inspired by recent proteomic data demonstrating the upregulation of carbon and glycogen metabolism in aging human hematopoietic stem and progenitor cells (HPCs, CD34+ cells), this report addresses whether this is caused by elevated glycolysis of the Hpcs on a per cell basis, or by a subpopulation that has become more glycolytic. the average glycogen content in individual CD34+ cells from older subjects (> 50 years) was 3.5 times higher and more heterogeneous compared to younger subjects (< 35 years). Representative glycolytic enzyme activities in HPCs confirmed a significant increase in glycolysis in older subjects. The HPCs from older subjects can be fractionated into three distinct subsets with high, intermediate, and low glucose uptake (GU) capacity, while the subset with a high GU capacity could scarcely be detected in younger subjects. Thus, we conclude that upregulated glycolysis in aging Hpcs is caused by the expansion of a more glycolytic Hpc subset. Since single-cell RnA analysis has also demonstrated that this subpopulation is linked to myeloid differentiation and increased proliferation, isolation and mechanistic characterization of this subpopulation can be utilized to elucidate specific targets for therapeutic interventions to restore the lineage balance of aging Hpcs. Glycogen accumulation upon aging has been reported in cells such as nerves, neurons, astrocytes, and muscle cells 1-5. Glycogen is the storage polyglucosan (PG) and periodic acid-Schiff (PAS) reaction has been established as the method to detect glycogen and other polysaccharides 6. Glycogen content is usually low in blood cells but high levels of glycogen are characteristically found in the leukemia cells of patients with acute lymphoblastic leukemia (ALL) 7,8. Before immuno-and molecular diagnostics for classification of acute leukemias has become routine, PAS-staining constituted an essential histochemical method for the classification of acute leukemias. Glycogen accumulation in form of PAS positive granules was prominently found in the blasts of ALL and was reported to indicate prognostic significance 8 .

Antimicrobial resistance is a major threat to public health. Although many commercial sanitisers contain a combination of cationic surfactants and aromatic alcohols, the physical mechanisms where these two substances bind to or how they disturb bacterial membranes are still largely unknown. In this study, we designed a well-defined model of Gram-negative bacteria surfaces based on the monolayer of lipopolysaccharides with uniform saccharide head groups. Since commonly used X-ray reflectivity is sensitive to changes in the thickness, roughness and electron density but is not sensitive to elements, we employed grazing incidence X-ray fluorescence. In the absence of Ca 2+ , cationic surfactants can penetrate into the membrane core with no extra support by disturbing the layer of K + coupled to negatively charged saccharide head group at z = 17 Å from the air/chain interface. On the other hand, Ca 2+ confined at z = 19 Å crosslink charged saccharides and prevent the incorporation of cationic surfactants. We found that the addition of nonlethal aromatic alcohols facilitate the incorporation of cationic surfactants by the significant roughening of the chain/saccharide interface. Combination of precise localisation of ions and molecular-level structural analysis quantitatively demonstrated the synegtestic interplay of ingredients to achieve a high antibacterial activity.

The heterogeneous response of acute myeloid leukemia (AML) to current anti-leukemic therapies is only partially explained by mutational heterogeneity. We previously identified GPR56 as a surface marker associated with poor outcome across genetic groups, which characterizes two leukemia stem cell (LSC)-enriched compartments with different self-renewal capacities. How these compartments self-renew remained unclear. Here, we show that GPR56 + LSC compartments are promoted in a complex network involving epithelial-to-mesenchymal transition (EMT) regulators besides Rho, Wnt, and Hedgehog (Hh) signaling. Unexpectedly, Wnt pathway inhibition increased the more immature, slowly cycling GPR56 + CD34 + fraction and Hh/EMT gene expression, while Wnt activation caused opposite effects. Our data suggest that the crucial role of GPR56 lies in its ability to co-activate these opposing signals, thus ensuring the constant supply of both LSC subsets. We show that CDK7 inhibitors suppress both LSC-enriched subsets in vivo and synergize with the Bcl-2 inhibitor venetoclax. Our data establish reciprocal transition between LSC compartments as a novel concept underlying the poor outcome in GPR56 high AML and propose combined CDK7 and Bcl-2 inhibition as LSC-directed therapy in this disease.

This work was supported by Deutsche Forschungsgemeinschaft Grants FA378/10-2 and SFB1129 (to O.T.F.) and SFB1129 (to M.T.), and the Nakatani Foundation (to M.T.). N. Tsopoulidis was supported by a Heidelberg Biosciences International Graduate School fellowship. O.T.F. and M.T. are members of the CellNetworks Cluster of Excellence (EXO81). O.T.F. designed the study, interpreted results, and wrote the manuscript together with B.S. M.L.-M. conducted and analyzed the experiments shown in Figs. 1-3 and 5. S.K. conducted and analyzed the in vivo homing experiments. B.S. carried out the transendothelial migration experiments together with R.L., conducted the Seahorse analyses with help from J.W. and G.C., and analyzed the data. N. Tsopoulidis recorded the movies analyzed in Figs. 4 and 5. J.T. and M.T. generated and interpreted the power spectrum analyses (Fig. 4B-G).