Decoding Human Hematopoietic Stem Cell Self-Renewal

Purpose of Review: Hematopoietic stem cells (HSCs) maintain blood and immune cell homeostasis by balancing quiescence, self-renewal, and differentiation. HSCs can be used in lifesaving transplantation treatments to create a healthy hematopoietic system in patients suffering from malignant or inherited blood diseases. However, lack of matching bone marrow donors, and the low quantity of HSCs in a single cord blood graft, are limitations for successful transplantation. The enormous regenerative potential of HSCs has raised the hope that HSC self-renewal could be recapitulated in culture to achieve robust expansion of HSCs for therapeutic use. Yet, when HSCs are cultured ex vivo their function becomes compromised, limiting successful expansion. Recent Findings: After decades of efforts to expand human HSCs ex vivo that resulted in minimal increase in transplantable units, recent studies have helped define culture conditions that can increase functional HSCs. These studies have provided new insights into how HSC stemness can be controlled from the nucleus by transcriptional, posttranscriptional and epigenetic regulators, or by improving the HSC microenvironment using 3D scaffolds, niche cells, or signaling molecules that mimic specific aspects of human HSC niche. Recent studies have also highlighted the importance of mitigating culture induced cellular stress and balancing mitochondrial, endoplasmic reticulum, and lysosomal functions. These discoveries have provided better markers for functional human HSCs and new insights into how HSC self-renewal and engraftment ability may be controlled ex vivo. Summary: Uncovering the mechanisms that control the human HSC self-renewal process may help improve the ex vivo expansion of HSCs for clinical purposes

Critical current throughout the BCS-BEC crossover with the inclusion of pairing fluctuations

The present work aims at providing a systematic analysis of the current density versus momentum characteristics for a fermionic superfluid throughout the BCS-BEC crossover, even in the fully homogeneous case. At low temperatures, where pairing fluctuations are not strong enough to invalidate a quasiparticle approach, a sharp threshold for the inception of a back-flow current is found, which sets the onset of dissipation and identifies the critical momentum according to Landau. This momentum is seen to smoothly evolve from the BCS to the BEC regimes, whereby a single expression for the single-particle current density that includes pairing fluctuations enables us to incorporate on equal footing two quite distinct dissipative mechanisms, namely, pair breaking and phonon excitations in the two sides of the BCS-BEC crossover, respectively. At finite temperature, where thermal fluctuations broaden the excitation spectrum and make the dissipative (kinetic and thermal) mechanisms intertwined with each other, an alternative criterion due to Bardeen is instead employed to signal the loss of superfluid behavior. In this way, detailed comparison with available experimental data in linear and annular geometries is significantly improved with respect to previous approaches, thereby demonstrating the crucial role played by quantum fluctuations in renormalizing the single-particle excitation spectrum

Proliferation of cerebellar precursor cells is negatively regulated by nitric oxide in newborn rat.

The diffusible messenger, nitric oxide plays multiple roles in neuroprotection, neurodegeneration and brain plasticity. Its involvement in neurogenesis has been disputed, on the basis of results on models in vivo and in culture. We report here that pharmacological blockade of nitric oxide production in rat pups resulted, during a restricted time window of the first three postnatal days, in increased cerebellar proliferation rate, as assessed through tritiated thymidine or BrdU incorporation into DNA. This was accompanied by increased expression of Myc, a transcription factor essential for cerebellar development, and of the cell cycle regulating gene, cyclin D1. These effects were mediated downstream by the nitric oxide-dependent second messenger, cGMP. Schedules of pharmacological NO deprivation targeted to later developmental stages (from postnatal day 3 to 7), no longer increased proliferation, probably because of partial escape of the cGMP level from nitric oxide control. Though limited to a brief temporal window, the proliferative effect of neonatal nitric oxide deprivation could be traced into adulthood. Indeed, the number of BrdU-labeled surviving cells, most of which were of neuronal phenotype, was larger in the cerebellum of 60-day-old rats that had been subjected to NO deprivation during the first three postnatal days than in control rats. Experiments on cell cultures from neonatal cerebellum confirmed that nitric oxide deprivation stimulated proliferation of cerebellar precursor cells and that this effect was not additive with the proliferative action of sonic hedgehog peptide. The finding that nitric oxide deprivation during early cerebellar neurogenesis, stimulates a brief increase in cell proliferation may contribute to a better understanding of the controversial role of nitric oxide in brain development

Queries with negation and inequalities over lightweight ontologies

While the problem of answering positive existential queries, in particular, conjunctive queries (CQs) and unions of CQs, over description logic ontologies has been studied extensively, there have been few attempts to analyse queries with negated atoms. Our aim is to sharpen the complexity landscape of the problem of answering CQs with negation and inequalities in lightweight description logics of the DL-Lite and EL families. We begin by considering queries with safe negation and show that there is a surprisingly significant increase in the complexity from AC0 to undecidability (even if the ontology and query are fixed and only the data is regarded as input). We also investigate the problem of answering queries with inequalities and show that answering a single CQ with one inequality over DL-Lite with role inclusions is undecidable. In the light of our undecidability results, we explore syntactic restrictions to attain efficient query answering with negated atoms. In particular, we identify a novel class of local CQs with inequalities, for which query answering over DL-Lite is decidable

Comparative absorption of curcumin formulations

BACKGROUND: The potential health benefits of curcumin are limited by its poor solubility, low absorption from the gut, rapid metabolism and rapid systemic elimination. The purpose of this study was the comparative measurement of the increases in levels of curcuminoids (curcumin, demethoxycurcumin, bisdemethoxycurcumin) and the metabolite tetrahydrocurcumin after oral administration of three different curcumin formulations in comparison to unformulated standard. METHODS: The relative absorption of a curcumin phytosome formulation (CP), a formulation with volatile oils of turmeric rhizome (CTR) and a formulation of curcumin with a combination of hydrophilic carrier, cellulosic derivatives and natural antioxidants (CHC) in comparison to a standardized curcumin mixture (CS) was investigated in a randomized, double-blind, crossover human study in healthy volunteers. Samples were analyzed by HPLC-MS/MS. RESULTS: Total curcuminoids appearance in the blood was 1.3-fold higher for CTR and 7.9-fold higher for CP in comparison to unformulated CS. CHC showed a 45.9-fold higher absorption over CS and significantly improved absorption over CP (5.8-fold) and CTR (34.9-fold, all p < 0.001). CONCLUSION: A formulation of curcumin with a combination of hydrophilic carrier, cellulosic derivatives and natural antioxidants significantly increases curcuminoid appearance in the blood in comparison to unformulated standard curcumin CS, CTR and CP

Feasibility of stereotactic ablative reirradiation in breast cancer patient undergoing palbociclib: a case report

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Modelling hCDKL5 heterologous expression in bacteria

hCDKL5 refers to the human cyclin-dependent kinase like 5 that is primarily expressed in the brain. Mutations in its coding sequence are often causative of hCDKL5 deficiency disorder, a devastating neurodevelopmental disorder currently lacking a cure. The large-scale recombinant production of hCDKL5 is desirable to boost the translation of preclinical therapeutic approaches into the clinic. However, this is hampered by the intrinsically disordered nature of almost two-thirds of the hCDKL5 sequence, making this region more susceptible to proteolytic attack, and the observed toxicity when the enzyme is accumulated in the cytoplasm of eukaryotic host cells. The bacterium Pseudoalteromonas haloplanktis TAC125 (PhTAC125) is the only prokaryotic host in which the full-length production of hCDKL5 has been demonstrated. To date, a system-level understanding of the metabolic burden imposed by hCDKL5 production is missing, although it would be crucial for upscaling of the production process. Here, we combined experimental data on protein production and nutrients assimilation with metabolic modelling to infer the global consequences of hCDKL5 production in PhTAC125 and to identify potential overproduction targets. Our analyses showed a remarkable accuracy of the model in simulating the recombinant strain phenotype and also identified priority targets for optimised protein production

Oncogenic c-Myc induces replication stress by increasing cohesins chromatin occupancy in a CTCF-dependent manner.

Oncogene-induced replication stress is a crucial driver of genomic instability and one of the key events contributing to the onset and evolution of cancer. Despite its critical role in cancer, the mechanisms that generate oncogene-induced replication stress remain not fully understood. Here, we report that an oncogenic c-Myc-dependent increase in cohesins on DNA contributes to the induction of replication stress. Accumulation of cohesins on chromatin is not sufficient to cause replication stress, but also requires cohesins to accumulate at specific sites in a CTCF-dependent manner. We propose that the increased accumulation of cohesins at CTCF site interferes with the progression of replication forks, contributing to oncogene-induced replication stress. This is different from, and independent of, previously suggested mechanisms of oncogene-induced replication stress. This, together with the reported protective role of cohesins in preventing replication stress-induced DNA damage, supports a double-edge involvement of cohesins in causing and tolerating oncogene-induced replication stress