Phospho-regulation of ASCL1-mediated chromatin opening during cellular reprogramming.

The proneural transcription factor ASCL1 regulates neurogenesis and drives somatic cell reprogramming into neurons. However, not all cell types can be reprogrammed by ASCL1, raising the questions of what provides competence and how we can overcome barriers to enable directed differentiation. Here, we investigate how levels of ASCL1 and its phosphorylation modulate its activity over progressive lineage restriction of mouse embryonic stem cells.

Palbociclib releases the latent differentiation capacity of neuroblastoma cells.

Neuroblastoma is the most common extracranial solid tumor in infants, arising from developmentally stalled neural crest-derived cells. Driving tumor differentiation is a promising therapeutic approach for this devastating disease. Here, we show that the CDK4/6 inhibitor palbociclib not only inhibits proliferation but induces extensive neuronal differentiation of adrenergic neuroblastoma cells.

Optimisation of Sample Preparation from Primary Mouse Tissue to Maintain RNA Integrity for Methods Examining Translational Control.

The protein output of different mRNAs can vary by two orders of magnitude; therefore, it is critical to understand the processes that control gene expression operating at the level of translation. Translatome-wide techniques, such as polysome profiling and ribosome profiling, are key methods for determining the translation rates occurring on specific mRNAs. These techniques are now widely used in cell lines; however, they are underutilised in tissues and cancer models.

Evaluation of an ester-linked immunosuppressive payload: A case study in understanding the stability and cleavability of ester-containing ADC linkers.

In spite of their value in prodrug applications, the use of esters in antibody-drug-conjugate (ADC) payloads and linkers has generally been avoided due to the ubiquitous and promiscuous nature of human esterases. ADCs generally have a long circulating half life (3-7 days) that makes them susceptible to esterase-mediated metabolism. Moreover, it is largely unclear whether lysosomal and cytosolic esterases cleave ester-containing linkers upon ADC internalization.

Differential regulation of mRNA fate by the human Ccr4-Not complex is driven by coding sequence composition and mRNA localization.

Background: Regulation of protein output at the level of translation allows for a rapid adaptation to dynamic changes to the cell's requirements. This precise control of gene expression is achieved by complex and interlinked biochemical processes that modulate both the protein synthesis rate and stability of each individual mRNA. A major factor coordinating this regulation is the Ccr4-Not complex.

Codon optimality in cancer.

A key characteristic of cancer cells is their increased proliferative capacity, which requires elevated levels of protein synthesis. The process of protein synthesis involves the translation of codons within the mRNA coding sequence into a string of amino acids to form a polypeptide chain. As most amino acids are encoded by multiple codons, the nucleotide sequence of a coding region can vary dramatically without altering the polypeptide sequence of the encoded protein.

Advancing early gastric cancer detection.

Important factors in combating cancer are early detection and accurate assessment of the best course of treatment. In a study published in this issue, Wang et al. identify possible miRNA biomarkers for improved determination of gastric cancer stage and prognosis.

The mTOR regulated RNA-binding protein LARP1 requires PABPC1 for guided mRNA interaction.

The mammalian target of rapamycin (mTOR) is a critical regulator of cell growth, integrating multiple signalling cues and pathways. Key among the downstream activities of mTOR is the control of the protein synthesis machinery. This is achieved, in part, via the co-ordinated regulation of mRNAs that contain a terminal oligopyrimidine tract (TOP) at their 5'ends, although the mechanisms by which this occurs downstream of mTOR signalling are still unclear.

mRNA structural elements immediately upstream of the start codon dictate dependence upon eIF4A helicase activity.

Background: The RNA helicase eIF4A1 is a key component of the translation initiation machinery and is required for the translation of many pro-oncogenic mRNAs. There is increasing interest in targeting eIF4A1 therapeutically in cancer, thus understanding how this protein leads to the selective re-programming of the translational landscape is critical. While it is known that eIF4A1-dependent mRNAs frequently have long GC-rich 5'UTRs, the details of how 5'UTR structure is resculptured by eIF4A1 to enhance the translation of specific mRNAs are unknown.

eIF4A2 drives repression of translation at initiation by Ccr4-Not through purine-rich motifs in the 5'UTR.

Background: Regulation of the mRNA life cycle is central to gene expression control and determination of cell fate. miRNAs represent a critical mRNA regulatory mechanism, but despite decades of research, their mode of action is still not fully understood.

Results: Here, we show that eIF4A2 is a major effector of the repressive miRNA pathway functioning via the Ccr4-Not complex.

DEAD-box helicase eIF4A2 inhibits CNOT7 deadenylation activity.

The CCR4-NOT complex plays an important role in the translational repression and deadenylation of mRNAs. However, little is known about the specific roles of interacting factors. We demonstrate that the DEAD-box helicases eIF4A2 and DDX6 interact directly with the MA3 and MIF domains of CNOT1 and compete for binding.

The quantitative story behind the quality improvement storyboards: a synthesis of quality improvement projects conducted by the multi-state learning collaborative.

Context: The Multi-State Learning Collaborative: Lead States in Public Health Quality Improvement (MLC) brought state and local health departments in 16 states together with public health system and national partners to prepare for national voluntary accreditation and to implement quality improvement (QI) practices.

Objective: The MLC has collected the single largest repository of qualitative public health QI data to date. A preliminary study was conducted to explore the potential merits of further mining data sets of this size and scope and examining them quantitatively.

Promoting quality improvement and achieving measurable change: the lead states initiative.

Along with the development of a national voluntary accreditation program for public health departments that holds quality improvement as its core goal, the application of quality improvement in public health has been gaining momentum. The 16 states participating in the Multi-State Learning Collaborative: Lead States in Public Health Quality Improvement (MLC) represent best practices in these activities. The MLC brings together partnerships in 16 US states to prepare for accreditation and implement quality-improvement practices.

The multistate learning collaborative, states as laboratories: informing the national public health accreditation dialogue.

The Multistate Learning Collaborative on Performance and Capacity Assessment or Accreditation of Public Health Departments (MLC) is an initiative undertaken with the Exploring Accreditation Project (EAP). The EAP is jointly funded by the Robert Wood Johnson Foundation (RWJF) and the Centers for Disease Control and Prevention (CDC), and staffed collaboratively by the Association of State and Territorial Health Officials (ASTHO) and the National Association of County and City Health Officials (NACCHO) to explore the implications and feasibility of a national public health accreditation system. The MLC, also financially supported through grants from RWJF, is designed under the auspices of the National Network of Public Health Institutes (NNPHI) and the Public Health Leadership Society (PHLS) to enhance the accreditation/assessment activities already underway in each of the grantee states; to promote learning among the states participating in the collaborative; to disseminate information to state and local health departments nationally; and to inform the work of the EAP.