Targeting pericentric non-consecutive motifs for heterochromatin initiation.

Pericentric heterochromatin is a critical component of chromosomes marked by histone H3 K9 (H3K9) methylation1-3. However, what recruits H3K9-specific histone methyltransferases to pericentric regions in vertebrates remains unclear4, as does why pericentric regions in different species share the same H3K9 methylation mark despite lacking highly conserved DNA sequences2,5. Here we show that zinc-finger proteins ZNF512 and ZNF512B specifically localize at pericentric regions through direct DNA binding. Notably, both ZNF512 and ZNF512B are sufficient to initiate de novo heterochromatin formation at ectopically targeted repetitive regions and pericentric regions, as they directly recruit SUV39H1 and SUV39H2 (SUV39H) to catalyse H3K9 methylation. SUV39H2 makes a greater contribution to H3K9 trimethylation, whereas SUV39H1 seems to contribute more to silencing, probably owing to its preferential association with HP1 proteins. ZNF512 and ZNF512B from different species can specifically target pericentric regions of other vertebrates, because the atypical long linker residues between the zinc-fingers of ZNF512 and ZNF512B offer flexibility in recognition of non-consecutively organized three-nucleotide triplets targeted by each zinc-finger. This study addresses two long-standing questions: how constitutive heterochromatin is initiated and how seemingly variable pericentric sequences are targeted by the same set of conserved machinery in vertebrates.

Spatial metabolomics reveals key features of hippocampal lipid changes in rats with postoperative cognitive dysfunction.

Postoperative cognitive dysfunction (POCD) is a common complication after cardiac surgery. Numerous evidence suggest that dysregulation of lipid metabolism is associated with cognitive impairment; however, its precise role in the development of POCD is still obscure. In this study, we established a cardiopulmonary bypass (CPB) model in rats and employed the Barnes maze to assess cognitive function, selecting POCD rats for subsequent experimentation. Utilizing mass spectrometry imaging, we detected plenty of lipids accumulates within the hippocampal CA1in the POCD group. Immunofluorescence staining revealed a significant reduction in the fluorescence intensity of calcium-independent phospholipases A2 (iPLA2) in the POCD group compared to the control, while serine palmitoyl transferase (SPT) was markedly increased in the POCD group. Transmission electron microscopy revealed that the number of synapses in hippocampal CA1decreased significantly and postsynaptic density became thinner in POCD group. Furthermore, after reversing the metabolic disorders of iPLA2 and SPT in the rat brain with docosahexaenoic acid and myriocin, the incidence of POCD after CPB was significantly reduced and the disrupted lipid metabolism in the hippocampus was also normalized. These findings may offer a novel perspective for exploring the etiology and prevention strategies of POCD after CPB.

Methylation entropy landscape of Chinese long-lived individuals reveals lower epigenetic noise related to human healthy aging.

The transition from ordered to noisy is a significant epigenetic signature of aging and age-related disease. As a paradigm of healthy human aging and longevity, long-lived individuals (LLI, >90 years old) may possess characteristic strategies in coping with the disordered epigenetic regulation. In this study, we constructed high-resolution blood epigenetic noise landscapes for this cohort by a methylation entropy (ME) method using whole genome bisulfite sequencing (WGBS). Although a universal increase in global ME occurred with chronological age in general control samples, this trend was suppressed in LLIs. Importantly, we identified 38,923 genomic regions with LLI-specific lower ME (LLI-specific lower entropy regions, for short, LLI-specific LERs). These regions were overrepresented in promoters, which likely function in transcriptional noise suppression. Genes associated with LLI-specific LERs have a considerable impact on SNP-based heritability of some aging-related disorders (e.g., asthma and stroke). Furthermore, neutrophil was identified as the primary cell type sustaining LLI-specific LERs. Our results highlight the stability of epigenetic order in promoters of genes involved with aging and age-related disorders within LLI epigenomes. This unique epigenetic feature reveals a previously unknown role of epigenetic order maintenance in specific genomic regions of LLIs, which helps open a new avenue on the epigenetic regulation mechanism in human healthy aging and longevity.

Scrutiny of genome-wide somatic mutation profiles in centenarians identifies the key genomic regions for human longevity.

Somatic mutations accumulate with age and are associated closely with human health, their characterization in longevity cohorts remains largely unknown. Here, by analyzing whole genome somatic mutation profiles in 73 centenarians and 51 younger controls in China, we found that centenarian genomes are characterized by a markedly skewed distribution of somatic mutations, with many genomic regions being specifically conserved but displaying a high function potential. This, together with the observed more efficient DNA repair ability in the long-lived individuals, supports the existence of key genomic regions for human survival during aging, with their integrity being of essential to human longevity.

Asymmetric Friedel-Crafts reaction of unsaturated carbonyl-tethered heteroarenes via vinylogous activation of Pd0-π-Lewis base catalysis.

The alkyne group can undergo facile transformations under palladium catalysis, such as hydropalladation, Wacker reaction, etc. Here we demonstrate that a chiral Pd0 complex can chemoselectively dihapto-coordinate to the alkyne moiety of 2-indolyl propiolates, and raise the Highest Occupied Molecular Orbital (HOMO)-energy ofthe deactivated heteroarenes via π-Lewis base catalysis. As a result, asymmetric C3-selective Friedel-Crafts addition to activated alkenes occurs, finally affording [3 + 2] or [3 + 4] annulation products with high enantioselectivity and exclusive E-selectivity. Moreover, this π-Lewis base vinylogous HOMO-activation strategy can be extended to remote Friedel-Crafts reaction of diverse five-membered heteroarenes tethered to a 2-enone or 2-acrylate motif with imines or 1-azadienes, and excellent enantiocontrol is generally achieved for the multifunctional adducts, which can be effectively converted to diverse frameworks with higher molecular complexity. In addition, NMR and density functional theory calculation studies are conducted to elucidate the catalytic mechanism.

Insights into the missing apiosylation step in flavonoid apiosides biosynthesis of Leguminosae plants.

Apiose is a natural pentose containing an unusual branched-chain structure. Apiosides are bioactive natural products widely present in the plant kingdom. However, little is known on the key apiosylation reaction in the biosynthetic pathways of apiosides. In this work, we discover an apiosyltransferase GuApiGT from Glycyrrhiza uralensis. GuApiGT could efficiently catalyze 2″-O-apiosylation of flavonoid glycosides, and exhibits strict selectivity towards UDP-apiose. We further solve the crystal structure of GuApiGT, determine a key sugar-binding motif (RLGSDH) through structural analysis and theoretical calculations, and obtain mutants with altered sugar selectivity through protein engineering. Moreover, we discover 121 candidate apiosyltransferase genes from Leguminosae plants, and identify the functions of 4 enzymes. Finally, we introduce GuApiGT and its upstream genes into Nicotiana benthamiana, and complete de novo biosynthesis of a series of flavonoid apiosides. This work reports an efficient phenolic apiosyltransferase, and reveals mechanisms for its sugar donor selectivity.

A highly selective C-rhamnosyltransferase from Viola tricolor and insights into its mechanisms.

C-Glycosides are important natural products with various bioactivities. In plant biosynthetic pathways, the C-glycosylation step is usually catalyzed by C-glycosyltransferases (CGTs), and most of them prefer to accept uridine 5'-diphosphate glucose (UDP-Glc) as sugar donor. No CGTs favoring UDP-rhamnose (UDP-Rha) as sugar donor has been reported, thus far. Herein, we report the first selective C-rhamnosyltransferase VtCGTc from the medicinal plant Viola tricolor. VtCGTc could efficiently catalyze C-rhamnosylation of 2-hydroxynaringenin 3-C-glucoside, and exhibited high selectivity towards UDP-Rha. Mechanisms for the sugar donor selectivity of VtCGTc were investigated by molecular dynamics (MD) simulations and molecular mechanics with generalized Born and surface area solvation (MM/GBSA) binding free energy calculations. Val144 played a vital role in recognizing UDP-Rha, and the V144T mutant could efficiently utilize UDP-Glc. This work provides a new and efficient approach to prepare flavonoid C-rhamnosides such as violanthin and iso-violanthin.

Functional characterization, structural basis, and regio-selectivity control of a promiscuous flavonoid 7,4'-di-O-glycosyltransferase from Ziziphus jujuba var. spinosa.

A highly efficient and promiscuous 7,4'-di-O-glycosyltransferase ZjOGT3 was discovered from the medicinal plant Ziziphus jujuba var. spinosa. ZjOGT3 could sequentially catalyse 4'- and 7-O-glycosylation of flavones to produce 7,4'-di-O-glycosides with obvious regio-selectivity. For 7,4'-dihydroxyl flavanones and 3-O-glycosylated 7,4'-dihydroxyl flavones, ZjOGT3 selectively catalyses 7-O-glycosylation. The crystal structure of ZjOGT3 was solved. Structural analysis, DFT calculations, MD simulations, and site-directed mutagenesis reveal that the regio-selectivity is mainly controlled by the enzyme microenvironment for 7,4'-dihydroxyl flavones and 3-O-glycosylated 7,4'-dihydroxyl flavones. For 7,4'-dihydroxyl flavanones, the selectivity is mainly controlled by intrinsic reactivity. ZjOGT3 is the first plant flavonoid 7,4'-di-O-glycosyltransferase with a crystal structure. This work could help understand the catalytic mechanisms of multi-site glycosyltransferases and provides an efficient approach to synthesise O-glycosides with medicinal potential.

Two new alkaloids produced by Dothideomycetes sp. BMC-101 isolated from the Magnolia grandiflora.

AbstactA total of 16 fungal strains were isolated from fresh leaves and flowers of Magnolia grandiflora and the EtOAc extracts of them were assayed for antitumor activities. Among these, the fungus Dothideomycetes sp. BMC-101 with broad spectrum inhibition was selected for further study. Four alkaloids (1-4) including two new compounds (2-(hydroxyimino)-3-phenylpropanoyl)-L-phenylalanine (1) and 8-Acetyl-bisdethiobis(methylsulfanyl)apoaranotin (4)) were isolated from Dothideomycetes sp. BMC-101. The structure of 1 was characterized with an oxime moiety formed by the condensation of two phenylalanines. To our knowledge, this is the first report on a fungal phenylalanine derivative with an oxime moiety.

Simulated vestibular spatial disorientation mouse model under coupled rotation revealing potential involvement of Slc17a6.

Spatial disorientation (SD) is the main contributor to flight safety risks, but research progress in animals has been limited, impeding a deeper understanding of the underlying mechanisms of SD. This study proposed a method for constructing and evaluating a vestibular SD mouse model, which adopted coupled rotational stimulation with visual occlusion. Physiological parameters were measured alongside behavioral indices to assess the model, and neuronal changes were observed through immunofluorescent staining. The evaluation of the model involved observing decreased colonic temperature and increased arterial blood pressure in mice exposed to SD, along with notable impairments in motor and cognitive function. Our investigation unveiled that vestibular SD stimulation elicited neuronal activation in spatially associated cerebral areas, such as the hippocampus. Furthermore, transcriptomic sequencing and bioinformatics analysis revealed the potential involvement of Slc17a6 in the mechanism of SD. These findings lay a foundation for further investigation into the molecular mechanisms underlying SD.

Efficacy of High-Flow Nasal Cannula versus Conventional Oxygen Therapy in Obese Patients during the Perioperative Period: A Systematic Review and Meta-Analysis.

Background: Obesity is a risk factor for severe airway obstruction and hypoxemia. High-flow nasal cannula (HFNC) is considered as a novel method for oxygen therapy, but the efficacy of HFNC for obese patients is controversial. This meta-analysis aimed to assess the efficacy of HFNC compared with conventional oxygen therapy (COT) in obese patients during the perioperative period. Methods: We searched the PubMed, Embase, Web of Science, the Cochrane Library, and Google scholar databases for randomized controlled trials (RCTs) that compared the efficacy of HFNC with COT in obese patients during the perioperative period. The primary outcome was the incidence of hypoxemia, while the secondary outcomes included the lowest SpO2, the need for additional respiratory support, and the hospital length of stay (LOS). Results: Twelve trials with 798 obese patients during the perioperative period were included. Compared with COT, HFNC reduced the incidence of hypoxemia (RR, 0.60; 95% CI, 0.43 to 0.83; P=0.002; I 2 = 24%; 8 RCTs; n = 458), increased the lowest SpO2 (MD, 2.88; 95% CI, 1.53 to 4.22; P < 0.0001; I 2 = 32%; 5 RCTs; n = 264), decreased the need for additional respiratory support (RR, 0.43; 95% CI, 0.21 to 0.88; P=0.02; I 2 = 0%; 3 RCTs; n = 305), and shortened the hospital LOS (MD, -0.31; 95% CI, -0.57 to -0.04; P=0.02; I 2 = 0%; 3 RCTs; n = 214). Conclusions: This meta-analysis showed that compared with COT, the use of HFNC was able to reduce the incidence of hypoxemia, increase the lowest SpO2, decrease the need for additional respiratory support, and shorten the hospital LOS in obese patients during the perioperative period. Well-organized trials with large sample size should be conducted to support our findings.

Over 30 Years of Misidentification: A New Nothospecies Lycoris × jinzheniae (Amaryllidaceae) in Eastern China, Based on Molecular, Morphological, and Karyotypic Evidence.

Based on the complete chloroplast genome, morphology, and karyotype evidence, we identified a new nothospecies, Lycoris × jinzheniae S.Y. Zhang, P.C. Zhang & J.W. Shao, in eastern China. This new nothospecies has been inappropriately named Lycoris × albiflora in the previous literature for more than 30 years. However, the new nothospecies resulted from the hybridization of L. sprengeri and L. chinensis and had the following characteristics: the karyotype was 2n = 19 = 3V + 16I, the leaves emerged in the spring, the ratio of filament to corolla length was approximately 1.2, tepals were slightly undulated and curved, and it was distributed throughout eastern China. These characteristics are quite different from those of L. × albiflora; thus, in this study, we named it and provided a detailed morphological description and diagnosis.

ETS1 acts as a regulator of human healthy aging via decreasing ribosomal activity.

Adaptation to reduced energy production during aging is a fundamental issue for maintaining healthspan or prolonging life span. Currently, however, the underlying mechanism in long-lived people remains poorly understood. Here, we analyzed transcriptomes of 185 long-lived individuals (LLIs) and 86 spouses of their children from two independent Chinese longevity cohorts and found that the ribosome pathway was significantly down-regulated in LLIs. We found that the down-regulation is likely controlled by ETS1 (ETS proto-oncogene 1), a transcription factor down-regulated in LLIs and positively coexpressed with most ribosomal protein genes (RPGs). Functional assays showed that ETS1 can bind to RPG promoters, while ETS1 knockdown reduces RPG expression and alleviates cellular senescence in human dermal fibroblast (HDF) and embryonic lung fibroblast (IMR-90) cells. As protein synthesis/turnover in ribosomes is an energy-intensive cellular process, the decline in ribosomal biogenesis governed by ETS1 in certain female LLIs may serve as an alternative mechanism to achieve energy-saving and healthy aging.

High flow nasal oxygen versus conventional oxygen therapy in gastrointestinal endoscopy with conscious sedation: Systematic review and meta-analysis with trial sequential analysis.

OBJECTIVES: Although conventional oxygen therapy (COT) is widely used, hypoxemia frequently occurs in gastrointestinal endoscopy with conscious sedation and can lead to life-threatening consequences. High flow nasal oxygen (HFNO) has been applied to improve oxygenation in clinical entities. However, its efficacy to prevent hypoxemia in gastrointestinal endoscopy with conscious sedation has not been evaluated. METHODS: We searched databases to identify randomized controlled trials that compared the efficacy of HFNO with COT in gastrointestinal endoscopy with conscious sedation. The primary outcome was hypoxemia. Meta-analyses with trial sequential analysis were performed using a random-effects model. RESULTS: Eight trials with 3212 patients were included. Compared with COT, HFNO significantly reduced the risk of hypoxemia (eight trials; 3212 patients; risk ratio 0.30; 95% confidence interval [CI] 0.13-0.70). Trial sequential analysis showed that the cumulative Z curve did not cross the monitoring or futility boundaries, nor reach the required information size line, indicating that more trials are needed to reach a definitive conclusion. Subgroup analyses indicated the superiority of HFNO over COT with respect to hypoxemia in patients at low risk and high risk. HFNO further improved the lowest oxygen saturation (four trials; 459 patients; mean difference 2.30, 95% CI 0.84-3.77). CONCLUSIONS: Compared with COT, HFNO can reduce the risk of hypoxemia and improve the lowest oxygen saturation in gastrointestinal endoscopy with conscious sedation. However, the results should be interpreted with caution due to substantial heterogeneity and limited evidence. Further studies are needed to verify the preliminary findings.

Lycorisinsularis (Amaryllidaceae), a new species from eastern China revealed by morphological and molecular evidence.

Lycorisinsularis S.Y.Zhang & J.W.Shao, a new fertile diploid species from coastal provinces in eastern China is described. This new species is most similar to L.sprengeri in morphology and has been misidentified as the latter for a long time. However, it can be distinguished from the latter by the relatively longer perianth tube (1.5‒2.5 cm vs. less than 1.3 cm), a characteristic that was overlooked before. Phylogenetic analysis, based on complete plastid genome, showed that L.insularis is not genetically related to L.sprengeri in the genus. The former was a sister group of L.sanguinea, while the latter was closely related to L.longituba and L.chinensis and they were respectively located on different clades that were separated at the base of the phylogenetic tree. The chromosome number of L.insularis is 2n = 22. At present, as the new species is relatively widely distributed and the wild population can normally reproduce by seeds, we evaluate it as LC (Least Concern) according to criteria of the IUCN Red List.

Complete mitogenomes document substantial genetic contribution from the Eurasian Steppe into northern Pakistani Indo-Iranian speakers.

To elucidate whether Bronze Age population dispersals from the Eurasian Steppe to South Asia contributed to the gene pool of Indo-Iranian-speaking groups, we analyzed 19,568 mitochondrial DNA (mtDNA) sequences from northern Pakistani and surrounding populations, including 213 newly generated mitochondrial genomes (mitogenomes) from Iranian and Dardic groups, both speakers from the ancient Indo-Iranian branch in northern Pakistan. Our results showed that 23% of mtDNA lineages with west Eurasian origin arose in situ in northern Pakistan since ~5000 years ago (kya), a time depth very close to the documented Indo-European dispersals into South Asia during the Bronze Age. Together with ancient mitogenomes from western Eurasia since the Neolithic, we identified five haplogroups (~8.4% of maternal gene pool) with roots in the Steppe region and subbranches arising (age ~5-2 kya old) in northern Pakistan as genetic legacies of Indo-Iranian speakers. Some of these haplogroups, such as W3a1b that have been found in the ancient samples from the late Bronze Age to the Iron Age period individuals of Swat Valley northern Pakistan, even have sub-lineages (age ~4 kya old) in the southern subcontinent, consistent with the southward spread of Indo-Iranian languages. By showing that substantial genetic components of Indo-Iranian speakers in northern Pakistan can be traced to Bronze Age in the Steppe region, our study suggests a demographic link with the spread of Indo-Iranian languages, and further highlights the corridor role of northern Pakistan in the southward dispersal of Indo-Iranian-speaking groups.

Treatment of ammonia-embodied wastewater by a transition-metal-based photochemical catalysis strategy.

Inspired by the self-purification process and a low nitrogen content of the ocean, and the fact that the driving-force behind ecological cycle is solar irradiation, a novel photochemical strategy was designed to spontaneously remove inorganic ammonia nitrogen from wastewater with solar irradiation. This strategy is based on the principles of green chemistry and energy efficiency, and meanwhile the prevention from the introduction of accompanying pollution. In our strategy, a photo-Fe (or Mn)-O2 system was built to remove ammonia-nitrogen from its aqueous solution. The results show that with full band solar irradiation at a range of 10-30 mW cm-2, in weak alkaline condition, more than 90% of ammonia-nitrogen can be effectively removed from NH4Cl aqueous solution by the new strategy, with a residual concentration as low as 2 mg L-1. Mn(III) was proved to be a better catalyst than Fe(III). The catalytic mechanism of N-removal is the generation of •OH during the process of the photoreduction of transition metal hydroxides. DFT theory had been applied to help explaining the mechanism. Different from general knowledge, in our strategy, an alkaline environment, where the generation rate of radicals was relatively slow and comparable to oxidation rate of transition metal ions, can guarantee the stability and persistency of the catalytic reaction. No NOx was produced in this strategy. This new strategy provides a new possibility of cost-efficient and environmental-friendly wastewater treatment, and has certain meaning of understanding how self-purification works in nature.

The Application of Radiomics in Breast MRI: A Review.

Breast cancer has been a worldwide burden of women's health. Although concerns have been raised for early diagnosis and timely treatment, the efforts are still needed for precision medicine and individualized treatment. Radiomics is a new technology with immense potential to obtain mineable data to provide rich information about the diagnosis and prognosis of breast cancer. In our study, we introduced the workflow and application of radiomics as well as its outlook and challenges based on published studies. Radiomics has the potential ability to differentiate between malignant and benign breast lesions, predict axillary lymph node status, molecular subtypes of breast cancer, tumor response to chemotherapy, and survival outcomes. Our study aimed to help clinicians and radiologists to know the basic information of radiomics and encourage cooperation with scientists to mine data for better application in clinical practice.