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• Wound healing, especially the healing of chronic wounds, requires an increased demand for metabolic energy (ATP). • The physiological polymer polyphosphate (polyP) is an efficient source for the generation of ATP during wound regeneration. • In addition, polyP undergoes coacervation, a process during which bacteria are killed. • These two pillars are the basis for the successful regeneration of chronic wounds in humans. Insufficient metabolic energy, in the form of adenosine triphosphate (ATP), and bacterial infections are among the main causes for the development of chronic wounds. Previously we showed that the physiological inorganic polymer polyphosphate (polyP) massively accelerates wound healing both in animals (diabetic mice) and, when incorporated into mats, in patients with chronic wounds. Here, we focused on a hydrogel-based gel formulation, supplemented with both soluble sodium polyP (Na-polyP) and amorphous calcium polyP nanoparticles (Ca-polyP-NP). Exposure of human epidermal keratinocytes to the gel caused a significant increase in extracellular ATP level, an effect that was even enhanced when Na-polyP was combined with Ca-polyP-NP. Furthermore, it is shown that the added polyP in the gel is converted into a coacervate, leading to encapsulation and killing of bacteria. The data on human chronic wounds showed that the administration of hydrogel leads to the complete closure of these wounds. Histological analysis of biopsies showed an increased granulation of the wounds and an enhanced microvessel formation. The results indicate that the polyP hydrogel, due to its properties to entrap bacteria and generate metabolic energy, is a very promising formulation for a new therapy for chronic wounds. [ABSTRACT FROM AUTHOR]

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1–4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5–8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTXand OTX2. CBFA2T2is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.

The understanding of protein–protein interactions is crucial in order to generate a second level of functional genomic analysis in human disease. Within a cellular microenvironment, protein–protein interactions generate new functions that can be defined by single or multiple modes of protein interactions. We outline here the clinical importance of targeting of the Nme-1 (NDPK-A)–Prune-1 protein complex in cancer, where an imbalance in the formation of this protein–protein complex can result in inhibition of tumor progression. We discuss here recent functional data using a small synthetic competitive cell-permeable peptide (CPP) that has shown therapeutic efficacy for impairing formation of the Nme-1–Prune-1 protein complex in mouse preclinical xenograft tumor models (e.g., breast, prostate, colon, and neuroblastoma). We thus believe that further discoveries in the near future related to the identification of new protein–protein interactions will have great impact on the development of new therapeutic strategies against various cancers.

The understanding of protein–protein interactions is crucial in order to generate a second level of functional genomic analysis in human disease. Within a cellular microenvironment, protein–protein interactions generate new functions that can be defined by single or multiple modes of protein interactions. We outline here the clinical importance of targeting of the Nme-1 (NDPK-A)–Prune-1 protein complex in cancer, where an imbalance in the formation of this protein–protein complex can result in inhibition of tumor progression. We discuss here recent functional data using a small synthetic competitive cell-permeable peptide (CPP) that has shown therapeutic efficacy for impairing formation of the Nme-1–Prune-1 protein complex in mouse preclinical xenograft tumor models (e.g., breast, prostate, colon, and neuroblastoma). We thus believe that further discoveries in the near future related to the identification of new protein–protein interactions will have great impact on the development of new therapeutic strategies against various cancers.

Several genes encoding for proteins involved in proliferation, invasion, and apoptosis are known to be direct miR-34a targets. Here, we used proteomics to screen for targets of miR-34a in neuroblastoma (NBL), a childhood cancer that originates from precursor cells of the sympathetic nervous system. We examined the effect of miR-34a overexpression using a tetracycline inducible system in two NBL cell lines (SHEP and SH-SY5Y) at early time points of expression (6, 12, and 24 h). Proteome analysis using post-metabolic labeling led to the identification of 2,082 proteins, and among these 186 were regulated (112 proteins down-regulated and 74 up-regulated). Prediction of miR-34a targets via bioinformatics showed that 32 transcripts held miR-34a seed sequences in their 3′-UTR. By combining the proteomics data with Kaplan Meier gene-expression studies, we identified seven new gene products (ALG13, TIMM13, TGM2, ABCF2, CTCF, Ki67, and LYAR) that were correlated with worse clinical outcomes. These were further validated in vitroby 3′-UTR seed sequence regulation. In addition, Michigan Molecular Interactions searches indicated that together these proteins affect signaling pathways that regulate cell cycle and proliferation, focal adhesions, and other cellular properties that overall enhance tumor progression (including signaling pathways such as TGF-β, WNT, MAPK, and FAK). In conclusion, proteome analysis has here identified early targets of miR-34a with relevance to NBL tumorigenesis. Along with the results of previous studies, our data strongly suggest miR-34a as a useful tool for improving the chance of therapeutic success with NBL.

Emerging evidence suggest that infection-dependent hyperactivation of complement system (CS) may worsen COVID-19 outcome. We investigated the role of predicted high impact rare variants — referred as qualifying variants (QVs) — of CS genes in predisposing asymptomatic COVID-19 in elderly individuals, known to be more susceptible to severe disease.

Long-chain polyphosphates inhibit SARS-CoV-2 infection by targeting a host receptor and a viral RNA polymerase.