T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here we integrated large-scale profiling data of alterations in gene expression, allelic copy number ...(CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identify novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM toward a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.
T‐regulatory (Treg) cells are like other cells present throughout the body in being subject to biochemical modifications in response to extracellular signals. An important component of these ...responses involves changes in posttranslational modifications (PTMs) of histones and many nonhistone proteins, including phosphorylation/dephosphorylation, ubiquitination/deubiquitination, and acetylation/deacetylation. Foxp3, the key transcription factor of Tregs, is constantly being rapidly turned over, and a number of these PTMs determine its level of expression and activity. Of interest in the transplant setting, modulation of the acetylation or deacetylation of key lysine residues in Foxp3 can promote the stability and function, leading to increased Treg production and increased Treg suppressive activity. This mini‐review focuses on recent data concerning the roles that histone/protein deacetylases (HDACs) play in control of Treg function, and how small molecule HDAC inhibitors can be used to promote Treg‐dependent allograft survival in experimental models. These data are discussed in the light of increasing interest in the identification and clinical evaluation of isoform‐selective HDAC inhibitors, and their potential application as tools to modulate Foxp3+ Treg cell numbers and function in transplant recipients.
Biochemical and molecular studies show that the functions of Foxp3+ regulatory T cells can be pharmacologically enhanced with isoform‐specific histone/protein deacetylase inhibitors, providing real‐world options for sustained therapy in transplant recipients.
Objective To compare the assessment of endometrial maturation parameters in endometrial secretion samples obtained by a novel minimally invasive technique with those assessed in tissue biopsies.
...Design Prospective study.
Setting University Hospital.
Population Healthy female volunteers attending a gynaecological outpatient clinic.
Methods Endometrial secretion fluid and tissue sampling 5 days after a spontaneous ovulation assessed with ultrasound.
Main outcome measures Progesterone (P) receptor, Ki‐67 expression and the Noyes criteria were used to date endometrial biopsies. In the endometrial fluid samples, glycodelin A (GdA), leukaemia inhibitory factor (LIF) and P levels were analysed, and protein content and electrophoresis patterns were determined.
Results All data were correlated to estradiol (E2) and P serum concentrations. The dating according to histology and immunohistochemical staining patterns correlated significantly with GdA levels (r = 0.376, P =0.048) in endometrial fluid samples as well with serum levels of E2 (r = 0.568, P =0.001) and P (r = 0.408, P =0.023). No correlation was observed between tissue dating and LIF levels and protein content in endometrial fluid samples.
Conclusions The measurement of GdA in endometrial secretion samples may provide a less invasive method for assessing endometrial maturation in potential conception cycles without disrupting implantation.
Tests on B−L symmetry breaking models are important probes to search for new physics. One proposed model with Δ(B−L)=2 involves the oscillations of a neutron to an antineutron. In this paper, a new ...limit on this process is derived for the data acquired from all three operational phases of the Sudbury Neutrino Observatory experiment. The search concentrated on oscillations occurring within the deuteron, and 23 events were observed against a background expectation of 30.5 events. These translated to a lower limit on the nuclear lifetime of 1.48×1031 yr at 90% C.L. when no restriction was placed on the signal likelihood space (unbounded). Alternatively, a lower limit on the nuclear lifetime was found to be 1.18×1031 yr at 90% C.L. when the signal was forced into a positive likelihood space (bounded). Values for the free oscillation time derived from various models are also provided in this article. This is the first search for neutron-antineutron oscillation with the deuteron as a target.
The long baseline between Earth and the Sun makes solar neutrinos an excellent test beam for exploring possible neutrino decay. The signature of such decay would be an energy-dependent distortion of ...the traditional survival probability which can be fit for using well-developed and high-precision analysis methods. Here a model including neutrino decay is fit to all three phases of B8 solar neutrino data taken by the Sudbury Neutrino Observatory (SNO). This fit constrains the lifetime of neutrino mass state ν2 to be >8.08×10−5 s/eV at 90% confidence. An analysis combining this SNO result with those from other solar neutrino experiments results in a combined limit for the lifetime of mass state ν2 of >1.92×10−3 s/eV at 90% confidence.
This paper reports results from a search for nucleon decay through invisible modes, where no visible energy is directly deposited during the decay itself, during the initial water phase of SNO+. ...However, such decays within the oxygen nucleus would produce an excited daughter that would subsequently deexcite, often emitting detectable gamma rays. A search for such gamma rays yields limits of 2.5×1029 y at 90% Bayesian credibility level (with a prior uniform in rate) for the partial lifetime of the neutron, and 3.6×1029 y for the partial lifetime of the proton, the latter a 70% improvement on the previous limit from SNO. We also present partial lifetime limits for invisible dinucleon modes of 1.3×1028 y for nn, 2.6×1028 y for pn and 4.7×1028 y for pp, an improvement over existing limits by close to 3 orders of magnitude for the latter two.
Here, a measurement of the 8B solar neutrino flux has been made using a 69.2 kt-day dataset acquired with the SNO+ detector during its water commissioning phase. At energies above 6 MeV the dataset ...is an extremely pure sample of solar neutrino elastic scattering events, owing primarily to the detector’s deep location, allowing an accurate measurement with relatively little exposure. In that energy region the best fit background rate is 0.25+0.09–0.07 events/kt–day, significantly lower than the measured solar neutrino event rate in that energy range, which is 1.03+0.13–0.12 events/kt–day. Also using data below this threshold, down to 5 MeV, fits of the solar neutrino event direction yielded an observed flux of 2.53+0.31–0.28(stat)+0.13–0.10(syst) × 106 cm–2 s–1, assuming no neutrino oscillations. This rate is consistent with matter enhanced neutrino oscillations and measurements from other experiments.
The SNO+ Collaboration reports the first evidence of reactor antineutrinos in a Cherenkov detector. The nearest nuclear reactors are located 240 km away in Ontario, Canada. This analysis uses events ...with energies lower than in any previous analysis with a large water Cherenkov detector. Two analytical methods are used to distinguish reactor antineutrinos from background events in 190 days of data and yield consistent evidence for antineutrinos with a combined significance of 3.5σ.
Contents
Early embryonic development, implantation and maintenance of a pregnancy are critically dependent on an intact embryo‐maternal communication. So far, only few signals involved in this ...dialogue have been identified. In bovine and other ruminants, interferon tau is the predominant embryonic pregnancy recognition signal, exhibiting antiluteolytic activity. However, this is just one aspect of the complex process of embryo‐maternal signalling, and a number of other systems are more likely to be involved. To gain a more comprehensive understanding of these important mechanisms, integrated projects involving specialists in embryology, reproductive biotechnology and functional genome research are necessary to perform a systematic analysis of interactions between pre‐implantation stage embryos and oviduct or uterine epithelial cells, respectively. State‐of‐the‐art transcriptomic and proteomic technologies will identify reciprocal signals between embryos and their maternal environment and the respective downstream reaction cascades. For in vivo studies, the use of monozygotic twins as recipient animals provides elegant model systems, thus eliminating genetic variability as a cause of differential gene expression. In addition, suitable systems for the co‐culture of oviduct epithelial or endometrium cells with the respective embryonic stages need to be established for functional validation of candidate genes potentially involved in the dialogue between embryos and their maternal environment. The knowledge of these mechanisms should help to increase the pregnancy rate following embryo transfer and to avoid embryonic losses. Candidate genes involved in embryo‐maternal communication will also be used to define new quality criteria for the selection of embryos for transfer to recipients. Another application is the supplementation of embryotrophic factors or components of embryo‐maternal signalling in optimized formulations, such as bioartificial matrices. As a long‐term goal, signalling mechanisms identified in bovine will also be functionally evaluated in other species, including the human.
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