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Photons with spin angular momentum possess intrinsic chirality, which underpins many phenomena including nonlinear optics 1 , quantum optics 2 , topological photonics 3 and chiroptics 4 . Intrinsic chirality is weak in natural materials, and recent theoretical proposals 5 – 7 aimed to enlarge circular dichroism by resonant metasurfaces supporting bound states in the continuum that enhance substantially chiral light–matter interactions. Those insightful works resort to three-dimensional sophisticated geometries, which are too challenging to be realized for optical frequencies 8 . Therefore, most of the experimental attempts 9 – 11 showing strong circular dichroism rely on false/extrinsic chirality by using either oblique incidence 9 , 10 or structural anisotropy 11 . Here we report on the experimental realization of true/intrinsic chiral response with resonant metasurfaces in which the engineered slant geometry breaks both in-plane and out-of-plane symmetries. Our result marks, to our knowledge, the first observation of intrinsic chiral bound states in the continuum with near-unity circular dichroism of 0.93 and a high quality factor exceeding 2,663 for visible frequencies. Our chiral metasurfaces may lead to a plethora of applications in chiral light sources and detectors, chiral sensing, valleytronics and asymmetric photocatalysis. Chiral metasurfaces have been produced, with experimental observation of intrinsic chiral bound states in the continuum, which may lead to applications in chiral light sources and detectors, chiral sensing, valleytronics and asymmetric photocatalysis.

Targeted saturation mutagenesis of crop genes could be applied to produce genetic variants with improved agronomic performance. However, tools for directed evolution of plant genes, such as error-prone PCR or DNA shuffling, are limited1. We engineered five saturated targeted endogenous mutagenesis editors (STEMEs) that can generate de novo mutations and facilitate directed evolution of plant genes. In rice protoplasts, STEME-1 edited cytosine and adenine at the same target site with C > T efficiency up to 61.61% and simultaneous C > T and A > G efficiency up to 15.10%. STEME-NG, which incorporates the nickase Cas9-NG protospacer-adjacent motif variant, was used with 20 individual single guide RNAs in rice protoplasts to produce near-saturated mutagenesis (73.21%) for a 56-amino-acid portion of the rice acetyl-coenzyme A carboxylase (OsACC). We also applied STEME-1 and STEME-NG for directed evolution of the OsACC gene in rice and obtained herbicide resistance mutations. This set of two STEMEs will accelerate trait development and should work in any plants amenable to CRISPR-based editing.Saturation mutagenesis using dual base editors improves the herbicide resistance of rice.

Background Circular RNAs (circRNAs) have been indicated as potentially critical mediators in various types of tumor progression, generally acting as microRNA (miRNA) sponges to regulate downstream gene expression. However, the aberrant expression profile and dysfunction of circRNAs in human clear cell renal cell carcinoma (ccRCC) need to be further investigated. This study mined key prognostic circRNAs and elucidates the potential role and molecular mechanism of circRNAs in regulating the proliferation and metastasis of ccRCC. Methods circCHST15 (hsa_circ_0020303) was identified by mining two circRNA microarrays from the Gene Expression Omnibus database and comparing matched tumor versus adjacent normal epithelial tissue pairs or matched primary versus metastatic tumor tissue pairs. These results were validated by quantitative real-time polymerase chain reaction and agarose gel electrophoresis. We demonstrated the biological effect of circCHST15 in ccRCC both in vitro and in vivo. To test the interaction between circCHST15 and miRNAs, we conducted a number of experiments, including RNA pull down assay, dual-luciferase reporter assay and fluorescence in situ hybridization. Results The expression of circCHST15 was higher in ccRCC tissues compared to healthy adjacent kidney tissue and higher in RCC cell lines compared to normal kidney cell lines. The level of circCHST15 was positively correlated with aggressive clinicopathological characteristics, and circCHST15 served as an independent prognostic indicator for overall survival and progression-free survival in patients with ccRCC after surgical resection. Our in vivo and in vitro data indicate that circCHST15 promotes the proliferation, migration, and invasion of ccRCC cells. Mechanistically, we found that circCHST15 directly interacts with miR-125a-5p and acts as a microRNA sponge to regulate EIF4EBP1 expression. Conclusions We found that sponging of miR-125a-5p to promote EIF4EBP1 expression is the underlying mechanism of hsa_circ_0020303-induced ccRCC progression. This prompts further investigation of circCHST15 as a potential prognostic biomarker and therapeutic target for ccRCC.

Introduction The neutrophil-to-lymphocyte ratio (NLR) is a crucial prognosis predictor following several major operations. However, the association between NLR and the outcome after hip fracture surgery is unclear. In this meta-analysis, we investigated the correlation between NLR and postoperative mortality in geriatric patients following hip surgery. Method PubMed, Embase, Cochrane library, and Google Scholar were searched for studies up to June 2021 reporting the correlation between NLR and postoperative mortality in elderly patients undergoing surgery for hip fracture. Data from studies reporting the mean of NLR and its 95% confidence interval (CI) were pooled. Both long-term (≥ 1 year) and short-term (≤ 30 days) mortality rates were included for analysis. Result Eight retrospective studies comprising a total of 1563 patients were included. Both preoperative and postoperative NLRs (mean difference [MD]: 2.75, 95% CI: 0.23–5.27; P  = 0.03 and MD: 2.36, 95% CI: 0.51–4.21; P  = 0.01, respectively) were significantly higher in the long-term mortality group than in the long-term survival group. However, no significant differences in NLR were noted between the short-term mortality and survival groups (MD: − 1.02, 95% CI: − 3.98 to 1.93; P  = 0.5). Conclusion Higher preoperative and postoperative NLRs were correlated with a higher risk of long-term mortality following surgery for hip fracture in the geriatric population, suggesting the prognostic value of NLR for long-term survival. Further studies with well-controlled confounders are warranted to clarify the predictive value of NLR in clinical practice in geriatric patients with hip fracture.

Stomata in leaves regulate gas exchange between the plant and its atmosphere. Various environmental stimuli elicit abscisic acid (ABA); ABA leads to phosphoactivation of slow anion channel 1 (SLAC1); SLAC1 activity reduces turgor pressure in aperture-defining guard cells; and stomatal closure ensues. We used electrophysiology for functional characterizations of Arabidopsis thaliana SLAC1 (AtSLAC1) and cryoelectron microscopy (cryo-EM) for structural analysis of Brachypodium distachyon SLAC1 (BdSLAC1), at 2.97-Å resolution. We identified 14 phosphorylation sites in AtSLAC1 and showed nearly 330-fold channel-activity enhancement with 4 to 6 of these phosphorylated. Seven SLAC1-conserved arginines are poised in BdSLAC1 for regulatory interaction with the N-terminal extension. This BdSLAC1 structure has its pores closed, in a basal state, spring loaded by phenylalanyl residues in high-energy conformations. SLAC1 phosphorylation fine-tunes an equilibrium between basal and activated SLAC1 trimers, thereby controlling the degree of stomatal opening.

Centromere is a specialized chromatin domain that plays a vital role in chromosome segregation. In most eukaryotes, centromere is surrounded by the epigenetically distinct heterochromatin domain. Heterochromatin has been shown to contribute to centromere function, but the precise role of heterochromatin in centromere specification remains elusive. Centromeres in most eukaryotes, including fission yeast (Schizosaccharomyces pombe), are defined epigenetically by the histone H3 (H3) variant CENP-A. In contrast, the budding yeast Saccharomyces cerevisiae has genetically-defined point centromeres. The transition between regional centromeres and point centromeres is considered as one of the most dramatic evolutionary events in centromere evolution. Here we demonstrated that Cse4, the budding yeast CENP-A homolog, can localize to centromeres in fission yeast and partially substitute fission yeast CENP-ACnp1. But overexpression of Cse4 results in its localization to heterochromatic regions. Cse4 is subject to efficient ubiquitin-dependent degradation in S. pombe, and its N-terminal domain dictates its centromere distribution via ubiquitination. Notably, without heterochromatin and RNA interference (RNAi), Cse4 fails to associate with centromeres. We showed that RNAi-dependent heterochromatin mediates centromeric localization of Cse4 by protecting Cse4 from ubiquitin-dependent degradation. Heterochromatin also contributes to the association of native CENP-ACnp1 with centromeres via the same mechanism. These findings suggest that protection of CENP-A from degradation by heterochromatin is a general mechanism used for centromere assembly, and also provide novel insights into centromere evolution.

The zinc-activated channel (ZAC) is an atypical mammalian cys-loop receptor (CLR) that is activated by zinc ions and protons, allowing cations to pass through. The molecular mechanism that ligands use to activate ZAC remains elusive. Here, we present three cryo-electron microscopy reconstructions of human ZAC (hZAC) under different conditions. These three hZAC structures display highly similar conformations to one another, forming symmetrical homo-pentamers with a central ion-conduction pore. The hZAC protomer comprises an extracellular domain (ECD) and a transmembrane domain (TMD), sharing more structural similarity with anion-permeable CLRs, such as glycine receptors and type A γ-aminobutyric acid receptors. Notably, hZAC possesses a distinctive C-tail that establishes a disulfide bond with the loop M2-M3 in the TMD and occupies what is typically the canonical neurotransmitter orthosteric site in other mammalian CLRs. Moreover, the tip of the cys-loop creates an unprecedented orthosteric site in hZAC. The binding of Zn 2+ triggers a conformational shift in the cys-loop, which presumably prompts the loop M2-M3 to move and open the channel gate. This study sheds light on the assembly of the channel, its structural features, and the process of signal transduction in hZAC. ZAC is a Zn 2+ and H⁺-activated cation channel. Here, the authors report the structures of human ZAC and identify an unusual C-tail that functions in auto-inhibition. This work provides insights into the gating and activation mechanisms of ZAC.

Integrating genomics and histology for cancer prognosis demonstrates promise. Here, we develop a multi-classifier system integrating a lncRNA-based classifier, a deep learning whole-slide-image-based classifier, and a clinicopathological classifier to accurately predict post-surgery localized (stage I–III) papillary renal cell carcinoma (pRCC) recurrence. The multi-classifier system demonstrates significantly higher predictive accuracy for recurrence-free survival (RFS) compared to the three single classifiers alone in the training set and in both validation sets (C-index 0.831-0.858 vs. 0.642-0.777, p < 0.05). The RFS in our multi-classifier-defined high-risk stage I/II and grade 1/2 groups is significantly worse than in the low-risk stage III and grade 3/4 groups (p < 0.05). Our multi-classifier system is a practical and reliable predictor for recurrence of localized pRCC after surgery that can be used with the current staging system to more accurately predict disease course and inform strategies for individualized adjuvant therapy. Renal cell carcinoma consists of several subtypes, and recurrence is highly dependent on subtype. Here, the authors develop a multi-classifier using imaging, lncRNA and clinical data to predict recurrence in papillary renal cell carcinoma.

Background The obesity paradox, which suggests that high body weight is positively associated with survival in some diseases, has not been proven in patients with hip fracture. In this study, meta-analysis of previous studies on the impacts of body weight on postoperative mortality following hip fracture surgery in older adults was conducted. Methods PubMed, Embase, and Cochrane library were searched for studies investigating the correlation between mortality after hip fracture surgery and body weight. The search main items included: (“Body mass index” OR “BMI” or “body weight”) and (“hip fracture” or “hip fractures”). Studies contained data on short-term (≤ 30-day) and long-term (≥ 1 year) mortality after hip fracture and its association with distinct body weight or BMI groups were reported as full-text articles were included in this meta-analysis. Results Eleven separate studies were included. The definitions of underweight and obesity differed among the included studies, but the majority of the enrolled studies used the average body weight definition of a BMI of 18.5 to 24.9 kg/m 2 ; underweight referred to a BMI of < 18.5 kg/m 2 ; and obesity pertained to a BMI of > 30 kg/m 2 . Based on the generalized definitions of body-weight groups from the enrolled studies, the group with obesity had lower long-term (odds ratio [OR]: 0.63, 95% CI: 0.50–0.79, P  < 0.00001) and short-term (OR: 0.63, 95% CI: 0.58–0.68, P  ≤ 0.00001) mortality rates after hip fracture surgery when compared with patients with average-weight group. However, compared with the average-weight group, the underweight group had higher long-term (OR: 1.51, 95% CI: 1.15-1.98, P =0.003) and short-term (OR: 1.49, 95% CI: 1.29-1.72, P <0.00001) mortality rates after hip fracture surgery. Conclusions Current evidence demonstrates an inverse relation of body weight with long-term and short-term mortality after hip fracture surgery in older adults.

Melatonin supplementation during in vitro maturation (IVM) improves porcine oocyte maturation and embryonic development by exerting antioxidative effects. Nevertheless, the mechanism by which melatonin prevents polyspermy after in vitro fertilization (IVF) remains unclear. Here, we examined the effects of melatonin on cytoplasmic maturation and the incidence of polyspermic penetration in porcine oocytes. No statistically significant difference was observed in the rate of first polar body formation between the groups (Control, Melatonin, Melatonin + Luzindole, and Melatonin + 4-P-PDOT). Interestingly, melatonin supplementation significantly improved the cytoplasmic maturation of porcine oocytes by enhancing the normal distribution of organelles (Golgi apparatus, endoplasmic reticulum and mitochondria) and upregulating organelle-related gene expressions ( P  < 0.05). However, these promotional effects were counteracted by melatonin antagonists, suggesting that melatonin enhances cytoplasmic maturation through its receptors in porcine oocytes. Melatonin supplementation also significantly improved the rate of diploid and blastocyst formation after IVF by promoting the normal distribution of cortical granules ( P  < 0.05). In conclusion, melatonin supplementation during in vitro maturation of porcine oocyte improves fertilization efficiency and embryonic developmental competence by enhancing cytoplasmic maturation.