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.

Severe Wernicke's Encephalopathy Associated with Cortical Ribboning and Intracranial Hemorrhage.

Wernicke's encephalopathy (WE) is a neurological emergency that results from thiamine deficiency. It is most commonly associated with chronic alcohol consumption but can result from any cause of impaired thiamine absorption or dietary intake. The classic triad of ophthalmoparesis, ataxia, and altered sensorium is rarely seen in toto, and while certain radiographic findings strongly correlate with the disease, one should have a low threshold to suspect (and promptly treat) patients in order to mitigate the risk of morbidity and mortality.

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.

Evaluation of the EUROIMMUN Anti-SARS-CoV-2 ELISA Assay for detection of IgA and IgG antibodies.

As the Coronavirus 2019 (COVID-19) pandemic evolves, the development of immunoassays to help determine exposure and potentially predict immunity has become a pressing priority. In this report we present the performance of the EUROIMMUN enzyme-linked immunosorbent assay (ELISA) for semi-quantitative detection of IgA and IgG antibodies in serum and plasma samples using recombinant S1 domain of the SARS-CoV-2 spike protein as antigen. Specimens from patients, with and without COVID-19 infection, were tested at the University of Chicago Clinical Microbiology and Immunology Laboratory.

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.

Detection of HHV-6 and EBV and Cytokine Levels in Saliva From Children With Seizures: Results of a Multi-Center Cross-Sectional Study.

One third of children with epilepsy are refractory to medications. Growing data support a role of common childhood infections with neurotropic viruses and inflammation in epileptogenesis. Our objective was to determine the frequency of Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV) infection and cytokine levels in saliva from children with seizures compared to healthy controls and to controls with a febrile illness without seizures.

Timing of onset and self-management of multiple chronic conditions: A qualitative examination taking a lifespan perspective.

Objectives: Over two-thirds of older individuals live with multiple chronic conditions, yet chronic diseases are often studied in silos. Taking a lifespan approach to understanding the development of multiple chronic conditions in the older population helps to further elucidate opportunities for targeted interventions that address the complexities of multiple chronic conditions.

Methods: Semi-structured interviews were conducted with 38 older adults (age 64+) diagnosed with at least two chronic health conditions.

£5 million initiative to cut staff absence announced.

A DRIVE to improve NHS staff health will fail unless one of the main causes of stress, namely lack of staff, is tackled, say unions.

Staffing issues must be addressed if health push is to succeed, says RCN.

A £5 million initiative to tackle the health of NHS workers will fail unless one of the biggest causes of stress - lack of staff - is addressed, the RCN has warned.

Nursing directors urged to join safe staffing group.

ENGLAND'S CHIEF nurse Jane Cummings has written to nursing directors inviting them to become part of an expert group on safe staffing.

High turnover of nursing directors is damaging to trusts' performance.

Nearly one fifth of nursing directors in England have been in the post for a year or less, exclusive research by Nursing Standard reveals.