The episodic growth of high-elevation orogenic plateaux is controlled by a series of geodynamic processes. However, determining the underlying mechanisms that drive plateau growth dynamics over ...geological history and constraining the depths at which growth originates, remains challenging. Here we present He-CO
-N
systematics of hydrothermal fluids that reveal the existence of a lithospheric-scale fault system in the southeastern Tibetan Plateau, whereby multi-stage plateau growth occurred in the geological past and continues to the present. He isotopes provide unambiguous evidence for the involvement of mantle-scale dynamics in lateral expansion and localized surface uplift of the Tibetan Plateau. The excellent correlation between
He/
He values and strain rates, along the strike of Indian indentation into Asia, suggests non-uniform distribution of stresses between the plateau boundary and interior, which modulate southeastward growth of the Tibetan Plateau within the context of India-Asia convergence. Our results demonstrate that deeply-sourced volatile geochemistry can be used to constrain deep dynamic processes involved in orogenic plateau growth.
Sodium (Na) metal is one of the most promising electrode materials for next‐generation low‐cost rechargeable batteries. However, the challenges caused by dendrite growth on Na metal anodes restrict ...practical applications of rechargeable Na metal batteries. Herein, a nitrogen and sulfur co‐doped carbon nanotube (NSCNT) paper is used as the interlayer to control Na nucleation behavior and suppress the Na dendrite growth. The N‐ and S‐containing functional groups on the carbon nanotubes induce the NSCNTs to be highly “sodiophilic,” which can guide the initial Na nucleation and direct Na to distribute uniformly on the NSCNT paper. As a result, the Na‐metal‐based anode (Na/NSCNT anode) exhibits a dendrite‐free morphology during repeated Na plating and striping and excellent cycling stability. As a proof of concept, it is also demonstrated that the electrochemical performance of sodium–oxygen (Na–O2) batteries using the Na/NSCNT anodes show significantly improved cycling performances compared with Na–O2 batteries with bare Na metal anodes. This work opens a new avenue for the development of next‐generation high‐energy‐density sodium‐metal batteries.
A sodium‐metal‐based anode combining a nitrogen and sulfur co‐doped carbon nanotube (NSCNT) paper and sodium‐metal foil is developed, which exhibits high Coulombic efficiency and excellent cycling stability. The NSCNT papers are sodiophilic, and they guide the initial Na nucleation and direct the sodium to distribute uniformly in the porous NSCNT paper without dendrite formation.
Summary Background Intensive lifestyle interventions can reduce the incidence of type 2 diabetes in people with impaired glucose tolerance, but how long these benefits extend beyond the period of ...active intervention, and whether such interventions reduce the risk of cardiovascular disease (CVD) and mortality, is unclear. We aimed to assess whether intensive lifestyle interventions have a long-term effect on the risk of diabetes, diabetes-related macrovascular and microvascular complications, and mortality. Methods In 1986, 577 adults with impaired glucose tolerance from 33 clinics in China were randomly assigned to either the control group or to one of three lifestyle intervention groups (diet, exercise, or diet plus exercise). Active intervention took place over 6 years until 1992. In 2006, study participants were followed-up to assess the long-term effect of the interventions. The primary outcomes were diabetes incidence, CVD incidence and mortality, and all-cause mortality. Findings Compared with control participants, those in the combined lifestyle intervention groups had a 51% lower incidence of diabetes (hazard rate ratio HRR 0·49; 95% CI 0·33–0·73) during the active intervention period and a 43% lower incidence (0·57; 0·41–0·81) over the 20 year period, controlled for age and clustering by clinic. The average annual incidence of diabetes was 7% for intervention participants versus 11% in control participants, with 20-year cumulative incidence of 80% in the intervention groups and 93% in the control group. Participants in the intervention group spent an average of 3·6 fewer years with diabetes than those in the control group. There was no significant difference between the intervention and control groups in the rate of first CVD events (HRR 0·98; 95% CI 0·71–1·37), CVD mortality (0·83; 0·48–1·40), and all-cause mortality (0·96; 0·65–1·41), but our study had limited statistical power to detect differences for these outcomes. Interpretation Group-based lifestyle interventions over 6 years can prevent or delay diabetes for up to 14 years after the active intervention. However, whether lifestyle intervention also leads to reduced CVD and mortality remains unclear. Funding Centers for Disease Control and Prevention, WHO, the China-Japan Friendship Hospital, and Da Qing First Hospital.
Ferroptosis is a form of regulated cell death that is caused by the iron-dependent peroxidation of lipids
. The glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ...ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols
. Ferroptosis has previously been implicated in the cell death that underlies several degenerative conditions
, and induction of ferroptosis by the inhibition of GPX4 has emerged as a therapeutic strategy to trigger cancer cell death
. However, sensitivity to GPX4 inhibitors varies greatly across cancer cell lines
, which suggests that additional factors govern resistance to ferroptosis. Here, using a synthetic lethal CRISPR-Cas9 screen, we identify ferroptosis suppressor protein 1 (FSP1) (previously known as apoptosis-inducing factor mitochondrial 2 (AIFM2)) as a potent ferroptosis-resistance factor. Our data indicate that myristoylation recruits FSP1 to the plasma membrane where it functions as an oxidoreductase that reduces coenzyme Q
(CoQ) (also known as ubiquinone-10), which acts as a lipophilic radical-trapping antioxidant that halts the propagation of lipid peroxides. We further find that FSP1 expression positively correlates with ferroptosis resistance across hundreds of cancer cell lines, and that FSP1 mediates resistance to ferroptosis in lung cancer cells in culture and in mouse tumour xenografts. Thus, our data identify FSP1 as a key component of a non-mitochondrial CoQ antioxidant system that acts in parallel to the canonical glutathione-based GPX4 pathway. These findings define a ferroptosis suppression pathway and indicate that pharmacological inhibition of FSP1 may provide an effective strategy to sensitize cancer cells to ferroptosis-inducing chemotherapeutic agents.
Adenosine-to-inosine (A-to-I) editing is a highly prevalent posttranscriptional modification of RNA, mediated by ADAR (adenosine deaminase acting on RNA) enzymes. In addition to RNA editing, ...additional functions have been proposed for ADAR1. To determine the specific role of RNA editing by ADAR1, we generated mice with an editing-deficient knock-in mutation (Adar1E861A, where E861A denotes Glu861→Ala861). Adar1E861A/E861A embryos died at ∼E13.5 (embryonic day 13.5), with activated interferon and double-stranded RNA (dsRNA)–sensing pathways. Genome-wide analysis of the in vivo substrates of ADAR1 identified clustered hyperediting within long dsRNA stem loops within 3′ untranslated regions of endogenous transcripts. Finally, embryonic death and phenotypes of Adar1E861A/E861A were rescued by concurrent deletion of the cytosolic sensor of dsRNA, MDA5. A-to-I editing of endogenous dsRNA is the essential function of ADAR1, preventing the activation of the cytosolic dsRNA response by endogenous transcripts.
Environmental changes strongly affect plant growth and development. Phytohormones, endogenous plant-made small molecules such as ethylene, regulate a wide range of processes throughout the lifetime ...of plants 1, 2. The ability of plants to integrate external signals with endogenous regulatory pathways is vital for their survival 3, 4. Ethylene has been found to suppress hypocotyl elongation in darkness 5 while promoting it in light 6, 7. How ethylene regulates hypocotyl elongation in such opposite ways is largely unknown. In particular, how light modulates and even reverses the function of ethylene has yet to be characterized. Here we show that the basic-helix-loop-helix transcription factor phytochrome-interacting factor 3 (PIF3) is directly activated by ETHYLENE-INSENSITIVE 3 (EIN3) and is indispensible for ethylene-induced hypocotyl elongation in light. Ethylene via EIN3 concomitantly activates two contrasting pathways: the PIF3-dependent growth-promoting pathway and an ethylene response factor 1 (ERF1)-mediated growth-inhibiting pathway. In the light, growth-promoting PIFs are limiting due to light-dependent destabilization, and thus ethylene stimulates growth under these conditions. In contrast, ERF1 is destabilized, and thus limiting, under dark conditions, explaining why ethylene inhibits growth in the dark. Our findings provide a mechanistic insight into how light modulates internal hormone-regulated plant growth.
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► Ethylene-induced cell elongation depends on PIF3, an EIN3 direct target gene ► Ethylene-suppressed hypocotyl elongation is mediated by ERF1 ► PIF3 pathway gradually overrides ERF1 pathway upon increasing light irradiance ► Light degrades PIF3 but stabilizes ERF1 to modulate the output of ethylene action
We show that second-generation gravitational-wave detectors at their design sensitivity will allow us to directly probe the ringdown phase of binary black hole coalescences. This opens the ...possibility to test the so-called black hole no-hair conjecture in a statistically rigorous way. Using state-of-the-art numerical relativity-tuned waveform models and dedicated methods to effectively isolate the quasistationary perturbative regime where a ringdown description is valid, we demonstrate the capability of measuring the physical parameters of the remnant black hole and subsequently determining parameterized deviations from the ringdown of Kerr black holes. By combining information from O(5) binary black hole mergers with realistic signal-to-noise ratios achievable with the current generation of detectors, the validity of the no-hair conjecture can be verified with an accuracy of ∼1.5% at 90% confidence.
The arterial pulse wave (PW) is a rich source of information on cardiovascular (CV) health. It is widely measured by both consumer and clinical devices. However, the physical determinants of the PW ...are not yet fully understood, and the development of PW analysis algorithms is limited by a lack of PW data sets containing reference CV measurements. Our aim was to create a database of PWs simulated by a computer to span a range of CV conditions, representative of a sample of healthy adults. The typical CV properties of 25-75 yr olds were identified through a literature review. These were used as inputs to a computational model to simulate PWs for subjects of each age decade. Pressure, flow velocity, luminal area, and photoplethysmographic PWs were simulated at common measurement sites, and PW indexes were extracted. The database, containing PWs from 4,374 virtual subjects, was verified by comparing the simulated PWs and derived indexes with corresponding in vivo data. Good agreement was observed, with well-reproduced age-related changes in hemodynamic parameters and PW morphology. The utility of the database was demonstrated through case studies providing novel hemodynamic insights, in silico assessment of PW algorithms, and pilot data to inform the design of clinical PW algorithm assessments. In conclusion, the publicly available PW database is a valuable resource for understanding CV determinants of PWs and for the development and preclinical assessment of PW analysis algorithms. It is particularly useful because the exact CV properties that generated each PW are known.
First, a comprehensive literature review of changes in cardiovascular properties with age was performed. Second, an approach for simulating pulse waves (PWs) at different ages was designed and verified against in vivo data. Third, a PW database was created, and its utility was illustrated through three case studies investigating the determinants of PW indexes. Fourth, the database and tools for creating the database, analyzing PWs, and replicating the case studies are freely available.
The present study attempts to investigate the effect of H2S on lipopolysaccharide (LPS)‐induced inflammation in both primary cultured microglia and immortalized murine BV‐2 microglial cells. We found ...that exogenous application of sodium hydrosulfide (NaHS) (a H2S donor, 10–300 μmol/L) attenuated LPS‐stimulated nitric oxide (NO) in a concentration‐dependent manner. Stimulating endogenous H2S production decreased LPS‐stimulated NO production, whereas lowering endogenous H2S level increased basal NO production. Western blot analysis showed that both exogenous and endogenous H2S significantly attenuated the stimulatory effect of LPS on inducible nitric oxide synthase expression, which is mimicked by SB 203580, a specific p38 mitogen‐activated protein kinase (MAPK) inhibitor. Exogenously applied NaHS significantly attenuated LPS‐induced p38 MAPK phosphorylation in BV‐2 microglial cells. Moreover, both NaHS (300 μmol/L) and SB 203580 (1 μmol/L) significantly attenuated LPS‐induced tumor necrosis factor‐α secretion, another inflammatory indicator. In addition, NaHS (10–300 μmol/L) dose‐dependently decreased LPS‐stimulated NO production in primary cultured astrocytes, suggesting that the anti‐neuroinflammatory effect of H2S is not specific to microglial cells alone. Taken together, H2S produced an anti‐inflammatory effect in LPS‐stimulated microglia and astrocytes, which may be due to inhibition of inducible nitric oxide synthase and p38 MAPK signaling pathways. These findings may have important implications in the treatment of neuroinflammation‐related diseases.
As central nodes in cardiomyocyte signaling, nuclear AKT appears to play a cardio-protective role in cardiovascular disease. Here we describe a circular RNA, circ-Amotl1 that is highly expressed in ...neonatal human cardiac tissue, and potentiates AKT-enhanced cardiomyocyte survival. We hypothesize that circ-Amotl1 binds to PDK1 and AKT1, leading to AKT1 phosphorylation and nuclear translocation. In primary cardiomyocytes, epithelial cells, and endothelial cells, we found that forced circ-Amotl1 expression increased the nuclear fraction of pAKT. We further detected increased nuclear pAKT in circ-Amotl1-treated hearts. In vivo, circ-Amotl1 expression was also found to be protective against Doxorubicin (Dox)-induced cardiomyopathy. Putative PDK1- and AKT1-binding sites were then identified
. Blocking oligonucleotides could reverse the effects of exogenous circ-Amotl1. We conclude that circ-Amotl1 physically binds to both PDK1 and AKT1, facilitating the cardio-protective nuclear translocation of pAKT.
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