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Precise control of activating H3K4me3 and repressive H3K27me3 histone modifications at bivalent promoters is essential for normal development and frequently corrupted in cancer. By coupling a cell surface readout of bivalent MHC class I gene expression with whole-genome CRISPR-Cas9 screens, we identify specific roles for MTF2-PRC2.1, PCGF1-PRC1.1 and Menin-KMT2A/B complexes in maintaining bivalency. Genetic loss or pharmacological inhibition of Menin unexpectedly phenocopies the effects of polycomb disruption, resulting in derepression of bivalent genes in both cancer cells and pluripotent stem cells. While Menin and KMT2A/B contribute to H3K4me3 at active genes, a separate Menin-independent function of KMT2A/B maintains H3K4me3 and opposes polycomb-mediated repression at bivalent genes. Release of KMT2A from active genes following Menin targeting alters the balance of polycomb and KMT2A at bivalent genes, facilitating gene activation. This functional partitioning of Menin-KMT2A/B complex components reveals therapeutic opportunities that can be leveraged through inhibition of Menin.

UNLABELLED: Cancer cell metabolism is increasingly recognized as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of cell death in cancer cells has largely remained elusive. Here we report that the drug-like small-molecule ironomycin reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial metabolism. Ironomycin promotes the recruitment and activation of BAX/BAK, but the resulting mitochondrial outer membrane permeabilization (MOMP) does not lead to potent activation of the apoptotic caspases, nor is the ensuing cell death prevented by inhibiting the previously established pathways of programmed cell death. Consistent with the fact that ironomycin and BH3 mimetics induce MOMP through independent nonredundant pathways, we find that ironomycin exhibits marked in vitro and in vivo synergy with venetoclax and overcomes venetoclax resistance in primary patient samples. SIGNIFICANCE: Ironomycin couples targeting of cellular metabolism with cell death by reducing mitochondrial iron, resulting in the alteration of mitochondrial metabolism and the activation of BAX/BAK. Ironomycin induces MOMP through a different mechanism to BH3 mimetics, and consequently combination therapy has marked synergy in cancers such as acute myeloid leukemia. This article is highlighted in the In This Issue feature, p. 587.

There has been a lack of high-quality evidence concerning the association between childhood maltreatment and psychiatric diagnoses particularly for Axis II disorders. This study aimed to examine the association between childhood maltreatment exposure and Axis I and Axis II psychiatry disorders using electronic health records. In this study, the exposed group (n = 7473) comprised patients aged 0 to 19 years with a first-time record of maltreatment episode between January 1, 2001 and December 31, 2010, whereas the unexposed group (n = 26,834) comprised individuals of the same gender and age who were admitted into the same hospital in the same calendar year and month but had no records of maltreatment in the Hong Kong Clinical Data Analysis and Reporting System (CDARS). Data on their psychiatric diagnoses recorded from the date of admission to January 31, 2019 were extracted. A Cox proportional hazard regression model was fitted to estimate the hazard ratio (HR, plus 95% CIs) between childhood maltreatment exposure and psychiatric diagnoses, adjusting for age at index visit, sex, and government welfare recipient status. Results showed that childhood maltreatment exposure was significantly associated with subsequent diagnosis of conduct disorder/ oppositional defiant disorder (adjusted HR, 10.99 [95% CI 6.36, 19.01]), attention deficit hyperactivity disorder (ADHD) (7.28 [5.49, 9.65]), and personality disorders (5.36 [3.78, 7.59]). The risk of psychiatric disorders following childhood maltreatment did not vary by history of childhood sexual abuse, age at maltreatment exposure, and gender. Individuals with a history of childhood maltreatment are vulnerable to psychiatric disorders. Findings support the provision of integrated care within the primary health care setting to address the long-term medical and psychosocial needs of individuals with a history of childhood maltreatment.

There is increasing recognition of the prognostic significance of tumor cell major histocompatibility complex (MHC) class II expression in anti-cancer immunity. Relapse of acute myeloid leukemia (AML) following allogeneic stem cell transplantation (alloSCT) has recently been linked to MHC class II silencing in leukemic blasts; however, the regulation of MHC class II expression remains incompletely understood. Utilizing unbiased CRISPR-Cas9 screens, we identify that the C-terminal binding protein (CtBP) complex transcriptionally represses MHC class II pathway genes, while the E3 ubiquitin ligase complex component FBXO11 mediates degradation of CIITA, the principal transcription factor regulating MHC class II expression. Targeting these repressive mechanisms selectively induces MHC class II upregulation across a range of AML cell lines. Functionally, MHC class II+ leukemic blasts stimulate antigen-dependent CD4+ T cell activation and potent anti-tumor immune responses, providing fundamental insights into the graft-versus-leukemia effect. These findings establish the rationale for therapeutic strategies aimed at restoring tumor-specific MHC class II expression to salvage AML relapse post-alloSCT and also potentially to enhance immunotherapy outcomes in non-myeloid malignancies.

Growth differentiation factor-9 (GDF9) and bone morphogenetic protein-15 (BMP15) are co-expressed exclusively in oocytes throughout most of folliculogenesis and play central roles in controlling ovarian physiology. Although both growth factors exist as homodimers, recent evidence indicates that GDF9 and BMP15 can also heterodimerize to form the potent growth factor cumulin. Within the cumulin complex, BMP15 "activates" latent GDF9, enabling potent signaling in granulosa cells via type I receptors (i.e. activin receptor-like kinase-4/5 (ALK4/5)) and SMAD2/3 transcription factors. In the cumulin heterodimer, two distinct type I receptor interfaces are formed compared with homodimeric GDF9 and BMP15. Previous studies have highlighted the potential of cumulin to improve treatment of female infertility, but, as a noncovalent heterodimer, cumulin is difficult to produce and purify without contaminating GDF9 and BMP15 homodimers. In this study we addressed this challenge by focusing on the cumulin interface formed by the helix of the GDF9 chain and the fingers of the BMP15 chain. We demonstrate that unique BMP15 finger residues at this site (Arg301, Gly304, His307, and Met369) enable potent activation of the SMAD2/3 pathway. Incorporating these BMP15 residues into latent GDF9 generated a highly potent growth factor, called hereafter Super-GDF9. Super-GDF9 was >1000-fold more potent than WT human GDF9 and 4-fold more potent than cumulin in SMAD2/3-responsive transcriptional assays in granulosa cells. Our demonstration that Super-GDF9 can effectively promote mouse cumulus cell expansion and improve oocyte quality in vitro represents a potential solution to the current challenges of producing and purifying intact cumulin.

With the growing dominance of multi-storey buildings and other infrastructures, 2D-based cadastral systems are facing new challenges in recording, managing and visualising the spatial extent of vertically stratified cadastral spaces. In Malaysia, surveying and cadastral measurements are currently stored in the National Digital Cadastral Data Base (NDCDB), which is a 2D-based database in the form of planimetric coordinates (X, Y). However, in reality, cadastral objects are three dimensional and 2D-based approaches provide a fragmented view of these 3D spatial objects. Another challenge is that multiple pages of 2D drawings, which are used to show all the spaces of multi-storey buildings and surroundings, imposes a significant amount of cognitive effort for inexpert stakeholders who cannot easily understand the accurate location of cadastral boundaries obscured within physical structures. Therefore, the methods of data collection, calculation and adjustment of existing survey and processing data needs to be up raded for the purposes of implementing 3D cadastral database and producing 3D digital certified plans.

Preservatives deter microbial growth, providing crucial functions of safety and durability in composite materials, formulated products, and food packaging. Concern for human health and the environmental impact of some preservatives has led to regulatory restrictions and public pressure to remove individual classes of compounds, such as parabens and chromated copper arsenate, from consumer products. Bans do not address the need for safe, effective alternative preservatives, which are critical for both product performance (including lifespan and therefore life cycle metrics) and consumer safety. In this work, we studied both the safety and efficacy of a series of phenolic preservatives and compared them to common preservatives found in personal care products and building materials. We quantified antimicrobial activity against Aspergillus brasiliensis (mold) and Pseudomonas aeruginosa (Gram negative bacteria), and we conducted a hazard assessment, complemented by computational modeling, to evaluate the human and environmental health impacts of these chemicals. We found that octyl gallate demonstrates better antimicrobial activity and comparable or lower hazards, compared to current-use preservatives. Therefore, octyl gallate may serve as a viable small-molecule preservative, particularly in conjunction with low concentrations of other preservatives that act through complementary mechanisms.

In light of the measurements from the TIMED spacecraft and coordinated ground-based observations, we discuss results from a modeling study with our Numerical Spectral Model (NSM), which specifically deals with the non-migrating tides generated in the mesosphere. The NSM extends from the ground to the thermosphere, incorporates Hines' Doppler Spread Parameterization for small-scale gravity waves (GWs), and it describes the major dynamical features of the atmosphere including the wave driven equatorial oscillations (QBO and SAO), and the seasonal variations of tides and planetary waves (PWs). Accounting solely for the excitation Sources of the solar migrating tides, the NSM generates through nonlinear interactions also non-migrating tides in the mesosphere that are comparable in magnitude to those observed. (The important non-migrating tides generated explicitly by processes like tropospheric latent heat release and convection are not included.) Large non-migrating tides ire produced in the diurnal and semi-diurnal oscillations for the zonal mean (wave number m = 0) and in the semidiurnal oscillation for m = 1. In general, significant eastward and westward propagating tides are generated for all the zonal wave numbers m = 1-4. To identify the cause, the NSM is run without the solar heating for the zonal mean (m = 0), and the amplitudes of the resulting non-migrating tides are then negligibly small. In this case, the PWs generated by instabilities are artificially suppressed. This leads to the conclusion that the non-migrating tides are produced through nonlinear interactions between PWs and migrating tides, as had been previously proposed. In the accompanying paper, we present results from numerical experiments, which demonstrate that GW filtering contributes significantly to produce the nonlinear coupling that is involved. Published by Elsevier Ltd.

Numerical simulations of turbulent stratified convection are used to study models with approximately the same convective flux, but different radiative fluxes. As the radiative flux is decreased, for constant convective flux: the entropy jump at the top of the convection zone becomes steeper, the temperature fluctuations increase and the velocity fluctuations decrease in magnitude, and the distance that low entropy fluid from the surface can penetrate increases. Velocity and temperature fluctuations follow mixing length scaling laws.

We compare a new 3D radiative hydrodynamical simulation of the surface layers of Procyon A to a similar 3D simulation of the surface layers of the Sun. Both simulations include realistic input physics and are performed using the same numerical techniques and computer codes. Convection in the surface layers of Procyon A is very different from the Sun. Compared with the Sun, the atmospheric structure and convective flow in Procyon A exhibit the following characteristics. (i)The highly superadiabatic transition layer (SAL) is located at a much shallower optical depth; it is in a dynamically active region and its outer region is sometimes located in the optically thin atmosphere. (ii)The outer region of the SAL moves from an optically thin region to a thick region and back again over a time of 20-30 min. This motion, which is driven by the granulation, takes place in a time approximately half the turnover time of the largest granules. (iii)The peak rms velocity in the vertical direction is much larger in Procyon A. The main reason for the radically different radiative-convective behaviour in Procyon A compared with the Sun is the role played by turbulent eddies in determining the overall flow/thermal structure. The turbulent pressure and turbulent kinetic energy can exceed 50 per cent of the local gas pressure (compared with about 10-20 per cent in the Sun). In such regions, the mixing lengthy theory is a poor approximation. The Procyon A simulation thus reveals two distinct time-scales: the autocorrelation time of the vertical velocity and the characteristic time-scale of the SAL, which is tied to granulation. Just below the surface, the autocorrelation decay time is about 5 min in Procyon A and the SAL motion time-scale is 20-30 min. In the simulations, the peak value of the superadiabaticity varies between 0.5 and 3. When the SAL penetrates the optically thin region, there are efficient radiative losses and the peak of the SAL is low. We speculate that these losses d

The objective of this study is to modify a regional climate model (RCM)-the Regional Climate Model of the National Climate Center of China-to simulate the summer monsoon rainfall over South China and the South China Sea. Such a modification is necessary because this RCM was designed for studying the climate over central and north China where precipitation processes are very different from those occurring further south so that simulations using the basic parameters of the original model give precipitation amounts much less than those observed. Using the National Centers for Environmental Prediction/National Center for Atmospheric Research (NCEP/NCAR) reanalysis data, many sensitivity experiments have been carried out for the months of April to June 1998, which include modifying the cumulus parameterization scheme, the large-scale precipitation scheme, the radiation scheme, the surface exchange processes, and the size of the buffer zone. The design of all the experiments is either to enhance the moisture provision to the atmosphere over South China and the South China Sea, or to help the model atmosphere realize the moisture to form precipitation. It is found that indeed modifications to the various parameters can produce rainfall amounts much closer to those observed. Based on the results of these experiments, an "optimal" design of the RCM is reached and tested for its effectiveness using the NCEP reanalyses for two wet years (1994 and 1997) and two dry years (1996 and 1999) during which rainfall in May and June over South China were above/below normal respectively. The physical processes in this design include the Kuo scheme for convective precipitation, the Pal scheme for large-scale precipitation, the Holtslag scheme for the planetary boundary layer, the radiation transfer scheme of the NCAR Community Climate Model Version 3, and the Biosphere-Atmosphere Transfer Scheme for the land surface process. The width of the buffer zone is reduced and the effective cloud

This paper describes three-dimensional (3D) large eddy simulations of stellar surface convection using realistic model physics. The simulations include the present Sun, a subgiant of one solar mass and a lower-gravity subgiant, also of one solar mass. We examine the thermal structure (superadiabaticity) after modification by 3D turbulence, the overshoot of convective motions into the radiative atmosphere and the range of convection cell sizes. Differences between models based on the mixing length theory (MLT) and the simulations are found to increase significantly in the more evolved stages as the surface gravity decreases. We find that the full width at half maximum (FWHM) of the turbulent vertical velocity correlation provides a good objective measure of the vertical size of the convective cells. Just below the convection surface, the FWHM is close to the mean vertical size of the granules and 2 x FWHM is close to the mean horizontal diameter of the granules. For the Sun, 2 x FWHM = 1200 km, a value close to the observed mean granule size. For all the simulations, the mean horizontal diameter is close to 10 times the pressure scaleheight at the photospheric surface, in agreement with previous work.

The Numerical Spectral Model (NSM) extends from the ground into the thermosphere and incorporates Hines' Doppler Spread Parameterization for small-scale gravity waves (GWs). In the present version of the model we account for a tropospheric heat source in the zonal mean (m = 0), which reproduces qualitatively the observed zonal jets near the tropopause and the accompanying reversal in the latitudinal temperature variations. In the study presented here, we discuss the planetary waves (PWs) that are solely generated internally, i.e. without the explicit excitation sources related to tropospheric convection or topography. Our analysis shows that PWs are not produced when the zonally averaged heat source into the atmosphere is artificially suppressed, and that the PWs are generally weaker when the tropospheric source is not applied. Instabilities associated with the zonal mean temperature, pressure and wind fields, which still need to be explored, are exciting PWs that have amplitudes in the mesosphere comparable to those observed. Three classes of PWs are generated in the NSM. (1) Rossby type PWs, which slowly propagate westward relative to the mean zonal flow, are carried by the winds so that they appear (from the ground) to propagate, respectively, eastward and westward in the winter and summer hemispheres below 80 km. Depending on the zonal wave number and magnitudes of the zonal winds, and under the influence of the equatorial oscillations, these PWs typically have periods between 2 and 20 days. Their horizontal wind amplitudes can exceed 40 m/s in the lower mesosphere. (2) Rossby-gravity waves, which propagate westward at low latitudes and have periods around 2 days for zonal wave numbers m = 2 to 4. (3) Eastward propagating equatorial Kelvin waves, which are generated in the upper mesosphere with periods between 1 and 3 days depending on m. A survey of the PWs reveals that the largest wind amplitudes tend to occur below 80 km in the winter hemisphere; but above th

We analyze the performance of E-limited scheduling in Bluetooth piconets under bursty traffic for infinite and finite buffer cases. We show that E-limited service outperforms exhaustive service in terms of end-to-end delay and that the delays may be minimized through the proper choice of a single variable parameter: the number of packets to be exchanged during a single visit to a slave. Using analytical results for access delay and end-to-end delay, as well as suitable approximations thereof, we propose three novel admission algorithms. The simplest Algorithm is based on queue stability, which makes it suitable for battery power-limited masters. The second algorithm estimates the access delay of the slave upon admission using the estimated first and second moments of the vacation times and makes the admission decision on the basis of predefined access delay bounds. The third algorithm is based on the predefined cycle time bounds, which makes it suitable for applications that generate constant-bit-rate data flows. We also present results for the performance of TCP traffic under E-limited scheduling.

End-to-end packet delays in a Bluetooth scatternet with a Slave-Slave (SS) bridge can be minimized by adjusting the bridge residence times in accordance with traffic intensity and locality. This paper presents two algorithms to do so. One of these uses a fixed value of the bridge residence time, while the other adjusts the residence time dynamically according to the instantaneous intensity of inter-piconet traffic. We discuss the performance of these algorithms and show that the adaptive algorithm offers better performance than the fixed residence time one, provided the parameters are chosen appropriately. We also consider the stability of both algorithms and show that they have comparable stability limits. Copyright (C) 2004 John Wiley Sons, Ltd.

This paper is a contribution to the methodology of fully Bayesian inference in a multivariate Gaussian mixture model using the reversible jump Markov chain Monte Carlo algorithm. To follow the constraints of preserving the first two moments before and after the split or combine moves, we concentrate on a simplified multivariate Gaussian mixture model, in which the covariance matrices of all components share a common eigenvector matrix. We then propose an approach to the construction of the reversible jump Markov chain Monte Carlo algorithm for this model. Experimental results on several data sets demonstrate the efficacy of our algorithm.

At high latitudes in the upper mesosphere, horizontal wind oscillations have been observed with periods around 10 h. Waves with such a period are generated in our Numerical Spectral Model (NSM), and they are identified as planetary-scale inertio gravity waves (IGW). These IGWs have periods between 9 and I I h and appear above 60 kin in the zonal mean (m=0), as well as in m=l to 4, propagating eastward and westward. Under the influence of the Coriolis force, the amplitudes of the waves propagating westward are larger at high latitudes than those propagating eastward. The waves grow in magnitude at least up to about 100 km and have vertical wavelengths around 25 km. Applying a running window of 15 days for spectral analysis, the amplitudes in the wind field are typically between 10 and 20 m/s and can reach 30m/s in the westward propagating component for m=1 at the poles. In the temperature perturbations, the wave amplitudes above 100 km are typically 5 K and as large as 10 K for m=0 at the poles. The IGWs are intermittent but reveal systematic seasonal variations, with the largest amplitudes occurring generally in late winter and spring. Numerical experiments show that such waves are also generated without excitation of the migrating tides. The amplitudes and periods then are similar, indicating that the tides are not essential to generate the waves. However, the seasonal variations without tides are significantly different, which leads to the conclusion that non linear interactions between the semidiurnal tide and planetary waves must contribute to the excitation of the IGWs. Directly or indirectly through the planetary waves, the IGWs are apparently excited by the instabilities that arise in the zonal mean circulation. When the solar heating is turned off for m=0, both the PWs and IGWs essentially disappear. That the IGWs and PWs have common roots in their excitation mechanism is also indicated by the striking similarity of their seasonal variations in the lower mes

Performance of Bluetooth scatternets is critically dependent on the algorithm for bridge scheduling. As the current specification does not prescribe any particular algorithm, a number of proposals have been made. These proposals are classified into rendezvous-based and walk-in based algorithms, and their relative advantages and disadvantages are highlighted. Using the theory of queues with vacations, we derive the probability distributions for end-to-end packet delays (and a number of intermediate variables such as the duration of master-bridge exchanges, bridge cycle time, and piconet cycle time) under three different bridge scheduling algorithms. Analytical results are confirmed through discrete event simulation. (C) 2004 Elsevier B.V. All rights reserved.

In the polar region of the upper mesosphere, horizontal wind oscillations have been observed with periods around 10 hours. Waves with such periods are generated in our Numerical Spectral Model (NSM), and they are identified as planetary-scale inertio gravity waves (IGW). These waves have periods between 9 and 11 hours and appear above 70 km in the zonal mean (m = 0), as well as in m = 1 to 4 propagating eastward and westward. They grow in magnitude to altitudes near 100 km and have vertical wavelengths of about 25 km. The m = 1 westward IGWs have the largest amplitudes, up to 30 m/s at the poles. The IGWs occur intermittently but reveal systematic seasonal variations. Their amplitudes generally are largest in late winter and spring. Numerical experiments show that the waves also appear without tidal excitation. Like the planetary waves in the model, the IGWs are produced by instabilities that arise in the mean zonal circulation.