SPOC domain proteins in health and disease.

Since it was first described >20 yr ago, the SPOC domain (Spen paralog and ortholog C-terminal domain) has been identified in many proteins all across eukaryotic species. SPOC-containing proteins regulate gene expression on various levels ranging from transcription to RNA processing, modification, export, and stability, as well as X-chromosome inactivation. Their manifold roles in controlling transcriptional output implicate them in a plethora of developmental processes, and their misregulation is often associated with cancer. Here, we provide an overview of the biophysical properties of the SPOC domain and its interaction with phosphorylated binding partners, the phylogenetic origin of SPOC domain proteins, the diverse functions of mammalian SPOC proteins and their homologs, the mechanisms by which they regulate differentiation and development, and their roles in cancer.

The interplay between autophagy and cGAS-STING signaling and its implications for cancer.

Autophagy is an intracellular process that targets various cargos for degradation, including members of the cGAS-STING signaling cascade. cGAS-STING senses cytosolic double-stranded DNA and triggers an innate immune response through type I interferons. Emerging evidence suggests that autophagy plays a crucial role in regulating and fine-tuning cGAS-STING signaling. Reciprocally, cGAS-STING pathway members can actively induce canonical as well as various non-canonical forms of autophagy, establishing a regulatory network of feedback mechanisms that alter both the cGAS-STING and the autophagic pathway. The crosstalk between autophagy and the cGAS-STING pathway impacts a wide variety of cellular processes such as protection against pathogenic infections as well as signaling in neurodegenerative disease, autoinflammatory disease and cancer. Here we provide a comprehensive overview of the mechanisms involved in autophagy and cGAS-STING signaling, with a specific focus on the interactions between the two pathways and their importance for cancer.

Children living with disabilities are neglected in severe malnutrition protocols: a guideline review.

PURPOSE: Children living with disabilities are at high risk of malnutrition but have long been marginalised in malnutrition treatment programmes and research. The 2013 WHO guidelines for severe acute malnutrition (SAM) mention disability but do not contain specific details for treatment or support. This study assesses inclusion of children living with disabilities in national and international SAM guidelines. METHODS: National and international SAM guidelines available in English, French, Spanish or Portuguese were sourced online and via direct enquiries. Regional guidelines or protocols subspecialising in a certain patient group (eg, people living with HIV) were excluded. Eight scoping key informant interviews were conducted with experts involved in guideline development to help understand possible barriers to formalising malnutrition guidance for children living with disabilities. RESULTS: 71 malnutrition guidelines were reviewed (63 national, 8 international). National guidelines obtained covered the greater part of countries with a high burden of malnutrition. 85% of guidelines (60/71) mention disability, although mostly briefly. Only 4% (3/71) had a specific section for children living with disabilities, while the remaining lacked guidance on consistently including them in programmes or practice. Only one guideline mentioned strategies to include children living with disabilities during a nutritional emergency. Most (99%,70/71) did not link to other disability-specific guidelines. Of the guidelines that included children living with disabilities, most only discussed disability in general terms despite the fact that different interventions are often needed for children with different conditions. Interviews pointed towards barriers related to medical complexity, resource constraints, epidemiology (eg, unrecognised burden), lack of evidence and difficulty of integration into existing guidelines. CONCLUSION: Children living with disabilities are under-recognised in most SAM guidelines. Where they are recognised, recommendations are very limited. Better evidence is urgently needed to identify and manage children living with disabilities in malnutrition programmes. More inclusion in the 2022 update of the WHO malnutrition guidelines could support this vulnerable group.

H3K18 lactylation marks tissue-specific active enhancers.

BACKGROUND: Histone lactylation has been recently described as a novel histone post-translational modification linking cellular metabolism to epigenetic regulation. RESULTS: Given the expected relevance of this modification and current limited knowledge of its function, we generate genome-wide datasets of H3K18la distribution in various in vitro and in vivo samples, including mouse embryonic stem cells, macrophages, adipocytes, and mouse and human skeletal muscle. We compare them to profiles of well-established histone modifications and gene expression patterns. Supervised and unsupervised bioinformatics analysis shows that global H3K18la distribution resembles H3K27ac, although we also find notable differences. H3K18la marks active CpG island-containing promoters of highly expressed genes across most tissues assessed, including many housekeeping genes, and positively correlates with H3K27ac and H3K4me3 as well as with gene expression. In addition, H3K18la is enriched at active enhancers that lie in proximity to genes that are functionally important for the respective tissue. CONCLUSIONS: Overall, our data suggests that H3K18la is not only a marker for active promoters, but also a mark of tissue specific active enhancers.

Implantation depth measured by 64-slice computed tomography is associated with permanent pacemaker requirement following transcatheter aortic valve implantation with the Core Valve(®) system.

BACKGROUND: Patients undergoing transcatheter aortic valve implantation (TAVI) are at increased risk for post-interventional conduction disturbances leading to pacemaker (PM) implantation. We analyzed the association between implantation depth within the left ventricular outflow tract (LVOT), measured by 64-slice computed tomography (CT), and 'index electrocardiographic (ECG) changes' (new onset atrioventricular-block grade II or III or left bundle branch block with PR interval prolongation >200ms). METHODS: We evaluated patients who underwent TAVI with the Core Valve(®) revalving system (Medtronic, Minneapolis, MN, USA) for treatment of severe aortic stenosis at our department. Patients with a prior PM implantation and patients for whom no CT scan was available after 3 months were excluded from analysis. We assessed implantation depth of the prosthesis within the LVOT as possible risk factors for the development of post-interventional 'index ECG changes' resulting in PM implantation and compared it with individual patient data as well as echocardiographic and electrocardiographic parameters. RESULTS: The final study cohort comprised 53 patients for whom a 64-slice CT scan was available (mean age 81.7±5.1 years, 36% male). Twenty-eight of these finally underwent PM implantation due to 'index ECG changes' within the first 48hours after TAVI. Univariate logistic regression analysis could identify implantation depth of the prosthesis as the only significantly correlated risk factor for PM need in our cohort (OR 1.27, 95% CI: 1.08-1.51, p=0.004). A cut-off value of 6mm predicted this need with a sensitivity of 89% and specificity of 40%. CONCLUSION: Implantation depth of the Core Valve(®) into the LVOT was associated with post-procedural PM requirement. Thereby, a cut-off value of 6mm, as measured by 64-slice CT, proved useful to define patients at risk for PM requirement.