The combination of alkali metal electrodes and solid-state electrolytes is considered a promising strategy to develop high-energy rechargeable batteries. However, the practical applications of these ...two components are hindered by the large interfacial resistance and growth of detrimental alkali metal depositions (e.g., dendrites) during cycling originated by the unsatisfactory electrode/solid electrolyte contact. To tackle these issues, we propose a room temperature ultrasound solid welding strategy to improve the contact between Na metal and Na
Zr
Si
PO
(NZSP) inorganic solid electrolyte. Symmetrical Na|NZSP | Na cells assembled via ultrasonic welding show stable Na plating/stripping behavior at a current density of 0.2 mA cm
and a higher critical current density (i.e., 0.6 mA cm
) and lower interfacial impedance than the symmetric cells assembled without the ultrasonic welding strategy. The beneficial effect of the ultrasound welding is also demonstrated in Na|NZSP | Na
V
(PO
)
full coin cell configuration where 900 cycles at 0.1 mA cm
with a capacity retention of almost 90% can be achieved at room temperature.
DNA double-strand breaks (DSBs) are dangerous lesions that can lead to potentially oncogenic genomic rearrangements or cell death. The two major pathways for repair of DSBs are nonhomologous end ...joining (NHEJ) and homologous recombination (HR). NHEJ is an intrinsically error-prone pathway while HR results in accurate repair. To understand the origin of genomic instability in human cells it is important to know the contribution of each DSB repair pathway. Studies of rodent cells and human cancer cell lines have shown that the choice between NHEJ or HR pathways depends on cell cycle stage. Surprisingly, cell cycle regulation of DSB repair has not been examined in normal human cells with intact cell cycle checkpoints. Here we measured the efficiency NHEJ and HR at different cell cycle stages in hTERT-immortalized diploid human fibroblasts. We utilized cells with chromosomally-integrated fluorescent reporter cassettes, in which a unique DSB is introduced by a rare-cutting endonuclease. We show that NHEJ is active throughout the cell cycle, and its activity increases as cells progress from G1 to G2/M (G1 < S < G2/M). HR is nearly absentin G1, most active in the S phase, and declines in G2/M. Thus, inG2/M NHEJ is elevated, while HR is on decline. This is in contrastto a general belief that NHEJ is most active in G1, while HR isactive in S, G2 and M. The overall efficiency of NHEJ was higherthan HR at all cell cycle stages. We conclude that human somaticcells utilize error-prone NHEJ as the major DSB repair pathway atall cell cycle stages, while HR is used, primarily, in the S phase.
Sirtuin 6 (SIRT6) is a mammalian homolog of the yeast Sir2 deacetylase. Mice deficient for SIRT6 exhibit genome instability. Here, we show that in mammalian cells subjected to oxidative stress SIRT6 ...is recruited to the sites of DNA double-strand breaks (DSBs) and stimulates DSB repair, through both nonhomologous end joining and homologous recombination. Our results indicate that SIRT6 physically associates with polyadenosine diphosphate (ADP)—ribose polymerase 1 (PARP1) and mono-ADP-ribosylates PARP1 on lysine residue 521, thereby stimulating PARP1 poly-ADP-ribosylase activity and enhancing DSB repair under oxidative stress.
The naked mole rat (Heterocephalus glaber) displays exceptional longevity, with a maximum lifespan exceeding 30 years. This is the longest reported lifespan for a rodent species and is especially ...striking considering the small body mass of the naked mole rat. In comparison, a similarly sized house mouse has a maximum lifespan of 4 years. In addition to their longevity, naked mole rats show an unusual resistance to cancer. Multi-year observations of large naked mole-rat colonies did not detect a single incidence of cancer. Here we identify a mechanism responsible for the naked mole rat's cancer resistance. We found that naked mole-rat fibroblasts secrete extremely high-molecular-mass hyaluronan (HA), which is over five times larger than human or mouse HA. This high-molecular-mass HA accumulates abundantly in naked mole-rat tissues owing to the decreased activity of HA-degrading enzymes and a unique sequence of hyaluronan synthase 2 (HAS2). Furthermore, the naked mole-rat cells are more sensitive to HA signalling, as they have a higher affinity to HA compared with mouse or human cells. Perturbation of the signalling pathways sufficient for malignant transformation of mouse fibroblasts fails to transform naked mole-rat cells. However, once high-molecular-mass HA is removed by either knocking down HAS2 or overexpressing the HA-degrading enzyme, HYAL2, naked mole-rat cells become susceptible to malignant transformation and readily form tumours in mice. We speculate that naked mole rats have evolved a higher concentration of HA in the skin to provide skin elasticity needed for life in underground tunnels. This trait may have then been co-opted to provide cancer resistance and longevity to this species.
The two major pathways for repair of DNA double-strand breaks (DSBs) are homologous recombination (HR) and nonhomologous end joining (NHEJ). HR leads to accurate repair, while NHEJ is intrinsically ...mutagenic. To understand human somatic mutation it is essential to know the relationship between these pathways in human cells. Here we provide a comparison of the kinetics and relative contributions of HR and NHEJ in normal human cells. We used chromosomally integrated fluorescent reporter substrates for real-time
in vivo monitoring of the NHEJ and HR. By examining multiple integrated clones we show that the efficiency of NHEJ and HR is strongly influenced by chromosomal location. Furthermore, we show that NHEJ of compatible ends (NHEJ-C) and NHEJ of incompatible ends (NHEJ-I) are fast processes, which can be completed in approximately 30
min, while HR is much slower and takes 7
h or longer to complete. In actively cycling cells NHEJ-C is twice as efficient as NHEJ-I, and NHEJ-I is three times more efficient than HR. Our results suggest that NHEJ is a faster and more efficient DSB repair pathway than HR.
Cytidine base editors are powerful genetic tools that catalyse cytidine to thymidine conversion at specific genomic loci, and further improvement of the editing range and efficiency is critical for ...their broader applications. Through insertion of a non-sequence-specific single-stranded DNA-binding domain from Rad51 protein between Cas9 nickase and the deaminases, serial hyper cytidine base editors were generated with substantially increased activity and an expanded editing window towards the protospacer adjacent motif in both cell lines and mouse embryos. Additionally, hyeA3A-BE4max selectively catalysed cytidine conversion in TC motifs with a broader editing range and much higher activity (up to 257-fold) compared with eA3A-BE4max. Moreover, hyeA3A-BE4max specifically generated a C-to-T conversion without inducing bystander mutations in the haemoglobin gamma gene promoter to mimic a naturally occurring genetic variant for amelioration of β-haemoglobinopathy, suggesting the therapeutic potential of the improved base editors.
N‐doped carbons as one of the most prominent anode materials to replace standard graphite exhibit outstanding Li+ storage performance. However, N‐doped carbon anodes still suffer from low N‐doping ...levels and low initial Coulombic efficiency (ICE). In this study, high N‐doped and low graphitic‐N carbons (LGNCs) with enhanced ICE were synthesized by taking advantage of a denitrification strategy for graphitic carbon nitride (g‐C3N4). In brief, more than 14.5 at% of N from g‐C3N4 (55.1 at% N) was retained by reacting graphitic‐N with lithium, which was subsequently removed. As graphitic‐N is largely responsible for the irreversible capacity, the anode's performance was significantly increased. Compared to general N‐doped carbons with high graphitic‐N proportion (>50%) and low N content (<15 at%), LGNCs delivered a low proportion of 10.8%–17.2% within the high N‐doping content of 14.5–42.7 at%, leading to an enhanced specific capacity of 1499.9 mAh g−1 at an ICE of 93.7% for the optimal sample of LGNC (4:1). This study provides a facile strategy to control the N content and speciation, achieving both high Li+ storage capacity and high ICE, and thus promoting research and application of N‐doped carbon materials.
High N‐doped (14.5–42.7 at%) carbon with low graphitic‐N proportion (10.8%–17.2%) has been fabricated by denitrification for graphitic carbon nitride (g‐C3N4) using Li metal powder as both reductant and prelithiation reagent. As anode materials for lithium batteries, the optimal sample exhibits a high capacity of 1499.9 mAh g−1 with an enhanced ICE of 93.7%.
The unique luminescence properties of far-red emitting materials make them important components in the phosphor-converted LEDs (pc-LEDs) for plant cultivation. Mn
4+
-doped phosphors can realize ...deep-red and far-red emission in the range of 600–800 nm owing to the characteristic transition (
2
E
g
→
4
A
2g
) of Mn
4+
. Herein, a novel Sr
3
NaNbO
6
:Mn
4+
phosphor with far-red emitting was synthesized via the traditional high-temperature solid-state reaction method. The phase composition and morphological characteristics as well as the photoluminescent properties of Sr
3
NaNbO
6
:Mn
4+
were investigated in detail. The photoluminescence excitation spectra and photoluminescence spectra showed that Sr
3
NaNbO
6
:Mn
4+
phosphor has an emission band centered at 700 nm under the excitation of 370 nm. The emission band in the region of 600–800 nm of Sr
3
NaNbO
6
:Mn
4+
phosphor matches well with the far-red light absorption P
FR
phytochrome, suggesting that Sr
3
NaNbO
6
:Mn
4+
phosphor can meet the requirements of practical application for indoor plant cultivation.
Genomic instability is a hallmark of aging tissues. Genomic instability may arise from the inefficient or aberrant function of DNA double-stranded break (DSB) repair. DSBs are repaired by homologous ...recombination (HR) and nonhomologous DNA end joining (NHEJ). HR is a precise pathway, whereas NHEJ frequently leads to deletions or insertions at the repair site. Here, we used normal human fibroblasts with a chromosomally integrated HR reporter cassette to examine the changes in HR efficiency as cells progress to replicative senescence. We show that HR declines sharply with increasing replicative age, with an up to 38-fold decrease in efficiency in presenescent cells relative to young cells. This decline is not explained by a reduction of the number of cells in S/G ₂/M stage as presenescent cells are actively dividing. Expression of proteins involved in HR such as Rad51, Rad51C, Rad52, NBS1, and Sirtuin 6 (SIRT6) diminished with cellular senescence. Supplementation of Rad51, Rad51C, Rad52, and NBS1 proteins, either individually or in combination, did not rescue the senescence-related decline of HR. However, overexpression of SIRT6 in “middle-aged” and presenescent cells strongly stimulated HR repair, and this effect was dependent on mono-ADP ribosylation activity of poly(ADP-ribose) polymerase (PARP1). These results suggest that in aging cells, the precise HR pathway becomes repressed giving way to a more error-prone NHEJ pathway. These changes in the processing of DSBs may contribute to age-related genomic instability and a higher incidence of cancer with age. SIRT6 activation provides a potential therapeutic strategy to prevent the decline in genome maintenance.
Magnesium alloy composites play an important role in the biomaterials field. In this study, a novel Mg-Zn-Ca matrix composite was reinforced by adding 1.0 wt.% MgO nanoparticles via the high shear ...casting process. Hereafter, friction stir processing (FSP) was used to achieve a good dispersion of MgO particles and improve the mechanical properties of the composites. After the preparation of the novel composite materials, varied characterization and performance test methods have been selected for comparison. The results illustrate that through FSP, the corresponding microstructure and properties of as-cast MgO/Mg-Zn-Ca composites were significantly modified, and the best combination of the key parameters is 1200 rpm and 60 mm/min for rotational velocity and traveling speed, respectively. After the optimized FSP treatment, the grain size in FSP-processed composites was refined by 42%, to reach 1.04 μm. Due to the grain refinement and the redistribution of MgO particles, the hardness of the FSP-processed MgO/Mg-Zn-Ca composites was increased by 40%, to reach 101.2 HV. Further, it displayed excellent corrosion resistance as well as strength. Compared to the strengthening through grain refinement, particle strengthening is more dominant based on the study. And meanwhile, the modified grains and added MgO particles are beneficial to the properties of the nugget zones.
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