Perform a gyro test of general relativity in a satellite and develop associated control technology

The progress accomplished in the Stanford Gyro Relativity program during the period November 1974 to October 1975 was described. Gyro developments were continued in the main laboratory dewar, concentrating on the operation of a three axis gyro readout and on improvements to the methods of canceling trapped fields in the rotor; these efforts culminated in the first successful observation of the London moment in the spinning gyro rotor in March 1975. Following a review meeting at that time, a new goal was formulated for the next 12 to 18 months, namely to operate a gyroscope in the new ultra-low field facility with readout resolution approaching 1 arc-second. The following other tasks were also completed: (1) sputtering work, (2) magnetometry, (3) construction and installation of the North Star simulator, (4) analysis of torques on the gyro, especially in inclined orbits, (5) equivalence principle accelerometer, and (6) analysis of a twin-satellite test of relativity

Etude d'un épisode photochimique à l'alde d'un modèle méso-échelle et de mesures intensives sur la région de Grenoble

La ville de Grenob le, située au carrefour de trois vallées, est systématiquement soumise à des périodes de smog estival avec de fortes concentrations en ozone (0 3), Au cours de l'été 1999, l'Association pour le contrôle et la préservation de l'air dans la région grenobloise (ASCOPARG) et l'École Polytechnique Fédérale de Lausanne (EPFL) ont mené conjointement -une campagne de mesures en déployant, durant un mois, un réseau de mesures au sol renforcé par des moyens de mesures à la vertical e. Deux périodes d'observations intensives (POl) ont eu lieu, la première fin juillet, et la deuxième dé but août. Les simulations ont été réa lisées pour la première POl (24-27 juill et) avec le modèle METeorological PHOtochem istry MODel (METPHOMOD) utilisant le mécanisme chimique Regional Atmospheric Chemistry Mechanism (RACM). Une technique de nesting one-way est utilisée avec une grande grille de 198 km de côté et une résolution de 6 x 6 km et une petite grille de 78 x 68 km avec une résolution de 2 x 2 km. À la verticale, 24 niveaux sont pris en compte jusqu'à 8 000 m. Au sol, les champs de vents, les concentrations d'03 et de dioxyde d'azote (NOx) sont bien reproduits par le modèle et mettent en évidence le déplacement horizontal du panache d'03 vers le sud avec un maximum d'03 de 95 ppb. Pour la verticale, les mesures et les simulations montrent une couche de mélange convective (CMC) supérieure à 2 000 rn, le transport horizontal du panache dans la CMC et la formation de la couche réservoir d'03' La CMC est donc plus haute en terrain de montagne qu'en plaine. Une stratification verticale spécifique de l'atmosphère, suivant trois couches, a été mise en évidence lors de cet épisode photoch imique sur Grenoble. Une simulation sans émissions sur le petit domaine de calcul a permis d'évaluer la production locale d'03de la ville à 32 ppb, soit un tiers de la concentration maximale mesurée et simulée dans le sud de l'agglomération

An inter-comparison exercise of mesoscale flow models applied to an ideal case simulation

An exercise is described aiming at the comparison of the results of seven mesoscale models used for the simulation of an ideal circulation case. The exercise foresees the simulation of the flow over an ideal sea–land interface including ideal topography in order to verify model deviations on a controlled case. All models involved use the same initial and boundary conditions, circulation and temperature forcings as well as grid resolution in the horizontal and simulate the circulation over a 24-h period of time. The model differences at start are reduced to the minimum by the case specification and consist mainly of the parameterisation and numerical formulation of the fundamental equations of the atmospheric flow. The exercise reveals that despite the reduction of the differences in the case configuration, the differences in model results are still remarkable. An ad hoc investigation using one model of the original seven identifies the treatment of the boundary conditions, the parameterisation of the horizontal diffusion and of the surface heat flux as the main cause for the model deviations. The analysis of ideal cases represents a revealing and interesting exercise to be performed after the validation of models against analytical solution but prior to the application to real cases

Evidence of traffic-generated air pollution in Havana

In Havana, transport is blamed as a likely source of pollution issues, which is usually supported on arguments referring to a vehicle fleet mainly made of old cars (i.e., most models are American from the 1950s or Russian from the 1980s) with poor technical conditions. Most of the existing studies are based on measurements from passive samplers collected for 24 h, which may not be representative of conditions where pollutant concentrations (particles or gases) fluctuate or are not homogeneous, such as transport-related pollution. The goal of this paper is to explore the transport-generated pollution by examining short-time correlations between traffic flows, pollutant concentrations and meteorological parameters. To do that, statistical relationships among all variables were analyzed, which revealed that PM10, NO2 and SO2 concentration levels are influenced by vehicular traffic, mainly with low-speed winds blowing perpendicular to the street axis. Furthermore, southeast and northeast winds force drag pollution from sources other than traffic. These conclusions depend on the specific conditions of the summer season at the measurement area. A more complete analysis could be conducted when more data becomes available for each season

Current views on the role of Notch signaling and the pathogenesis of human leukemia

The Notch signaling pathway is highly conserved from Drosophila to humans and plays an important role in the regulation of cellular proliferation, differentiation and apoptosis

Long-term in vitro maintenance of clonal abundance and leukaemia-initiating potential in acute lymphoblastic leukaemia

Lack of suitable in vitro culture conditions for primary acute lymphoblastic leukaemia (ALL) cells severely impairs their experimental accessibility and the testing of new drugs on cell material reflecting clonal heterogeneity in patients. We show that Nestin-positive human mesenchymal stem cells (MSCs) support expansion of a range of biologically and clinically distinct patient-derived ALL samples. Adherent ALL cells showed an increased accumulation in the S phase of the cell cycle and diminished apoptosis when compared with cells in the suspension fraction. Moreover, surface expression of adhesion molecules CD34, CDH2 and CD10 increased several fold. Approximately 20% of the ALL cells were in G0 phase of the cell cycle, suggesting that MSCs may support quiescent ALL cells. Cellular barcoding demonstrated long-term preservation of clonal abundance. Expansion of ALL cells for >3 months compromised neither feeder dependence nor cancer initiating ability as judged by their engraftment potential in immunocompromised mice. Finally, we demonstrate the suitability of this co-culture approach for the investigation of drug combinations with luciferase-expressing primograft ALL cells. Taken together, we have developed a preclinical platform with patient-derived material that will facilitate the development of clinically effective combination therapies for ALL

The KMT2A recombinome of acute leukemias in 2023

Chromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from 3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2A gene and the involved translocation partner genes (TPGs) and KMT2A-partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2A gene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5’-KMT2A, two patients had a 5’-KMT2A deletion, and one ETV6::RUNX1 patient had an KMT2A insertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A, 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2A recombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival.publishedVersionPeer reviewe

A functional SUMO-interacting motif in the transactivation domain of c-Myb regulates its myeloid transforming ability

c-Myb is an essential hematopoietic transcription factor that controls proliferation and differentiation of progenitors during blood cell development. Whereas sumoylation of the C-terminal regulatory domain (CRD) is known to have a major impact on the activity of c-Myb, no role for noncovalent binding of small ubiquitin-like modifier (SUMO) to c-Myb has been described. Based on the consensus SUMO-interacting motif (SIM), we identified and examined putative SIMs in human c-Myb. Interaction and reporter assays showed that the SIM in the in the transactivation domain of c-Myb (V 267 NIV) is functional. This motif is necessary for c-Myb to be able to interact noncovalently with SUMO, preferentially SUMO2/3. Destroying the SUMO-binding properties by mutation resulted in a large increase in the transactivation potential of c-Myb. Mutational analysis and overexpression of conjugation-defective SUMO argued against intramolecular repression caused by sumoylated CRD and in favor of SUMO-dependent repression in trans. Using both a myeloid cell line-based assay and a primary hematopoietic cell assay, we addressed the transforming abilities of SUMO binding and conjugation mutants. Interestingly, only loss of SUMO binding, and not SUMO conjugation, enhanced the myeloid transformational potential of c-Myb. c-Myb with the SIM mutated conferred a higher proliferative ability than the wild-type and caused an effective differentiation block. This establishes SUMO binding as a mechanism involved in modulating the transactivation activity of c-Myb, and responsible for keeping the transforming potential of the oncoprotein in check

Spontaneous development of Epstein-Barr Virus associated human lymphomas in a prostate cancer xenograft program

Prostate cancer research is hampered by the lack of in vivo preclinical models that accurately reflect patient tumour biology and the clinical heterogeneity of human prostate cancer. To overcome these limitations we propagated and characterised a new collection of patient-derived prostate cancer xenografts. Tumour fragments from 147 unsupervised, surgical prostate samples were implanted subcutaneously into immunodeficient Rag2-/-γC-/- mice within 24 hours of surgery. Histologic and molecular characterisation of xenografts was compared with patient characteristics, including androgen-deprivation therapy, and exome sequencing. Xenografts were established from 47 of 147 (32%) implanted primary prostate cancers. Only 14% passaged successfully resulting in 20 stable lines; derived from 20 independent patient samples. Surprisingly, only three of the 20 lines (15%) were confirmed as prostate cancer; one line comprised of mouse stroma, and 16 were verified as human donor-derived lymphoid neoplasms. PCR for Epstein-Barr Virus (EBV) nuclear antigen, together with exome sequencing revealed that the lymphomas were exclusively EBV-associated. Genomic analysis determined that 14 of the 16 EBV+ lines had unique monoclonal or oligoclonal immunoglobulin heavy chain gene rearrangements, confirming their B-cell origin. We conclude that the generation of xenografts from tumour fragments can commonly result in B-cell lymphoma from patients carrying latent EBV. We recommend routine screening, of primary outgrowths, for latent EBV to avoid this phenomenon

Enhanced Notch Activation Is Advantageous but Not Essential for T Cell Lymphomagenesis in Id1 Transgenic Mice

T cell lymphoblastic leukemia (T-ALL) is known to be associated with chromosomal abnormalities that lead to aberrant expression of a number of transcription factors such as TAL1, which dimerizes with basic helix-loop-helix (bHLH) E proteins and inhibits their function. Activated Notch receptors also efficiently induce T cell leukemogenesis in mouse models. Interestingly, gain-of-function mutations or cryptic transcription initiation of the Notch1 gene have been frequently found in both human and mouse T-ALL. However, the correlations between these alterations and overall Notch activities or leukemogenesis have not been thoroughly evaluated. Therefore, we made use of our collection of T cell lymphomas developed in transgenic mice expressing Id1, which like TAL1, inhibits E protein function. By comparing expression levels of Notch target genes in Id1-expressing tumors to those in tumors induced by a constitutively active form of Notch1, N1C, we were able to assess the overall activities of Notch pathways and conclude that the majority of Id1-expressing tumors had elevated Notch function to a varying degree. However, 26% of the Id1-expressing tumors had no evidence of enhanced Notch activation, but that did not delay the onset of tumorigenesis. Furthermore, we examined the genetic or epigenetic alterations thought to contribute to ligand-independent activation or protein stabilization of Notch1 and found that some of the Id1-expressing tumors acquired these changes, but they are not uniformly associated with elevated Notch activities in Id1 tumor samples. In contrast, N1C-expressing tumors do not harbor any PEST domain mutations nor exhibit intragenic transcription initiation. Taken together, it appears that Notch activation provides Id1-expressing tumor cells with selective advantages in growth and survival. However, this may not be absolutely essential for lymphomagenesis in Id1 transgenic mice and additional factors could also cooperate with Id1 to induce T cell lymphoma. Therefore, a broad approach is necessary in designing T-ALL therapy