Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma.

Unlabelled: Multiple myeloma (MM) is a malignancy that is often driven by MYC and that is sustained by IRF4, which are upregulated by super-enhancers. IKZF1 and IKZF3 bind to super-enhancers and can be degraded using immunomodulatory imide drugs (IMiD). Successful IMiD responses downregulate MYC and IRF4; however, this fails in IMiD-resistant cells.

Porous crystals in charged sphere suspensions by aggregate-driven phase separation.

The kinetics of phase transition processes often governs the resulting material microstructure. Using optical microscopy, we here investigate the formation and stabilization of a porous crystalline microstructure forming in low-salt suspensions of charged colloidal spheres containing aggregates comprising some 5-10 of these colloids. We observe the transformation of an initially crystalline colloidal solid with homogeneously incorporated aggregates to individual, compositionally refined crystallites of perforated morphology coexisting with an aggregate-enriched fluid phase filling the holes and separating individual crystallites.

Quantifying the potential persuasive returns to political microtargeting.

Much concern has been raised about the power of political microtargeting to sway voters' opinions, influence elections, and undermine democracy. Yet little research has directly estimated the persuasive advantage of microtargeting over alternative campaign strategies. Here, we do so using two studies focused on U.

Rhabdomyosarcoma-Induced Uterine Inversion.

Nonpuerperal uterine inversion is a rare clinical condition that involves prolapse of the uterine fundus into the uterine cavity and vaginal vault and possibly passed the introitus. The majority of these cases commonly involve benign tumors such as leiomyoma. However, another common cause of nonpuerperal uterine inversion is due to malignancies such as sarcomas.

The (minimal) persuasive advantage of political video over text.

Concerns about video-based political persuasion are prevalent in both popular and academic circles, predicated on the assumption that video is more compelling than text. To date, however, this assumption remains largely untested in the political domain. Here, we provide such a test.

An empirical correction for moderate multiple scattering in super-heterodyne light scattering.

Frequency domain super-heterodyne laser light scattering is utilized in a low angle integral measurement configuration to determine flow and diffusion in charged sphere suspensions showing moderate to strong multiple scattering. We introduce an empirical correction to subtract the multiple scattering background and isolate the singly scattered light. We demonstrate the excellent feasibility of this simple approach for turbid suspensions of transmittance T ≥ 0.

Thrombin stimulates albumin transcytosis in lung microvascular endothelial cells via activation of acid sphingomyelinase.

Transcellular albumin transport occurs via caveolae that are abundant in lung microvascular endothelial cells. Stimulation of albumin transcytosis by proinflammatory mediators may contribute to alveolar protein leak in lung injury, yet the regulation of albumin transport and its underlying molecular mechanisms are so far incompletely understood. Here we tested the hypothesis that thrombin may stimulate transcellular albumin transport across lung microvascular endothelial cells in an acid-sphingomyelinase dependent manner.

Differential regulation of lung endothelial permeability in vitro and in situ.

In the lungs, increased vascular permeability can lead to acute lung injury. Because vascular permeability is regulated primarily by endothelial cells, many researchers have studied endothelial cell monolayers in culture, in order to understand the pathomechanisms of pulmonary edema. Such studies are based on the assumption that endothelial cells in culture behave like endothelial cells in situ.

Topology and control of the cell-cycle-regulated transcriptional circuitry.

Nearly 20% of the budding yeast genome is transcribed periodically during the cell division cycle. The precise temporal execution of this large transcriptional program is controlled by a large interacting network of transcriptional regulators, kinases, and ubiquitin ligases. Historically, this network has been viewed as a collection of four coregulated gene clusters that are associated with each phase of the cell cycle.

Psy2 targets the PP4 family phosphatase Pph3 to dephosphorylate Mth1 and repress glucose transporter gene expression.

The reversible nature of protein phosphorylation dictates that any protein kinase activity must be counteracted by protein phosphatase activity. How phosphatases target specific phosphoprotein substrates and reverse the action of kinases, however, is poorly understood in a biological context. We address this question by elucidating a novel function of the conserved PP4 family phosphatase Pph3-Psy2, the yeast counterpart of the mammalian PP4c-R3 complex, in the glucose-signaling pathway.

Chk1 inhibits E2F6 repressor function in response to replication stress to maintain cell-cycle transcription.

Background: In eukaryotic cells, detection of replication stress results in the activation of the DNA replication checkpoint, a signaling cascade whose central players are the kinases ATR and Chk1. The checkpoint response prevents the accumulation of DNA damage and ensures cell viability by delaying progression into mitosis. However, the role and mechanism of the replication checkpoint transcriptional response in human cells, which is p53 independent, is largely unknown.

Repression of G1/S transcription is mediated via interaction of the GTB motifs of Nrm1 and Whi5 with Swi6.

In Saccharomyces cerevisiae, G1/S transcription factors MBF and SBF regulate a large family of genes important for entry to the cell cycle and DNA replication and repair. Their regulation is crucial for cell viability, and it is conserved throughout evolution. MBF and SBF consist of a common component, Swi6, and a DNA-specific binding protein, Mbp1 and Swi4, respectively.

Turned on by genotoxic stress.

Comment on: Travesa A, et al. EMBO J 2012; 31:1811-22.

DNA replication stress differentially regulates G1/S genes via Rad53-dependent inactivation of Nrm1.

MBF and SBF transcription factors regulate a large family of coordinately expressed G1/S genes required for early cell-cycle functions including DNA replication and repair. SBF is inactivated upon S-phase entry by Clb/CDK whereas MBF targets are repressed by the co-repressor, Nrm1. Using genome-wide expression analysis of cells treated with methyl methane sulfonate (MMS), hydroxyurea (HU) or camptothecin (CPT), we show that genotoxic stress during S phase specifically induces MBF-regulated genes.

Npr2, yeast homolog of the human tumor suppressor NPRL2, is a target of Grr1 required for adaptation to growth on diverse nitrogen sources.

Npr2, a putative "nitrogen permease regulator" and homolog of the human tumor suppressor NPRL2, was found to interact with Grr1, the F-box component of the SCF(Grr1) (Skp1-cullin-F-box protein complex containing Grr1) E3 ubiquitin ligase, by mass spectrometry-based multidimensional protein identification technology. Npr2 has two PEST sequences and has been previously identified among ubiquitinated proteins. Like other Grr1 targets, Npr2 is a phosphoprotein.

[Clinical and radiological results after distal radius fracture: intramedullary locking nail versus volar locking plate osteosynthesis].

Aim: Treatment of distal radius fractures with the volar locking plate provides a stable fixation and early postoperative function. However, after intramedullary osteosynthesis systems for long bones had been established an intramedullary locking nail (Targon DR, Aesculap) for treatment of distal radius fractures was developed. Thus, the aim of this study was to compare the outcomes after volar locking plate osteosynthesis (Aptus, Medartis) and intramedullary osteosynthesis (Targon DR nail) for the distal radius.

Whi5 regulation by site specific CDK-phosphorylation in Saccharomyces cerevisiae.

The Whi5 transcriptional repressor is a negative regulator of G1 cell cycle progression in Saccharomyces cerevisiae and is functionally equivalent to the Retinoblastoma (Rb) tumor suppressor protein in mammals. In early G1, Whi5 binds to and inhibits SBF (Swi4/Swi6) transcriptional complexes. At Start, Cln:Cdc28 kinases phosphorylate and inactivate Whi5, causing its dissociation from SBF promoters and nuclear export, allowing activation of SBF transcription and entry into late G1.

All eukaryotes: before turning off G1-S transcription, please check your DNA.

The DNA replication and DNA damage checkpoints are required for the efficient response to genotoxic stress, which is critical for genome stability and cell survival. The DNA replication and damage checkpoints delay progression into mitosis, and at the same time induce the transcription of genes that promote repair of cellular lesions including stabilization of stalled replication forks and induction of DNA repair functions. The elucidation of the mechanism by which the DNA replication checkpoint activates transcription of G1/S genes is provided by our recent study reported in the August issue of Proceedings of the National Academy of Sciences.

Stb1 collaborates with other regulators to modulate the G1-specific transcriptional circuit.

G(1)-specific transcription in the budding yeast Saccharomyces cerevisiae depends upon SBF and MBF. Whereas inactivation of SBF-regulated genes during the G(1)/S transition depends upon mitotic B-type cyclins, inactivation of MBF has been reported to involve multiple regulators, Nrm1 and Stb1. Nrm1 is a transcriptional corepressor that inactivates MBF-regulated transcription via negative feedback as cells exit G(1) phase.

[Joint infection in a young patient caused by Streptococcus uberis, a pathogen of bovine mastitis--a case report].

In a 40-year-old, previously healthy person presenting with initial septic signs, a purulent infection of the knee joint caused by Streptococcus uberis was detected. Known as a pathogen for bovine mastitis this Streptococcus can cause a purulent joint infection in healthy, young humans by haematogenic spread with a persistent loss of function.