The meaning of mas

No abstract available

Restricted mobility of Dnmt1 in preimplantation embryos: implications for epigenetic reprogramming

BACKGROUND: Mouse preimplantation development is characterized by both active and passive genomic demethylation. A short isoform of the prevalent maintenance DNA methyltransferase (Dnmt1S) is found in the cytoplasm of preimplantation embryos and transiently enters the nucleus only at the 8-cell stage. RESULTS: Using GFP fusions we show that both the long and short isoforms of Dnmt1 localize to the nucleus of somatic cells and the cytoplasm of preimplantation embryos and that these subcellular localization properties are independent of phosphorylation. Importantly, photobleaching techniques and salt extraction revealed that Dnmt1S has a very restricted mobility in the cytoplasm, while it is highly mobile in the nucleus of preimplantation embryos. CONCLUSION: The restricted mobility of Dnmt1S limits its access to DNA and likely contributes to passive demethylation and epigenetic reprogramming during preimplantationdevelopment

A pre-specified statistical analysis plan for the VERIFY study : Vildagliptin efficacy in combination with metformin for early treatment of T2DM

Aims To ensure the integrity of the planned analyses and maximize the clinical utility of the VERIFY study results by describing the detailed concepts behind its statistical analysis plan (SAP) before completion of data collection and study database lock. The SAP will be adhered to for the final primary data analysis of the VERIFY trial. Materials and Methods Vildagliptin efficacy in combination with metformin for early treatment of T2DM (VERIFY) is an ongoing, multicentre, randomized controlled trial aiming to demonstrate the clinical benefits of glycaemic durability and glucose control achieved with an early combination therapy in newly-diagnosed type 2 diabetes (T2DM) patients. Results The SAP was initially designed at the study protocol conception phase and later modified, as reported here, in collaboration between the steering committee members, statisticians, and the VERIFY study leadership team. All authors were blinded to treatment allocation. An independent statistician has additionally retrieved and presented unblinded data to the independent data safety monitoring committee. An overview of the trial design with a focus on describing the fine-tuning of the analysis plan for the primary efficacy endpoint, risk of initial treatment failure, and secondary, exploratory and pre-specified subgroup analyses is provided here. Conclusion According to optimal trial practice, the details of the statistical analysis and data-handling plan prior to locking the database are reported here. The SAP accords with high-quality standards of internal validity to minimize analysis bias and will enhance the utility of the reported results for improved outcomes in the management of T2DM.Peer reviewe

Analiza proteinskih adukata kao biomarkera kratkotrajne izloženosti etilen oksidu i rezultati biomonitoringa

An accidental exposure of six workers to ethylene oxide (EO) provided the rationale for a biomonitoring and follow-up study, whose aim was to analyse protein adduct kinetics and examine the differentiation between accidental and environmental exposure, e.g., from tobacco smoke. For this purpose, the decrease in the concentration of the haemoglobin adduct N-2-hydroxyethylvaline (HEV) was followed during a fi ve-month period after the accident, together with N-2-cyanoethylvaline (CEV) and urinary cotinine, two well-established biomarkers for smoking. The follow-up study showed that EO adduct concentrations significantly increased after a short but presumably high exposure. Initial biomonitoring revealed HEV levels above 500 pmol g-1 globin in all cases, with a maximum of about 2,400 pmol g-1 globin. This compares to a German EKA value (exposure equivalent for carcinogenic substances) for a daily 8-h-exposure to 1 ppm EO of 90 μg L-1 blood (~3,900 pmol g-1 globin). The adduct levels dropped in accordance with the expected zero-order kinetics for a single exposure. After the five-month observation interval, the HEV concentrations in blood refl ected the individual background from tobacco smoking. The results of this study show that even a short exposure to ethylene oxide may result in a signifi cant rise in haemoglobin adduct levels. Although protein adducts and their occupational-medical assessment values are considered for long-term exposure surveillance, they can also be used for monitoring accidental exposures. In these cases, the calculation of daily ‘ppm-equivalents’ may provide a means for a comparison with the existing assessment values.U radu su prikazani rezultati biomonitoringa provedenog neposredno nakon akcidentalnog izlaganja šestorice radnika etilen oksidu i studije praćenja (follow up) provedene u cilju procjene kinetike razgradnje proteinskih adukata i utvrđivanja razlika nakon kratkotrajne izloženosti i izlaganja čimbenicima iz okoliša kao što je duhanski dim. U tu smo svrhu tijekom petomjesečnoga razdoblja nakon nezgode pratili smanjenje koncentracije hemoglobinskog adukta N-2-hidroksietilvalina usporedo s mjerenjem razina N-2-cijanoetilvalina i kotinina u mokraći, koji su pouzdani biomarkeri za dokazivanje pušenja duhana. Studija praćenja je pokazala da su koncentracije adukata etilen oksida značajno porasle nakon kratkotrajnoga izlaganja visokoj razini etilen oksida. U početnom biomonitoringu svih radnika izmjerene su razine N-2-hidroksietilvalina iznad 500 pmol g-1 globina, s maksimalnom vrijednošću od oko 2400 pmol g-1 globina. Ti su podaci usporedivi s vrijednostima njemačkih normi ekvivalenata izlaganja kancerogenim tvarima (EKA) od 90 μg L-1 krvi (~3900 pmol g-1 globina) kroz osmosatno dnevno izlaganje koncentraciji od 1 ppm etilen oksida. Razine adukata smanjile su se u skladu s očekivanom kinetikom nultoga reda za jednokratno izlaganje. Koncentracije N-2-hidroksietilvalina izmjerene u krvi radnika nakon petomjesečnoga praćenja mogu se povezati s njihovim osobnim pušačkim navikama. Rezultati toga istraživanja pokazuju da čak i kratkotrajna izloženost etilen oksidu može znatno povisiti razine adukata hemoglobina. Premda se u zdravstvenom nadzoru u okviru medicine rada proteinski adukti i njihove vrijednosti razmatraju u procjeni dugotrajnoga izlaganja, oni se mogu koristiti i za praćenje akcidentalnih izlaganja. U tim slučajevima izračun dnevnih vrijednosti (tzv. ppm-ekvivalenata) može poslužiti za usporedbu s postojećim procijenjenim vrijednostima

Time-resolved density correlations as probe of squeezing in toroidal Bose-Einstein condensates

I study the evolution of mean field and linear quantum fluctuations in a toroidal Bose-Einstein condensate, whose interaction strength is quenched from a finite (repulsive) value to zero. The azimuthal equal-time density-density correlation function is calculated and shows temporal oscillations with twice the (final) excitation frequencies after the transition. These oscillations are a direct consequence of positive and negative frequency mixing during non-adiabatic evolution. I will argue that a time-resolved measurement of the equal-time density correlator might be used to calculate the moduli of the Bogoliubov coefficients and thus the amount of squeezing imposed on a mode, i.e., the number of atoms excited out of the condensate.Comment: 18 pages, IOP styl

Bringing order to protein disorder through comparative genomics and genetic interactions

Abstract Background Intrinsically disordered regions are widespread, especially in proteomes of higher eukaryotes. Recently, protein disorder has been associated with a wide variety of cellular processes and has been implicated in several human diseases. Despite its apparent functional importance, the sheer range of different roles played by protein disorder often makes its exact contribution difficult to interpret. Results We attempt to better understand the different roles of disorder using a novel analysis that leverages both comparative genomics and genetic interactions. Strikingly, we find that disorder can be partitioned into three biologically distinct phenomena: regions where disorder is conserved but with quickly evolving amino acid sequences (flexible disorder); regions of conserved disorder with also highly conserved amino acid sequences (constrained disorder); and, lastly, non-conserved disorder. Flexible disorder bears many of the characteristics commonly attributed to disorder and is associated with signaling pathways and multi-functionality. Conversely, constrained disorder has markedly different functional attributes and is involved in RNA binding and protein chaperones. Finally, non-conserved disorder lacks clear functional hallmarks based on our analysis. Conclusions Our new perspective on protein disorder clarifies a variety of previous results by putting them into a systematic framework. Moreover, the clear and distinct functional association of flexible and constrained disorder will allow for new approaches and more specific algorithms for disorder detection in a functional context. Finally, in flexible disordered regions, we demonstrate clear evolutionary selection of protein disorder with little selection on primary structure, which has important implications for sequence-based studies of protein structure and evolution

Kinin B2 receptor regulates chemokines CCL2 and CCL5 expression and modulates leukocyte recruitment and pathology in experimental autoimmune encephalomyelitis (EAE) in mice

<p>Abstract</p> <p>Background</p> <p>Kinins are important mediators of inflammation and act through stimulation of two receptor subtypes, B₁and B₂. Leukocyte infiltration contributes to the pathogenesis of autoimmune inflammation in the central nervous system (CNS), occurring not only in multiple sclerosis (MS) but also in experimental autoimmune encephalomyelitis (EAE). We have previously shown that the chemokines CCL2 and CCL5 play an important role in the adhesion of leukocytes to the brain microcirculation in EAE. The aim of the present study was to evaluate the relevance of B₂receptors to leukocyte-endothelium interactions in the cerebral microcirculation, and its participation in CNS inflammation in the experimental model of myelin-oligodendrocyte-glycoprotein (MOG)_35–55-induced EAE in mice.</p> <p>Methods</p> <p>In order to evaluate the role of B2 receptor in the cerebral microvasculature we used wild-type (WT) and kinin B2 receptor knockout (B₂^-/-) mice subjected to MOG_35–55-induced EAE. Intravital microscopy was used to investigate leukocyte recruitment on pial matter vessels in B₂^-/-and WT EAE mice. Histological documentation of inflammatory infiltrates in brain and spinal cords was correlated with intravital findings. The expression of CCL5 and CCL2 in cerebral tissue was assessed by ELISA.</p> <p>Results</p> <p>Clinical parameters of disease were reduced in B₂^-/-mice in comparison to wild type EAE mice. At day 14 after EAE induction, there was a significant decrease in the number of adherent leukocytes, a reduction of cerebral CCL5 and CCL2 expressions, and smaller inflammatory and degenerative changes in B₂^-/-mice when compared to WT.</p> <p>Conclusion</p> <p>Our results suggest that B₂receptors have two major effects in the control of EAE severity: (i) B₂regulates the expression of chemokines, including CCL2 and CCL5, and (ii) B₂modulates leukocyte recruitment and inflammatory lesions in the CNS.</p

Acute high altitude exposure, acclimatization and re-exposure on nocturnal breathing

Background: Effects of prolonged and repeated high-altitude exposure on oxygenation and control of breathing remain uncertain. We hypothesized that prolonged and repeated high-altitude exposure will improve altitude-induced deoxygenation and breathing instability. Methods: 21 healthy lowlanders, aged 18-30y, underwent two 7-day sojourns at a high-altitude station in Chile (4-8 hrs/day at 5,050 m, nights at 2,900 m), separated by a 1-week recovery period at 520 m. Respiratory sleep studies recording mean nocturnal pulse oximetry (SpO2), oxygen desaturation index (ODI, >3% dips in SpO2), breathing patterns and subjective sleep quality by visual analog scale (SQ-VAS, 0-100% with increasing quality), were evaluated at 520 m and during nights 1 and 6 at 2,900 m in the 1st and 2nd altitude sojourn. Results: At 520 m, mean ± SD nocturnal SpO2 was 94 ± 1%, ODI 2.2 ± 1.2/h, SQ-VAS 59 ± 20%. Corresponding values at 2,900 m, 1st sojourn, night 1 were: SpO2 86 ± 2%, ODI 23.4 ± 22.8/h, SQ-VAS 39 ± 23%; 1st sojourn, night 6: SpO2 90 ± 1%, ODI 7.3 ± 4.4/h, SQ-VAS 55 ± 20% (p < 0.05, all differences within corresponding variables). Mean differences (Δ, 95%CI) in acute effects (2,900 m, night 1, vs 520 m) between 2nd vs 1st altitude sojourn were: ΔSpO2 0% (-1 to 1), ΔODI -9.2/h (-18.0 to -0.5), ΔSQ-VAS 10% (-6 to 27); differences in acclimatization (changes night 6 vs 1), between 2nd vs 1st sojourn at 2,900 m were: ΔSpO2 -1% (-2 to 0), ΔODI 11.1/h (2.5 to 19.7), ΔSQ-VAS -15% (-31 to 1). Conclusion: Acute high-altitude exposure induced nocturnal hypoxemia, cyclic deoxygenations and impaired sleep quality. Acclimatization mitigated these effects. After recovery at 520 m, repeated exposure diminished high-altitude-induced deoxygenation and breathing instability, suggesting some retention of adaptation induced by the first altitude sojourn while subjective sleep quality remained similarly impaired. Keywords: altitude (MeSH); hypoxia; respiration - physiology; respiratory polygraphy; sleep-disordered breathing