Genetic and epigenetic aberrations contribute to the initiation and progression of acute myeloid leukemia (AML). GFI1, a zinc-finger transcriptional repressor, exerts its function by recruiting ...histone deacetylases to target genes. We present data that low expression of GFI1 is associated with an inferior prognosis of AML patients. To elucidate the mechanism behind this, we generated a humanized mouse strain with reduced GFI1 expression (GFI1-KD). Here we show that AML development induced by onco-fusion proteins such as MLL-AF9 or NUP98-HOXD13 is accelerated in mice with low human GFI1 expression. Leukemic cells from animals that express low levels of GFI1 show increased H3K9 acetylation compared to leukemic cells from mice with normal human GFI1 expression, resulting in the upregulation of genes involved in leukemogenesis. We investigated a new epigenetic therapy approach for this subgroup of AML patients. We could show that AML blasts from GFI1-KD mice and from AML patients with low GFI1 levels were more sensitive to treatment with histone acetyltransferase inhibitors than cells with normal GFI1 expression levels. We suggest therefore that GFI1 has a dose-dependent role in AML progression and development. GFI1 levels are involved in epigenetic regulation, which could open new therapeutic approaches for AML patients.
BACKGROUND:The incidence of acute cardiovascular complications is highly time-of-day dependent. However, the mechanisms driving rhythmicity of ischemic vascular events are unknown. Although enhanced ...numbers of leukocytes have been linked to an increased risk of cardiovascular complications, the role that rhythmic leukocyte adhesion plays in different vascular beds has not been studied.
METHODS:We evaluated leukocyte recruitment in vivo by using real-time multichannel fluorescence intravital microscopy of a tumor necrosis factor-α–induced acute inflammation model in both murine arterial and venous macrovasculature and microvasculature. These approaches were complemented with genetic, surgical, and pharmacological ablation of sympathetic nerves or adrenergic receptors to assess their relevance for rhythmic leukocyte adhesion. In addition, we genetically targeted the key circadian clock gene Bmal1 (also known as Arntl) in a lineage-specific manner to dissect the importance of oscillations in leukocytes and components of the vessel wall in this process.
RESULTS:In vivo quantitative imaging analyses of acute inflammation revealed a 24-hour rhythm in leukocyte recruitment to arteries and veins of the mouse macrovasculature and microvasculature. Unexpectedly, although in arteries leukocyte adhesion was highest in the morning, it peaked at night in veins. This phase shift was governed by a rhythmic microenvironment and a vessel type–specific oscillatory pattern in the expression of promigratory molecules. Differences in cell adhesion molecules and leukocyte adhesion were ablated when disrupting sympathetic nerves, demonstrating their critical role in this process and the importance of β2-adrenergic receptor signaling. Loss of the core clock gene Bmal1 in leukocytes, endothelial cells, or arterial mural cells affected the oscillations in a vessel type–specific manner. Rhythmicity in the intravascular reactivity of adherent leukocytes resulted in increased interactions with platelets in the morning in arteries and in veins at night with a higher predisposition to acute thrombosis at different times as a consequence.
CONCLUSIONS:Together, our findings point to an important and previously unrecognized role of artery-associated sympathetic innervation in governing rhythmicity in vascular inflammation in both arteries and veins and its potential implications in the occurrence of time-of-day–dependent vessel type–specific thrombotic events.
Optimal oxygen saturation (SpO2) targets for extremely low gestational age neonates (ELGANs, gestational age GA <28 weeks) are unknown. Conflicting results from five recently published multicentre ...trials, which randomised ELGANs to high (91 to 95%) or low (85 to 89%) SpO2 targets from birth up to a corrected GA of 36 weeks, prompted us to examine our experience with two different SpO2 policies.
We retrospectively compared outcomes of two cohorts of ELGANs which were exposed to two different SpO2 target policies adapted to the infants' corrected GA. Between 1 January 2000 and 30 June 2007, SpO2 targets were 85 to 95% at <30 weeks and 88 to 97% at ≥30 weeks (high SpO2 target cohort, n = 157). Between 1 July 2007 and 31 December 2011, SpO2 targets were lowered to 80 to 90% at <30 weeks, 85 to 95% between 30 and 34 weeks and finally 88 to 97% at ≥34 weeks (low SpO2 target cohort, n = 84).
There were no statistically significant differences between the high and low SpO2 target cohorts in mortality rates (15.9 vs 17.9%, risk ratio RR 0.89; 95% confidence interval CI 0.50-1.60), incidences of severe retinopathy of prematurity (2.3 vs 0%, RR 3.68; 95% CI 0.19-70.3), or moderate/severe bronchopulmonary dysplasia (14.4 vs 21.1%, RR 0.68; 95% CI 0.37-1.26).
Adapting SpO2 targets to the advancing corrected GA seems safe and is associated with low incidences of short-term complications. Mortality rates did not vary with the two different SpO2 target policies utilised and were comparable to those reported from recently published randomised controlled SpO2 target trials.
In extremely preterm infants, the use of cerebral oximetry monitoring to guide treatment for the first 72 hours after birth did not reduce the risk of death or severe brain injury at 36 weeks’ ...postmenstrual age.
The KATRIN experiment is a next-generation direct neutrino mass experiment with a sensitivity of 0.2eV (90% C.L.) to the effective mass of the electron neutrino. It measures the tritium β-decay ...spectrum close to its endpoint with a spectrometer based on the MAC-E filter technique. The β-decay electrons are guided by a magnetic field that operates in the mT range in the central spectrometer volume; it is fine-tuned by a large-volume air coil system surrounding the spectrometer vessel. The purpose of the system is to provide optimal transmission properties for signal electrons and to achieve efficient magnetic shielding against background. In this paper we describe the technical design of the air coil system, including its mechanical and electrical properties. We outline the importance of its versatile operation modes in background investigation and suppression techniques. We compare magnetic field measurements in the inner spectrometer volume during system commissioning with corresponding simulations, which allows to verify the system's functionality in fine-tuning the magnetic field configuration. This is of major importance for a successful neutrino mass measurement at KATRIN.
Fragestellung:
In der Literatur wird als Nebenwirkung der antihypertensiven Therapie oft die Beeinflussung des Ruheenergieumsatzes (REE) genannt. Dabei stehen Betablocker oder ACE-Hemmer und AT
1
...-Antagonisten im Mittelpunkte des Interesses, während Calciumantagonisten und Diuretika als energiestoffwechselneutral gelten.
Ziel der vorliegenden Studie war es daher, mögliche Abweichungen des REE unter antihypertensiver Langzeittherapie (Betablocker, ACE-Hemmer oder AT
1
-Antagonisten) im Paarvergleich zu gematchten gesunden Kontrollen zu evaluieren.
Methode:
Monozentrische, prospektive Querschnittsstudie. Für die Studie wurden 47 männliche, Probanden (siehe Tab.) unter antihypertensiver Langzeittherapie (mind. 6 Monate) rekrutiert. Durch anschließende Matched-Pair-Analysen (Matchingkriterien: fettfreie Masse:± 5%, Skelettmuskelmasse: ± 5%, Alter: ± 5 Jahre) wurden 47 Männer als Kontrollgruppe eingeschlossen. Die indirekte Kalorimetrie erfolgte unter standardisierten Bedingungen über die Haubenmethodik (Cosmed, Quark RMR, Rom, Italien).
Ergebnisse:
Die Langzeiteinnahme von Antihypertensiva führte zu keinen Veränderungen im REE (siehe Tabelle).
Subgruppenanalysen zeigten, dass weder Betablocker (n = 20), noch Angiotensin-II-Hemmstoffe (n = 27) den REE veränderten (Betablocker: 1638 ± 155 vs. Kontrolle: 1627 ± 139 kcal/d; p = 0,881; ACE-Hemmer/AT
1
-Antagonisten: 1687 ± 188 vs. Kontrolle: 1649 ± 150 kcal/d; p = 0,247). Dosiswirkungsbeziehungen konnten bei einzelnen Wirkstoffen evaluiert werden, es wurden jedoch keine signifikanten Korrelationen ermittelt: Bisoprolol (n = 12): r = 0,007, p = 0,982; Ramipril (n = 6): r =-0,741, p = 0,092; Valsartan (n = 7): r =– 0,020, p = 0,96.
Hypertoniker (n = 47)
Kontrollen (n = 47)
p
Alter (Jahre)
64 ± 7,8
62 ± 7,6
0,308
Body Mass Index (kg/m
2)
28,4 ± 4,1
26,9 ± 2,6
0,068
Fettfreie Masse (kg)
61,7 ± 5,7
61,9 ± 6,2
0,952
Skelettmuskelmasse (kg)
29,7 ± 4,0
29,6 ± 3,7
0,737
Systole (mmHg)
143 ± 13,1
137 ± 20,7
0,012
Diastole (mmHg)
85,7 ± 8,7
84,6 ± 11,7
0,458
REE (kcal/d)
1666 ± 175
1639 ± 144
0,141
Schlussfolgerung:
Die antihypertensive Langzeittherapie scheint den REE nicht zu beeinflussen. Sie bedarf daher in der Einschätzung des Energiebedarfes keiner gesonderten Betrachtung.
AUTOSAR is a recent specification initiative which focuses on a model-driven architecture like methodology for automotive applications. However, needed engineering steps, or how-to-come from a ...logical to a technical architecture respectively implementation, are not well supported by tools, yet. In contrast, SystemC offers a comprehensive way to simulate, analyze, and verify software. Furthermore, it is even able to take the timing behavior of underlying hardware and communication paths into account. Already at a first glance, there are many similarities with respect to the modeling structure between the both concepts. Therefore, this paper discusses approaches on how to use SystemC during the design process of AUTOSAR-conform systems
The KATRIN experiment is a next-generation direct neutrino mass experiment with a sensitivity of 0.2 eV (90% C.L.) to the effective mass of the electron neutrino. It measures the tritium ...\(\beta\)-decay spectrum close to its endpoint with a spectrometer based on the MAC-E filter technique. The \(\beta\)-decay electrons are guided by a magnetic field that operates in the mT range in the central spectrometer volume; it is fine-tuned by a large-volume air coil system surrounding the spectrometer vessel. The purpose of the system is to provide optimal transmission properties for signal electrons and to achieve efficient magnetic shielding against background. In this paper we describe the technical design of the air coil system, including its mechanical and electrical properties. We outline the importance of its versatile operation modes in background investigation and suppression techniques. We compare magnetic field measurements in the inner spectrometer volume during system commissioning with corresponding simulations, which allows to verify the system's functionality in fine-tuning the magnetic field configuration. This is of major importance for a successful neutrino mass measurement at KATRIN.
Summary form only given.In a first step the stationary autostable injection locking of 5/spl times/5 array of vertical-cavity lasers (VCSEL) is demonstrated. One of the 25 emitters serves as master ...laser. All beams are collimated by a microlens array. The master laser beam is expanded and redirected onto the microlens array. In that way a very small part of the master laser radiation is injected frontally into each of the N=24 slave lasers. If the frequencies of the free-running slaves are close to the master frequency, i.e., inside the locking range, the slaves are running phase locked at the master frequency. The master laser radiation and the slave laser radiation are separated by an optical isolator. All VCSELs are driven by the same DC voltage source with small individual series resistors to tune their free-running frequencies to the master frequency. Small deviations of the slave frequency from the master frequency within the locking range in addition allow to shift the relative phase of the two lasers. Adjusting the relative phases of the slave lasers allows to get a strong diffraction-limited central peak in the common far-field power-density distribution of the slave lasers with an enhancement of the peak power density by nearly a factor of N compared to the incoherent operation. The coherent operation is autostable for hours, i.e., no phase, voltage or temperature control is needed. The optical output power is scalable with the number of slave lasers since there is no slave-slave interaction. The number of slave lasers can be one thousand or more.
The multipurpose batch station (MBS) system Hergenhan, Clemens B.; Rochkind, Mark M.
Proceedings of the May 6-10, 1974, national computer conference and exposition,
05/1974
Conference Proceeding
In 1971, Bell Laboratories undertook the development of a minicomputer based batch terminal system primarily to support remote computing activities at its many locations. The effort was to result in ...a high performance, cost effective system which could be used to improve upon an array of specialized terminals leased from a variety of vendors. In addition to functioning as a conventional remote batch terminal, the system, known now as the Multipurpose Batch Station (MBS), was to serve as an interlocation data link, as a local media conversion station and as a generalized communications interface between large central computers and foreign vendor peripherals. In terms of communications support, the MBS System was to accommodate synchronous disciplines, either 2-wire or 4-wire, at bit per second rates from 2,000 to at least 50,000. The system was to be interrupt driven and was to optimize thru-put for voice grade channels.
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