Molecular Mechanisms in Hematopoietic Stem Cell Aging

The blood is composed of many different cell types that through tightly regulated mechanisms are derived from hematopoietic stem cells (HSCs). In addition, HSCs are able to undergo self-renewing divisions whereby new HSCs are produced. This is an extremely important feature of HSCs in order to ensure the existence of the HSC pool that is paramount to provide life-long hematopoiesis. Aging is in general characterized by reduced ability to sustain tissue homeostasis and return to a homeostatic state after stress or trauma. Several alterations arise in the hematopoietic system with advancing age and several of these have been suggested to originate at the level of HSCs. With advancing age a bias toward myeloid cells arises within the hematopoietic system characterized by a reduced production of lymphoid cells. Despite an accumulation of HSCs in aged mice it has been suggested that aged HSCs display a decreased proliferation that depends on p16Ink4a activity. Although we observed (article I) a decreased replicative activity in physiologically aged HSC we found no evidence for increased p16Ink4a activity in these cells. In article II we demonstrated several hematopoietic defects reminiscent of premature HSC aging including anemia, lymphopenia, and myeloid lineage skewing in mice that rapidly accumulate mitochondrial DNA (mtDNA) mutations. This however, was due to distinct differentiation blocks and/or disappearance of downstream progenitors in the absence of several hallmarks of physiological HSC aging such as epigenetic alterations and accumulation of a myeloid biased subset of HSCs. These findings highlight the necessity of intact mitochondrial function for multilineage hematopoiesis but argue against mtDNA mutations as primary drivers of HSC aging. How growth factors and the relevant signaling pathways dictate HSC lineage specification is not fully understood. Aged mice, deficient in the signal adaptor protein LNK (article III), that acts to dampen several extrinsic signaling pathways, did not display repopulating defects otherwise observed in physiologically aged HSCs. This argues that enhanced cytokine signaling can counteract several key aspects of age-associated HSC decline

The Ideal Number of Lemmas in an Ideal Accounting Dictionary

Lemma lacunas in dictionaries are a traditional focus area for lexicographers, but the opposite problem, which we choose to call lemma flooding, has received very little attention. The study of this flooding could be relevant in order to save lexicographers spending thousands of hours producing dictionary entries which nobody reads.In Bergenholtz/Norddahl (2012) we showed that during a three-year period less than 33% of all dictionary articles out of 18 million dictionary consultations were consulted in a dictionary with 111,000 entries. We examined nine possible reasons why a given word might not be of interest to users and consequently could be ignored in order to avoid lemma flooding. We tried to demonstrate that while it is not possible to completely avoid lemma fl ooding, implementing a relatively simple rule could minimize it. But in reality the results were quite disappointing, because there were no clear rules or methods to avoid lemma fl ooding.Now we will try the same kind of analysis of log files for the English-Danish and the Danish-English Accounting Dictionaries. We see here that there are differences between different dictionaries (monolingual for English and Danish and bilingual for English-Danish and Danish-English). We will try to give some explanations, but must admit beforehand that we have not found satisfying explanations which could lead to a plan for future accounting dictionaries or other economic dictionaries thus avoiding the production of never used dictionary articles

Application of aquaporin-based forward osmosis membranes for processing of digestate liquid fractions

[EN] Forward osmosis is a low-energy water treatment emerging technology, which has demonstrated improved solute rejection and low fouling propensity. In this study, the applicability of aquaporin-based forward osmosis membranes during separation of biogas digestate liquid fractions was investigated. The results showed that Total Ammonia-Nitrogen rejection was higher than 95.5% in all experiments, independently of the type of draw solution (NaCl and hide preservation effluents), experimental period and the use of feed acidification. The results also confirmed that high draw osmotic pressures (i.e. 3.5¿M sodium chloride and hide preservation wastewater) combined with feed acidification had a negative effect on the membrane water permeability. Membrane rinsing after fouling was also successful in recovering the membrane initial water flux as well as removing the remaining foulants on the membrane surface. The membrane inspection results from Scanning-Electron Microscope, Energy-Dispersive X-Ray analysis and Fourier Transform Infrared¿Attenuated Total Reflectance showed that fouling in this application was mild and reversible after membrane rinsing. The applicability of aquaporin-based forward osmosis membranes during separation of biogas digestate liquid fractions has been demonstrated. The results showed the potential of this technology to achieve enhanced ammonia-nitrogen rejections and low-fouling propensity.The authors thank the tannery factory in the region of Murcia (Spain) for providing the wastewater samples as well as Depuración de Aguas del Mediterráneo (DAM, Spain) for funding the forward osmosis project. Thanks to August Bonmatí from IRTA GIRO Joint Research Unit IRTA-UPC, for providing the digestate liquid fractions, to Rebeca Vidal-Pérez as student assistant during the chemical analysis and to the Electron Microscopy Service from the Polytechnic University of Valencia (UPV, Spain). The authors further acknowledge funding from People Programme (Marie Curie Actions) of the European Union Seventh Framework Programme FP7/2007-2013/under REA grant agreement n° [289887].Camilleri-Rumbau, MDLS.; Soler-Cabezas, JL.; Christensen, KV.; Norddahl, B.; Mendoza Roca, JA.; Vincent Vela, MC. (2019). Application of aquaporin-based forward osmosis membranes for processing of digestate liquid fractions. Chemical Engineering Journal. 371:583-592. https://doi.org/10.1016/j.cej.2019.02.029S58359237

Exploring the structure-properties relationships of novel polyamide thin film composite membranes

Polysulfone (PSf) is a traditional material widely used for manufacturing microfiltration and ultrafiltration membranes by non-solvent induced phase separation (NIPS) process. However, the hydrophobic nature of PSf makes the membranes prone to protein fouling. In order to create non fouling surfaces and further decrease the pore size, the membrane pores can be modified by different strategies as atom transfer radical polymerization [1]. However, these strategies are not adopted by industry due to either cost or technical challenges. This contribution presents the preparation of asymmetric membranes by in situ interfacial polymerization (IP) of thin films (TF) on the PSf support surface in order to form a new polyamide (PA) layer [2]. The new PA is hydrophilic and negatively charged, and has prospects in application such as removal of bacteria and heavy metal ions from waste water. The pore size of the barrier layer can be controlled by adjusting the cross-linking degree and chemical composition of the PA network. This work is an attempt to prepare a new PA TF composite membrane and investigate the effect of different amines’ structures on the final membrane properties. Characterization of the PA surface morphology and chemical structure includes scanning electron microscopy, atomic force microscopy, attenuated total reflectance Fourier transform infrared spectroscopy, and streaming potential measurements. Rhodamine B cannot stain the TF composite membrane surface unlike the virgin PSf surface. Furthermore, the water flux decreases from 220 L/h/m²/bar for the PSf membrane to 1.5 L/h/m²/bar for the TF composite membrane. It is therefore concluded that a dense PA TF forms on the porous PSf support after the IP. In order to confirm the antifouling properties, bovine serum albumin/phosphate-bufered saline solution was tested as a model solution to measure flux recovery. References[1] Han-Bang Dong, You-Yi Xu, Zhuan Yi, Jun-Li Shi, Modification of polysulfone membranes via surface-initiated atom transfer radical polymerization, Applied Surface Science, 255, (2009), 8860-8866.[2] Yu Jun Song, Patricia Sun, Lawrence L. Henry, Benhui Sun, Mechanism of structure and performance controlled thin film composite membrane formation via interfacial polymerization process, Journal of Membrane Science, 251, (2005) 67-79

Critical Modulation of Hematopoietic Lineage Fate by Hepatic Leukemia Factor.

A gradual restriction in lineage potential of multipotent stem/progenitor cells is a hallmark of adult hematopoiesis, but the underlying molecular events governing these processes remain incompletely understood. Here, we identified robust expression of the leukemia-associated transcription factor hepatic leukemia factor (Hlf) in normal multipotent hematopoietic progenitors, which was rapidly downregulated upon differentiation. Interference with its normal downregulation revealed Hlf as a strong negative regulator of lymphoid development, while remaining compatible with myeloid fates. Reciprocally, we observed rapid lymphoid commitment upon reduced Hlf activity. The arising phenotypes resulted from Hlf binding to active enhancers of myeloid-competent cells, transcriptional induction of myeloid, and ablation of lymphoid gene programs, with Hlf induction of nuclear factor I C (Nfic) as a functionally relevant target gene. Thereby, our studies establish Hlf as a key regulator of the earliest lineage-commitment events at the transition from multipotency to lineage-restricted progeny, with implications for both normal and malignant hematopoiesis.This work was generously supported by project grants to DB from the Swedish Cancer Society, the Swedish Medical Research Council, the Swedish Pediatric Leukemia Foundation, Knut and Alice Wallenberg foundation and an ERC consolidator grant (615068). We would like to acknowledge Tom Serwold, Ewa Sitnicka and Mikael Sigvardsson for valuable scientific discussions, and Eva Erlandsson and Gerd Sten for expert technical assistance. The Genome Technology Access Center, Department of Genetics, Washington University School of Medicine, assisted with genomic analysis and is partially supported by NCI Cancer Center Support Grant P30 CA91842 to the Siteman Cancer Center, ICTS/CTSA Grant UL1TR000448 from the National Center for Research Resources (NCRR, a component of the NIH), and the NIH Roadmap for Medical Research

Effect of booster vaccination against Delta and Omicron SARS-CoV-2 variants in Iceland

Publisher Copyright: © 2022, The Author(s).By the end of July 2021, the majority of the Icelandic population had received vaccination against COVID-19. In mid-July a wave of SARS-CoV-2 infections, dominated by the Delta variant, spread through the population, followed by an Omicron wave in December. A booster vaccination campaign was initiated to curb the spread of the virus. We estimate the risk of infection for different vaccine combinations using vaccination data from 276,028 persons and 963,557 qPCR tests for 277,687 persons. We measure anti-Spike-RBD antibody levels and ACE2-Spike binding inhibitory activity in 371 persons who received one of four recommended vaccination schedules with or without an mRNA vaccine booster. Overall, we find different antibody levels and inhibitory activity in recommended vaccination schedules, reflected in the observed risk of SARS-CoV-2 infections. We observe an increased protection following mRNA boosters, against both Omicron and Delta variant infections, although BNT162b2 boosters provide greater protection against Omicron than mRNA-1273 boosters.Peer reviewe