Targeting the undruggables-the power of protein degraders.

Undruggable targets typically refer to a class of therapeutic targets that are difficult to target through conventional methods or have not yet been targeted, but are of great clinical significance. According to statistics, over 80% of disease-related pathogenic proteins cannot be targeted by current conventional treatment methods. In recent years, with the advancement of basic research and new technologies, the development of various new technologies and mechanisms has brought new perspectives to overcome challenging drug targets. Among them, targeted protein degradation technology is a breakthrough drug development strategy for challenging drug targets. This technology can specifically identify target proteins and directly degrade pathogenic target proteins by utilizing the inherent protein degradation pathways within cells. This new form of drug development includes various types such as proteolysis targeting chimera (PROTAC), molecular glue, lysosome-targeting Chimaera (LYTAC), autophagosome-tethering compound (ATTEC), autophagy-targeting chimera (AUTAC), autophagy-targeting chimera (AUTOTAC), degrader-antibody conjugate (DAC). This article systematically summarizes the application of targeted protein degradation technology in the development of degraders for challenging drug targets. Finally, the article looks forward to the future development direction and application prospects of targeted protein degradation technology.

Genome assembly of autotetraploid Actinidia arguta highlights adaptive evolution and enables dissection of important economic traits.

Actinidia arguta, the most widely distributed Actinidia species and the second cultivated species in the genus, can be distinguished from the currently cultivated Actinidia chinensis on the basis of its small and smooth fruit, rapid softening, and excellent cold tolerance. Adaptive evolution of tetraploid Actinidia species and the genetic basis of their important agronomic traits are still unclear. Here, we generated a chromosome-scale genome assembly of an autotetraploid male A. arguta accession. The genome assembly was 2.77 Gb in length with a contig N50 of 9.97 Mb and was anchored onto 116 pseudo-chromosomes. Resequencing and clustering of 101 geographically representative accessions showed that they could be divided into two geographic groups, Southern and Northern, which first diverged 12.9 million years ago. A. arguta underwent two prominent expansions and one demographic bottleneck from the mid-Pleistocene climate transition to the late Pleistocene. Population genomics studies using paleoclimate data enabled us to discern the evolution of the species' adaptation to different historical environments. Three genes (AaCEL1, AaPME1, and AaDOF1) related to flesh softening were identified by multi-omics analysis, and their ability to accelerate flesh softening was verified through transient expression assays. A set of genes that characteristically regulate sexual dimorphism located on the sex chromosome (Chr3) or autosomal chromosomes showed biased expression during stamen or carpel development. This chromosome-level assembly of the autotetraploid A. arguta genome and the genes related to important agronomic traits will facilitate future functional genomics research and improvement of A. arguta.

Hepatic-Accumulated Obeticholic Acid and Atorvastatin Self-Assembled Nanocrystals Potentiate Ameliorative Effects in Treatment of Metabolic-Associated Fatty Liver Disease.

Exploration of medicines for efficient and safe management of metabolic-associated fatty liver disease (MAFLD) remains a challenge. Obeticholic acid (OCA), a selective farnesoid X receptor agonist, has been reported to ameliorate injury and inflammation in various liver diseases. However, its clinical application is mainly limited by poor solubility, low bioavailability, and potential side effects. Herein a hepatic-targeted nanodrugs composed of OCA and cholesterol-lowering atorvastatin (AHT) with an ideal active pharmaceutical ingredient (API) content for orally combined treatment of MAFLD is created. Such carrier-free nanocrystals (OCAHTs) are self-assembled, not only improving the stability in gastroenteric environments but also achieving hepatic accumulation through the bile acid transporter-mediated enterohepatic recycling process. Orally administrated OCAHT outperforms the simple combination of OCA and AHT in ameliorating of liver damage and inflammation in both acetaminophen-challenged mice and high-fat diet-induced MAFLD mice with less systematic toxicity. Importantly, OCAHT exerts profoundly reverse effects on MAFLD-associated molecular pathways, including impairing lipid metabolism, reducing inflammation, and enhancing the antioxidation response. This work not only provides a facile bile acid transporter-based strategy for hepatic-targeting drug delivery but also presents an efficient and safe full-API nanocrystal with which to facilitate the practical translation of nanomedicines against MAFLD.

RNAi silencing CHS1 gene shortens the mortality time of Plutella xylostella feeding Bt-transgenic Brassica napus.

BACKGROUND: Insect-resistance genetically modified (GM) plants derived from Bacillus thuringiensis (Bt) have been cultivated to control pests, but continuous cultivation of Bt-transgenic plants at large-scale regions leads to the resistance evolution of target insects to transgenic plants. RNA interference (RNAi) technology is considered an effective strategy in delaying the resistance evolution of target insects. RESULTS: We here developed a single transgenic oilseed rape (Brassica napus) line with hairpin RNA of the chitin-synthase 1 gene (CHS1) of Plutella xylostella (hpPxCHS1) and a pyramid transgenic B. napus line harboring hpPxCHS1 and Bt gene (Cry1Ac). Escherichia coli HT115 delivered hpPxCHS1 showed negative effects on the growth of P. xylostella. The single transgenic and pyramid transgenic B. napus significantly reduced the larval weight and length of P. xylostella and increased its lethality rate, with down-regulation expression of the PxCHS1 gene in insects. CONCLUSION: Compared to Bt-transgenic B. napus, pyramid-transgenic B. napus shorted the mortality time of P. xylostella, indicating that RNAi technology synergistic with Bt protein improves the effectiveness of controlling target insects. Our results proved that RNAi can delay the resistance evolution of target insects to Bt-transgenic plants. © 2024 Society of Chemical Industry.

ABIN1 (Q478) is Required to Prevent Hematopoietic Deficiencies through Regulating Type I IFNs Expression.

A20-binding inhibitor of NF-κB activation (ABIN1) is a polyubiquitin-binding protein that regulates cell death and immune responses. Although Abin1 is located on chromosome 5q in the region commonly deleted in patients with 5q minus syndrome, the most distinct of the myelodysplastic syndromes (MDSs), the precise role of ABIN1 in MDSs remains unknown. In this study, mice with a mutation disrupting the polyubiquitin-binding site (Abin1Q478H/Q478H ) is generated. These mice develop MDS-like diseases characterized by anemia, thrombocytopenia, and megakaryocyte dysplasia. Extramedullary hematopoiesis and bone marrow failure are also observed in Abin1Q478H/Q478H mice. Although Abin1Q478H/Q478H cells are sensitive to RIPK1 kinase-RIPK3-MLKL-dependent necroptosis, only anemia and splenomegaly are alleviated by RIPK3 deficiency but not by MLKL deficiency or the RIPK1 kinase-dead mutation. This indicates that the necroptosis-independent function of RIPK3 is critical for anemia development in Abin1Q478H/Q478H mice. Notably, Abin1Q478H/Q478H mice exhibit higher levels of type I interferon (IFN-I) expression in bone marrow cells compared towild-type mice. Consistently, blocking type I IFN signaling through the co-deletion of Ifnar1 greatly ameliorated anemia, thrombocytopenia, and splenomegaly in Abin1Q478H/Q478H mice. Together, these results demonstrates that ABIN1(Q478) prevents the development of hematopoietic deficiencies by regulating type I IFN expression.

The Genome of Vitis zhejiang-adstricta Strengthens the Protection and Utilization of the Endangered Ancient Grape Endemic to China.

Vitis zhejiang-adstricta (V. zhejiang-adstricta) is one of the most important and endangered wild grapes. It is a national key protected wild, rare and endangered ancient grape endemic to China and used as a candidate material for resistance breeding owing to its excellent significant disease resistance. Here, we present a high-quality chromosome-level assembly of V. zhejiang-adstricta (IB-VB-01), comprising 506.66 Mb assembled into 19 pseudo-chromosomes. The contig N50 length is 3.91 Mb with 31,196 annotated protein-coding genes. Comparative genome and evolutionary analyses illustrated that V. zhejiang-adstricta has a specific position in the evolution of East Asian Vitis and shared a common ancestor with Vitis vinifera during the divergence of the two species about 10.42 (between 9.34 and 11.12) Mya. The expanded gene families compared with those in plants were related to disease resistance, and constructed gene families were related to plant growth and primary metabolism. With the analysis of gene family expansion and contraction, the evolution of environmental adaptability and especially the NBS-LRR gene family of V. zhejiang-adstricta was elucidated based on the pathways of resistance genes (R genes), unique genes and structural variations. The near-complete and accurate diploid V. zhejiang-adstricta reference genome obtained herein serves as an important complement to wild grape genomes and will provide valuable genomic resources for investigating the genomic architecture of V. zhejiang-adstricta as well as for improving disease resistance breeding strategies in grape.

Adenosinergic metabolism pathway: an emerging target for improving outcomes of solid organ transplantation.

Extracellular nucleotides are widely recognized as crucial modulators of immune responses in peripheral tissues. Adenosine triphosphate (ATP) and adenosine are key components of extracellular nucleotides, the balance of which contributes to immune homeostasis. Under tissue injury, ATP exerts its pro-inflammatory function, while the adenosinergic pathway rapidly degrades ATP to immunosuppressive adenosine, thus inhibiting excessive and uncontrolled inflammatory responses. Previous reviews have explored the immunoregulatory role of extracellular adenosine in various pathological conditions, especially inflammation and malignancy. However, current knowledge regarding adenosine and adenosinergic metabolism in the context of solid organ transplantation remains fragmented. In this review, we summarize the latest information on adenosine metabolism and the mechanisms by which it suppresses the effector function of immune cells, as well as highlight the protective role of adenosine in all stages of solid organ transplantation, including reducing ischemia reperfusion injury during organ procurement, alleviating rejection, and promoting graft regeneration after transplantation. Finally, we discuss the potential for future clinical translation of adenosinergic pathway in solid organ transplantation.

Chromosome-level genome of putative autohexaploid Actinidia deliciosa provides insights into polyploidisation and evolution.

Actinidia ('Mihoutao' in Chinese) includes species with complex ploidy, among which diploid Actinidia chinensis and hexaploid Actinidia deliciosa are economically and nutritionally important fruit crops. Actinidia deliciosa has been proposed to be an autohexaploid (2n = 174) with diploid A. chinensis (2n = 58) as the putative parent. A CCS-based assembly anchored to a high-resolution linkage map provided a chromosome-resolved genome for hexaploid A. deliciosa yielded a 3.91-Gb assembly of 174 pseudochromosomes comprising 29 homologous groups with 6 members each, which contain 39 854 genes with an average of 4.57 alleles per gene. Here we provide evidence that much of the hexaploid genome matches diploid A. chinensis; 95.5% of homologous gene pairs exhibited >90% similarity. However, intragenome and intergenome comparisons of synteny indicate chromosomal changes. Our data, therefore, indicate that if A. deliciosa is an autoploid, chromosomal rearrangement occurred following autohexaploidy. A highly diversified pattern of gene expression and a history of rapid population expansion after polyploidisation likely facilitated the adaptation and niche differentiation of A. deliciosa in nature. The allele-defined hexaploid genome of A. deliciosa provides new genomic resources to accelerate crop improvement and to understand polyploid genome evolution.

Discovery of small molecule degraders for modulating cell cycle.

The cell cycle is a complex process that involves DNA replication, protein expression, and cell division. Dysregulation of the cell cycle is associated with various diseases. Cyclin-dependent kinases (CDKs) and their corresponding cyclins are major proteins that regulate the cell cycle. In contrast to inhibition, a new approach called proteolysis-targeting chimeras (PROTACs) and molecular glues can eliminate both enzymatic and scaffold functions of CDKs and cyclins, achieving targeted degradation. The field of PROTACs and molecular glues has developed rapidly in recent years. In this article, we aim to summarize the latest developments of CDKs and cyclin protein degraders. The selectivity, application, validation and the current state of each CDK degrader will be overviewed. Additionally, possible methods are discussed for the development of degraders for CDK members that still lack them. Overall, this article provides a comprehensive summary of the latest advancements in CDK and cyclin protein degraders, which will be helpful for researchers working on this topic.

Runoff, sediment, organic carbon, and nutrient loads from a Canadian prairie micro-watershed under climate variability and land management practices.

This study conducted a spatio-temporal analysis of runoff, total suspended sediment, suspended particulate carbon, nitrogen, and phosphorus loadings within the 2.06 km2 Steppler subwatershed in southern Manitoba of Canada based on 11 years of field monitoring data collected at nine stations. Results showed that the nutrient losses were very small because of the implementation of multiple BMPs in the study area. However, a high spatio-temporal variation of runoff and water quality parameters was found for the nine fields within the subwatershed. The average runoff coefficient was 0.19 at the subwatershed outlet with sediment, suspended particulate carbon, total nitrogen, and total phosphorus losses of 73.8, 6.10, 4.54, and 0.76 kg/ha respectively. Spring snowmelt runoff was about 74.5% of the annual runoff at the subwatershed outlet, while for sediment, suspended particulate carbon, total nitrogen, and total phosphorus, the proportions were 61.1%, 63.6%, 74.9%, and 81.2% respectively during the monitoring period, which suggests that BMPs designed for reducing nutrient loadings from snowmelt runoff would be more effective than BMPs designed for reducing pollutant loading from rainfall storms in the study area. Research findings from this study will benefit the enhancement of current BMPs and the development of new BMPs in the region to minimize soil and nutrient losses from agricultural fields and improve water quality in receiving water bodies.

20(S)-protopanaxatriol inhibited D-galactose-induced brain aging in mice via promoting mitochondrial autophagy flow.

Previous reports have confirmed that saponins (ginsenosides) derived from Panax ginseng. C. A. Meyer exerted obvious memory-enhancing and antiaging effects, and the simpler the structure of ginsenosides, the better the biological activity. In this work, we aimed to explore the therapeutic effect and underlying molecular mechanism of 20(S)-protopanaxatriol (PPT), the aglycone of panaxatriol-type ginsenosides, by establishing D-galactose (D-gal)-induced subacute brain aging model in mice. The results showed that PPT treatment (10 and 20 mg/kg) for 4 weeks could significantly restore the D-gal (800 mg/kg for 8 weeks)-induced impaired memory function, choline dysfunction, and redox system imbalance in mice. Meanwhile, PPT also significantly reduced the histopathological changes caused by D-gal exposure. Moreover, PPT could increase TFEB/LAMP2 protein expression to promote mitochondrial autophagic flow. Importantly, the results from molecular docking showed that PPT had good binding ability with LAMP2 and TFEB, suggesting that TFEB/LAMP2 might play an important role in PPT to alleviate D-gal-caused brain aging.

Safety, tolerability, pharmacokinetics and immunogenicity of an antibody-drug conjugate (SHR-A1201) in patients with HER2-positive advanced breast cancer: an open, phase I dose-escalation study.

SHR-A1201 is an antibody-drug conjugate (ADC) that combines trastuzumab with DM1 (a chemotherapeutic agent) using a chemical connector. This phase I study investigated the safety, tolerability and pharmacokinetics of SHR-A1201 in patients with human epidermal growth factor receptor 2-positive advanced breast cancer. This phase I study enrolled patients in a traditional 3 + 3 dose-escalation design to receive a single dose of SHR-A1201 (1.2 mg/kg, 2.4 mg/kg, 3.6 mg/kg or 4.8 mg/kg). The observation period of dose-limiting toxicity (DLT) was 21 days. A total of 12 patients were enrolled and received SHR-A1201. Most treatment-emergent adverse events (TEAEs) were grade 1 or 2 in severity, with elevated aspartate aminotransferase (75%), thrombocytopenia (75%), and nausea (66.7%) being reported most frequently. The common grade 3 TEAEs were thrombocytopenia and decreased lymphocyte count, and there were no grade 4 or above TEAEs. There were no serious adverse events or drug-related deaths. One DLT occurred in one patient treated with SHR-A1201 4.8 mg/kg (asymptomatic grade 3 increased γ-glutamyltransferase). The maximum tolerated dose of SHR-A1201 was not lower than that of T-DM1 (3.6 mg/kg). A total of 8.3% (1/12) of patients had ADA-positive reactions 504 h after administration, but no differences were observed in the type, incidence, or severity of TEAEs between patients with and without ADA. SHR-A1201 exhibited the pharmacokinetics characteristics of typical ADCs. An encouraging antitumor effect was observed in the 4.8 mg/kg dose group. SHR-A1201 was well tolerated and safe in patients with advanced HER2-positive breast cancer. The pharmacokinetics parameters showed a linear trend, and the immunogenicity results met the clinical expectations.

Configurational Entropy Regulation in Polyolefin Elastomer/Paraffin Wax Vitrimers by Thermally Responsive Liquid-Solid Transition for Force Storage.

The work output of shape memory polymers during shape shifting is desired for practical application as actuators. Herein, a polyolefin elastomer (POE) and paraffin wax (PW) are co-cross-linked by dynamic boronic ester bonds to enhance the network elasticity and the stress transfer between the two phases, endowing high force storage capacity to the prepared vitrimers. Depending on the phase of PW, one-way force storage is realized by programming at a low temperature (25 °C), owing to which solid PW can promote the locking of POE chains in a low-entropy state, while reversible force storage can be realized by programming at a high temperature (75 °C), owing to which the relaxation of chains facilitated by liquid PW can promote the construction of a stable structure. Based on one-way force storage, a weight-lifting machine with a weight of 20 mg prestrained at 25 °C can lift a 100 g weight, showing a lifting ratio of no less than 5000, with a high work output of 0.98 J/g. A high-temperature alarm can be triggered at varied temperatures (43-56 °C) through controlled force release by adjusting the PW content and programmed prestrains. Based on the reversible force storage, crawling robots and artificial muscles with a work output of 0.025 J/g are demonstrated. The dynamic cross-linking network also confers mold-free self-healing capability to POE/PW vitrimers, and the repair efficiency is enhanced compared with the POE vitrimer due to the improved POE chain motion by liquid PW. The realized one-way and reversible force storage and self-healing by POE/PW vitrimers pave the way for the application of SMPs in the fields of soft robotic actuators.

Prediction of Clinical Molecular Typing of Breast Invasive Ductal Carcinoma Using 18F-FDG PET/CT Dual-Phase Imaging.

RATIONALE AND OBJECTIVES: To investigate the diagnostic value of Fluorine-18-labeled 2-fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography (18F-FDG PET/CT) dual-phase imaging for the different molecular subtypes of invasive ductal carcinoma of the breast. MATERIALS AND METHODS: Clinical imaging data of 164 women with invasive ductal carcinoma of the breast confirmed by pathology who underwent 18F-FDG PET/CT dual-phase imaging were retrospectively analyzed. The maximum standard uptake values (SUVmax) of the early and delayed phases of the lesion were measured and recorded as SUVmax1 and SUVmax2, respectively, and the retention index (RI) was calculated. We analyzed the change rule of SUVmax1, SUVmax2, and RI for the different molecular subtypes and molecular marker expression groups. The diagnostic threshold of different molecular marker expression status was determined using receiver operating characteristic curve analysis. RESULTS: SUVmax1 and SUVmax2 were highest in the TNBC group and lowest in the luminal A group (p<0.001). TNBC and HER2 overexpression groups had higher RI than the luminal A and B groups (p<0.001), with no significant difference between the TNBC and HER2 overexpression groups or between the luminal A and B groups (p=0.640 and 0.345, respectively). The ER- and PR-negative groups had significantly higher SUVmax1, SUVmax2, and RI than the PR-positive group (p<0.001). The HER2-positive group had higher SUVmax1 and SUVmax2 than the negative group (p<0.001). The Ki67 overexpression group had higher SUVmax1 and SUVmax2 levels than the low expression group (p<0.001). There was no significant difference in RI between HER2-positive and negative groups or between Ki67 high and low expression groups (p=0.904 and 0.216, respectively). For ER-negative and positive expression status, the maximum area under the curve (AUC) of SUVmax2 was 0.852, diagnostic threshold was 10.87, sensitivity was 79.6%, and specificity was 74.5%. For PR-negative and positive expression status, the AUC of SUVmax2 was 0.858, diagnostic threshold was 10.45, sensitivity was 83.1%, and specificity was 75.3%. For HER2-negative and positive expression status, the AUC of SUVmax1 was 0.714, diagnostic threshold was 9.28, sensitivity was 79.6%, and specificity was 60.9%. For Ki67 high- and low expression status, the AUC of SUVmax2 was 0.915 at maximum, diagnostic threshold was 10.21, sensitivity was 83.4%, and specificity was 93.9%. CONCLUSION: 18F-FDG PET/CT dual-phase imaging facilitates the prediction of the expression of molecular markers and subtypes of invasive ductal carcinoma of the breast and the development of more tailored treatment plans for patients with this disease.

Connecting the health of country with the health of people: Application of "caring for country" in improving the social and emotional well-being of Indigenous people in Australia and New Zealand.

Emerging evidence from the western literature suggests an increasing focus on applying nature-based interventions for mental health improvements. However, in Indigenous communities, caring for country has always been central to the Indigenous way of life. Knowing that nature-based interventions effectively improve mental health outcomes, this review collated evidence on the application of caring for country in improving social and emotional well-being (SEWB) of Indigenous peoples in Australia and New Zealand. Three studies from Australia and one from New Zealand, explored the role of country or whenua (land) in the lives of Indigenous people. Participation in caring-for country activities was associated with lower levels of psychological distress and strengthened guardianship relationship with country, which positively affected SEWB. This systematic review offers preliminary evidence on the role of caring for country activities in improving the SEWB of Indigenous peoples and highlights the need for strengths-based approaches to improve the SEWB of Indigenous peoples. Funding: None.

Does the critically endangered Rhododendron amesiae deserve top priority for conservation?

1.If a threatened plant has the problem of inaccurate species delimitation, its conservation programs that have previously been implemented might be debated.2.We made a comprehensive comparison of the critically endangered R. amesiae and its close relative R. concinnum, employing both morphological and population genomic data (ddRAD-seq).3.We suggest that the critically endangered R. amesiae can be merged into R. concinnum. Hence, the threatened status of R. amesiae is needed to be reevaluated.

Functionalized graphene grids with various charges for single-particle cryo-EM.

A major hurdle for single particle cryo-EM in structural determination lies in the specimen preparation impaired by the air-water interface (AWI) and preferential particle-orientation problems. In this work, we develop functionalized graphene grids with various charges via a dediazoniation reaction for cryo-EM specimen preparation. The graphene grids are paraffin-assistant fabricated, which appear with less contaminations compared with those produced by polymer transfer method. By applying onto three different types of macromolecules, we demonstrate that the high-yield charged graphene grids bring macromolecules away from the AWI and enable adjustable particle-orientation distribution for more robust single particle cryo-EM structural determination.

Association between Metabolic Dysfunction-associated Fatty Liver Disease and Cognitive Impairment.

Background and Aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a newly proposed term based on modified criteria. Although nonalcoholic fatty liver disease (NAFLD) has been well-documented as a multisystem disease, research on the correlation of MAFLD and extra-hepatic diseases is limited. This study aimed to clarify the association of MAFLD, as well as NAFLD status with cognitive function. Methods: A total of 5,662 participants 20-59 years of age who underwent cognitive tests and liver ultrasonography in the Third National Health and Nutrition Examination Survey were included in the analysis. Cognitive function was evaluated using three computer-administered tests, the serial digit learning test (SDLT), the simple reaction time test (SRTT) and the symbol digit substitution test (SDST). Results: Participants with MAFLD had significantly poorer performance on the SRTT [odds ratio (OR) 1.47, 95% confidence interval (CI): 1.14-1.89)]. MAFLD with moderate-severe liver steatosis was associated with higher risks of scoring low in the SDLT (OR 1.37, 95% CI: 1.04-1.82) and SRTT (OR 1.55, 95% CI: 1.19-2.02). NAFLD combined with metabolic dysfunction, instead of NAFLD without metabolic disorders, was associated an increased risk of a low SRTT score (OR 1.44, 95% CI: 1.10-1.82). MAFLD patients had a high probability of fibrosis, prediabetes, and diabetes and were also significantly associated with increased risks based on the SDST or SRTT score. Conclusions: MAFLD was significantly associated with increased risk of cognitive impairment, especially among MAFLD patients with a high degree of liver fibrosis, moderate-severe steatosis, or hyperglycemia.

tRNA-m1A modification promotes T cell expansion via efficient MYC protein synthesis.

Naive T cells undergo radical changes during the transition from dormant to hyperactive states upon activation, which necessitates de novo protein production via transcription and translation. However, the mechanism whereby T cells globally promote translation remains largely unknown. Here, we show that on exit from quiescence, T cells upregulate transfer RNA (tRNA) m1A58 'writer' proteins TRMT61A and TRMT6, which confer m1A58 RNA modification on a specific subset of early expressed tRNAs. These m1A-modified early tRNAs enhance translation efficiency, enabling rapid and necessary synthesis of MYC and of a specific group of key functional proteins. The MYC protein then guides the exit of naive T cells from a quiescent state into a proliferative state and promotes rapid T cell expansion after activation. Conditional deletion of the Trmt61a gene in mouse CD4+ T cells causes MYC protein deficiency and cell cycle arrest, disrupts T cell expansion upon cognate antigen stimulation and alleviates colitis in a mouse adoptive transfer colitis model. Our study elucidates for the first time, to our knowledge, the in vivo physiological roles of tRNA-m1A58 modification in T cell-mediated pathogenesis and reveals a new mechanism of tRNA-m1A58-controlled T cell homeostasis and signal-dependent translational control of specific key proteins.

Vitrimeric Polylactide by Two-step Alcoholysis and Transesterification during Reactive Processing for Enhanced Melt Strength.

Because of its rather low melt strength, polylactide (PLA) has yet to fulfill its promise as advanced biobased and biodegradable foams to replace fossil-based polymer foams. In this work, PLA vitrimers were prepared by two-step reactive processing from commercial PLA thermoplastics, glycerol, and diphenylmethane diisocyanate (MDI) using Zn(II)-catalyzed addition and transesterification chemistry. The transesterification reaction of PLA and glycerol occurs with zinc acetate as the catalyst, and chain scission will take place due to the alcoholysis of the PLA chains by the free hydroxyl groups from the glycerol. Long-chain PLA with hydroxyl groups can be obtained and then cross-linked with MDI. Rheological analysis shows that the formed cross-linked network can significantly improve melt strength and promote strain hardening under extensional flow. PLA vitrimers still maintain the ability of thermoplastic processing via extrusion and compression. The enhanced melt strength and the rearrangement of network topology facilitate the foaming processing. An expansion ratio as large as 49.2-fold and microcellular foam with a uniform cell morphology can be obtained for PLA vitrimers with a gel fraction of 51.8% through a supercritical carbon dioxide foaming technique. This work provides a new way with the scale-up possibility to enhance the melt strength of PLA, and the broadened range of PLA applicability brought by PLA vitrimers is truly valuable in terms of the realization of a sustainable society.