Mutated Ptpn11 alters leukemic stem cell frequency and reduces the sensitivity of acute myeloid leukemia cells to Mcl1 inhibition

PTPN11 encodes the Shp2 non-receptor protein-tyrosine phosphatase implicated in several signaling pathways. Activating mutations in Shp2 are commonly associated with juvenile myelomonocytic leukemia but are not as well defined in other neoplasms. Here we report that Shp2 mutations occur in human acute myeloid leukemia (AML) at a rate of 6.6% (6/91) in the ECOG E1900 data set. We examined the role of mutated Shp2 in leukemias harboring MLL translocations, which co-occur in human AML. The hyperactive Shp2E76K mutant, commonly observed in leukemia patients, significantly accelerated MLL-AF9-mediated leukemogenesis in vivo. Shp2E76K increased leukemic stem cell frequency and affords MLL-AF9 leukemic cells IL3 cytokine hypersensitivity. As Shp2 is reported to regulate anti-apoptotic genes, we investigated Bcl2, Bcl-xL and Mcl1 expression in MLL-AF9 leukemic cells with and without Shp2E76K. Although the Bcl2 family of genes was upregulated in Shp2E76K cells, Mcl1 showed the highest upregulation in MLL-AF9 cells in response to Shp2E76K. Indeed, expression of Mcl1 in MLL-AF9 cells phenocopies expression of Shp2E76K, suggesting Shp2 mutations cooperate through activation of anti-apoptotic genes. Finally, we show Shp2E76K mutations reduce sensitivity of AML cells to small-molecule-mediated Mcl1 inhibition, suggesting reduced efficacy of drugs targeting MCL1 in patients with hyperactive Shp2

Fate of Hematopoiesis During Aging. What Do We Really Know, and What are its Implications?

This article is made available for unrestricted research re-use and secondary analysis in any form or be any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.There is an ongoing shift in demographics such that older persons will outnumber young persons in the coming years, and with it age-associated tissue attrition and increased diseases and disorders. There has been increased information on the association of the aging process with dysregulation of hematopoietic stem (HSC) and progenitor (HPC) cells, and hematopoiesis. This review provides an extensive up-to date summary on the literature of aged hematopoiesis and HSCs placed in context of potential artifacts of the collection and processing procedure, that may not be totally representative of the status of HSCs in their in vivo bone marrow microenvironment, and what the implications of this are for understanding aged hematopoiesis. This review covers a number of interactive areas, many of which have not been adequately explored. There are still many unknowns and mechanistic insights to be elucidated to better understand effects of aging on the hematopoietic system, efforts that will take multidisciplinary approaches, and that could lead to means to ameliorate at least some of the dysregulation of HSCs and HPCs associated with the aging process.Some of the studies reported in this review, and the writing of this review were supported by the following U.S. Public Health Grants from the National Institutes of Health to H.E.B.: R35 HL139599 (Outstanding Investigator Award), R01 DK109188, U54 DK106846; A.A., J.P.R., and T.T. were supported by T32 DK007519 to H.E.B. R01 HL150624, R56 DK119524, R56 AG052501, DoD W81XWH-13-1-0187, DoD W81XWH-18-1-0265 and DoD W81XWH-19-1-0575, the Leukemia and Lymphoma Society Translational Research Program award 6581-20 and the St. Baldrick’s Foundation Scholar Award to Y.L. MLC was supported by R01 DK109188. CO was supported by National Institute of Allergy and Infectious Diseases (NIAID) contracts HHSN266200500043C and HHSN272201000046C and grants 1U01AI107340-01 and 2R44 AI088288-03A1, National Institute on Aging (NIA) grant R01AG046246-01, and Department of Defense grants PR140896, PR141527, and PR140433P1

Nitrogen fixation and transfer in open ocean diatom–cyanobacterial symbioses

Many diatoms that inhabit low-nutrient waters of the open ocean live in close association with cyanobacteria. Some of these associations are believed to be mutualistic, where N2-fixing cyanobacterial symbionts provide N for the diatoms. Rates of N2 fixation by symbiotic cyanobacteria and the N transfer to their diatom partners were measured using a high-resolution nanometer scale secondary ion mass spectrometry approach in natural populations. Cell-specific rates of N2 fixation (1.15–71.5 fmol N per cell h−1) were similar amongst the symbioses and rapid transfer (within 30 min) of fixed N was also measured. Similar growth rates for the diatoms and their symbionts were determined and the symbiotic growth rates were higher than those estimated for free-living cells. The N2 fixation rates estimated for Richelia and Calothrix symbionts were 171–420 times higher when the cells were symbiotic compared with the rates estimated for the cells living freely. When combined, the latter two results suggest that the diatom partners influence the growth and metabolism of their cyanobacterial symbionts. We estimated that Richelia fix 81–744% more N than needed for their own growth and up to 97.3% of the fixed N is transferred to the diatom partners. This study provides new information on the mechanisms controlling N input into the open ocean by symbiotic microorganisms, which are widespread and important for oceanic primary production. Further, this is the first demonstration of N transfer from an N2 fixer to a unicellular partner. These symbioses are important models for molecular regulation and nutrient exchange in symbiotic systems

High Frequency Model for Power Electronics Capacitors

International audienc

Analog set-up for non linear dielectric measurements up to 100 kHz

In this paper, we present a new analog set-up for non linear dielectric measurements. The device is based on the auto-balanced bridge principle used in impedance analyzers. Its main advantage is to operate at high frequencies in comparison with a classical current amplifier. This extension consists in extracting the harmonics of a non sinusoidal current crossing the material. The set-up is used to perform non linear dielectric measurements on a ferroelectric liquid crystal and shows better performances than a previously published digital set-up

MARTIRIO DI PACE: MEMORIA STORICA DEL MARTIRIO NEL XVII CENTENARIO DI VITALE E AGRICOLA

Il capitolo compilato dallo scrivente - pp. 105- 183 ha per titolo: “Dal simbolo al manufatto: storia materiale della cripta dei Santi Vitale e Agricola in Arena a Bologna” In questa ricerca chi scrive ha avuto modo di utilizzare tutti gli strumenti scientifici acquisiti in decenni di lavoro: dalla conoscenza delle pietre a quella delle patine superficiali da interazione ambientale; dalla conoscenza della policromia antica a quella della stratigrafia archeologica; si è inoltre avvalso della perfetta conoscenza delle tecniche di analisi strumentale per la datazione assoluta di materiali fittili. I risultati di questo lavoro sono molto importanti a livello non solo locale ma anche internazionale. L’aver riconosciuto un antica basilica risalente all’VIII secolo e un’iscrizione de V secolo sposta di almeno 300-500 anni, al di la di Cronache ritenute dai più favole, l’inizio della Storia del Cristianesimo a Bologna. L’aver riconosciuto pilastri cruciformi o polilobati in cotto realizzati tra il 700 e il 750 sposta di almeno 300 anni a ritroso l’inizio del protoromanico a Bologna (e non solo a Bologna)

Anomalous Dielectric Spectra of Ferro- and Ferrielectric Liquid Crystalline Phase in MHPNBC

MHPOBC analogue with long achiral alkyl chain has been investigated by dielectric spectroscopy studies in the wide temperature range. Low frequency dielectric spectroscopy revealed the existence of normal ferroelectric phase (in a narrow gap), two ferri- and three antiferroelectric phases in addition to paraelectric phase and alpha sub-phase. The compound studied shows exceptionally strong dependence of the dielectric permittivities on measuring electric field in the temperature range of ferro- and ferrielectric phases