Marine fungus Aspergillus c1. sp metabolite activates the HSF1/PGC-1α axis, inducing a thermogenic program for treating obesity

Background and aims: Obesity is one of the most prevalent diseases worldwide with less ideal approved agents in clinic. Activating the HSF1/PGC-1α axis in adipose tissues has been reported to induce thermogenesis in mice, which presents a promising therapeutic avenue for obesity treatment. The present study aimed to identified novel natural HSF1 activator and evaluated the therapeutic effects of the newly discovered compound on obesity-associated metabolic disorders and the molecular mechanisms of these effects.Methods: Our previous reported HSF1/PGC-1α activator screening system was used to identify novel natural HSF1 activator. The PGC-1α luciferase activity, immunoblot, protein nuclear-translocation, immunofluorescence, chromatin immunoprecipitation assays were used to evaluate the activity of compound HN-001 in activating HSF1. The experiments of mitochondrial number measurement, TG assay and imaging, cellular metabolic assay, gene assays, and CRISPR/Cas 9 were applied for investigating the metabolic effect of HN-001 in C3H10-T1/2 adipocytes. The in vivo anti-obesity efficacies and beneficial metabolic effects of HN-001 were evaluated by performing body and fat mass quantification, plasma chemical analysis, GTT, ITT, cold tolerance test, thermogenesis analysis.Results: HN-001 dose- and time-dependently activated HSF1 and induced HSF1 nuclear translocation, resulting in an enhancement in binding with the gene Pgc-1α. This improvement induced activation of adipose thermogenesis and enhancement of mitochondrial oxidation capacity, thus inhibiting adipocyte maturation. Deletion of HSF1 in adipocytes impaired mitochondrial oxidation and abolished the above beneficial metabolic effects of HN-001, including adipocyte browning induction, improvements in mitogenesis and oxidation capacity, and lipid-lowering ability. In mice, HN-001 treatment efficiently alleviated diet-induced obesity and metabolic disorders. These changes were associated with increased body temperature in mice and activation of the HSF1/PGC-1α axis in adipose tissues. UCP1 expression and mitochondrial biogenesis were increased in both white and brown adipose tissues of HN-001-treated mice.Conclusion: These data indicate that HN-001 may have therapeutic potential for obesity-related metabolic diseases by increasing the capacity of energy expenditure in adipose tissues through a mechanism involving the HSF1/PGC-1α axis, which shed new light on the development of novel anti-obesity agents derived from marine sources

Fabrication of high silicalite-1 content filled PDMS thin composite pervaporation membrane for the separation of ethanol from aqueous solutions

Sedimentation of silicalite-1 occurs in the fabrication of thin silicalite-1 filled polydimethylsiloxane (PDMS) hybrid composite membranes if the viscosity of membrane solution is low, which makes this preparation challenging. In this work, a new method that use a platinum catalytic agent to assist the pre-polymerization of PDMS polymer to increase the viscosity of the membrane solution was studied. With this method, supported silicalite-1 filled PDMS hybrid composite membranes were fabricated and applied in the pervaporative separation of a 5 wt% dilute ethanol aqueous solution. The effect of the concentration of platinum catalytic agent on the membrane properties was first investigated using CRM, DSC and extraction experiment. Optimum of viscosity of the composite membrane solution was then conducted and a selective layer of as thin as 5 gm thickness was obtained with a flux of 5.52 kg/m(2)h in combination with a separation factor of 15.5 at 50 degrees C. After that the separation performances of different thick membranes, interfacial adhesion properties of hybrid membranes, comparisons with other reported results and membrane stability were investigated. Results showed homemade silicalite-1-PDMS hybrid composite membrane offers relatively high separation performance, indicating a potential industrial application for the separation of ethanol from aqueous solutions.</p

Tpz1 controls a telomerase-nonextendible telomeric state and coordinates switching to an extendible state via Ccq1

Telomeres are nucleoprotein complexes comprising telomeric DNA repeats bound by the multiprotein shelterin complex. A dynamic binary switch between telomerase-extendible and telomerase-nonextendible telomeric states determines telomere length homeostasis. However, the molecular nature of the nonextendible state is largely unknown. Here, we show that, in fission yeast, Tpz1 (the ortholog of human TPP1)-mediated complete linkage within the shelterin complex, bridging telomeric dsDNA to ssDNA, controls the telomerase-nonextendible state. Disruption of this linkage leads to unregulated telomere elongation while still retaining the shelterin components on telomeres. Therefore, the linkage within the shelterin components, rather than the individual shelterin components per se, defines the telomerase-nonextendible state. Furthermore, epistasis analyses reveal that Tpz1 also participates in the activation of telomeres to the extendible state via its interaction with Ccq1. Our results suggest critical regulatory roles of Tpz1 in the telomere binary switch

Basis of petroleum geological theory and exploration direction for ultra-deep exploration of 10 000-meter depth

Oil and gas resources are of important strategic importance for China's economic development. After more than 50 years of mining in main oil fields, the water cut of oil fields in China has exceeded 90%. China's external dependence on oil and natural gas has increased from 58.9% and 29.2% in 2013 to 71.2% and 40.2% in 2022 respectively, reaching the oil security warning line and impeding national security. In order to find more replacement reserves, oil and gas exploration has been promoted to the "deeper and more complicated" ultra-deep exploration area of 10 000-meter depth. Recently, domestic oil companies have successively implemented the "Deep Sea No. 1" and "Deep Earth No. 1" oil and gas exploration plans, which have explored and practiced new technologies of intelligent drilling and promoted the implementation of the 10 000-meter exploration plans, and reservoirs have been encountered by wells over 9 000 m deep. Based on recent exploration practice, this paper demonstrates the basis of petroleum geological theory for exploration of 10 000-meter depth from the aspects of ultra-deep hydrocarbon generation, storage and accumulation mechanisms, and it suggests that multi-source hydrocarbon generation can be identified in ultra-deep strata and the hydrocarbon generation threshold has exceeded 120-160 ℃. The "three-element controlling reservoir" theory points out that deep and ultra-deep reservoirs can be developed at depths greater than 4 500 meters and multi-phase hydrocarbon accumulation and preservation constitute a favorable condition for the development of ultra-deep large-scale oil and gas reservoirs. The Sichuan Basin has the total resources of about 15.22×1012 m3 in deep marine strata, wherein the Sinian system on the margin of Mianyang-Changning taphrogenic trough, the Longwangmiao Formation on the margin of central Sichuan palaeo-uplift, the Longwangmiao Formation in Micang Mountain-Daba Mountain areas to the east of Chengkou oceanic trough, and the Upper Paleozoic in western Sichuan have a resource potential of more than hundreds of billions of cubic meters. The Tarim Basin has about 15.262×109 tons of equivalent oil in deep marine strata, wherein the Middle-Lower Ordovician karst area in the Tabei uplift, Tazhong uplift and Maigaiti slope, the Middle-Lower Cambrian platform marginal zone on the western margin of Manjiaer Sag, and the Middle and Lower Cambrian intraplatform shoal of Awat-Shuntuoguole are all oil potential areas of hundreds of millions of tons. There are important oil and gas discovery in the Middle Neoproterozoic in the southwest edge of Ordos Basin. Additionally, the field of clastic rocks such as the deep strata in the central deep depression zone in Junggar Basin and the Kuqa Depression in Tarim Basin are also important areas of exploration of 10 000-meter depth

Multi-step coordination of telomerase recruitment in fission yeast through two coupled telomere-telomerase interfaces

Tightly controlled recruitment of telomerase, a low-abundance enzyme, to telomeres is essential for regulated telomere synthesis. Recent studies in human cells revealed that a patch of amino acids in the shelterin component TPP1, called the TEL-patch, is essential for recruiting telomerase to telomeres. However, how TEL-patch-telomerase interaction integrates into the overall orchestration of telomerase regulation at telomeres is unclear. In fission yeast, Tel1(ATM)/Rad3(ATR)-mediated phosphorylation of shelterin component Ccq1 during late S phase is involved in telomerase recruitment through promoting the binding of Ccq1 to a telomerase accessory protein Est1. Here, we identify the TEL-patch in Tpz1(TPP1), mutations of which lead to decreased telomeric association of telomerase, similar to the phosphorylation-defective Ccq1. Furthermore, we find that telomerase action at telomeres requires formation and resolution of an intermediate state, in which the cell cycle-dependent Ccq1-Est1 interaction is coupled to the TEL-patch-Trt1 interaction, to achieve temporally regulated telomerase elongation of telomeres

The cooperative assembly of shelterin bridge provides a kinetic gateway that controls telomere length homeostasis.

Shelterin is a six-protein complex that coats chromosome ends to ensure their proper protection and maintenance. Similar to the human shelterin, fission yeast shelterin is composed of telomeric double- and single-stranded DNA-binding proteins, Taz1 and Pot1, respectively, bridged by Rap1, Poz1&nbsp;and Tpz1. The assembly of the proteinaceous Tpz1-Poz1-Rap1 complex occurs cooperatively and disruption of this shelterin bridge leads to unregulated telomere elongation. However, how this biophysical property of bridge assembly is integrated into shelterin function is not known. Here, utilizing synthetic bridges with a range of binding properties, we find that synthetic shelterin bridge lacking cooperativity requires a linker pair that matches the native bridge in complex lifespan but has dramatically higher affinity. We find that cooperative assembly confers kinetic properties on the shelterin bridge allowing disassembly to function as a molecular timer, regulating the duration of the telomere open state, and consequently telomere lengthening to achieve a defined species-specific length range

Stable carbon isotopic composition of amino sugars in heterotrophic bacteria and phytoplankton: Implications for assessment of marine organic matter degradation

Compound‐specific isotope analysis has opened up a new realm for resolving the sources and transformation processes of marine organic matter. However, the stable carbon isotope patterns of amino sugars remain unknown. We examined δ 13 C of amino sugars in marine phytoplankton and heterotrophic bacteria, and the variations in amino sugar δ 13 C during 66‐d planktonic organic matter degradation experiments, to investigate the metabolic sources and transformations of amino sugars by bacterial reworking. The δ 13 C values of glucosamine (GlcN) and galactosamine (GalN) were comparable in heterotrophic bacteria (difference Δδ 13 C GlcN–GalN = 0.4–4.0‰) but pronouncedly different in phytoplankton (Δδ 13 C GlcN–GalN = 4.3–16.6‰), suggesting similar synthesis pathways of GlcN and GalN in bacteria that differed from phytoplankton. Compared to GlcN and GalN, bacteria preferentially use isotopically light organic compounds for muramic acid (MurA) synthesis. During simulated microbial degradation of organic matter, the δ 13 C difference between GlcN and GalN decreased from 5.8‰ on the initial day to 1‰ at a late stage in the experiment, but the difference between GlcN and MurA remained at 5.3‰. This difference is consistent with the pattern in cultured phytoplankton (average Δδ 13 C GlcN–GalN = 5.9‰ ± 1.4‰) and heterotrophic bacteria (average Δδ 13 C GlcN–MurA = 4.6‰ ± 3.4‰), indicating enhanced bacterial resynthesis as degradation proceeded. Based on the difference in δ 13 C among GlcN, GalN, and MurA, we propose a novel index of variation in amino sugar δ 13 C, representing amino sugar resynthesis, to describe the diagenetic state of organic matter. Together, these findings suggest that amino sugar δ 13 C can be used as a new tool to track heterotrophic processes of marine organic matter

Quality-Control Mechanism for Telomerase RNA Folding in the Cell.

Long non-coding RNAs can often fold into different conformations. Telomerase RNA, an essential component of the telomerase ribonucleoprotein (RNP) enzyme, must fold into a defined structure to fulfill its function with the protein catalytic subunit (TERT) and other accessory factors. However, the mechanism by which the correct folding of telomerase RNA is warranted in a cell is still unknown. Here we show that La-related protein Pof8 specifically recognizes the conserved pseudoknot region of telomerase RNA and instructs the binding of the Lsm2-8 complex to its mature 3' end, thus selectively protecting the correctly folded RNA from exonucleolytic degradation. In the absence of Pof8, TERT assembles with misfolded RNA and produces little telomerase activity. Therefore, Pof8 plays a key role in telomerase RNA folding quality control, ensuring that TERT only assembles with functional telomerase RNA to form active telomerase. Our finding reveals a mechanism for non-coding RNA folding quality control

Field study of monotonic and cyclic lateral behaviour of piles in soft soils improved with and without vacuum preloading

Project Oufei is the largest individual reclamation project in Wenzhou city, China, and the main infrastructure consists of seawalls, sluices and separation dikes. These infrastructures face repeated horizontal forces from wind and waves; thus, it is essential to evaluate the lateral bearing of single pile used for sluice gates. This paper presents a case study on lateral monotonic and cyclic behaviour of bored piles in soft soils. Four instrumented piles were loaded monotonically and cyclically to assess the contribution of soil improvement by vacuum preloading with prefabricated vertical drains. The test results show that the ultimate horizontal capacities were 200 kPa and 100 kPa for piles in the treated zone and untreated zone, respectively, under monotonic loading and up to 220 kPa and 120 kPa for piles in the treated zone and untreated zone, respectively, under cyclic loading, indicating that the ultimate horizontal capacity of piles in the treated zone can meet the design requirement of 130 kPa. Moreover, soil improvement decreased the maximum bending moment of the bored piles and enhanced the pile head stiffness, and the influence depth of soil improvement is up to 10 m. This indicates that soil improvement by vacuum preloading with prefabricated vertical drains is effective and can be used for lateral loading in reclamation project