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Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.
Aims/hypothesis Paternal high-fat diet prior to mating programmes impaired glucose tolerance in female offspring. We examined whether the metabolic consequences in offspring could be abolished by folate treatment of either the male rats before mating or the corresponding female rats during pregnancy. Methods Male F0 rats were fed either control diet or high-fat, high-sucrose and high-salt diet (HFSSD), with or without folate, before mating. Male rats were mated with control-diet-fed dams. After mating, the F0 dams were fed control diet with or without folate during pregnancy.
Fatty acid synthase (FASN) catalyzing the terminal steps in the de novo biogenesis of fatty acids is correlated with low survival and high disease recurrence in patients with bladder cancer. Pyruvate kinase M2 (PKM2) regulates the final step of glycolysis levels and provides a growth advantage to tumors. However, it is unclear whether the change of PKM2 has an effect on FASN and what is the mechanisms underlying. Here we describe a novel function of PKM2 in control of lipid metabolism by mediating transcriptional activation of FASN, showing the reduced expression of sterol regulatory element binding protein 1c (SREBP-1c). We first discovered that PKM2 physically interacts with the SREBP-1c using biochemical approaches, and downregulation of PKM2 reduced the expression of SREBP-1c by inactivating the AKT/mTOR signaling pathway, which in turn directly suppressed the transcription of major lipogenic genes FASN to reduce tumor growths. Furthermore, either PKM2 inhibitor-Shikonin or FASN inhibitor-TVB-3166 alone induced a strong antiproliferative and anticolony forming effect in bladder cancer cell line. The combination of both inhibitors exhibits a super synergistic effect on blocking the bladder cancer cells growth. It provides a new target and scientific basis for the treatment of bladder cancer.
A number of sedimentary provenance studies have been undertaken in order to determine whether the palaeo-Red River was once a river of continental proportions into which the upper reaches of the Yangtze, Salween, Mekong, Irrawaddy, and Yarlung drained. We have assessed the evidence that the Yarlung originally flowed into the palaeo-Red river, and then sequentially into the Irrawaddy and Brahmaputra, connecting to the latter first via the Lohit and then the Siang. For this river system, we have integrated our new data from the Paleogene-Recent Irrawaddy drainage basin (detrital zircon U-Pb with Hf and fission track, rutile U-Pb, mica Ar-Ar, bulk rock Sr-Nd, and petrography) with previously published data, to produce a palaeodrainage model that is consistent with all datasets. In our model, the Yarlung never flowed into the Irrawaddy drainage: during the Paleogene, the Yarlung suture zone was an internally drained basin, and from Neogene times onwards the Yarlung drained into the Brahmaputra in the Bengal Basin. The Central Myanmar Basin, through which the Irrawaddy River flows today, received predominantly locally-derived detritus until the Middle Eocene, the Irrawaddy initiated as a through-going river draining the Mogok Metamorphic Belt and Bomi-Chayu granites to the north sometime in the Late Eocene to Early Oligocene, and the river was dominated by a stable MMB-dominated drainage throughout the Neogene to present day. Existing evidence does not support any connection between the Yarlung and the Red River in the past, but there is a paucity of suitable palaeo-Red River deposits with which to make a robust comparison. We argue that this limitation also precludes a robust assessment of a palaeo-connection between the Yangtze/ Salween/Mekong and the Red River; it is difficult to unequivocally interpret the recorded provenance changes as the result of specific drainage reorganisations. We highlight the palaeo-Red River deposits of the Hanoi Basin as a potential location for future research focus in view of the near-complete Cenozoic record of palaeo-Red River deposits at this location. A majority of previous studies consider that if a major continental-scale drainage ever existed at all, it fragmented early in the Cenozoic. Such a viewpoint would agree with the growing body of evidence from palaeoaltitude studies that large parts of SE Tibet were uplifted by this period. This then leads towards the intriguing question as to the mechanisms which caused the major period of river incision in the Miocene in this region.