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Background:VEXAS syndrome is an adult-onset, X-linked, life-threatening, autoinflammatory disease with predominant hematological involvement caused by somatic mutation in UBA1 gene whose pathophysiology is still unknown.Objectives:To achieve a molecular and phenotypic characterization of hematopoiesis of VEXAS patients and to develop cellular and humanized mouse models by gene editing.Methods:Six VEXAS patients (p.Met41>Thr; p.Met41>Val; p.Met41>Leu; c.118-1 G>C) were recruited from our Unit. Variant allele frequency (VAF) of UBA1 mutant cells was quantified by targeted sequencing in isolated hematopoietic lineages and hematopoietic stem/progenitor cells (HSPCs). Multiparametric immunophenotypic analysis and single cell RNA seq were performed on peripheral blood and bone marrow (BM), focusing on HSPCs. Circulating monocytes were analyzed by whole RNA-seq and metabolome analysis. Healthy age and sex-matched controls were included. To introduce UBA1 mutations and develop VEXAS models, cutting-edge gene editing technologies were adopted in healthy human HSPCs.Results:Targeted sequencing in VEXAS patients showed >0.8 VAF in HSPCs. Conversely, VAF largely differed across mature cells, averaging 0.81 in neutrophils, 0.64 in monocytes, 0.42 in NK, 0.07 in T cells, and 0.09 in B cells, supporting a myeloid skewing of mutant HSPCs. Multiparametric immunophenotypic analyses showed unbalanced composition of HSPCs in the BM, with 2-to-3-fold reduction of primitive stem cells, multipotent and lymphoid progenitors, and 2-fold increase of myeloid progenitors, compared to matched healthy individuals. HSPCs, myeloid-biased HSPCs and immature myeloid cells were increased by 3-to-4 fold in the circulation (p<0.03). Gene expression analysis of circulating monocytes displayed upregulation of inflammatory pathways and metabolic rewiring (Figure. 1, panels A-B). Metabolomic analyses confirmed hyperactivation of the glycolytic pathway and specific lipid metabolism (Figure. 1, C-D). Single-cell RNA-seq of bone marrow mononuclear cells identified a subpopulation of CD34+ cell specific of VEXAS patients and revealed upregulated stress response and immune activation pathways across VEXAS cell clusters compared with healthy controls. Models of VEXAS generated by gene editing recapitulated patients’ hematopoiesis and pathophysiology in vitro and in vivo. UBA1 mutations were installed at VAF>0.9 in HSPCs and generated a myeloid bias in vitro. Transplantation of edited HSPCs in immunodeficient mice resulted in a 100-fold reduction in circulating B cells, while NK and myeloid compartments were preserved. Human BM HSPCs were 5-fold lower than control mice, largely myeloid-biased and presented abnormal vacuolar morphology. Concordantly, VAF was >0.8 in myeloid cells and HSPCs and <0.3 in B cells. Figure 1. Panel A. Gene expression analysis of peripheral monocytes in VEXAS patients compared to controls. Panel B. Gene-enrichmed pathway analysis in VEXAS patients compared to controls. Panel C. Metabolic analysis in VEXAS patients compared to controls. Panel D. Metabolic-enriched pathway analysis in VEXAS patients compared to controls.Figure 1.Conclusion:Mutations in UBA1 drive expansion of HSPCs and enhance myelopoiesis-guided accumulation of myeloid precursors. Mutant lymphoid cells are negatively selected and their myeloid counterpart in peripheral blood displays upregulation of transcriptomic signatures and metabolic pathways indicative of inflammatory activation. Gene editing-based models hold promise to enable preclinical testing and validation of novel therapeutics to treat VEXAS syndrome.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Corrado Campochiaro: None declared, Raffaella Molteni: None declared, Guido Pacini: None declared, Martina Fiumara: None declared, Alessandro Tomelleri: None declared, Elisa Diral: None declared, Davide Stefanoni: None declared, Angelica Varesi: None declared, Alessandra Weber: None declared, Roberta Alfieri: None declared, Luisa Albano: None declared, Maddalena Panigada: None declared, Eleonora Cantoni: None declared, Daniele Canarutto: None declared, Luca Bassoricci: None declared, Pamela Quaranta: None declared, Angelo D’Alessandro: None declared, Marco Matucci-Cerinic: None declared, Raffaella Di Micco: None declared, Alessandro Aiuti: None declared, Fabio Ciceri: None declared, Ivan Merelli: None declared, Lorenzo Dagna: None declared, Serena Scala: None declared, Simone Cenci: None declared, Luigi Naldini: None declared, Samuele Ferrari: None declared, Giulio Cavalli Novartis, Novartis.

This paper proposes a non-isolated high step-up switched-capacitor dual-switch DC-DC converter for low-power applications. The proposed converter benefits from high voltage gain, low voltage stress on the devices, continuous input current, availability of common-ground point, and simple structure. The proposed converter provides the voltage gain of 10 at mild duty cycle of 50%, where the per-unit voltage stress of S 1 and S 2 switches are 20 and 40%, respectively. In such condition, the highest voltage stress on the diodes will be limited to 67%. The synchronous operation of the switches in proposed converter leads to only 2 operational modes in continuous conduction mode (CCM), which makes the control of the converter very straightforward. The interleaved structure divides the input current between the inductors, which accordingly reduces the losses on the input devices. This study contains detailed steady-state analysis of proposed converter in CCM and DCM operations. It also provides the loss (and efficiency) analysis as well as the design procedure of the devices. The comparison section evaluates the competitiveness of the proposed converter compared to other existing similar counterparts. The average state-space method and small signal analysis have been used to model the proposed topology. The appropriate dynamic operation of proposed converter has been verified by simulation analysis. The experimental results confirm the correct performance of the proposed converter.

Controlling a state of material between its crystalline and glassy phase has fostered many real-world applications. Nevertheless, design rules for crystallization and vitrification kinetics still lack predictive power. Here, we identify stoichiometry trends for these processes in phase change materials, i.e. along the GeTe-GeSe, GeTe-SnTe, and GeTe-Sb 2 Te 3 pseudo-binary lines employing a pump-probe laser setup and calorimetry. We discover a clear stoichiometry dependence of crystallization speed along a line connecting regions characterized by two fundamental bonding types, metallic and covalent bonding. Increasing covalency slows down crystallization by six orders of magnitude and promotes vitrification. The stoichiometry dependence is correlated with material properties, such as the optical properties of the crystalline phase and a bond indicator, the number of electrons shared between adjacent atoms. A quantum-chemical map explains these trends and provides a blueprint to design crystallization kinetics. Tailoring the crystallization kinetics of materials is important for targeting applications. Here the authors observe a remarkable dependence of crystallization and vitrification kinetics and attribute it to systematic bonding changes for a class of materials between metallic and covalent bonding.

Base and prime editors (BEs and PEs) may provide more precise genetic engineering than nuclease-based approaches because they bypass the dependence on DNA double-strand breaks. However, little is known about their cellular responses and genotoxicity. Here, we compared state-of-the-art BEs and PEs and Cas9 in human hematopoietic stem and progenitor cells with respect to editing efficiency, cytotoxicity, transcriptomic changes and on-target and genome-wide genotoxicity. BEs and PEs induced detrimental transcriptional responses that reduced editing efficiency and hematopoietic repopulation in xenotransplants and also generated DNA double-strand breaks and genotoxic byproducts, including deletions and translocations, at a lower frequency than Cas9. These effects were strongest for cytidine BEs due to suboptimal inhibition of base excision repair and were mitigated by tailoring delivery timing and editor expression through optimized mRNA design. However, BEs altered the mutational landscape of hematopoietic stem and progenitor cells across the genome by increasing the load and relative proportions of nucleotide variants. These findings raise concerns about the genotoxicity of BEs and PEs and warrant further investigation in view of their clinical application. Base and prime editors induce double-strand breaks, deletions and translocations in hematopoietic cells.

Gut microbiota is emerging as a key regulator of many disease conditions and its dysregulation is implicated in the pathogenesis of several gastrointestinal and extraintestinal disorders. More recently, gut microbiome alterations have been linked to neurodegeneration through the increasingly defined gut microbiota brain axis, opening the possibility for new microbiota-based therapeutic options. Although several studies have been conducted to unravel the possible relationship between Alzheimer’s Disease (AD) pathogenesis and progression, the diagnostic and therapeutic potential of approaches aiming at restoring gut microbiota eubiosis remain to be fully addressed. In this narrative review, we briefly summarize the role of gut microbiota homeostasis in brain health and disease, and we present evidence for its dysregulation in AD patients. Based on these observations, we then discuss how dysbiosis might be exploited as a new diagnostic tool in early and advanced disease stages, and we examine the potential of prebiotics, probiotics, fecal microbiota transplantation, and diets as complementary therapeutic interventions on disease pathogenesis and progression, thus offering new insights into the diagnosis and treatment of this devastating and progressive disease.

Cells subjected to treatment with anti-cancer therapies can evade apoptosis through cellular senescence. Persistent senescent tumor cells remain metabolically active, possess a secretory phenotype, and can promote tumor proliferation and metastatic dissemination. Removal of senescent tumor cells (senolytic therapy) has therefore emerged as a promising therapeutic strategy. Here, using single-cell RNA-sequencing, we find that senescent tumor cells rely on the anti-apoptotic gene Mcl-1 for their survival. Mcl-1 is upregulated in senescent tumor cells, including cells expressing low levels of Bcl-2, an established target for senolytic therapy. While treatment with the Bcl-2 inhibitor Navitoclax results in the reduction of metastases in tumor bearing mice, treatment with the Mcl-1 inhibitor S63845 leads to complete elimination of senescent tumor cells and metastases. These findings provide insights on the mechanism by which senescent tumor cells survive and reveal a vulnerability that can be exploited for cancer therapy. Cell senescence remains a barrier to tumor elimination in many cancers. Here, the authors use single cell RNA-seq to identify a role for Mcl-1 in senescent cell survival, and show that Mcl-1 inhibition may be an effective therapeutic strategy.

This paper proposes a unity-gain active-neutral-point-clamped (ANPC) multilevel inverter topology utilizing two DC sources, ten switches, and four DC-link capacitors. The proposed inverter generates 17 and 25 output voltage levels by leveraging input voltage ratios of V 2  = 3 V 1 (triple) and V 2  = 5 V 1 (quintuple), respectively. Unlike conventional designs, the topology eliminates the need for an H-bridge to produce bipolar voltage waveforms, thereby reducing the number of switches exposed to the maximum output voltage from four (in H-bridge-based structures) to two. Additionally, the inverter supports diverse load types across a wide range of power factors. Comparative analysis demonstrates that the proposed topology achieves the lowest number of conducting switches (only three) to generate any output voltage level, minimizing voltage drop, device losses, and conduction losses while enhancing overall efficiency and output voltage quality. Furthermore, it requires fewer DC sources and switches compared to existing 25-level inverters. Experimental results from a laboratory-scale prototype validate the effective operation of the proposed ANPC inverter in both 17- and 25-level configurations.

Phase change materials based on chalcogenides are key enabling technologies for optical storage, such as rewritable CD and DVD and recently also electrical nonvolatile memory, named phase change memory (PCM). In a PCM, the amorphous or crystalline phase affects the material band structure, hence the device resistance. Although phase transformation is extremely fast and repeatable, the amorphous phase suffers structural relaxation and crystallization at relatively low temperatures, which may affect the temperature stability of PCM state. To improve the time/temperature stability of the PCM, novel operation modes of the device should be identified. Here, we present bipolar switching operation of PCM, which is interpreted by ion migration in the solid state induced by elevated temperature and electric field similar to the bipolar switching in metal oxides. The temperature stability of the high resistance state is demonstrated and explained based on the local depletion of chemical species from the electrode region.

The human microbiota refers to a large variety of microorganisms (bacteria, viruses, and fungi) that live in different human body sites, including the gut, oral cavity, skin, and eyes. In particular, the presence of an ocular surface microbiota with a crucial role in maintaining ocular surface homeostasis by preventing colonization from pathogen species has been recently demonstrated. Moreover, recent studies underline a potential association between gut microbiota (GM) and ocular health. In this respect, some evidence supports the existence of a gut–eye axis involved in the pathogenesis of several ocular diseases, including age-related macular degeneration, uveitis, diabetic retinopathy, dry eye, and glaucoma. Therefore, understanding the link between the GM and these ocular disorders might be useful for the development of new therapeutic approaches, such as probiotics, prebiotics, symbiotics, or faecal microbiota transplantation through which the GM could be modulated, thus allowing better management of these diseases.