecular basis for increased apoptosis and activation of caspase-1 by YopJKIM in Yersinia-infected macrophages was studied. Site directed mutagenesis showed that the F177L and K206E substitutions in YopJKIM were important for enhanced apoptosis, caspase-1 activation, and IL-1β secretion. As compared to YopJCO92, YopJKIM displayed an enhanced capacity to inhibit phosphorylation of IκB-α in macrophages and to bind IKKβ in vitro. YopJKIM also showed a moderately increased ability to inhibit phosphorylation of MAPKs. Increased caspase-1 cleavage and IL-1β secretion occurred in IKKβ-deficient macrophages infected with Y. pestis expressing YopJCO92, confirming that the NF-κB pathway can negatively regulate inflammasome activation. K+ efflux, NLRP3 and ASC were important for secretion of IL-1β in response to Y. pestis KIM infection as shown using macrophages lacking inflammasome components or by the addition of exogenous KCl. These data show that caspase-1 is activated in naïve macrophages in response to infection with a pathogen that inhibits IKKβ and MAPK kinases and induces TLR4-dependent apoptosis. This pro-inflammatory form of apoptosis may represent an early innate immune response to highly virulent pathogens such as Y. pestis KIM that have evolved an enhanced ability to inhibit host signaling pathways

Circadian-Related Sleep Disorders and Sleep Medication Use in the New Zealand Blind Population: An Observational Prevalence Survey

STUDY OBJECTIVES: To determine the prevalence of self-reported circadian-related sleep disorders, sleep medication and melatonin use in the New Zealand blind population. DESIGN: A telephone survey incorporating 62 questions on sleep habits and medication together with validated questionnaires on sleep quality, chronotype and seasonality. PARTICIPANTS: PARTICIPANTS WERE GROUPED INTO: (i) 157 with reduced conscious perception of light (RLP); (ii) 156 visually impaired with no reduction in light perception (LP) matched for age, sex and socioeconomic status, and (iii) 156 matched fully-sighted controls (FS). SLEEP HABITS AND DISTURBANCES: The incidence of sleep disorders, daytime somnolence, insomnia and sleep timing problems was significantly higher in RLP and LP compared to the FS controls (p<0.001). The RLP group had the highest incidence (55%) of sleep timing problems, and 26% showed drifting sleep patterns (vs. 4% FS). Odds ratios for unconventional sleep timing were 2.41 (RLP) and 1.63 (LP) compared to FS controls. For drifting sleep patterns, they were 7.3 (RLP) and 6.0 (LP). MEDICATION USE: Zopiclone was the most frequently prescribed sleep medication. Melatonin was used by only 4% in the RLP group and 2% in the LP group. CONCLUSIONS: Extrapolations from the current study suggest that 3,000 blind and visually impaired New Zealanders may suffer from circadian-related sleep problems, and that of these, fewer than 15% have been prescribed melatonin. This may represent a therapeutic gap in the treatment of circadian-related sleep disorders in New Zealand, findings that may generalize to other countries