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Metabolic gatekeeper function of B-lymphoid transcription factors.
B-lymphoid transcription factors, such as PAX5 and IKZF1, are critical for early B-cell development, yet lesions of the genes encoding these transcription factors occur in over 80% of cases of pre-B-cell acute lymphoblastic leukaemia (ALL). The importance of these lesions in ALL has, until now, remained unclear. Here, by combining studies using chromatin immunoprecipitation with sequencing and RNA sequencing, we identify a novel B-lymphoid program for transcriptional repression of glucose and energy supply. Our metabolic analyses revealed that PAX5 and IKZF1 enforce a state of chronic energy deprivation, resulting in constitutive activation of the energy-stress sensor AMPK. Dominant-negative mutants of PAX5 and IKZF1, however, relieved this glucose and energy restriction. In a transgenic pre-B ALL mouse model, the heterozygous deletion of Pax5 increased glucose uptake and ATP levels by more than 25-fold. Reconstitution of PAX5 and IKZF1 in samples from patients with pre-B ALL restored a non-permissive state and induced energy crisis and cell death. A CRISPR/Cas9-based screen of PAX5 and IKZF1 transcriptional targets identified the products of NR3C1 (encoding the glucocorticoid receptor), TXNIP (encoding a glucose-feedback sensor) and CNR2 (encoding a cannabinoid receptor) as central effectors of B-lymphoid restriction of glucose and energy supply. Notably, transport-independent lipophilic methyl-conjugates of pyruvate and tricarboxylic acid cycle metabolites bypassed the gatekeeper function of PAX5 and IKZF1 and readily enabled leukaemic transformation. Conversely, pharmacological TXNIP and CNR2 agonists and a small-molecule AMPK inhibitor strongly synergized with glucocorticoids, identifying TXNIP, CNR2 and AMPK as potential therapeutic targets. Furthermore, our results provide a mechanistic explanation for the empirical finding that glucocorticoids are effective in the treatment of B-lymphoid but not myeloid malignancies. Thus, B-lymphoid transcription factors function as metabolic gatekeepers by limiting the amount of cellular ATP to levels that are insufficient for malignant transformation
Tantalus, a Novel ASX-Interacting Protein with Tissue-Specific Functions
AbstractThe Drosophila trithorax- and Polycomb-group (trxG and PcG) proteins maintain activated and repressed transcriptional states at specific target gene loci. The Additional sex combs (Asx) gene is of particular interest as it appears to function in both protein complexes and yet its effects on target genes are more restricted. A novel protein, Tantalus (TAN), was identified in a yeast two-hybrid screen for ASX-interacting proteins that might confer tissue-specific ASX functions. TAN contains consensus nuclear localization sites and binds DNA in vitro. However, its subcellular localization varies in a tissue-specific fashion. In salivary glands, TAN is predominantly nuclear and associates with 66 euchromatic sites on polytene chromosomes, more than half of which overlap with ASX. These loci do not include the homeotic genes of the ANT and BX complexes bound by other PcG and trxG proteins. Rather, tan mutant defects are restricted to sensory organs. We show that one of these defects, shared by Asx, is genetically enhanced by Asx. Taken together, the data suggest that TAN is a tissue-specific cofactor for ASX, and that its activity may be partially controlled by subcellular trafficking
The fast declining Type Ia supernova 2003gs, and evidence for a significant dispersion in near-infrared absolute magnitudes of fast decliners at maximum light
We obtained optical photometry of SN 2003gs on 49 nights, from 2 to 494 days
after T(B_max). We also obtained near-IR photometry on 21 nights. SN 2003gs was
the first fast declining Type Ia SN that has been well observed since SN
1999by. While it was subluminous in optical bands compared to more slowly
declining Type Ia SNe, it was not subluminous at maximum light in the near-IR
bands. There appears to be a bimodal distribution in the near-IR absolute
magnitudes of Type Ia SNe at maximum light. Those that peak in the near-IR
after T(B_max) are subluminous in the all bands. Those that peak in the near-IR
prior to T(B_max), such as SN 2003gs, have effectively the same near-IR
absolute magnitudes at maximum light regardless of the decline rate Delta
m_15(B).
Near-IR spectral evidence suggests that opacities in the outer layers of SN
2003gs are reduced much earlier than for normal Type Ia SNe. That may allow
gamma rays that power the luminosity to escape more rapidly and accelerate the
decline rate. This conclusion is consistent with the photometric behavior of SN
2003gs in the IR, which indicates a faster than normal decline from
approximately normal peak brightness.Comment: 41 pages, 13 figures, to be published in the December, 2009, issue of
the Astronomical Journa
Infrared Observations of AR Ursae Majoris: Modeling the Ellipsoidal Variations
We have obtained time-series infrared photometry for the highly magnetic
cataclysmic variable AR UMa. Our J and K' band observations occurred during a
low state and they show a distinctive double-humped structure. Using detailed
models for the expected ellipsoidal variations in the infrared due to the
non-spherical secondary star, we find that the most likely value for the system
inclination is 70 degrees. We also model low state V band photometry and find
that its observed double-humped structure is not caused by ellipsoidal
variations, as they have been ascribed to, but are due to beamed cyclotron
radiation. We use this result to estimate the magnetic field strength of the
active southern accretion region (B <= 190 MG) and its magnetic longitude (330
degrees).Comment: Accepted to AJ, to appear Jan 2001 issu
A comparison of the development of audiovisual integration in children with autism spectrum disorders and typically developing children
This study aimed to investigate the development of audiovisual integration in children with Autism Spectrum Disorder (ASD). Audiovisual integration was measured using the McGurk effect in children with ASD aged 7–16 years and typically developing children (control group) matched approximately for age, sex, nonverbal ability and verbal ability. Results showed that the children with ASD were delayed in visual accuracy and audiovisual integration compared to the control group. However, in the audiovisual integration measure, children with ASD appeared to ‘catch-up’ with their typically developing peers at the older age ranges. The suggestion that children with ASD show a deficit in audiovisual integration which diminishes with age has clinical implications for those assessing and treating these children
Femtosecond X-ray emission study of the spin cross-over dynamics in haem proteins
In haemoglobin (consisting of four globular myoglobin-like subunits), the
change from the low-spin (LS) hexacoordinated haem to the high spin (HS)
pentacoordinated domed form upon ligand detachment and the reverse process upon
ligand binding, represent the transition states that ultimately drive the
respiratory function. Visible-ultraviolet light has long been used to mimic the
ligand release from the haem by photodissociation, while its recombination was
monitored using time-resolved infrared to ultraviolet spectroscopic tools.
However, these are neither element- nor spin-sensitive. Here we investigate the
transition state in the case of Myoglobin-NO (MbNO) using femtosecond Fe Kalpha
and Kbeta non-resonant X-ray emission spectroscopy (XES) at an X-ray
free-electron laser upon photolysis of the Fe-NO bond. We find that the
photoinduced change from the LS (S = 1/2) MbNO to the HS (S = 2)
deoxy-myoglobin (deoxyMb) haem occurs in ca. 800 fs, and that it proceeds via
an intermediate (S = 1) spin state. The XES observables also show that upon NO
recombination to deoxyMb, the return to the planar MbNO ground state is an
electronic relaxation from HS to LS taking place in ca. 30 ps. Thus, the entire
ligand dissociation-recombination cycle in MbNO is a spin cross-over followed
by a reverse spin cross-over process
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