Inherited Bone Marrow Failure and Chromosome Instability Syndromes and their Cancer Predisposition

Inherited bone marrow failure syndromes (IBMFS) and chromosome instability syndromes (CIS) are the most classic and representative genetic syndromes. They are classified as genetic rare diseases, typically with complex medical complications in the delay of mental and physical development. Commonly, these syndromes present with different degrees of dysmorphics; organs/systems dysfunction generally and these syndromes have higher risk of inherited solid cancer and leukemia predisposition due to the similar pathway of DNA defects. These syndromes are often hard to diagnose and they overlap with their phenotypes clinically. Very importantly cancers from the germ line mutation of these syndromes require different treatment strategies with the sporadic malignancies. The significance of recognition of such diseases is not only beneficial to patients phenotypically affected but also to individuals phenotypically unaffected and members/relatives of the family. Remarkable advances have been made in the definition and classification of these genetic syndromes. Identification of the IBMFS and CIS has led to important advances in the understanding of the genotypes, guiding the clinical practice of the phenotypes. Interestingly, such studies provided insights into the function of the various DNA repair pathways. Fanconi anemia studies are an example in IBMFS and CIS is named as the paradigm of the studies of cancer and aging

Milestone Histories and Paradigmatic Genetic Discoveries of Chronic Myeloid Leukemia (CML)

Chronic myeloid leukemia (CML) is classified as a hematological malignant rare disease by National Organization for Rare Disease (NORD, USA) based on the estimated incidence of 1–2 cases/100,000 per year internationally. CML occurs in all ages but commonly seen in the 45–55 years group. Males are slightly more affected than females. CML is one of the oldest known diseases with new faces and one of the fastest developing diseases with many extraordinary discoveries in human history of conquering the disease. CML possesses at least Nine First findings in leukemia and cancer research and even in human medical histories: the First named as leukemia in 1845, the First of a live case of CML patient diagnosed in 1846, the First used of arsenic in CML treatment in 1865, the First defined as a myeloproliferative disorder in 1951, the First finding of Philadelphia chromosome (Ph chromosome) in 1960, the First finding of chromosome 9 and 22 translocations in 1973, the First identified as a clonal hematological malignancy derived from the stage of pluripotent bone hematopoietic stem cells in 1977, the First finding of the chromosomal fusion gene-BCR-ABL as an oncogene in 1984, and the First designed target therapy of use of tyrosine kinase inhibitor (TKI) in 1998. The footprints of the studies on CML established the milestone histories. Remarkable and fascinating genetic discoveries were made of the mysteries of human diseases, the multiway translocation of Ph chromosome, and the latest issues. The association of the combination of chronic myeloid leukemia and chronic lymphocytic leukemia will be reviewed in this chapter with the aim of increasing the understanding of CML further from laboratory bench to clinical bedside

Recovery of oil with unsaturated fatty acids and polyphenols from chaenomelessinensis (Thouin) Koehne: Process optimization of pilot-scale subcritical fluid assisted extraction

The potential effects of three modern extraction technologies (cold-pressing, microwaves and subcritical fluids) on the recovery of oil from Chaenomelessinensis (Thouin) Koehne seeds have been evaluated and compared to those of conventional chemical extraction methods (Soxhlet extraction). This oil contains unsaturated fatty acids and polyphenols. Subcritical fluid extraction (SbFE) provided the highest yield—25.79 g oil/100 g dry seeds—of the three methods. Moreover, the fatty acid composition in the oil samples was analysed using gas chromatography–mass spectrometry. This analysis showed that the percentages of monounsaturated (46.61%), and polyunsaturated fatty acids (42.14%), after applying SbFE were higher than those obtained by Soxhlet, cold-pressing or microwave-assisted extraction. In addition, the oil obtained under optimized SbFE conditions (35 min extraction at 35 °C with four extraction cycles), showed significant polyphenol (527.36 mg GAE/kg oil), and flavonoid (15.32 mg RE/kg oil), content, had a good appearance and was of high quality

Probing Primordial Gravitational Waves: Ali CMB Polarization Telescope

In this paper, we will give a general introduction to the project of Ali CMB Polarization Telescope (AliCPT), which is a Sino-US joint project led by the Institute of High Energy Physics (IHEP) and has involved many different institutes in China. It is the first ground-based Cosmic Microwave Background (CMB) polarization experiment in China and an integral part of China's Gravitational Waves Program. The main scientific goal of AliCPT project is to probe the primordial gravitational waves (PGWs) originated from the very early Universe. The AliCPT project includes two stages. The first stage referred to as AliCPT-1, is to build a telescope in the Ali region of Tibet with an altitude of 5,250 meters. Once completed, it will be the worldwide highest ground-based CMB observatory and open a new window for probing PGWs in northern hemisphere. AliCPT-1 telescope is designed to have about 7,000 TES detectors at 90GHz and 150GHz. The second stage is to have a more sensitive telescope (AliCPT-2) with the number of detectors more than 20,000. Our simulations show that AliCPT will improve the current constraint on the tensor-to-scalar ratio $r$ by one order of magnitude with 3 years' observation. Besides the PGWs, the AliCPT will also enable a precise measurement on the CMB rotation angle and provide a precise test on the CPT symmetry. We show 3 years' observation will improve the current limit by two order of magnitude.Comment: 11 pages, 7 figures, 2 table

P311 induces the transdifferentiation of epidermal stem cells to myofibroblast-like cells by stimulating transforming growth factor β1 expression

Background: Epithelial to mesenchymal transition, especially to myofibroblasts, plays an important role in wound healing, fibrosis, and carcinogenesis. Epidermal stem cells (EpSCs) are responsible for epidermal renewal and wound re-epithelialization. However, it remains unclear whether and how EpSCs transdifferentiate into myofibroblasts or myofibroblast-like cells (MFLCs). Here, we provide the first evidence showing that P311 induces EpSC to MFLC transdifferentiation (EpMyT) via TGF β 1/Smad signaling. Methods: Wound healing and mesenchymal features were observed in the P311 KO and P311 WT mouse model of superficial second-degree burns. After the primary human or mouse EpSCs were forced to highly express P311 using an adenoviral vector, EpMyT was observed by immunofluorescence, real-time PCR, and western blot. The activity of TGF β 1 and Smad2/3 in EpSCs with different P311 levels was observed by western blot. The T β RI/II inhibitor LY2109761 and Smad3 siRNA were applied to block the EpMyT in P311-overexpressing EpSCs and exogenous TGF β 1 was to restore the EpMyT in P311 KO EpSCs. Furthermore, the mechanism of P311 regulating TGF β 1 was investigated by bisulfite sequencing PCR, luciferase activity assay, and real-time PCR. Results: P311 KO mouse wounds showed delayed re-epithelialization and reduced mesenchymal features. ThehumanormouseEpSCswithoverexpressedP311exhib ited fusiform morphological changes, upregulated expression of myofibroblast markers ( α -SMA and vimentin), and downregu lated expression of EpSC markers ( β 1-integrin and E-cadherin). P311-expressing EpSCs showed decreased TGF β 1mRNAandincreasedTGF β 1 protein, T β RI/II mRNA, and activated Smad2/3. Moreover, LY2109761 and Smad3 siRNA reversed P311-induced EpMyT. Under the stimulation of exogenous TGF β 1, the phosphorylation of Smad2 and Smad3 in P311 KO EpSCs was significantly lower than that in P311 WT EpSCs and the EpMyT in P311 KO EpSCs was restored. Furthermore, P311 enhanced the methylation of TGF β 1 promoter and increased activities of TGF β 15 ′ /3 ′ untranslated regions (UTRs) to stimulate TGF β 1 expression. P311 + α -SMA + cells and P311 + vimentin + cells were observed in the epidermis of human burn wounds. Also, P311 was upregulated by IL-1 β , IL-6, TNF α ,andhypoxia. Conclusions: P311 is a novel TGF β 1/Smad signaling-mediated regulator o f transdifferentiation in EpSCs during cutaneous wound healing. Furthermore, P311 might stimulate TGF β 1 expression by promoting TGF β 1 promoter methylation and by activating the TGF β 15 ′ /3 ′ UTR

Increasing temperature elevates the variation and spatial differentiation of pesticide tolerance in a plant pathogen

Climate change and pesticide resistance are two of the most imminent challenges human society is facing today. Knowledge of how the evolution of pesticide resistance may be affected by climate change such as increasing air temperature on the planet is important for agricultural production and ecological sustainability in the future but is lack in scientific literatures reported from empirical research. Here, we used the azoxystrobin-Phytophthora infestans interaction in agricultural systems to investigate the contributions of environmental temperature to the evolution of pesticide resistance and infer the impacts of global warming on pesticide efficacy and future agricultural production and ecological sustainability. We achieved this by comparing azoxystrobin sensitivity of 180 P. infestans isolates sampled from nine geographic locations in China under five temperature schemes ranging from 13 to 25 degrees C. We found that local air temperature contributed greatly to the difference of azoxystrobin tolerance among geographic populations of the pathogen. Both among-population and within-population variations in azoxystrobin tolerance increased as experimental temperatures increased. We also found that isolates with higher azoxystrobin tolerance adapted to a broader thermal niche. These results suggest that global warming may enhance the risk of developing pesticide resistance in plant pathogens and highlight the increased challenges of administering pesticides for effective management of plant diseases to support agricultural production and ecological sustainability under future thermal conditions

ATP-citrate lyase inhibitor improves ectopic lipid accumulation in the kidney in a db/db mouse model

AimWe evaluated a novel treatment for obesity-related renal, an ATP-citrate lyase (ACL) inhibitor, to attenuate ectopic lipid accumulation (ELA) in the kidney and the ensuing inflammation.Materials and methodsAn ACL inhibitor was administered intragastrically to 12-week-old db/db mice for 30 days. The appearance of ELA was observed by staining kidney sections with Oil Red O, and the differences in tissue lipid metabolites were assessed by mass spectrometry. The anti-obesity and renoprotection effects of ACL inhibitors were observed by histological examination and multiple biochemical assays.ResultsUsing the AutoDock Vina application, we determined that among the four known ACL inhibitors (SB-204990, ETC-1002, NDI-091143, and BMS-303141), BMS-303141 had the highest affinity for ACL and reduced ACL expression in the kidneys of db/db mice. We reported that BMS-303141 administration could decrease the levels of serum lipid and renal lipogenic enzymes acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), HMG-CoA reductase (HMGCR), and diminish renal ELA in db/db mice. In addition, we found that reducing ELA improved renal injuries, inflammation, and tubulointerstitial fibrosis.ConclusionACL inhibitor BMS-303141 protects against obesity-related renal injuries