High-Entropy Alloy Electrocatalysts Bidirectionally Promote Lithium Polysulfide Conversions for Long-Cycle-Life Lithium-Sulfur Batteries.

High-entropy alloys (HEAs) have attracted considerable attention, owing to their exceptional characteristics and high configurational entropy. Recent findings demonstrated that incorporating HEAs into sulfur cathodes can alleviate the shuttling effect of lithium polysulfides (LiPSs) and accelerate their redox reactions. Herein, we synthesized nano Pt0.25Cu0.25Fe0.15Co0.15Ni0.2 HEAs on hollow carbons (HCs; denoted as HEA/HC) by a facile pyrolysis strategy. The HEA/HC nanostructures were further integrated into hypha carbon nanobelts (HCNBs). The solid-solution phase formed by the uniform mixture of the five metal elements, i.e., Pt0.25Cu0.25Fe0.15Co0.15Ni0.2 HEAs, gave rise to a strong interaction between neighboring atoms in different metals, resulting in their adsorption energy transformation across a wide, multipeak, and nearly continuous spectrum. Meanwhile, the HEAs exhibited numerous active sites on their surface, which is beneficial to catalyzing the cascade conversion of LiPSs. Combining density functional theory (DFT) calculations with detailed experimental investigations, the prepared HEAs bidirectionally catalyze the cascade reactions of LiPSs and boost their conversion reaction rates. S/HEA@HC/HCNB cathodes achieved a low 0.034% decay rate for 2000 cycles at 1.0 C. Notably, the S/HEA@HC/HCNB cathode delivered a high initial areal capacity of 10.2 mAh cm-2 with a sulfur loading of 9 mg cm-2 at 0.1 C. The assembled pouch cell exhibited a capacity of 1077.9 mAh g-1 at the first discharge at 0.1 C. The capacity declined to 71.3% after 43 cycles at 0.1 C. In this work, we propose to utilize HEAs as catalysts not only to improve the cycling stability of lithium-sulfur batteries, but also to promote HEAs in energy storage applications.

METTL3-dependent m6A modification of PSEN1 mRNA regulates craniofacial development through the Wnt/ß-catenin signaling pathway.

Craniofacial malformations, often associated with syndromes, are prevalent birth defects. Emerging evidence underscores the importance of m6A modifications in various bioprocesses such as stem cell differentiation, tissue development, and tumorigenesis. Here, in vivo, experiments with zebrafish models revealed that mettl3-knockdown embryos at 144 h postfertilization exhibited aberrant craniofacial features, including altered mouth opening, jaw dimensions, ethmoid plate, tooth formation and hypoactive behavior. Similarly, low METTL3 expression inhibited the proliferation and migration of BMSCs, HEPM cells, and DPSCs. Loss of METTL3 led to reduced mRNA m6A methylation and PSEN1 expression, impacting craniofacial phenotypes. Co-injection of mettl3 or psen1 mRNA rescued the level of Sox10 fusion protein, promoted voluntary movement, and mitigated abnormal craniofacial phenotypes induced by mettl3 knockdown in zebrafish. Mechanistically, YTHDF1 enhanced the mRNA stability of m6A-modified PSEN1, while decreased METTL3-mediated m6A methylation hindered ß-catenin binding to PSEN1, suppressing Wnt/ß-catenin signaling. Pharmacological activation of the Wnt/ß-catenin pathway partially alleviated the phenotypes of mettl3 morphant and reversed the decreases in cell proliferation and migration induced by METTL3 silencing. This study elucidates the pivotal role of METTL3 in craniofacial development via the METTL3/YTHDF1/PSEN1/ß-catenin signaling axis.

Platinum Electrocatalyst Promoting Redox Kinetics of Li2S and Regulating Li2S Nucleation for Lithium-Sulfur Batteries.

The development of lithium-sulfur batteries (LSBs) is impeded by the shuttle effect of polysulfides (LiPSs) and the sluggish nucleation of Li2S. To address these challenges, incorporating electrocatalysts into sulfur host materials represents an effective strategy for promoting polysulfide conversion, in tandem with the rational design of multifunctional sulfur host materials. In this study, Pt nanoparticles are integrated into biomass-derived carbon materials by solution deposition method. Pt, as an electrocatalyst, not only enhances the electrical conductivity of sulfur cathodes and effectively immobilizes LiPSs but also catalyzes the redox reactions of sulfur species bidirectionally. Additionally, Pt helps regulate the 3D deposition and growth of Li2S while reducing the reaction energy barrier. Consequently, this accelerates the conversion of LiPSs in LSBs. Furthermore, the catalytic ability of Pt for the redox reactions of sulfur species, along with its influence on the 3D deposition and growth of Li2S, is elucidated using electrochemical kinetic analyses and classical models of electrochemical deposition. The cathodes exhibit a high initial specific capacity of 1019.1 mAh g-1 at 1 C and a low decay rate of 0.045% over 1500 cycles. This study presents an effective strategy to regulate Li2S nucleation and enhance the kinetics of polysulfide conversion in LSBs.

The association of aldehyde exposure with the risk of periodontitis: NHANES 2013-2014.

OBJECTIVES: Three distinct models were utilized to investigate the combined impacts of serum aldehyde exposure and periodontitis. MATERIALS AND METHODS: We performed a cross-sectional analysis using data from 525 participants in the 2013-2014 National Health and Nutrition Examination Survey (NHANES). The directed acyclic graphs (DAG) were used to select a minimal sufficient adjustment set of variables (MSAs). To investigate the relationship between aldehydes and periodontitis, we established three models including multiple logistic regression model, restricted cubic spline (RCS) model, and Bayesian kernel machine regression (BKMR) model. RESULTS: After taking all covariates into account, the multiple logistic regression model revealed that elevated concentrations of isopentanaldehyde and propanaldehyde were strongly associated with periodontitis (isopentanaldehyde: OR: 2.38, 95% CI: 1.34-4.23; propanaldehyde: OR: 1.51, 95% CI: 1.08-2.13). Furthermore, the third tertile concentration of isopentanaldehyde was associated with a 2.04-fold increase in the incidence of periodontitis (95% CI: 1.05-3.95) compared to the first tertile concentration, with a P for trend = 0.04. RCS models showed an "L"-shaped relationship between isopentanaldehyde and periodontitis (P for nonlinear association < 0.01), with inflection point of 0.43 ng/mL. BKMR identified a strong connection between mixed aldehydes and periodontitis, with isopentanaldehyde exhibiting the greatest posterior inclusion probability (PIP) with 0.901 and propanaldehyde exhibiting a PIP with 0.775. CONCLUSIONS: Isopentanaldehyde and propanaldehyde are positively associated with the risk of periodontitis. CLINICAL RELEVANCE: Periodontitis may be associated with exposure to mixed aldehyde. This study emphasizes the important role of aldehydes in primary prevention of periodontitis.

FGFR1 variants contributed to families with tooth agenesis.

BACKGROUND: Tooth agenesis is a common dental anomaly that can substantially affect both the ability to chew and the esthetic appearance of patients. This study aims to identify possible genetic factors that underlie various forms of tooth agenesis and to investigate the possible molecular mechanisms through which human dental pulp stem cells may play a role in this condition. RESULTS: Using whole-exome sequencing of a Han Chinese family with non-syndromic tooth agenesis, a rare mutation in FGFR1 (NM_001174063.2: c.103G > A, p.Gly35Arg) was identified as causative and confirmed by Sanger sequencing. Via GeneMatcher, another family with a known variant (NM_001174063.2: c.1859G > A, p.Arg620Gln) was identified and diagnosed with tooth agenesis and a rare genetic disorder with considerable intrafamilial variability. Fgfr1 is enriched in the ectoderm during early embryonic development of mice and showed sustained low expression during normal embryonic development of Xenopus laevis frogs. Functional studies of the highly conserved missense variant c.103G > A showed deleterious effects. FGFR1 (c.103G > A) was overexpressed compared to wildtype and promoted proliferation while inhibiting apoptosis in HEK293 and human dental pulp stem cells. Moreover, the c.103G > A variant was found to suppress the epithelial-mesenchymal transition. The variant could downregulate ID4 expression and deactivate the TGF-beta signaling pathway by promoting the expression of SMAD6 and SMAD7. CONCLUSION: Our research broadens the mutation spectrum associated with tooth agenesis and enhances understanding of the underlying disease mechanisms of this condition.

Novel Method for the Arsenic Removal Experiment and Mechanism Analysis.

This study focuses on the hydrothermal synthesis of magnetically activated carbon and its efficacy in As(III) adsorption. The successful incorporation of magnetite nanoparticles within the porous carbon structure was confirmed, enriching the adsorbent's properties. Comprehensive characterization was performed to analyze the pore size distribution, zeta potential at varying pH levels, and thermostability using thermogravimetric analysis. These adsorbents exhibited high As(III) removal efficiency with a uniform pore distribution. The zeta potentials were observed to decrease with an increase in pH, suggesting a relationship between adsorbent charge and pH. Adsorption dynamics were rigorously modeled using pseudo-first-order, pseudo-second-order, Elovich, and intraparticle diffusion models for different adsorbents labeled as a,b,c, and d. Each adsorbent displayed unique fitted parameters, revealing varied adsorption capabilities. The study further explored the adsorption kinetics and found that the pseudo-second-order kinetics model and the Langmuir model were most appropriate for describing the adsorption process. Adsorption thermodynamics was also fitted to elucidate the underlying adsorption mechanisms. For the a,b,c, and d adsorbents, the pseudo-first-order model, the qe(cal) values for the four adsorbents were 434.2, 418.4, 283.5, and 279.5 µg/g, respectively. Take adsorbent a as an example; the qm values for 298, 303, 308, and 313 K were 702, 673, 605, and 589 µg/g, respectively, and KL values of these temperatures were 0.021, 0.031, 0.018, and 0.009 L/µg, respectively. For the Langmuir model, the R2 values at the four temperatures were 0.999, 0.978, 0.985, and 0.993, respectively, which indicated that the Langmuir model showed higher fitness. For the Freundlich model, the KL values (L/µg) at the parameters of these temperatures are 432, 409, 328, and 294, respectively. For the Freundlich model, the 1/n values at temperatures of 298, 303, 308, and 313 K are 0.049, 0.045, 0.052, and 0.035, respectively. For the Freundlich model, the R2 values at parameters of 298, 303, 308, and 313 K are 0.986, 0.989, 0.982, and 0.872, respectively. For the Temkin model, the B values (in J/mol) are 30.93, 0.894, 0.824, and 0.782 at these temperatures, respectively. The KT values (in L/µg) are 1.02 × 106, 0.07 × 106, 0.003 × 106, and 0.002 × 106, respectively. The R2 values are 0.973, 0.958, 0.972, and 0.894, respectively. In the end, the ΔH, ΔS, and ΔG values for different adsorbents were calculated. Collectively, these findings contribute significant insights into the design and application of magnetically activated carbon adsorbents for effective As(III) removal.

Engineering of the DNA replication and repair machinery to develop binary mutators for rapid genome evolution of Corynebacterium glutamicum.

Corynebacterium glutamicum is an important industrial workhorse for production of amino acids and chemicals. Although recently developed genome editing technologies have advanced the rational genetic engineering of C. glutamicum, continuous genome evolution based on genetic mutators is still unavailable. To address this issue, the DNA replication and repair machinery of C. glutamicum was targeted in this study. DnaQ, the homolog of ϵ subunit of DNA polymerase III responsible for proofreading in Escherichia coli, was proven irrelevant to DNA replication fidelity in C. glutamicum. However, the histidinol phosphatase (PHP) domain of DnaE1, the α subunit of DNA polymerase III, was characterized as the key proofreading element and certain variants with PHP mutations allowed elevated spontaneous mutagenesis. Repression of the NucS-mediated post-replicative mismatch repair pathway or overexpression of newly screened NucS variants also impaired the DNA replication fidelity. Simultaneous interference with the DNA replication and repair machinery generated a binary genetic mutator capable of increasing the mutation rate by up to 2352-fold. The mutators facilitated rapid evolutionary engineering of C. glutamicum to acquire stress tolerance and protein overproduction phenotypes. This study provides efficient tools for evolutionary engineering of C. glutamicum and could inspire the development of mutagenesis strategy for other microbial hosts.

Directed evolution of a neutrophilic and mesophilic methanol dehydrogenase based on high-throughput and accurate measurement of formaldehyde.

Methanol is a promising one-carbon feedstock for biomanufacturing, which can be sustainably produced from carbon dioxide and natural gas. However, the efficiency of methanol bioconversion is limited by the poor catalytic properties of nicotinamide adenine dinucleotide (NAD+)-dependent methanol dehydrogenase (Mdh) that oxidizes methanol to formaldehyde. Herein, the neutrophilic and mesophilic NAD+-dependent Mdh from Bacillus stearothermophilus DSM 2334 (MdhBs) was subjected to directed evolution for enhancing the catalytic activity. The combination of formaldehyde biosensor and Nash assay allowed high-throughput and accurate measurement of formaldehyde and facilitated efficient selection of desired variants. MdhBs variants with up to 6.5-fold higher Kcat/KM value for methanol were screened from random mutation libraries. The T153 residue that is spatially proximal to the substrate binding pocket has significant influence on enzyme activity. The beneficial T153P mutation changes the interaction network of this residue and breaks the α-helix important for substrate binding into two short α-helices. Reconstructing the interaction network of T153 with surrounding residues may represent a promising strategy to further improve MdhBs, and this study provides an efficient strategy for directed evolution of Mdh.

A TP63 mutation identified in a Han Chinese family with ectodermal dysplasia.

OBJECTIVE: The purpose of this study was to identify a pathogenic mutation located in TP63 in a nuclear Han Chinese family. DESIGN: Whole-exome sequencing and Sanger sequencing were performed to identify candidate variants. The AlphaFold and PyMOL predicted the three-dimensional structure of the protein. Single-cell RNA-sequencing data and spatiotemporal transcriptomic atlas were used to generate the dissection of candidate gene expression at single-cell resolution. Significant genes (Pearson's coefficient ≥0.8 and P < 0.05) were identified for Gene Ontology (GO) analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathways analysis. RESULTS: A heterozygous missense variant at TP63 exon 8 (c.1010 G>A:p.Arg337Gln) was identified in the proband. This variant was predicted deleterious and likely to impair the local stability of the protein. In addition, single-cell RNA-sequencing indicated that TP63 was highly expressed in skin tissues. Furthermore, spatial transcriptome data of mice embryos showed TP63 was mainly enriched in the mucosal epithelium, thymus, epidermis, mesenchyme, and surface ectoderm. GO and KEGG pathway annotation analysis revealed that TP63 played a positive role in the process of ectoderm via the TGF-beta signaling pathway. CONCLUSIONS: The missense variant of TP63 (c.1010 G>A:p.Arg337Gln) was associated with ectodermal dysplasia.

Effectiveness and safety of first-line immune checkpoint inhibitors for patients with extensive-stage small cell lung carcinoma: A systematic review and network meta-analysis.

Objective: In recent years, the introduction of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of extensive-stage small cell lung carcinoma (ES-SCLC), but the optimal combination of ICI and standard chemotherapy strategy is yet to be established. The aim of this network meta-analysis (NMA) was to identify which first-line combination strategy is optimal for patients with ES-SCLC. Methods: PubMed, Embase, Cochrane Library, and the proceedings of international conferences, including American Society of Clinical Oncology and European Society for Medical Oncology meetings, were searched for randomized controlled trials (RCTs) published through October 31, 2022. The collected primary outcomes were overall survival (OS), progression-free survival (PFS), and grade 3-5 treatment-related adverse events (TRAEs). Results: Our NMA study included six phase 3 and three phase 2 RCTs including 4037 patients and 10 first-line regimens. Regarding effectiveness, the addition of programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors to standard chemotherapy provided greater efficacy than chemotherapy alone. However, cytotoxic T lymphocyte-associated antigen-4 inhibitors were not associated with satisfactory prognoses. Serplulimab plus carboplatin-etoposide (vs. standard chemotherapy, hazard ratio [HR] = 0.63; 95% CI = 0.49-0.82) and nivolumab plus platinum-etoposide (HR = 0.65; 95% confidence interval [CI] = 0.46-0.91) displayed the greatest benefit regarding OS. In terms of PFS, serplulimab plus carboplatin-etoposide yielded the best benefit of all treatments (HR = 0.48; 95% CI = 0.39-0.6). The combination of ICIs and chemotherapy caused more toxicity in general, but durvalumab plus platinum-etoposide (odds ratio [OR] = 0.98; 95% CI = 0.68-1.4), atezolizumab plus carboplatin-etoposide (OR = 1.04; 95% CI = 0.68-1.6), and adebrelimab plus platinum-etoposide (OR = 1.02; 95% CI = 0.52-2) displayed similar safety as standard chemotherapy. Subgroup analysis by race illustrated that serplulimab plus carboplatin-etoposide was associated with the best OS in Asian patients. And in non-Asian patients, the combination of PD-1/PD-L1 inhibitors and chemotherapy (pembrolizumab plus platinum-etoposide, durvalumab plus platinum-etoposide, and durvalumab and tremelimumab plus platinum-etoposide) displayed superiority to standard chemotherapy. Conclusions: The results of our NMA study suggested that serplulimab plus carboplatin-etoposide and nivolumab plus platinum-etoposide are associated with the best OS as first-line treatments for patients with ES-SCLC. Serplulimab plus carboplatin-etoposide was associated with the best PFS. In Asian patients, serplulimab plus carboplatin-etoposide had the best OS. Systematic review registration: This study is registered with PROSPERO, number CRD42022345850.

Cu(I)-Catalyzed Chemo- and Enantioselective Desymmetrizing C-O Bond Coupling of Acyl Radicals.

Transition-metal-catalyzed enantioselective functionalization of acyl radicals has so far not been realized, probably due to their relatively high reactivity, which renders the chemo- and stereocontrol challenging. Herein, we describe Cu(I)-catalyzed enantioselective desymmetrizing C-O bond coupling of acyl radicals. This reaction is compatible with (hetero)aryl and alkyl aldehydes and, more importantly, displays a very broad scope of challenging alcohol substrates, such as 2,2-disubstituted 1,3-diols, 2-substituted-2-chloro-1,3-diols, 2-substituted 1,2,3-triols, 2-substituted serinols, and meso primary 1,4-diols, providing enantioenriched esters characterized by challenging acyclic tetrasubstituted carbon stereocenters. Partnered by one- or two-step follow-up transformations, this reaction provides a convenient and practical strategy for the rapid preparation of chiral C3 building blocks from readily available alcohols, particularly the industrially relevant glycerol. Mechanistic studies supported the proposed C-O bond coupling of acyl radicals.

Novel diagnostic biomarkers of T cell-mediated tumor killing characteristics for early-stage triple negative breast cancer: A SEER analysis and molecular portraits.

The primary objective was to investigate the epidemiology, molecular characteristics, and clinical survival to identify potential transcriptome biomarkers to promote early diagnosis and screening of triple-negative breast cancer patients. Early-stage triple-negative breast cancer patients (E-TNBC) and late-stage triple-negative breast cancer patients (L-TNBC) were identified from the Surveillance, Epidemiology, and End Results database from 2010 to 2019. The difference in cancer specific survival (CSS) and overall survival (OS) between E-TNBC and L-TNBC was analyzed via a Kaplan-Meier plotter. 118 triple-negative breast cancer samples and 114 normal samples with the RNA sequencing expression data were selected from the cohort of TCGA breast cancer from UCSC Xena Database. The study involved 13,690 patients with L-TNBC and 44,994 patients with E-TNBC. L-TNBC patients were more frequently to be ≤ 60 years old (54.9% vs 52.2%), multiple primary site (44.0% vs 30.1%), and were more likely to receive radiotherapy (49.6% vs 47.4%) and chemotherapy (81.1% vs 72.1%), while L-TNBC patients were less likely to be white (68.7% vs 73.0%), married or with domestic partner (46.7% vs 54.7%), poorly differentiated grade (54.0% vs 61.9%), < 3 months from diagnosis to treatment (91.6% vs 96.4%), and were less likely to receive surgery (72.3% vs 95.4%). Stage-stratified survival analysis revealed that the prognosis of L-TNBC was worse when compared to E-TNBC, Kaplan-Meier analysis demonstrated that there were striking differences in OS and CSS between E-TNBC and L-TNBC. In the multivariable regression models, L-TNBC was the single highest risk factor, with a death risk that was 4.741 and 6.074 times higher than E-TNBC in terms of OS and CSS, respectively. The results also showed that treatment with surgery, radiation, or chemotherapy was effective for a better prognosis. Transcriptome analyses revealed that the top 5 upregulated genes in L-TNBC were, respectively, ISX, ALOX15B, MADCAM1, TP63, and ARG1 compared with E-TNBC. And the top 5 downregulated genes were, respectively, CTAG1B, CT45A1, MAGEC2, TFF2, and TNFRSF11B. The L-TNBC exhibited a lower rate of survival than E-TNBC, and the 2 groups differed in terms of transcriptome characteristics. To date, the diagnostic value of T cell-mediated tumor killing portraits on E-TNBC may not be completely recognized.

Copper-Catalyzed Chemo- and Enantioselective Radical 1,2-Carbophosphonylation of Styrenes.

The copper-catalyzed enantioselective radical difunctionalization of alkenes from readily available alkyl halides and organophosphorus reagents possessing a P-H bond provides an appealing approach for the synthesis of α-chiral alkyl phosphorus compounds. The major challenge arises from the easy generation of a P-centered radical from the P-H-type reagent and its facile addition to the terminal side of alkenes, leading to reverse chemoselectivity. We herein disclose a radical 1,2-carbophosphonylation of styrenes in a highly chemo- and enantioselective manner. The key to the success lies in not only the implementation of dialkyl phosphites with a strong bond dissociation energy to promote the desired chemoselectivity but also the utilization of an anionic chiral N,N,N-ligand to forge the chiral C(sp3 )-P bond. The developed Cu/N,N,N-ligand catalyst has enriched our library of single-electron transfer catalysts in the enantioselective radical transformations.

Mechanical dissection and culture of mouse cranial neural crest cells.

Owing to the contribution of cranial neural crest cells (CNCCs) to the majority of craniofacial structures, they have been studied extensively for the pathogenesis of craniofacial diseases. To investigate and summarize how to isolate and culture the CNCCs from wild-type mice, a literature search was performed in online databases (PubMed and Web of Science) using optimized keywords "mouse," "cranial neural crest cell" and "culture." The literature was checked by two investigators according to the screening and exclusion criteria. Initially, 197 studies were retrieved from PubMed and 169 from Web of Science, and after excluding replicate studies, 293 articles were considered. Finally, 17 studies met all the criteria and were included in this review. The results showed that obtaining purified stem cells and balancing the need to promote cell growth and prevent unwanted early cell differentiation were the two key points in the isolation and culture of CNCCs. However, no standard criteria are available for answering these questions. Thus, it is important to emphasize the necessity for standardization of CNCC isolation, culture, and identification in research on craniofacial diseases.

A Genome-wide association study of premolar agenesis in a chinese population.

OBJECTIVE: Premolar agenesis is a common subtype of tooth agenesis. Although a genome-wide study (GWAS) has identified some variants involved in tooth agenesis in Europeans, the genetic mutation related to premolar agenesis in the Chinese population remains unclear. MATERIALS AND METHODS: We present a GWAS in 218 premolar agenesis cases and 1,222 controls using the Illumina Infinium® Global Screening Array. 5,585,618 single nucleotide polymorphisms (SNPs) were used for tests of associations with premolar agenesis. RESULTS: Four independent SNPs on chromosome 2 were identified as susceptibility loci, including rs147680216, rs79743039, rs60540881, and rs6738629. The genome-wide significant SNP rs147680216 (p = 6.09 × 10-9 ) was predicted to change the structure of the WNT10A protein and interact with hedgehog signaling pathway components. Meta-analysis showed that the rs147680216 A allele significantly increased the risk of tooth agenesis (p = 0.000). The other three SNPs with nominal significance are novel susceptibility loci. Of them, rs6738629 (p = 5.40 × 10-6 ) acts as a potential transcriptional regulator of GCC2, a gene playing a putative role in dental and craniofacial development. CONCLUSION: Our GWAS indicates that rs147680216 and additional three novel susceptibility loci on chromosome 2 are associated with the risk of premolar agenesis in the Chinese population.

Genetic architecture of non-syndromic skeletal class III malocclusion.

Non-syndromic skeletal Class III malocclusion is a major craniofacial disorder characterized by genetic and environmental factors. Patients with severe skeletal Class III malocclusion require orthognathic surgery to obtain aesthetic facial appearance and functional occlusion. Recent studies have demonstrated that susceptible chromosomal regions and genetic variants of candidate genes play important roles in the etiology of skeletal Class III malocclusion. Here, we provide a comprehensive review of our current understanding of the genetic factors that affect non-syndromic skeletal Class III malocclusion, including the patterns of inheritance and multiple genetic approaches. We then summarize the functional studies on related loci and genes using cell biology and animal models, which will help to implement individualized therapeutic interventions.

Nanobiotherapeutic strategies to target immune microenvironment of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the subtype with the least favourable outcomes in breast cancer. Besides chemotherapy, there is a chronic lack of other effective treatments. Advances in omic technologies have liberated us from the ambiguity of TNBC heterogeneity in terms of cancer cell and immune microenvironment in recent years. This new understanding of TNBC pathology has already led to the exploitation of novel nanoparticulate systems, including tumor vaccines, oncolytic viruses, and antibody derivatives. The revolutionary ideas in the therapeutic landscape provide new opportunities for TNBC patients. Translating these experimental medicines into clinical benefit is both appreciated and challenging. In this review, we describe the prospective nanobiotherapy of TNBC that has been developed to overcome clinical obstacles, and provide our vision for this booming field at the overlap of cancer biotherapy and nanomaterial design.

IL2RA is a prognostic indicator and correlated with immune characteristics of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and incurable cancer with a dismal prognosis. In this study, we aimed to explore potential predictors for the prognosis and immunological characteristics of PDAC. Estimation of stromal and immune cells in malignant tumors, using expression data (ESTIMATE) method was applied to calculate the immune and stromal scores of 206 PDAC samples from GSE71729. R package of "limma" was utilized to identify differentially expressed genes (DEGs). Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses were conducted for functional exploration. Protein-protein interaction (PPI) network and Univariate Cox analysis were conducted to select key prognostic genes of PDAC. Gene set enrichment analysis (GSEA) was applied to investigate the roles of IL2RA in PDAC. Single sample GSEA (ssGSEA) was performed to evaluate the immunological characteristics of PDAC samples. Wilcoxon rank sum test was conducted to compare the difference of immunological characteristics of PDAC samples between low IL2RA and high IL2RA. Spearman correlation analysis was used to explore the correlations of IL2RA expression and immune checkpoint genes. A total of 747 DEGs were identified between low and high immune/stromal groups. Functional exploration revealed upregulated DEGs were associated with immune-related activities, whereas downregulated DEGs were involved in inflammatory-related activities. IL2RA was selected as the critical gene by overlapping the hub genes in PPI network and prognostic genes. Significantly, IL2RA expression was significantly elevated in PDAC and patients with higher IL2RA expression had worse prognoses. The immunological and oncogenic roles of IL2RA in PDAC were evidenced by GSEA. Furthermore, PDAC samples with high IL2RA expression exhibited increased immune infiltration and better immunotherapy responses. IL2RA expression was positively correlated with PDCD1, CD274, CTLA4, IDO1, TDO2, and TIGT. Higher expression of IL2RA predicts worse survival outcomes and increased immune infiltration in PDAC. PDAC patients with high IL2RA expression might potentially benefit from immunotherapy.

Engineering of the Translesion DNA Synthesis Pathway Enables Controllable C-to-G and C-to-A Base Editing in Corynebacterium glutamicum.

Expanding the base conversion type is expected to largely broaden the application of base editing, whereas it requires decipherment of the machinery controlling the editing outcome. Here, we discovered that the DNA polymerase V-mediated translesion DNA synthesis (TLS) pathway controlled the C-to-A editing by a glycosylase base editor (GBE) in Escherichia coli. However, C-to-G conversion was surprisingly found to be the main product of the GBE in Corynebacterium glutamicum and subsequent gene inactivation identified the decisive TLS enzymes. Introduction of the E. coli TLS pathway into a TLS-deficient C. glutamicum mutant completely changed the GBE outcome from C-to-G to C-to-A. Combining the canonical C-to-T editor, a pioneering C-to-N base editing toolbox was established in C. glutamicum. The expanded base conversion capability produces greater genetic diversity and promotes the application of base editing in gene inactivation and protein evolution. This study demonstrates the possibility of engineering TLS systems to develop advanced genome editing tools.

Multi-scale characterization of tumor-draining lymph nodes in resectable lung cancer treated with neoadjuvant immune checkpoint inhibitors.

BACKGROUND: Regional lymph node (LN) acts as a pivotal organ for antitumor immunity. Paradoxically, tumor-draining LNs (TDLNs) are usually the first site of tumor metastasis in lung cancer. It is largely unknown about the association between the status of TDLNs and the response of primary tumor beds to immune checkpoint inhibitors (ICIs) in lung cancer patients. Also, studies characterizing the TDLNs in response to ICIs are scarce. METHODS: We characterized and compared the radiological, metabolic (18F-FDG) and pathologic responses between primary tumor beds and paired TDLNs (invaded/non-invaded) from 68 lung cancer patients who underwent neoadjuvant ICIs plus surgery. Additionally, we performed the spatial profiling of immune and non-immune cells within TDLNs using multiplexed immunofluorescence. Therapy responses (e.g., pathologic complete (pCR) or major response (MPR)) of primary lung tumor beds and paired TDLNs were investigated separately. FINDINGS: We observed that responses of TDLNs to ICIs markedly differ from their paired primary lung tumors regarding the radiological, metabolic (18F-FDG uptake), and pathologic alterations. Neoadjuvant ICIs therapy specifically decreased 18F-FDG-reflected metabolic activity in the primary tumor beds with pCR/MPR but not their TDLNs counterparts. Furthermore, the presence of invaded TDLNs was associated with poor pathologic responses in the matched primary tumor beds and predictive of rapid post-treatment tumor relapse. Spatial profiling demonstrated exclusion of T cell infiltrates within the metastatic lesions of invaded TDLNs, and diminished multiple immune and non-immune compositions in non-involved regions surrounding the metastatic lesions. INTERPRETATION: These results provide the first clinically-relevant evidence demonstrating unique response patterns of TDLNs under ICIs treatment and revealing the underappreciated association of TDLNs status with the response of their paired primary tumors to ICIs in lung cancer. FUNDING: This work was supported by the National Natural Science Foundation of China (82072570 to F. Yao; 82002941 to B. Sun), the excellent talent program of Shanghai Chest Hospital (to F.Y), the Basic Foundation Program for Youth of Shanghai Chest Hospital (2021YNJCQ2 to H.Yang), and the Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-ZLCX20212302 to F. Yao).