Reticular dysgenesis-associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress.

Adenylate kinases (AKs) are phosphotransferases that regulate the cellular adenine nucleotide composition and play a critical role in the energy homeostasis of all tissues. The AK2 isoenzyme is expressed in the mitochondrial intermembrane space and is mutated in reticular dysgenesis (RD), a rare form of severe combined immunodeficiency (SCID) in humans. RD is characterized by a maturation arrest in the myeloid and lymphoid lineages, leading to early onset, recurrent, and overwhelming infections. To gain insight into the pathophysiology of RD, we studied the effects of AK2 deficiency using the zebrafish model and induced pluripotent stem cells (iPSCs) derived from fibroblasts of an RD patient. In zebrafish, Ak2 deficiency affected hematopoietic stem and progenitor cell (HSPC) development with increased oxidative stress and apoptosis. AK2-deficient iPSCs recapitulated the characteristic myeloid maturation arrest at the promyelocyte stage and demonstrated an increased AMP/ADP ratio, indicative of an energy-depleted adenine nucleotide profile. Antioxidant treatment rescued the hematopoietic phenotypes in vivo in ak2 mutant zebrafish and restored differentiation of AK2-deficient iPSCs into mature granulocytes. Our results link hematopoietic cell fate in AK2 deficiency to cellular energy depletion and increased oxidative stress. This points to the potential use of antioxidants as a supportive therapeutic modality for patients with RD

MOESM1 of Host choice in a bivoltine bee: how sensory constraints shape innate foraging behaviors

Additional file 1. Detailed procedures applied for color measurements, bee color hexagon, sampling of floral scents, electrophysiology and chemical analyses

Pulseq-CEST : Towards multi-site multi-vendor compatibility and reproducibility of CEST experiments using an open-source sequence standard

PURPOSE: As the field of CEST grows, various novel preparation periods using different parameters are being introduced. At the same time, large, multisite clinical studies require clearly defined protocols, especially across different vendors. Here, we propose a CEST definition standard using the open Pulseq format for a shareable, simple, and exact definition of CEST protocols.METHODS: We present the benefits of such a standard in three ways: (1) an open database on GitHub, where fully defined, human-readable CEST protocols can be shared; (2) an open-source Bloch-McConnell simulation to test and optimize CEST preparation periods in silico; and (3) a hybrid MR sequence that plays out the CEST preparation period and can be combined with any existing readout module.RESULTS: The exact definition of the CEST preparation period, in combination with the flexible simulation, leads to a good match between simulations and measurements. The standard allowed finding consensus on three amide proton transfer-weighted protocols that could be compared in healthy subjects and a tumor patient. In addition, we could show coherent multisite results for a sophisticated CEST method, highlighting the benefits regarding protocol sharing and reproducibility.CONCLUSION: With Pulseq-CEST, we provide a straightforward approach to standardize, share, simulate, and measure different CEST preparation schemes, which are inherently completely defined

Reticular dysgenesis–associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress

Adenylate kinases (AKs) are phosphotransferases that regulate the cellular adenine nucleotide composition and play a critical role in the energy homeostasis of all tissues. The AK2 isoenzyme is expressed in the mitochondrial intermembrane space and is mutated in reticular dysgenesis (RD), a rare form of severe combined immunodeficiency (SCID) in humans. RD is characterized by a maturation arrest in the myeloid and lymphoid lineages, leading to early onset, recurrent, and overwhelming infections. To gain insight into the pathophysiology of RD, we studied the effects of AK2 deficiency using the zebrafish model and induced pluripotent stem cells (iPSCs) derived from fibroblasts of an RD patient. In zebrafish, Ak2 deficiency affected hematopoietic stem and progenitor cell (HSPC) development with increased oxidative stress and apoptosis. AK2-deficient iPSCs recapitulated the characteristic myeloid maturation arrest at the promyelocyte stage and demonstrated an increased AMP/ADP ratio, indicative of an energy-depleted adenine nucleotide profile. Antioxidant treatment rescued the hematopoietic phenotypes in vivo in ak2 mutant zebrafish and restored differentiation of AK2-deficient iPSCs into mature granulocytes. Our results link hematopoietic cell fate in AK2 deficiency to cellular energy depletion and increased oxidative stress. This points to the potential use of antioxidants as a supportive therapeutic modality for patients with RD