Old concepts, new tricks: How peptide vaccines are reshaping cancer immunotherapy?

Over the past few decades, research on cancer immunotherapy has firmly established immune cells as key players in effective cancer treatment. Peptide vaccines directly targeting immune cells have demonstrated immense potential due to their specificity and applicability. However, developing peptide vaccines to generate tumor-reactive T cells remains challenging, primarily due to suboptimal immunogenicity and overcoming the immunosuppressive tumor microenvironment (TME). In this review, we discuss various elements of effective peptide vaccines, including antigen selection, peptide epitope optimization, vaccine adjuvants, and the combination of multiple immunotherapies, in addition to recent advances in tumor neoantigens as well as epitopes bound by non-classical human leukocyte antigen (HLA) molecules, to increase the understanding of cancer peptide vaccines and provide multiple references for the design of subsequent T cell-based peptide vaccines.

Ultrasensitive and on-site diagnosis of rice bakanae disease based on CRISPR-LbCas12a coupled with LAMP.

BACKGROUND: Rice bakanae disease (RBD) has longstanding challenges impacted rice production, which is predominantly induced by Fusarium fujikuroi Nirenberg. Early diagnosis of F. fujikuroi is important to control RBD and improve quality and quantity of rice production. This study presents a novel on-site diagnosis platform combined with CRISPR/LbCas12a and LAMP to detect F. fujikuroi. RESULTS: LAMP amplification of TEF1-α, a characteristic gene of F. fujikuroi were performed, followed with trans-cleavage reaction of LbCas12a, cleaving the single-stranded DNA reporter, which is modified by the terminal fluorophore and quencher groups, producing fluorescence signal. The platform was confirmed with high specificity and sensitivity (LOD <1 aM). Furthermore, we designed a lateral flow strip experiment based on the trans-cleavage activity of LbCas12a, which was identified with similar sensitivity and specificity to the fluorescence detection method. CONCLUSION: In summary, this study achieved a platform with remarkable sensitivity and specificity for F. fujikuroi detection and provide potential for on-site and ultrasensitive diagnostic tools for RBD. © 2024 Society of Chemical Industry.

The relationship between childhood psychological abuse and social media addiction among college students: the mediating role of fear of missing out and the moderating role of left-behind experience.

Introduction: Mobile social media is a new type of online media that is participatory, open, and communicative, among other characteristics. Due to the increasing popularity of social media, this technology has become an indispensable part of people's social lives. This study aims to examine the relationship between childhood psychological maltreatment and social media addiction among university students as well as the mediating role of fear of missing out and the moderating effect of left-behind experience in this context. Material and methods: A voluntary anonymous online survey of 1694 university students was conducted using the Childhood Psychological Maltreatment Scale, the Fear of Missing Out Scale, and the Social Media Addiction Scale. Results: First, significant positive correlations were observed between childhood psychological maltreatment and both fear of missing out and social media addiction among university students. Fear of missing out partially mediated the relationship between childhood psychological maltreatment and social media addiction. Second, left-behind experience was found to moderate the direct path from childhood psychological maltreatment to social media addiction as well as the first half of the mediating effect of missed anxiety. Conclusions: Childhood psychological maltreatment can predict social media addiction among university students not only directly but also indirectly through the mediating role of missed anxiety. The direct effect of childhood psychological maltreatment on social media addiction is moderated by left-behind experience. The first half of the mediating role of missed anxiety is also moderated by left-behind experience.

Developing a CRISPR/FrCas9 system for core promoter editing in rice.

Small mutations in the core promoter region of a gene may result in substantial changes in expression strengths. However, targeting TA-rich sequences of core promoters may pose a challenge for Cas9 variants such as SpCas9 and other G-rich PAM-compatible Cas9s. In this study, we engineered a unique FrCas9 system derived from Faecalibaculum rodentium for plant genome editing. Our findings indicate that this system is efficient in rice when the TATA sequence is used as a PAM. In addition, FrCas9 demonstrated activity against all 16 possible NNTA PAMs, achieving an efficiency of up to 35.3% in calli and generating homozygous or biallelic mutations in 31.3% of the T0 transgenic plants. A proof-of-concept experiment to examine editing of the rice WX core promoter confirmed that FrCas9-induced mutations could modify gene expression and amylose content. Multiplex mutations and deletions were produced by bidirectional editing, mediated by FrCas9, using a single palindromic TATA sequence as a PAM. Moreover, we developed FrCas9-derived base editors capable of programmable conversion between A·T and G·C pairs in plants. This study highlights a versatile FrCas9 toolset for plant core promoter editing, offering great potential for the fine-tuning of gene expression and creating of new germplasms. Supplementary Information: The online version contains supplementary material available at 10.1007/s42994-024-00157-5.

Molecular insight into interactions between the Taf14, Yng1 and Sas3 subunits of the NuA3 complex.

The NuA3 complex is a major regulator of gene transcription and the cell cycle in yeast. Five core subunits are required for complex assembly and function, but it remains unclear how these subunits interact to form the complex. Here, we report that the Taf14 subunit of the NuA3 complex binds to two other subunits of the complex, Yng1 and Sas3, and describe the molecular mechanism by which the extra-terminal domain of Taf14 recognizes the conserved motif present in Yng1 and Sas3. Structural, biochemical, and mutational analyses show that two motifs are sandwiched between the two extra-terminal domains of Taf14. The head-to-toe dimeric complex enhances the DNA binding activity of Taf14, and the formation of the hetero-dimer involving the motifs of Yng1 and Sas3 is driven by sequence complementarity. In vivo assays in yeast demonstrate that the interactions of Taf14 with both Sas3 and Yng1 are required for proper function of the NuA3 complex in gene transcription and DNA repair. Our findings suggest a potential basis for the assembly of three core subunits of the NuA3 complex, Taf14, Yng1 and Sas3.

Comparative population genomics reveals convergent and divergent selection in the apricot-peach-plum-mei complex.

The economically significant genus Prunus includes fruit and nut crops that have been domesticated for shared and specific agronomic traits; however, the genomic signals of convergent and divergent selection have not been elucidated. In this study, we aimed to detect genomic signatures of convergent and divergent selection by conducting comparative population genomic analyses of the apricot-peach-plum-mei (APPM) complex, utilizing a haplotype-resolved telomere-to-telomere (T2T) genome assembly and population resequencing data. The haplotype-resolved T2T reference genome for the plum cultivar was assembled through HiFi and Hi-C reads, resulting in two haplotypes 251.25 and 251.29 Mb in size, respectively. Comparative genomics reveals a chromosomal translocation of ~1.17 Mb in the apricot genomes compared with peach, plum, and mei. Notably, the translocation involves the D locus, significantly impacting titratable acidity (TA), pH, and sugar content. Population genetic analysis detected substantial gene flow between plum and apricot, with introgression regions enriched in post-embryonic development and pollen germination processes. Comparative population genetic analyses revealed convergent selection for stress tolerance, flower development, and fruit ripening, along with divergent selection shaping specific crop, such as somatic embryogenesis in plum, pollen germination in mei, and hormone regulation in peach. Notably, selective sweeps on chromosome 7 coincide with a chromosomal collinearity from the comparative genomics, impacting key fruit-softening genes such as PG, regulated by ERF and RMA1H1. Overall, this study provides insights into the genetic diversity, evolutionary history, and domestication of the APPM complex, offering valuable implications for genetic studies and breeding programs of Prunus crops.

Conditional knockdown of OsMLH1 to improve plant prime editing systems without disturbing fertility in rice.

BACKGROUND: High-efficiency prime editing (PE) is desirable for precise genome manipulation. The activity of mammalian PE systems can be largely improved by inhibiting DNA mismatch repair by coexpressing a dominant-negative variant of MLH1. However, this strategy has not been widely used for PE optimization in plants, possibly because of its less conspicuous effects and inconsistent performance at different sites. RESULTS: We show that direct RNAi knockdown of OsMLH1 in an ePE5c system increases the efficiency of our most recently updated PE tool by 1.30- to 2.11-fold in stably transformed rice cells, resulting in as many as 85.42% homozygous mutants in the T0 generation. The high specificity of ePE5c is revealed by whole-genome sequencing. To overcome the partial sterility induced by OsMLH1 knockdown of ePE5c, a conditional excision system is introduced to remove the RNAi module by Cre-mediated site-specific recombination. Using a simple approach of enriching excision events, we generate 100% RNAi module-free plants in the T0 generation. The increase in efficiency due to OsMLH1 knockdown is maintained in the excised plants, whose fertility is not impaired. CONCLUSIONS: This study provides a safe and reliable plant PE optimization strategy for improving editing efficiency without disturbing plant development via transient MMR inhibition with an excisable RNAi module of MLH1.

The effect of self-compassion on social media addiction among college students - The mediating role of gratitude: An observational study.

In contemporary society, social media pervades every aspect of daily life, offering significant benefits such as enhanced access to information, improved interconnectivity, and fostering community among its users. However, its usage, particularly when excessive, can lead to negative psychological outcomes, including the prevalence of social media addiction (SMA) among adolescents. While extensive research has been conducted on the phenomenon of SMA, there is a notable paucity of studies examining the link between individual levels of self-compassion and susceptibility to SMA. This study aims to investigate the correlation between self-compassion and SMA in college students, while also examining the potential mediating influence of gratitude. The study sampled 1131 college students who engaged in an anonymous online survey. This survey utilized the Chinese translations of the Self-Compassion Scale, Gratitude Questionnaire, and SMA Scale. For data analysis, validated factor analysis was performed using IBM® SPSS® AMOS™ version 23. Correlation analyses were carried out with IBM® SPSS® version 22.0, and the PROCESS macro (Model 4) was employed to assess path and mediation effects. Higher levels of positive self-compassion were found to mitigate the effects of SMA, while elevated levels of negative self-compassion were associated with an increase in such addiction. The study further revealed that gratitude played a partial mediating role in the relationship between self-compassion and SMA. Specifically, positive self-compassion can reduce symptoms of SMA by enhancing levels of gratitude, whereas negative self-compassion may worsen these symptoms by diminishing gratitude. Positive self-compassion is instrumental in fostering personal growth among college students, with gratitude serving as a significant mediator in reducing SMA.

Emerging Roles of UDP-GalNAc Polypeptide N-Acetylgalactosaminyltransferases in Cardiovascular Disease.

UDP-GalNAc polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts) catalyze mucin-type O-glycosylation by transferring α-N-acetylgalactosamine (GalNAc) from UDP-GalNAc to Ser or Thr residues of target proteins. This post-translational modification is common in eukaryotes, yet its biological functions remain unclear. Recent studies have identified specific receptors in the heart and vascular wall cells that can be mucin-type O-glycosylated, and there is now substantial evidence confirming that patients with various cardiovascular diseases (CVDs), such as heart failure, coronary artery disease, myocardial hypertrophy, and vascular calcification, exhibit abnormal changes in GalNAc-Ts. This review aims to highlight recent advances in GalNAc-Ts and their roles in the cardiovascular system, intending to provide evidence for clinical treatment and prevention of CVDs.

Fatty acid-binding proteins 3, 7, and 8 bind cholesterol and facilitate its egress from lysosomes.

Cholesterol from low-density lipoprotein (LDL) can be transported to many organelle membranes by non-vesicular mechanisms involving sterol transfer proteins (STPs). Fatty acid-binding protein (FABP) 7 was identified in our previous study searching for new regulators of intracellular cholesterol trafficking. Whether FABP7 is a bona fide STP remains unknown. Here, we found that FABP7 deficiency resulted in the accumulation of LDL-derived cholesterol in lysosomes and reduced cholesterol levels on the plasma membrane. A crystal structure of human FABP7 protein in complex with cholesterol was resolved at 2.7 Å resolution. In vitro, FABP7 efficiently transported the cholesterol analog dehydroergosterol between the liposomes. Further, the silencing of FABP3 and 8, which belong to the same family as FABP7, caused robust cholesterol accumulation in lysosomes. These two FABP proteins could transport dehydroergosterol in vitro as well. Collectively, our results suggest that FABP3, 7, and 8 are a new class of STPs mediating cholesterol egress from lysosomes.

A natural variation in OsDSK2a modulates plant growth and salt tolerance through phosphorylation by SnRK1A in rice.

Plants grow rapidly for maximal production under optimal conditions; however, they adopt a slower growth strategy to maintain survival when facing environmental stresses. As salt stress restricts crop architecture and grain yield, identifying genetic variations associated with growth and yield responses to salinity is critical for breeding optimal crop varieties. OsDSK2a is a pivotal modulator of plant growth and salt tolerance via the modulation of gibberellic acid (GA) metabolism; however, its regulation remains unclear. Here, we showed that OsDSK2a can be phosphorylated at the second amino acid (S2) to maintain its stability. The gene-edited mutant osdsk2aS2G showed decreased plant height and enhanced salt tolerance. SnRK1A modulated OsDSK2a-S2 phosphorylation and played a substantial role in GA metabolism. Genetic analysis indicated that SnRK1A functions upstream of OsDSK2a and affects plant growth and salt tolerance. Moreover, SnRK1A activity was suppressed under salt stress, resulting in decreased phosphorylation and abundance of OsDSK2a. Thus, SnRK1A preserves the stability of OsDSK2a to maintain plant growth under normal conditions, and reduces the abundance of OsDSK2a to limit growth under salt stress. Haplotype analysis using 3 K-RG data identified a natural variation in OsDSK2a-S2. The allele of OsDSK2a-G downregulates plant height and improves salt-inhibited grain yield. Thus, our findings revealed a new mechanism for OsDSK2a stability and provided a valuable target for crop breeding to overcome yield limitations under salinity stress.

Decoding the transcriptional heterogeneity, differentiation lineage, clinical significance in tissue-resident memory CD8 T cell of the small intestine by single-cell analysis.

Resident memory T (Trm) cells which are specifically located in non-lymphoid tissues showed distinct phenotypes and functions compared to circulating memory T cells and were vital for the initiation of robust immune response within tissues. However, the heterogeneity in the transcriptional features, development pathways, and cancer response of Trm cells in the small intestine was not demonstrated. Here, we integrated scRNA-seq and scTCR-seq data pan-tissue T cells to explore the heterogeneity of Trm cells and their development pathways. Trm were enriched in tissue-specific immune response and those in the DUO specially interacted with B cells via TNF and MHC-I signatures. T cell lineage analyses demonstrated that Trm might be derived from the T_CD4/CD8 subset within the same organ or migrated from spleen and mesenteric lymph nodes. We compared the immune repertoire of Trm among organs and implied that clonotypes in both DUO and ILE were less expanded and hydrophilic TRB CDR3s were enriched in the DUO. We further demonstrated that Trm in the intestine infiltrated the colorectal cancer and several effector molecules were highly expressed. Finally, the TCGA dataset of colorectal cancer implied that the infiltration of Trm from the DUO and the ILE was beneficial for overall survival and the response to immune checkpoint blockade.

An epi-allele of SMS causes Sanming dominant genic male sterility in rice.

Male sterility is an important trait in rice for hybrid rice (Oryza sativa) breeding. However, the factors involved in dominant male sterility are largely unknown. Here, we identified a gene from Sanming dominant genic male sterile rice, named Sanming dominant male sterility (SMS), and reported that an epi-allele of this locus contributes to male sterility. Segregation analysis attributed dominant male sterility to a single locus, SMS, which we characterized using a male-sterile near isogenic line (NIL) of rice cultivar 93-11. The SMS locus was heterozygous in the male-sterile 93-11 NIL, containing an epi-allele identical to that in 93-11, and an epi-allele identical to that in rice cultivar Nipponbare, which we refer to as SMS9 and SMSN, respectively. SMS9 is silent and hyper-methylated, whereas SMSN is expressed and hypo-methylated in the 93-11 NIL. Overexpressing SMSN led to male sterility. Mutations in SMS rescued the male sterility of the 93-11 NIL. Interestingly, we observed the duplication of SMSN in Nipponbare, but did not observe the duplication of SMS9 in 93-11. Together, these findings suggest that the reduced methylation and enhanced expression of the SMSN epi-allele in the 93-11 NIL is responsible for its role in conferring dominant male sterility.

Mesocosm experimental study on sustainable riparian restoration using sediment-modified planting eco-concrete.

The continued deterioration of riparian ecosystems is a worldwide concern, which can lead to soil erosion, plant degradation, biodiversity loss, and water quality decline. Here, taking into account waste resource utilization and eco-environmental friendliness, the sediment-modified planting eco-concrete with both H. verticillata and T. orientalis (SEC-H&T) was prepared and explored for the first time to achieve sustainable riparian restoration. Concrete mechanical characterizations showed that the compressive strength and porosity of SEC with 30% sediment content could reach up to 15.8 MPa and 21.25%, respectively. The mechanical properties and the sediment utilization levels of SEC were appropriately balanced, and potentially toxic element leaching results verified the environmental safety of eco-concrete modified with dredged sediments. Plant physiological parameters of both aquatic plants (biomass, chlorophyll, protein and starch) were observed to reach the normal levels in SEC during the 30-day culture period, and T. orientalis seemed better adapted to SEC environment than H. verticillate. Importantly, compared to SEC-H and SEC-T, SEC-H&T could effectively reduce the concentrations of COD, TN and TP by 58.59%, 74.00% and 79.98% in water, respectively. Notably, water purification mechanisms by SEC-H&T were further elucidated from the perspective of microbial community responses. Shannon index of bacterial diversity and proliferation of specific populations dominating nutrient transformation (such as Bacillus and Nitrospira) was increased under the synergy of SEC and aquatic plants. Correspondingly, functional genes involved in nitrogen and phosphorus transformation (such as nosZ and phoU) were also enriched. Our study can not only showcase an effective and flexible approach to recycle dredged sediments into eco-concrete with low environment impacts, but also provide a promising alternative for sustainable riparian restoration.

Structural basis of the TCR-pHLA complex provides insights into the unconventional recognition of CDR3ß in TCR cross-reactivity and alloreactivity.

Evidence shows that some class I human leucocyte antigen (HLA) alleles are related to durable HIV controls. The T18A TCR, which has the alloreactivity between HLA-B∗42:01 and HLA-B∗81:01 and the cross-reactivity with different antigen mutants, can sustain long-term HIV controls. Here the structural basis of the T18A TCR binding to the immunodominant HIV epitope TL9 (TPQDLNTML180-188) presented by HLA-B∗42:01 was determined and compared to T18A TCR binding to the TL9 presented by the allo-HLA-B∗81:01. For differences between HLA-B∗42:01 and HLA-B∗81:01, the CDR1α and CDR3α loops adopt a small rearrangement to accommodate them. For different conformations of the TL9 presented by different HLA alleles, not like the conventional recognition of CDR3s to interact with peptide antigens, CDR3ß of the T18A TCR shifts to avoid the peptide antigen but intensively recognizes the HLA only, which is different with other conventional TCR structures. Featured sequence pairs of CDR3ß and HLA might account for this and were additionally found in multiple other diseases indicating the popularity of the unconventional recognition pattern which would give insights into the control of diseases with epitope mutating such as HIV.

Preparation and cytotoxicity evaluation of folic acid-modified YF8-OA self-assembled lipid prodrug nanoparticles.

This study aimed to improve the use of YF8, a matrine derivative obtained through chemical transformation of matrine extracted from Sophora alopecuroides. YF8 has demonstrated improved cytotoxicity compared to matrine, but its hydrophobic nature hinders its application. To overcome this, the lipid prodrug YF8-OA was synthesized by linking oleic acid (OA) to YF8 through an ester bond. Although YF8-OA could self-assemble into unique nanostructures in water, it was not sufficiently stable. To enhance the stability of YF8-OA lipid prodrug nanoparticles (LPs), we employed the strategy of PEGylation using DSPE-mPEG2000 or DSPE-mPEG2000 conjugated with folic acid (FA). This resulted in the formation of uniform spherical nanoparticles with greatly improved stability and a maximum drug load capacity upto 58.63%. Cytotoxicity was evaluated in A549, HeLa, and HepG2 cell lines. The results showed that in HeLa cells, the IC50 value of YF8-OA/LPs with FA-modified PEGylation was significantly lower than that of YF8-OA/LPs modified by PEGylation alone. However, no significant enhancement was observed in A549 and HepG2 cells. In conclusion, the lipid prodrug YF8-OA can form nanoparticles in aqueous solution to address its poor water solubility. Modification with FA resulted in further enhanced cytotoxicity, providing a potential avenue for exerting the antitumor activity of matrine analogs.

A New Outlier Removal Strategy Based on Reliability of Correspondence Graph for Fast Point Cloud Registration.

Registration is a basic yet crucial task in point cloud processing. In correspondence-based point cloud registration, matching correspondences by point feature techniques may lead to an extremely high outlier (false correspondence) ratio. Current outlier removal methods still suffer from low efficiency, accuracy, and recall rate. We use an intuitive method to describe the 6-DOF (degree of freedom) curtailment process in point cloud registration and propose an outlier removal strategy based on the reliability of the correspondence graph. The method constructs the corresponding graph according to the given correspondences and designs the concept of the reliability degree of the graph node for optimal candidate selection and the reliability degree of the graph edge to obtain the global maximum consensus set. The presented method achieves fast and accurate outliers removal along with gradual aligning parameters estimation. Extensive experiments on simulations and challenging real-world datasets demonstrate that the proposed method can still perform effective point cloud registration even the correspondence outlier ratio is over 99%, and the efficiency is better than the state-of-the-art. Code is available at https://github.com/WPC-WHU/GROR.

Molecular insight into the PCNA-binding mode of FBH1.

F-box DNA helicase 1 (FBH1) is involved in the regulation of cell responses to replicative stress. FBH1 is recruited to stalled DNA replication fork by PCNA where it inhibits homologous recombination and catalyzes fork regression. Here, we report the structural basis for the molecular recognition of two distinctly different motifs of FBH1, FBH1PIP and FBH1APIM, by PCNA. The crystal structure of PCNA in complex with FBH1PIP and analysis of NMR perturbations reveal overlapped FBH1PIP and FBH1APIM binding sites of PCNA and the dominant contribution of FBH1PIP in this interaction.

A comparative study of modern total ankle replacement and ankle arthrodesis for ankle osteoarthritis at different follow-up times: a systematic review and meta-analysis.

PURPOSE: Total ankle replacement (TAR) or ankle arthrodesis (AA) is the main surgical treatment for end-stage ankle osteoarthritis. However, the therapeutic effect of the two surgical procedures at different follow-up times remains controversial. The purpose of this meta-analysis is to compare the short-term, medium-term, and long-term safety and efficiency of the two modern surgical treatments. METHODS: We conducted a comprehensive search in PubMed, EMBASE, Cochrane library databases, Web of Science, and Scopus. The main results were the patient's reported outcome measure (PROM) score, satisfaction, complications, reoperation, and surgery success rate. Different follow-up times and implant designs were used to evaluate the source of heterogeneity. We used a fixed effects model for meta-analysis and I2 statistic for evaluating heterogeneity. RESULTS: Thirty-seven comparative studies were included. In the short term, TAR significantly improved clinical scores (AOFAS score: WMD = 7.07, 95% Cl: 0.41-13.74, I2 = 0.0%; SF-36 PCS score: WMD = 2.40, 95% Cl: 2.22-2.58, I2 = 0.0%; SF-36 MCS score: WMD = 0.40, 95% Cl: 0.22-0.57, I2 = 0.0%; VAS for pain: WMD = - 0.50, 95% Cl: - 0.56-0.44, I2 = 44.3%) and had the lower incidence of revision (RR = 0.43, 95% CI: 0.23-0.81, I2 = 0.0%) and complications (RR = 0.67, 95% Cl: 0.50-0.90, I2 = 0.0%). In the medium term, there were still higher improvements in both the clinical scores (SF-36 PCS score: WMD = 1.57, 95% Cl: 1.36-1.78, I2 = 20.9%; SF-36 MCS score: WMD = 0.81, 95% Cl: 0.63-0.99, I2 = 48.8%) and the patient satisfaction (RR = 1.24, 95% Cl: 1.08-1.41, I2 = 12.1%) in the TAR group, but its total complications rate (RR = 1.84, 95% Cl: 1.26-2.68, I2 = 14.9%) and revision rate (RR = 1.58, 95% CI: 1.17-2.14, I2 = 84.6%) were significantly higher than that of the AA group. In the long term, there was no significant difference in clinical score and satisfaction, and a higher incidence of revision (RR = 2.32, 95% Cl: 1.70-3.16, I2 = 0.0%) and complications (RR = 3.18, 95% Cl: 1.69-5.99, I2 = 0.0%) was observed in TAR than in AA. The result of the third-generation design subgroup was consistent with that of the above pooled results. CONCLUSION: TAR had advantages over AA in the short term due to better performance in terms of PROMs, complications, and reoperation rates, but its complications become a disadvantage in the medium term. In the long term, AA seems to be favored because of lower complications and revision rates, although there is no difference in clinical scores.