Coupling-dependent metabolic ultradian rhythms in confluent cells.

Ultradian rhythms in metabolism and physiology have been described previously in mammals. However, the underlying mechanisms for these rhythms are still elusive. Here, we report the discovery of temperature-sensitive ultradian rhythms in mammalian fibroblasts that are independent of both the cell cycle and the circadian clock. The period in each culture is stable over time but varies in different cultures (ranging from 3 to 24 h). We show that transient, single-cell metabolic pulses are synchronized into stable ultradian rhythms across contacting cells in culture by gap junction-mediated coupling. Coordinated rhythms are also apparent for other metabolic and physiological measures, including plasma membrane potential (Δψp), intracellular glutamine, α-ketoglutarate, intracellular adenosine triphosphate (ATP), cytosolic pH, and intracellular calcium. Moreover, these ultradian rhythms require extracellular glutamine, several different ion channels, and the suppression of mitochondrial ATP synthase by α-ketoglutarate, which provides a key feedback mechanism. We hypothesize that cellular coupling and metabolic feedback can be used by cells to balance energy demands for survival.

Unlocking the Potential of Tin-Based Perovskites: Properties, Progress, and Applications in New-Era Electronics.

Electronics have greatly promoted the development of modern society and the exploration of new semiconducting materials with low cost and high mobility continues to attract interest in the advance of next-generation electronic devices. Among emerging semiconductors, the metal-halide perovskite, especially the nontoxic tin (Sn)-based candidates, has recently made breakthroughs in the field of diverse electronic devices due to its excellent charge transport properties and cost-effective large-area deposition capability at low temperatures. To enable a more comprehensive understanding of this emerging research field and promote the development of new-generation perovskite electronics, this review aims to provide an in-depth understanding with the discussion of unique physical properties of Sn-based perovskites and the summarization of recent research progress of Sn-based perovskite field-effect transistors (FETs) and diverse electronic devices. The unique character of negligible ion migration is also discussed, which is fundamentally different from the lead-based counterparts and provides a great prerequisite for device application. The following section highlights the potential broad applications of Sn-perovskite FETs as a competitive and feasible technology. Finally, an outlook and remaining challenges are given to advance the progression of Sn-based perovskite FETs, especially on the origin and solution of stability problems toward high-performance Sn-based perovskite electronics.

Tissue-specific FAH deficiency alters sleep-wake patterns and results in chronic tyrosinemia in mice.

Fumarylacetoacetate hydrolase (FAH) is the last enzyme in tyrosine catabolism, and mutations in the FAH gene are associated with hereditary tyrosinemia type I (HT1 or TYRSN1) in humans. In a behavioral screen of N-ethyl-N-nitrosourea mutagenized mice we identified a mutant line which we named "swingshift" (swst, MGI:3611216) with a nonsynonymous point mutation (N68S) in Fah that caused age-dependent disruption of sleep-wake patterns. Mice homozygous for the mutation had an earlier onset of activity (several hours before lights off) and a reduction in total activity and body weight when compared with wild-type or heterozygous mice. Despite abnormal behavioral entrainment to light-dark cycles, there were no differences in the period or phase of the central clock in mutant mice, indicating a defect downstream of the suprachiasmatic nucleus. Interestingly, these behavioral phenotypes became milder as the mice grew older and were completely rescued by the administration of NTBC [2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione], an inhibitor of 4-hydroxyphenylpyruvate dioxygenase, which is upstream of FAH. Mechanistically, the swst mutation had no effect on the enzymatic activity of FAH, but rather promoted the degradation of the mutant protein. This led to reduced FAH protein levels and enzymatic activity in the liver and kidney (but not the brain or fibroblasts) of homozygous mice. In addition, plasma tyrosine-but not methionine, phenylalanine, or succinylacetone-increased in homozygous mice, suggesting that swst mutants provide a model of mild, chronic HT1.

New Mechanism of Gemcitabine and Its Phosphates: DNA Polymerization Disruption via 3'-5' Exonuclease Inhibition.

Gemcitabine (dFdC), a modified deoxycytidine (dC) widely used in tumor treatment, is a prodrug that is phosphorylated to generate mono-, di-, and triphosphates. The triphosphate (dFdCTP) is incorporated into DNA to terminate DNA synthesis in cancer. Some incorporated dFdC nucleotides can be partially removed by the 3'-5' exonuclease activity, namely its editing function, and the others escape the editing. However, whether there is an active mechanism for dFdC to escape the editing remains unclear. We have first discovered that unlike dFdC, its mono-, di-, and triphosphates can inhibit the 3'-5' exonuclease of DNA polymerase I, suppress editing, and allow the active escaping mechanism, whereas its polymerase activity is not remarkably affected. As such, these phosphates can prevent the removal of the incorporated dFdC residue, thereby actively blocking DNA extension and synthesis. The inhibition efficiency of these phosphates follows the increased order of the mono-, di-, and triphosphates of gemcitabine (dFdC < dFdCMP < dFdCDP < dFdCTP). In addition, after the deletion of the 3'-5' exonuclease of cellular DNA polymerase I, the Escherichia coli mutant is more sensitive to dFdCTP than is wild-type E. coli. Our new discovery of the ability of these dFdC phosphates to inhibit exonuclease activity suggests a novel anticancer mechanism of gemcitabine and its phosphate derivatives.

Circadian Oscillations of NADH Redox State Using a Heterologous Metabolic Sensor in Mammalian Cells.

It is known that there are mechanistic links between circadian clocks and metabolic cycles. Reduced nicotinamide adenine dinucleotide (NADH) is a key metabolic cofactor in all living cells; however, it is not known whether levels of NADH oscillate or not. Here we employed REX, a bacterial NADH-binding protein, fused to the VP16 activator to convert intracellular endogenous redox balance into transcriptional readouts by a reporter gene in mammalian cells. EMSA results show that the DNA binding activity of both T- and S-REX::VP16 fusions is decreased with a reduced-to-oxidized cofactor ratio increase. Transient and stabilized cell lines bearing the REX::VP16 and the REX binding operator (ROP) exhibit two circadian luminescence cycles. Consistent with these results, NADH oscillations are observed in host cells, indicating REX can act as a NADH sensor to report intracellular dynamic redox homeostasis in mammalian cells in real time. NADH oscillations provide another metabolic signal for coupling the circadian clock and cellular metabolic states.

Drug-inducible synergistic gene silencing with multiple small hairpin RNA molecules for gene function study in animal model.

Gene targeting is a critical tool for construction of disease models. However, the application of traditional homologous recombination-mediated gene knockout technology is limited by the absence of rapid frequency-guaranteed targeting methods. Although conventional small hairpin RNA (shRNA)-mediated gene silencing offers an alternative for gene targeting, its application is frequently compromised by lower expression efficiency via RNA interference compared to gene knockout. Here we provide an efficient gene targeting strategy involving drug-inducible synergistic silencing with multiple shRNA molecules. On induction, the levels of the target proteins decreased to undetectable levels in all the tested stable transgenic mammalian cell lines, including HEK293 and embryonic stem cell-derived progenies carrying shRNA silencing cassettes. In a transgenic mouse model carrying a silencing cassette targeting the rhodopsin gene, short-time inducer treatment was sufficient to ablate the rhodopsin protein in the retina, resulting in similar retinal phenotypic changes as those observed in rhodopsin mutant mice. Therefore, on a broad basis, this inducible shRNA gene targeting strategy offers a true gene knockout alternative comparable to conventional RNA interference approaches.

Emodin-mediated cross-linking enhancement for extracellular matrix homeostasis.

The extracellular matrix (ECM) is an essential element of mammalian organisms, and its cross-linking formation plays a vital role in ECM development and postnatal homeostasis. Defects in cross-link formation caused by aging, genetic, or environmental factors are known to cause numerous diseases in mammals. To augment the cross-linking formation of ECM, the present study established a ZsGreen reporter system controlled by the promoter of lysyl oxidase-like 1 gene (LOXL1), which serves as both a scaffold element and a cross-linking enzyme in the ECM. By using this system in a drug screen, we identified emodin as a strong enhancer of LOXL1 expression that promoted cross-linking formation of ECM in all the tested systems, including human fibroblast cells, cultured human skin tissues, and animals that received long-term emodin treatment. Collectively, the results suggest that emodin may serve as an effective drug or supplement for ECM homeostasis.

Dopant-induced Morphology of Organic Semiconductors Resulting in High Doping Performance.

Doping plays a crucial role in modulating and enhancing the performance of organic semiconductor (OSC) devices. In this study, the critical role of dopants is underscored in shaping the morphology and structure of OSC films, which in turn profoundly influences their properties. Two dopants, trityl tetrakis(pentafluorophenyl) (TrTPFB) and N,N-dimethylanilinium tetrakis(pentafluorophenyl)borate (DMA-TPFB), are examined for their doping effects on poly(3-hexylthiophene) (P3HT) and PBBT-2T host OSCs. It is found that although TrTPFB exhibits higher doping efficiency, OSCs doped with DMA-TPFB achieve comparable or even enhanced electrical conductivity. Indeed, the electrical conductivity of DMA-TPFB-doped P3HT reaches over 67 S cm-1, which is a record-high value for mixed-solution-doped P3HT. This can be attributed to DMA-TPFB inducing a higher degree of crystallinity and reduced structural disorder. Moreover, the beneficial impact of DMA-TPFB on the OSC films' morphology and structure results in superior thermoelectric performance in the doped OSCs. These findings highlight the significance of dopant-induced morphological and structural considerations in enhancing the film characteristics of OSCs, opening up a new avenue for optimization of dopant performance.

Impaired activity-dependent plasticity of quantal amplitude at the neuromuscular junction of Rab3A deletion and Rab3A earlybird mutant mice.

Rab3A is a small GTPase associated with synaptic vesicles that is required for some forms of activity-dependent plasticity. It is thought to regulate the number of vesicles that fuse through an effect on docking, vesicle maturation, or mobilization. We recently showed that at the neuromuscular junction, loss of Rab3A led to an increase in the occurrence of miniature endplate currents (mepcs) with abnormally long half-widths (Wang et al., 2008). Here we show that such events are also increased after short-term activity blockade, and this process is not Rab3A-dependent. However, in the course of these experiments we discovered that the homeostatic increase in mepc amplitude after activity blockade is diminished in the Rab3A deletion mouse and abolished in the Rab3A Earlybird mouse which expresses a point mutant of Rab3A. We show that homeostatic plasticity at the neuromuscular junction does not depend on tumor necrosis factor α, is not accompanied by an increase in the levels of VAChT, the vesicular transporter for ACh, and confirm that there is no increase in ACh receptors at the junction, three characteristics distinct from that of CNS homeostatic plasticity. Activity blockade does not produce time course changes in mepcs that would be consistent with a fusion pore mechanism. We conclude that Rab3A is involved in a novel presynaptic mechanism to homeostatically regulate the amount of transmitter in a quantum.

A double perovskite participation for promoting stability and performance of Carbon-Based CsPbI2Br perovskite solar cells.

All-inorganic perovskite materials (Typically: CsPbI2Br) have attracted enormous attention due to their illustrious thermal stability and appropriate bandgap, and their use in perovskite solar cells (PSCs) has been extensively investigated. However, the inevitable defects of the perovskite layer, energy level mismatch between perovskite and carbon electrodes, and the phase instability of CsPbI2Br limit the power conversion efficiency (PCE) and stability of carbon-based CsPbI2Br PSCs. Herein, we demonstrate a simple and effective strategy for regulating energy level, inhibiting carrier recombination, and delaying the degradation of perovskite by modifying the surface of CsPbI2Br with a new type of 2D perovskite Cs2PtI6. The carbon-based CsPbI2Br PSCs achieve a higher PCE (13.69 %) than the control device (11.10 %). The excellent matching of the energy level and suppression of charge carrier recombination should be responsible for the improvement in efficiency. Furthermore, the excellent hydrophobic performance of Cs2PtI6 enhances the moisture resistance of the device. This study provides a potential strategy for improving the performance and stability of all-inorganic CsPbI2Br PSCs.

Carrier Transport Layer-Free Perovskite Solar Cells.

Power conversion efficiencies (PCEs) of up to 25.5 % have been reported for perovskite solar cells (PSCs). Thus, they have shown great potential for commercial applications. Therefore, simplifying technological process and reducing production costs have been a widespread concern among scientific and industrial communities. In this study, PSCs are prepared with the simplest device architecture (FTO/MAPbI3 /carbon). A high-quality perovskite film with few interface defects and good carrier transport is obtained by tuning the p-n properties, matching energy levels, and enhancing carrier collection and transport. A PCE of 12.01 % is achieved, which is the best reported to date for this device structure. The device also shows excellent long-term stability, owing to the elimination of charge transport layers and the usage of hydrophobic materials. This study provides a new approach to reduce production costs and simplify production of PSCs.

Theoretical study of the influence of doped niobium on the electronic properties of CsPbBr3.

In the family of inorganic perovskite solar cells (PSCs), CsPbBr3 has attracted widespread attention due to its excellent stability under high humidity and high temperature conditions. However, power conversion efficiency (PCE) improvement of CsPbBr3-based PSCs is markedly limited by the large optical absorption loss coming from the wide band gap and serious charge recombination at interfaces and/or within the perovskite film. In this work, using density functional theory calculations, we systemically studied the electronic properties of niobium (Nb)-doped CsPbBr3 with different concentration ratios. As a result, it is found that doped CsPbBr3 compounds are metallic at high Nb doping concentration but semiconducting at low Nb doping concentration. The calculated electronic density of states shows that the conduction band is predominantly constructed of doped Nb. These characteristics make them very suitable for solar cell and energy storage applications.

Adjustment of genomic waves in signal intensities from whole-genome SNP genotyping platforms.

Whole-genome microarrays with large-insert clones designed to determine DNA copy number often show variation in hybridization intensity that is related to the genomic position of the clones. We found these 'genomic waves' to be present in Illumina and Affymetrix SNP genotyping arrays, confirming that they are not platform-specific. The causes of genomic waves are not well-understood, and they may prevent accurate inference of copy number variations (CNVs). By measuring DNA concentration for 1444 samples and by genotyping the same sample multiple times with varying DNA quantity, we demonstrated that DNA quantity correlates with the magnitude of waves. We further showed that wavy signal patterns correlate best with GC content, among multiple genomic features considered. To measure the magnitude of waves, we proposed a GC-wave factor (GCWF) measure, which is a reliable predictor of DNA quantity (correlation coefficient = 0.994 based on samples with serial dilution). Finally, we developed a computational approach by fitting regression models with GC content included as a predictor variable, and we show that this approach improves the accuracy of CNV detection. With the wide application of whole-genome SNP genotyping techniques, our wave adjustment method will be important for taking full advantage of genotyped samples for CNV analysis.

Novel Lead-Free Material Cs2PtI6 with Narrow Bandgap and Ultra-Stability for Its Photovoltaic Application.

Lead halide perovskite has in recent years gained widespread interest due to its excellent physical and chemical properties, as well as superior optoelectronic performance. However, some restrictions still preclude full industrialization of the material, in particular toxicity issues and instability as a result to sensitivity to humidity. Lead-free all-inorganic double perovskite materials have thus recently become a focus of research. Herein, a new narrow bandgap lead-free double perovskite solar cell with a high-quality Cs2PtI6 film is proposed. It exhibits an optical bandgap of 1.37 eV, absorption within a wide range of wavelengths, and a high absorption coefficient. Following optimization, the device displays a best power conversion efficiency of 0.72% with an open-circuit voltage of 0.73 V, a short-circuit current of 1.2 mA/cm2, and a fill factor of 0.82. Crucially, it also demonstrates excellent stability when exposed to extreme conditions such as high humidity, high temperature, and UV-light irradiation. Stability tests show that the PSCs can retain almost 80% of the original efficiency over 60 days stored in ambient temperature without any encapsulation, boosting prospects for applications of lead-free perovskite solar cells.

Excellent Moisture Stability and Efficiency of Inverted All-Inorganic CsPbIBr2 Perovskite Solar Cells through Molecule Interface Engineering.

All-inorganic lead halide perovskite solar cells (PSCs) have drawn widespread interest because of its excellent thermal stability compared to its organic-inorganic hybrid counterpart. Poor phase stability caused by moisture, however, has thus far limited their commercial application. Herein, by modifying the interface between the hole-transport layer (HTL) and the perovskite light absorption layer, and by optimizing the HTL for better energy alignment, we controlled the growth of perovskite, reduced carrier recombination, facilitated carrier injection and transport, and improved the PSC's power conversion efficiency (PCE) and moisture stability. When testing using a positive bias scan, we obtained a significant improvement in PCE, 9.49%, which is the champion efficiency of CsPbIBr2-based inverted PSC at present. The stability measurement shows that the passivated CsPbIBr2-based inverted PSCs can retain 86% of its initial efficiency after 1000 h preserved in ambient air with 65% relative humidity. This study paves a new way for enhancing the moisture stability and power conversion efficiency of CsPbIBr2-based PSCs.

Epigenetic inheritance of circadian period in clonal cells.

Circadian oscillations are generated via transcriptional-translational negative feedback loops. However, individual cells from fibroblast cell lines have heterogeneous rhythms, oscillating independently and with different period lengths. Here we showed that heterogeneity in circadian period is heritable and used a multi-omics approach to investigate underlying mechanisms. By examining large-scale phenotype-associated gene expression profiles in hundreds of mouse clonal cell lines, we identified and validated multiple novel candidate genes involved in circadian period determination in the absence of significant genomic variants. We also discovered differentially co-expressed gene networks that were functionally associated with period length. We further demonstrated that global differential DNA methylation bidirectionally regulated these same gene networks. Interestingly, we found that depletion of DNMT1 and DNMT3A had opposite effects on circadian period, suggesting non-redundant roles in circadian gene regulation. Together, our findings identify novel gene candidates involved in periodicity, and reveal DNA methylation as an important regulator of circadian periodicity.

Alternative electrodes for HTMs and noble-metal-free perovskite solar cells: 2D MXenes electrodes.

The high cost of hole transporting materials (HTMs) and noble metal electrodes limits the application of perovskite solar cells (PSCs). Carbon materials have been commonly utilized for HTMs and noble-metal-free PSCs. In this paper, a more conductive 2D MXene material (Ti3C2), showing a similar energy level to carbon materials, has been used as a back electrode in HTMs and noble-metal-free PSCs for the first time. Seamless interfacial contact between the perovskite layer and Ti3C2 material was obtained using a simple hot-pressing method. After the adjustment of key parameters, the PSCs based on the Ti3C2 electrode show more stability and higher power conversion efficiencies (PCE) (13.83%, 27% higher than that (10.87%) of the PSCs based on carbon electrodes) due to the higher conductivity and seamless interfacial contact of the MXene electrode. Our work proposes a promising future application for MXene and also a good electrode candidate for HTM and the noble-metal-free PSCs.

Niobium Incorporation into CsPbI2Br for Stable and Efficient All-Inorganic Perovskite Solar Cells.

All-inorganic perovskites are attracting increasing attention due to their superior thermal stability than that of the traditional CH3NH3PbI3, while their inferior phase stability in ambient conditions is still an unsolved issue. Here, for the first time, we report the incorporation of niobium (Nb5+) ions into the CsPbI2Br perovskite. Results indicate that Nb5+ can effectively stabilize the photoactive α-CsPbI2Br phase by the possible substitution of Pb2+. With 0.5% Nb doping, the carbon electrode-based all-inorganic perovskite solar cells achieved a high photoconversion efficiency value of 10.42%, 15% higher than that of the control device. The Nb5+ incorporation reduces the charge recombination in the perovskite, leading to a champion Voc value of 1.27 V and a negligible hysteresis effect. This work explicates the high compatibility of all-inorganic perovskite materials and unlocks the opportunities for the use of high-valence ions for perovskite property modification.

Tomato UV-B receptor SlUVR8 mediates plant acclimation to UV-B radiation and enhances fruit chloroplast development via regulating SlGLK2.

Plants utilize energy from sunlight to perform photosynthesis in chloroplast, an organelle that could be damaged by solar UV radiation. The ultraviolet-B (UV-B) photoreceptor UVR8 is required for UV-B perception and signal transduction. However, little is known about how UVR8 influence chloroplast development under UV-B radiation. Here, we characterized tomato UVR8 gene (SlUVR8) and our results indicated that SlUVR8 facilitate plant acclimation to UV-B stress by orchestrating expression of the UVB-responsive genes (HY5 and CHS) and accumulating UV-absorptive compounds. In addition, we also discovered that SlUVR8 promotes fruit chloroplast development through enhancing accumulation of transcription factor GOLDEN2-LIKE2 (SlGLK2) which determines chloroplast and chlorophyll levels. Furthermore, UV-B radiation could increase expression of SlGLK2 and its target genes in fruits and leaves. SlUVR8 is required for UVB-induced SlGLK2 expression. Together, our work not only identified the conserved functions of SlUVR8 gene in response to UV-B stress, but also uncovered a novel role that SlUVR8 could boost chloroplast development by accumulating SlGLK2 proteins.

The tomato DDI2, a PCNA ortholog, associating with DDB1-CUL4 complex is required for UV-damaged DNA repair and plant tolerance to UV stress.

CULLIN 4 (CUL4)-DAMAGED DNA binding protein 1 (DDB1)-based ubiquitin E3 ligase modulates diverse cellular processes including repair of damaged genomic DNA. In this study, an uncharacterized gene termed as DDB1-Interacting protein 2 (DDI2) was identified in yeast two-hybrid screening with bait gene DDB1. The co-immunoprecipitation (co-IP) assays further demonstrated that DDI2 is associated with tomato DDB1-CUL4 complex in vivo. It appears that DDI2 encodes an ortholog of proliferating cell nuclear antigen (PCNA). Confocal microscope observation indicated that DDI2-GFP fusion protein was localized in nuclei. The expression of DDI2 gene is constitutive but substantially enhanced by UV-C irradiation. The transgenic tomato plants with overexpression or knockdown of DDI2 gene displayed the increased or decreased tolerance, respectively, to UV-C stress and chemical mutagen cisplatin. The quantitative analysis of UV-induced DNA lesions indicated that the dark repair of DNA damage was accelerated in DDI2 overexpression lines but delayed in knockdown lines. Conclusively, tomato DDI2 gene is required for UV-induced DNA damage repair and plant tolerance to UV stress. In addition, fruits of DDI2 transgenic plants are indistinguishable from that of wild type, regarding fresh weight and nutrient quality. Therefore, overexpression of DDI2 offers a suitable strategy for genetic manipulation of enhancing plant tolerance to UV stress.