Across the first frontier: The behavioural ecology of the Sydney region aborigines

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DNA-Binding Specificity Changes in the Evolution of Forkhead Transcription Factors

The evolution of transcriptional regulatory networks entails the expansion and diversification of transcription factor (TF) families. The forkhead family of TFs, defined by a highly conserved winged helix DNA-binding domain (DBD), has diverged into dozens of subfamilies in animals, fungi, and related protists. We have used a combination of maximum-likelihood phylogenetic inference and independent, comprehensive functional assays of DNA-binding capacity to explore the evolution of DNA-binding specificity within the forkhead family. We present converging evidence that similar alternative sequence preferences have arisen repeatedly and independently in the course of forkhead evolution. The vast majority of DNA-binding specificity changes we observed are not explained by alterations in the known DNA-contacting amino acid residues conferring specificity for canonical forkhead binding sites. Intriguingly, we have found forkhead DBDs that retain the ability to bind very specifically to two completely distinct DNA sequence motifs.We propose an alternate specificity-determining mechanism whereby conformational rearrangements of the DBD broaden the spectrum of sequence motifs that a TF can recognize. DNA-binding bispecificity suggests a previously undescribed source of modularity and flexibility in gene regulation and may play an important role in the evolution of transcriptional regulatory networks.Organismic and Evolutionary Biolog

Clinical Symptoms and Therapies for Multiple Sclerosis

Multiple Sclerosis (MS) is a chronic form, progressive and immune mediated central nervous system disorder that affects both adults and children. MS is characterized by the development of multiple lesions with the nerve fibers in the spinal cord, optic nerves and brain. Multiple sclerosis affects the approximately 2.5 million people worldwide. A triad of symptoms characterize the disease: fatigue, changes in sensation, ataxia, muscle weakness, dysarthria, dysphagia, visual problems, chronic or acute pain, difficulties of bladder and bowel. The diagnosis of Multiple Sclerosis is made on the foundation of the signs and symptoms, with magnetic resonance imaging and additional laboratory tests playing a helpful role. Every tests are non precise and simply supply supportive indication for diagnosis. A few people have a inadequate number of “relapses” or “attacks” and remain fairly healthy for decades, others may worsen rapidly from the time of analysis, through shortened lifespan and poor excellence of the life. The  prognosis  is problematical to forecast; it depends on the initial symptom, subtype of the illness, the individual patient’s disorder characteristics. The substantial variability in multiple sclerosis manifestations leads to elevated figure of misdiagnoses each year, but advances in knowledge and pharmaceuticals are leading to more exact identification and successful management. Early diagnosis and management is essential in reducing the severity of disease

SUMOylation inhibits FOXM1 activity and delays mitotic transition

The forkhead box transcription factor FOXM1 is an essential effector of G2/M-phase transition, mitosis and the DNA damage response. As such, it is frequently deregulated during tumorigenesis. Here we report that FOXM1 is dynamically modified by SUMO1 but not by SUMO2/3 at multiple sites. We show that FOXM1 SUMOylation is enhanced in MCF-7 breast cancer cells in response to treatment with epirubicin and mitotic inhibitors. Mutation of five consensus conjugation motifs yielded a SUMOylation-deficient mutant FOXM1. Conversely, fusion of the E2 ligase Ubc9 to FOXM1 generated an auto-SUMOylating mutant (FOXM1-Ubc9). Analysis of wild-type FOXM1 and mutants revealed that SUMOylation inhibits FOXM1 activity, promotes translocation to the cytoplasm and enhances APC/Cdh1-mediated ubiquitination and degradation. Further, expression of the SUMOylation-deficient mutant enhanced cell proliferation compared with wild-type FOXM1, whereas the FOXM1-Ubc9 fusion protein resulted in persistent cyclin B1 expression and slowed the time from mitotic entry to exit. In summary, our findings suggest that SUMOylation attenuates FOXM1 activity and causes mitotic delay in cytotoxic drug response

Otpornost na antibiotike kod bakterija izolovanih od riba iz Srbije

Introduction. Bacteria isolated from skin, gills, and fish intestines from aquaculture ponds, ornamental fish stores/aquariums and live fish markets were investigated. Materials and Methods. Disk diffusion and E-test were used for susceptibility testing to carbapenems, ureidopenicillins with or without ß-lactamase inhibitor, 3rd and 4th generation cephalosporins, aminoglycosides, colistin, fluoroquinolones, and chloramphenicol. PCR was used to detect resistance genes in the bacterial isolates. Results and Conclusions. Among the total number of bacteria tested, regardless of the genus and species, 56.7% of isolates were found to be sensitive to all antibiotics, 23.1% of isolates were resistant to one or two antibiotics, and 20.2% of isolates were resistant to three and up to 16 antibiotics. In A. hydrophila isolated from a guppy (Poecilia reticulata) sampled in an ornamental fish store aquarium, 16S rRNA methyltransferase was confirmed by finding the rmtB gene. Pseudomonas isolates showing phenotypic resistance to carbapenems, ureidopenicillins with or without ß-lactamase inhibitor and 3rd and 4th generation cephalosporins were tested and found negative for different resistance genes by PCR (MßL, ESBL, KPC, OXA-23, OXA-24, OXA-40, OXA-58, VIM, IMP, SPM, GIM, NDM, TEM, SHV, CTX-M-1, CTX-M-9, OXA-1, OXA-9 and the AmpC group, as well as single genes, MOXM, CITM, ACCM, EBCM, FOXM, DHAM). Based on E-test results, three Pseudomonas isolates from common carp (Cyprinus carpio) were found to be resistant to colistin with MIC values of 4 μg/mL.Uvod. U ovom ispitivanju izolovane su bakterija koje su sastavni deo mikrobioma kože, škrga i creva riba iz različitih sredina (ribnjaci, akvarijumi, riblje pijace). Materijal i metode. Primenom disk difuzionog testa i E testa ispitivano je fenotipsko ispoljavanje rezistencije na karbapeneme, ureidopeniciline sa i bez inhibitora beta-laktamaza, cefalosporine III i IV generacije, aminoglikozide, tetraciklin, kolistin, flurohinolone i hloramfenikol. Prisustvo gena rezistencije vršeno je primenom metode PCR. Rezultati i zaključak. Posmatrano na ukupan broj ispitanih sojeva, bez obzira na rod i vrstu bakterija, 56,7% sojeva je osetljivo na sve antibiotike, 23,1% sojeva je rezistentno na 1 do 2 antibiotikaa 20,2% sojeva je rezistentno na 3 do 16 antibiotika. Kod soja A. hydrophila izolovanom iz akvarijumske ribice gupi nalazom gena rmtBpotvrđeno je prisustvo 16S rRNK metiltransferaze odgovornim za rezistenciju na aminoglikozide. Pseudomonas izolati koji su pokazali fenotipsku rezistenciju na karbapeneme, ureidopeniciline sa i bez inhibitora beta-laktamaza, kao i na cefalosporine III i IV generacije, testirani su i bili negativni na sledeće gene (MßL, ESBL, KPC, OXA-23, OXA-24, OXA-40, OXA-58, VIM, IMP, SPM, GIM, NDM, TEM, SHV, CTX-M-1, CTX-M-9, OXA-1, OXA-9, AmpC grupni kao i pojedinačni geni, MOXM, CITM, ACCM, EBCM, FOXM, DHAM). Na osnovu dobijenih rezultata primenom E testa, kod 3 soja iz roda Pseudomonas izolovanih od šarana nađena je rezistencija na kolistin sa dobijenim vrednostima MIK 4 μg/mL

The forkhead box transcription factors, FKH1 and FKH2, along with the Anaphase-Promoting Complex regulate Saccharomyces cerevisiae lifespan

Forkhead box (Fox) transcription factors have a conserved function in regulating lifespan and onset of age related disease in organisms from worms to mammals. Key functions in this process are the regulation of the cell cycle, oxidative stress response, and apoptosis. A complex post-translational code from nutrient, growth factor, and stress induced signals regulates Fox activity, target specificity, stability, and subcellular localization; however, many of the Fox mechanisms and targets responsible for regulating lifespan remain elusive. The budding yeast, Saccharomyces cerevisiae, is a powerful model for unravelling the genetic mechanism and pathways. Yeast encodes four Fox transcription factors, Fkh1, Fkh2, Fhl1 and Hcm1, and their roles in aging are only recently being examined. In this study, we utilized the chronological lifespan and oxidative stress assays, to explore evolutionary conservation of lifespan regulation in two of the yeast Fox orthologs, FKH1 and FKH2. We observed that deletion of both FKH genes in S. cerevisiae, impedes normal lifespan and stress resistance. Furthermore, fkh1Δ fkh2Δ cells were found to be non-responsive to caloric restriction, an intervention that extends lifespan from yeast to mammals. Conversely, increased expression of the FKHs leads to extended lifespan and improved stress resistance. Additionally, we show the Anaphase-Promoting Complex (APC) genetically interacts with the FKHs, likely functioning in a linear pathway under normal conditions, as fkh1Δ fkh2Δ post-mitotic survival defect is epistatic to that observed in apc5CA mutants. However, under stress conditions, post-mitotic survival is dramatically impaired in apc5CA fkh1Δ fkh2Δ beyond either apc5CA or fkh1Δ fkh2Δ. Finally, we observed that both the FKHs and APC genetically interact with nutrient-responsive lifespan-regulating kinase encoding genes SCH9 and TOR1. This study establishes that the yeast FKHs play a role as regulators of lifespan in yeast and identifies the APC as a novel component of this mechanism. We speculate this involves combined regulation of stress response, genomic stability, and cell cycle

Global Models of Intermediate Timescale Variability on the Sun

In recent years a number of advances in both observation and theory have increased our understanding of the solar interior and how to model it. For climate studies, the timescale of interest for changes in the Sun ranges from decades to centuries. Some of the theoretical advances that will contribute to the building of global models of the Sun's variability on intermediate timescales are described. The current constraints on the important components are discussed. Finally a short discussion presenting some implications for input to climate modeling is presented

Branching Fractions for D0 -> K+K- and D0 -> pi+pi-, and a Search for CP Violation in D0 Decays

Using the large hadroproduced charm sample collected in experiment E791 at Fermilab, we have measured ratios of branching fractions for the two-body singly-Cabibbo-suppressed charged decays of the D0: (D0 -> KK)/(D0 -> Kpi) = 0.109 +- 0.003 +- 0.003, (D0 -> pipi)/(D0 -> Kpi) = 0.040 +- 0.002 +- 0.003, and (D0 -> KK)/(D0 -> pipi) = 2.75 +- 0.15 +- 0.16. We have looked for differences in the decay rates of D0 and D0bar to the CP eigenstates K+K- and pi+pi-, and have measured the CP asymmetry parameters A_CP(K+K-) = -0.010 +- 0.049 +- 0.012 and A_CP(pi+pi-) = -0.049 +- 0.078 +- 0.030, both consistent with zero.Comment: 10 Postscript pages, including 2 figures. Submitted to Phys. Lett.

Metastatic Group 3 Medulloblastoma in a Patient With Tuberous Sclerosis Complex: Case Description and Molecular Characterization of the Tumor

Medulloblastoma is the most common pediatric brain tumor. We describe a child with tuberous sclerosis complex that developed a Group 3, myc overexpressed, metastatic medulloblastoma (MB). Considering the high risk of treatment-induced malignancies, a tailored therapy, omitting radiation, was given. Based on the evidence of mammalian target of rapamycin mTORC, mTOR Complex; RAS, Rat sarcoma; RAF, rapidly accelerated fibrosarcoma (mTOR) pathway activation in the tumor, targeted therapy was applied resulting in complete remission of disease. Although the PI3K/AKT/mTOR signaling pathway plays a role in MB, we did not find TSC1/TSC2 (TSC, tuberous sclerosis complex) mutation in our patient. We speculate that a different pathway resulting in mTOR activation is the basis of both TSC and MB in this child; H&E, haematoxilin and eosin; Gd, gadolinium

Antimicrobial Susceptibility and Multiplex PCR Screening of AmpC Genes From Isolates of Enterobacter cloacae, Citrobacter freundii, and Serratia marcescens

Background/PurposeThe emergence of multiple drug resistance in Enterobacteriaceae is of particular concern. The aim of this study was to evaluate the antimicrobial susceptibility and screen for the ampC gene in three members of the Enterobacteriaceae family (Enterobacter cloacae, Citrobacter freundii, and Serratia marcescens) found at Taichung Veterans General Hospital during the past 5 years using multiplex polymerase chain reaction (PCR).MethodsThe susceptibility of thirty isolates from each of the three Enterobacteriaceae family members to five antimicrobial agents (ceftazidime, flomoxef, imipenem, moxifloxacin, and colistin) was assessed. The susceptibility was analyzed by disk diffusion, screening and confirmatory tests for extended-spectrum β-lactamases (ESBL) and minimum inhibitory concentration tests according to the recommendations of the Clinical and Laboratory Standards Institute. The detection of ampC genes (3 families, including DHA, EBC and CIT) was performed by multiplex PCR. To detect the coexistence of ESBL genes, PCR was performed using five primer pairs: TEM, SHV, SHV-5, CTX-M-3, and CTX-M-14.ResultsOf the 90 isolates, 53 (58.9%) were positive in the screening test for ESBL. Resistance genes were detected in 12 (22.6%) of these isolates: ampC gene of DHA type in one E. cloacae isolate and EBC type in three E. cloacae isolates; ampC gene of CIT type in four C. freundii isolates; CTX-M-3-like in one C. freundii isolate and one S. marcescens isolate; TEM in three E. cloacae isolates, three C. freundii isolates and two S. marcescens isolates; SHV in one C. freundii isolate.ConclusionAntibiotic phenotypes cannot accurately distinguish the resistance mechanisms caused by ampC or ESBL, and especially in ESBL-ampC combinations. However, PCR is a useful technique for the identification of the different types of resistance genes