Numerous studies of changes in the climate, vegetation and landscape responses of the Tibetan Plateau (TP) during the Holocene have been published in recent decades. However, several conflicting ...interpretations are evident within these studies and a comprehensive review of the topic is needed to reconcile them, and thus to provide an improved understanding of the history and forcing mechanisms of Holocene environmental changes within the region. Here we review the evidence for changes in climate (temperature, precipitation/moisture), vegetation and landscape attributes (glacier and eolian activity) on the TP during the Holocene. Our main conclusions are as follows. 1) The patterns of Holocene mean annual temperature change on the TP remain controversial; however, an early to middle Holocene summer temperature maximum is evident, which coincided with high summer insolation and a strengthening of the Indian summer monsoon (ISM). This suggests that the summer land-sea thermal gradient, impacted by the temperature of the TP, may be an important factor driving orbital-scale ISM changes. 2) Lake-level records indicate an optimum in moisture conditions on the southwestern (SW) TP in the early Holocene, while on the northeastern (NE) TP the optimum occurred in the middle to late Holocene. This out-of-phase or anti-phased relationship may be linked to the role of the ISM in dominating precipitation on the SW TP, while the westerlies and East Asian summer monsoon dominated the precipitation on the NE TP. 3) Most of the lake-sediment-based stable isotope records (δ18O and leaf wax δD) exhibit a pattern similar to that of stalagmite δ18O records from monsoonal Asia, reflecting the dominance of large-scale patterns of atmospheric circulation, rather than localized moisture changes reflected by lake level records. 4) A synthesis of pollen records reveals that the extent of forest was maximal in the mid-Holocene, while from the early Holocene onwards alpine steppe shrunk and alpine meadow and desert gradually expanded. 5) Evidence of glacier advance increased slightly during the early Holocene, decreased during the mid-Holocene, and then increased substantially after 3 ka BP. 6) The integrated ages of eolian sand and loess from the NE TP reveal that eolian activity intensified during the early and late Holocene. Site inter-comparisons reveal that regional climate change played a major role in modulating changes in vegetation and other landscape attributes. Overall, producing Holocene climate reconstructions for the entire TP remains a major challenge even though much progress has been made. Further improvements in terms of the spatial coverage of high-resolution paleoclimatic records with robust chronological control, and a deeper understanding of the specific climatic significance of several climatic proxies, will facilitate an improved understanding of how the monsoon and the westerlies interacted and their impacts on vegetation and landscape changes on the TP.
•First comprehensive review of Holocene climatic and environmental changes for TP.•Early to middle Holocene summer temperature maximum on TP, driving a strong ISM.•Divergent patterns of changes in moisture conditions between the northern and southern TP.•Regional climate change modulating changes in vegetation and other landscape attributes.
Zinc-finger nuclease, transcription activator-like effector nuclease and CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9) are becoming major tools ...for genome editing. Importantly, knock-in in several non-rodent species has been finally achieved thanks to these customizable nucleases; yet the rates remain to be further improved. We hypothesize that inhibiting non-homologous end joining (NHEJ) or enhancing homology-directed repair (HDR) will improve the nuclease-mediated knock-in efficiency. Here we show that the in vitro application of an HDR enhancer, RS-1, increases the knock-in efficiency by two- to five-fold at different loci, whereas NHEJ inhibitor SCR7 has minimal effects. We then apply RS-1 for animal production and have achieved multifold improvement on the knock-in rates as well. Our work presents tools to nuclease-mediated knock-in animal production, and sheds light on improving gene-targeting efficiencies on pluripotent stem cells.
Laboratory animal models play an important role in the study of human diseases. Using appropriate animals is critical not only for basic research but also for the development of therapeutics and ...diagnostic tools. Rabbits are widely used for the study of human atherosclerosis. Because rabbits have a unique feature of lipoprotein metabolism (like humans but unlike rodents) and are sensitive to a cholesterol diet, rabbit models have not only provided many insights into the pathogenesis and development of human atherosclerosis but also made a great contribution to translational research. In fact, rabbit was the first animal model used for studying human atherosclerosis, more than a century ago. Currently, three types of rabbit model are commonly used for the study of human atherosclerosis and lipid metabolism: (1) cholesterol-fed rabbits, (2) Watanabe heritable hyperlipidemic rabbits, analogous to human familial hypercholesterolemia due to genetic deficiency of LDL receptors, and (3) genetically modified (transgenic and knock-out) rabbits. Despite their importance, compared with the mouse, the most widely used laboratory animal model nowadays, the use of rabbit models is still limited. In this review, we focus on the features of rabbit lipoprotein metabolism and pathology of atherosclerotic lesions that make it the optimal model for human atherosclerotic disease, especially for the translational medicine. For the sake of clarity, the review is not an attempt to be completely inclusive, but instead attempts to summarize substantial information concisely and provide a guideline for experiments using rabbits.
Pachymic acid (PA), a triterpenoid from Poria cocos, has various pharmacological effects, including anti-inflammatory, anti-cancer, anti-aging, and insulin-like properties. PA has gained considerable ...research attention, but the mechanism of its anti-cancer effects remains unclear. In this study, pyruvate kinase M2 (PKM2) was discovered as a PA target via the drug affinity responsive target stability. Molecular docking and enzyme assay revealed that PA is a competing activator of PKM2, and mimics the natural activator, fructose-1,6-bisphosphate. PKM2 activation should augment the flux of glycolysis. However, decreased glucose uptake and lactate production after PA treatment was observed in SK-BR-3 breast carcinoma cells, indicating a blockage or downregulation of glycolysis. The potential of previously reported triterpenoids in blocking hexokinase II (HK2) activity inspired us to investigate the inhibition effect of PA on HK2 activity. Molecular docking and enzyme assay confirmed that PA was an inhibitor of HK2, with an IC50 of 5.01 µM. The possible consequences of glycometabolic regulation by PA, such as dissociation of HK2 from the mitochondria, release of mitochondrial cytochrome (Cyt) c, depletion of ATP, and generation of reactive oxygen species, were further validated. Furthermore, the details of the possible linkage of targeting PKM2 and HK2 with previously reported actions of PA were discussed. The results of our study provided valuable information on the anti-cancer mechanisms of PA.
Transcription factor EB (TFEB) is a master regulator of autophagy and lysosome biogenesis. We investigated the function of TFEB in vascular biology and pathophysiology and demonstrated that TFEB in ...endothelial cells inhibited inflammation and reduced atherosclerosis development. Laminar shear stress, which protects against atherosclerosis, increased TFEB abundance in cultured primary human endothelial cells. Furthermore, TFEB overexpression in these cells was anti-inflammatory, whereas TFEB knockdown aggravated inflammation. The anti-inflammatory effect of TFEB was, at least, partially due to reduced oxidative stress because TFEB overexpression in endothelial cells decreased the concentrations of reactive oxygen species and increased the expression of the antioxidant genes HO1 (which encodes heme oxygenase 1) and SOD2 (which encodes superoxide dismutase 2). In addition, transgenic mice with endothelial cell-specific expression of TFEB exhibited reduced leukocyte recruitment to endothelial cells and decreased atherosclerosis development. Our study suggests that TFEB is a protective transcription factor against endothelial cell inflammation and a potential target for treating atherosclerosis and associated cardiovascular diseases.
Rapid lake expansions along with intensive glacier loss in the Tibetan Plateau (TP) in recent decades indicate an enhanced hydrological circulation. Well-preserved paleo-shorelines up to ∼200 m above ...modern levels in the TP attest to much greater lake expansions in the past and serve as analogues for future lake evolution under climate changes. Mega-lakes in the inner TP, defined by the highest paleo-shorelines, were mainly formed in the early–middle Holocene and are mainly attributed to a high monsoonal rainfall. However, the effect of melting glaciers on the mega-lakes was rarely evaluated, and reliable mega-lake ages are scarce, especially in the northwestern TP (NWTP). We studied six mega-lakes in the NWTP by dating the highest paleo-shorelines using optical dating of multiple and single grains and then reconstructing the paleo-hydrology. The results show that four mega-lakes existed during the last deglacial (16.3–12.6 ka). They had lake levels 53–269 m higher than today and areas up to 7.3 times larger than the modern lakes, containing up to 105.4 km3 more water. A comparison of mega-lakes across the TP and correlation with independent paleoclimatic records reveal that these mega-lakes attained larger relative sizes (lake area/basin land area ratio) under a dry climate and intensive glacier melting during the last deglacial than the non-glacier-fed mega-lakes that developed in response to the early–middle Holocene rainfall maximum. We suggest that they were formed by melting glaciers, and therefore glaciers had major impacts on long-term lake evolution in the NWTP.
•Post-IR IRSL dating of K-feldspar single-grains determined paleo-shoreline ages.•Four mega-lakes developed in the northwestern Tibetan Plateau in the last deglacial.•The last deglacial mega-lakes were formed by melting glaciers.
This study aimed to investigate moisture absorption behaviors, dimensional stability, and mechanical performance evolution of continuous carbon fibers reinforced with polyamide 6 composites (CF/PA6) ...under a hygrothermal environment. 3D Fickian model determined the principal three-dimensional (3D) diffusion coefficients by using an optimization algorithm. Three-dimensional changes of samples were measured to quantify the relationship between swelling coefficient and water content. After hygrothermal aging, the tensile properties of PA6 resin and CF/PA6 composites in the transverse direction decreased significantly, but the longitudinal tensile properties of CF/PA6 composites were insensitive to hygrothermal aging. DMA (Dynamic Mechanical Analysis), SEM (Scanning Electron Microscopy) and FTIR (Fourier Transform Infrared) tests were also applied to analyze the mechanism of mechanical properties degradation.
Nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH) has reached epidemic proportions with no pharmacological therapy approved. Lower circulating glycine is ...consistently reported in patients with NAFLD, but the causes for reduced glycine, its role as a causative factor, and its therapeutic potential remain unclear. We performed transcriptomics in livers from humans and mice with NAFLD and found suppression of glycine biosynthetic genes, primarily alanine-glyoxylate aminotransferase 1 (
). Genetic (
mice) and dietary approaches to limit glycine availability resulted in exacerbated diet-induced hyperlipidemia and steatohepatitis, with suppressed mitochondrial/peroxisomal fatty acid β-oxidation (FAO) and enhanced inflammation as the underlying pathways. We explored glycine-based compounds with dual lipid/glucose-lowering properties as potential therapies for NAFLD and identified a tripeptide (Gly-Gly-L-Leu, DT-109) that improved body composition and lowered circulating glucose, lipids, transaminases, proinflammatory cytokines, and steatohepatitis in mice with established NASH induced by a high-fat, cholesterol, and fructose diet. We applied metagenomics, transcriptomics, and metabolomics to explore the underlying mechanisms. The bacterial genus
sensu stricto was markedly increased in mice with NASH and decreased after DT-109 treatment. DT-109 induced hepatic FAO pathways, lowered lipotoxicity, and stimulated de novo glutathione synthesis. In turn, inflammatory infiltration and hepatic fibrosis were attenuated via suppression of NF-κB target genes and TGFβ/SMAD signaling. Unlike its effects on the gut microbiome, DT-109 stimulated FAO and glutathione synthesis independent of NASH. In conclusion, impaired glycine metabolism may play a causative role in NAFLD. Glycine-based treatment attenuates experimental NAFLD by stimulating hepatic FAO and glutathione synthesis, thus warranting clinical evaluation.
This paper is focused on formability of multi-agent systems （MASs）. The problem is concerned with the existence of a protocol that has the ability to drive the MAS involved to the desired formation, ...and thus, is of essential importance in designing formation protocols. Formability of an MAS depends on several key factors： agents＇ dynamic structures, connectivity topology, properties of the desired formation and the admissible control set. Agents of the MASs considered here are described by a general continuous linear time-invariant （LTI） model. By using the matrix analysis and algebraic graph theory, some necessary and sufficient conditions on formability of LTI-MASs are obtained. These conditions characterize in some sense the relationship of formability, connectivity topology, formation properties and agent dynamics with respect to some typical and widely used admissible protocol sets.
Hyperthyroidism has been identified as a risk factor for cognitive disorders. The hippocampus is a key brain region associated with cognitive function, among which excitatory synapse transmission ...plays an important role in the process of learning and memory. However, the mechanism by which hyperthyroidism leads to cognitive dysfunction through a synaptic mechanism remains unknown. We investigated the synaptic mechanisms in the effects of hyperthyroidism in an animal model that involved repeated injection of triiodothyronine (T3). These mice displayed impaired learning and memory in the Novel object recognition test, Y-maze test, and Morris Water Maze test, as well as elevated anxiety in the elevated plus maze. Mature dendritic spines in the hippocampal CA1 region of hyperthyroid mice were significantly decreased, accompanied by decreased level of AMPA- and NMDA-type glutamate receptors in the hippocampus. In primary cultured hippocampal neurons, levels of AMPA- and NMDA-type glutamate receptors also decreased and whole-cell patch-clamp recording revealed that excitatory synaptic function was obviously attenuated after T3 treatment. Notably, pharmacological activation of AMPAR or NMDAR by intraperitoneal injection of CX546, an AMPAR agonist, or NMDA, an NMDAR agonist can restore excitatory synaptic function and corrected impaired learning and memory deficit in hyperthyroid mice. Together, our findings uncovered a previously unrecognized AMPAR and NMDAR-dependent mechanism involved in regulating hippocampal excitatory synaptic transmission and learning and memory disorders in hyperthyroidism.
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