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The histone deacetylase (HDAC) enzymes have emerged as an important class of molecular targets in cancer therapy, with five inhibitors in clinical use. Recently, it has been shown that a lack of selectivity between the 11 Zn-dependent HDAC isoforms may lead to unwanted side-effects. In this paper, we show that piano stool Ru complexes can act as HDAC inhibitors, and variation in the capping arene leads to differences in HDAC isoform selectivity.

Additive Manufacturing (AM) is an advanced technology that has been primarily driven by the demand for production efficiency, minimized energy consumption, and reduced carbon footprints. This process involves layer-by-layer material deposition based on a Computer-Aided Design (CAD) model. Compared to traditional manufacturing methods, AM has enabled the development of complex and topologically functional geometries for various service parts in record time. However, there are limitations to mass production, the building rate, the build size, and the surface quality when using metal additive manufacturing. To overcome these limitations, the combination of additive manufacturing with traditional techniques such as milling and casting holds the potential to provide novel manufacturing solutions, enabling mass production, improved geometrical features, enhanced accuracy, and damage repair through net-shape construction. This amalgamation is commonly referred to as hybrid manufacturing or multi-material additive manufacturing. This review paper aimed to explore the processes and complexities in hybrid materials, joining techniques, with a focus on maraging steels. The discussion is based on existing literature and focuses on three distinct joining methods: direct joining, gradient path joining, and intermediate section joining. Additionally, current challenges for the development of the ideal heat treatment for hybrid metals are discussed, and future prospects of hybrid additive manufacturing are also covered.

Background: Patients treated with an inhibitor of the mechanistic target of rapamycin (mTORI) in a calcineurin inhibitor (CNI)-free immunosuppressive regimen after heart transplantation (HTx) show a higher risk for transplant rejection. We developed an immunological monitoring tool that may improve the identification of mTORI-treated patients at risk for rejection. Methods: Circulating dendritic cells (DCs) and regulatory T cells (Tregs) were analysed in 19 mTORI- and 20 CNI-treated HTx patients by flow cytometry. Principal component and cluster analysis were used to identify patients at risk for transplant rejection. Results: The percentages of total Tregs (p = 0.02) and CD39+ Tregs (p = 0.05) were higher in mTORI-treated patients than in CNI-treated patients. The principal component analysis revealed that BDCA1+, BDCA2+ and BDCA4+ DCs as well as total Tregs could distinguish between non-rejecting and rejecting mTORI-treated patients. Most mTORI-treated rejectors showed higher levels of BDCA2+ and BDCA4+ plasmacytoid DCs and lower levels of BDCA1+ myeloid DCs and Tregs than mTORI non-rejectors. Conclusion: An mTORI-based immunosuppressive regimen induced a sufficient, tolerance-promoting reaction in Tregs, but an insufficient, adverse effect in DCs. On the basis of patient-specific immunological profiles, we established a flow cytometry-based monitoring tool that may be helpful in identifying patients at risk for rejection.

Activity-dependent neuroprotective protein (ADNP) mutations are linked with cognitive dysfunctions characterizing the autistic-like ADNP syndrome patients, who also suffer from delayed motor maturation. We thus hypothesized that ADNP is deregulated in versatile myopathies and that local ADNP muscle deficiency results in myopathy, treatable by the ADNP fragment NAP. Here, single-cell transcriptomics identified ADNP as a major constituent of the developing human muscle. ADNP transcript concentrations further predicted multiple human muscle diseases, with concentrations negatively correlated with the ADNP target interacting protein, microtubule end protein 1 (EB1). Reverting back to modeling at the single-cell level of the male mouse transcriptome, Adnp mRNA concentrations age-dependently correlated with motor disease as well as with sexual maturation gene transcripts, while Adnp expressing limb muscle cells significantly decreased with aging. Mouse Adnp heterozygous deficiency exhibited muscle microtubule reduction and myosin light chain (Myl2) deregulation coupled with motor dysfunction. CRISPR knockdown of adult gastrocnemius muscle Adnp in a Cas9 mouse resulted in treadmill (male) and gait (female) dysfunctions that were specifically ameliorated by treatment with the ADNP snippet, microtubule interacting, Myl2—regulating, NAP (CP201). Taken together, our studies provide new hope for personalized diagnosis/therapeutics in versatile myopathies.

This paper presents results of strength and fracture toughness properties of low-carbon high-strength Hardox-400 steel. Experimental tests were carried out for specimens of different thickness at wide temperature range from −100 to 20 °C. The dependences of the characteristic of material strength and fracture toughness on temperature based on experimental data are shown. Numerical calculation of the stress and strain distributions in area before crack tip using the finite element method (FEM) was done. Based on results of numerical calculation and observation of the fracture surfaces by scanning electron microscope (SEM), the critical local stress level at which brittle fracture takes place was assessed. Consideration of the levels of stress and strain in the analysis of the metal state at the tip of the crack allowed to justify the occurrence of the brittle-to-ductile fracture mechanism. On the basis of the results of stretch zone width measurements and stress components, the values of fracture toughness at the moment of crack initiation were calculated.