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Subdivisions of Ladinian–Carnian boundary beds and the lower Carnian strata in South China are challenging owing to a paucity of west Tethyan ammonoids. We investigated a conodont fauna in a continuous section at Yize in eastern Yunnan Province to provide a biostratigraphic solution. Five genera and 24 conodont species are recognized, and five conodont zones are established. The zones are, in ascending order, the Paragondolella inclinata Zone, the Quadralella polygnathiformis Zone, the Quadralella praelindae Zone, the Quadralella auriformis Zone and the Quadralella robusta Zone. The Ladinian–Carnian boundary is provisionally defined by the first occurrences of Quadralella polygnathiformis and Quadralella intermedia in the cherty limestone member of the Zhuganpo Formation. Regional correlations via conodont biostratigraphy indicate that the Zhuganpo Formation is probably diachronous, with a maximal range spanning the upper Ladinian to the lower Carnian. Amongst all common late Ladinian – early Carnian conodont genera, Paragondolella, Quadralella and Mazzaella are probably cosmopolitan. Budurovignathus was restricted to a few basins and probably preferred offshore or deep-water environments.

The endogenous peptides AtPepl-8 in Arabidopsis mature from the conserved C-terminal portions of their precursor proteins PROPEP1-8, respectively. The two homologous leucine-rich repeat-receptor kinases （LRR-RKs） PEPR1 and PEPR2 act as receptors of AtPeps. AtPep binding leads to stable association of PEPR1,2 with the shared receptor LRR-RK BAK1, eliciting immune responses similar to those induced by pathogens. Here we report a crystal structure of the extraceUular LRR domain of PEPRI （PEPR1LRR） in complex with AtPepl. The structure reveals that AtPepl adopts a fully extended conformation and binds to the inner surface of the superhelical PEPRILRR. Biochemical assays showed that AtPepl is capable of inducing PEPR1LRR-BAK1LRR heterodimerization. The conserved C-terminal portion of AtPepl dominates AtPepl binding to PEPRILRR, with the last amino acid of AtPepl Asn23 forming extensive interactions with PEPR1LRR. Deletion of the last residue of AtPepl significantly compromised AtPep1 interaction with PEPRILRR. Together, our data reveal a conserved structural mechanism of AtPep1 recognition by PEPR1, providing significant insight into prediction of recognition of other peptides by their cognate LRR-RKs.

Posttranslational modifications (PTMs) of tubulin, termed the “tubulin code”, play important roles in regulating microtubule functions within subcellular compartments for specialized cellular activities. While numerous tubulin PTMs have been identified, a comprehensive understanding of the complete repertoire is still underway. In this study, we report that α-tubulin lactylation is catalyzed by HDAC6 by using lactate to increase microtubule dynamics in neurons. We identify lactylation on lysine 40 of α-tubulin in the soluble tubulin dimers. Notably, lactylated α-tubulin enhances microtubule dynamics and facilitates neurite outgrowth and branching in cultured hippocampal neurons. Moreover, we discover an unexpected function of HDAC6, acting as the primary lactyltransferase to catalyze α-tubulin lactylation. HDAC6-catalyzed lactylation is a reversible process, dependent on lactate concentrations. Intracellular lactate concentration triggers HDAC6 to lactylate α-tubulin, a process dependent on its deacetylase activity. Additionally, the lactyltransferase activity may be conserved in HDAC family proteins. Our study reveals the primary role of HDAC6 in regulating α-tubulin lactylation, establishing a link between cell metabolism and cytoskeleton functions. The mechanisms regulating protein lactylation, a post-translational modification, are not fully understood. Here, the authors discover that Histone deacetylase 6 (HDAC6) acts as the primary lactyltransferase for α-tubulin, regulating microtubule dynamics.

The organization of the human genome in space and time is critical for transcriptional regulation and cell fate determination. However, robust methods for tracking genome organization or genomic interactions over time in living cells are lacking. Here, we developed a multicolor DNA labeling system, ParSite, to simultaneously track triple genomic loci in the U2OS cells. The tricolor ParSite system is derived from the T . thermophilus ParB/ParSc ( Tt ParB/ParSc) system by rational design. We mutated the interface between Tt ParB and ParSc and generated a new pair of Tt ParBm and ParSm for genomic DNA labeling. The insertions of 16 base-pair palindromic ParSc and ParSm into genomic loci allow dual-color DNA imaging in living cells. A pair of genomic loci labeled by ParSite could be colocalized with p53-binding protein 1 (53BP1) in response to CRISPR/Cas9-mediated double-strand breaks (DSBs). The ParSite permits tracking promoter and terminator dynamics of the APP gene, which spans 290 kilobases in length. Intriguingly, the hybrid ParS (ParSh) of half-ParSc and half-ParSm enables for the visualization of a third locus independent of ParSc or ParSm. We simultaneously labeled 3 loci with a genomic distance of 36, 89, and 352 kilobases downstream the C3 repeat locus, respectively. In sum, the ParSite is a robust DNA labeling system for tracking multiple genomic loci in space and time in living cells.

Investigating the risk factors and underlying mechanisms of problematic WeChat use(PWU) holds significant promise for preemptively addressing and mitigating such behaviors among college students, thereby fostering improvements in their mental well-being. The present study aims to characterize PWU and to examine differences in social support and life satisfaction potentially across these profiles. In addition, this study also employs latent profile analysis to delve into the influence of social support and life satisfaction on PWU among college students. Using convenience sampling, a sample of 7000 Chinese college students from three universities completed a questionnaire assessing social support, PWU and life satisfaction. The latent profile analysis identifed six PWU profiles, which were labelled as lowest, very lower, low PWU and high, very higher, highest PWU. Moreover, life satisfaction played a mediating role in the relationship between social support and PWU, but this effect exhibited significant differences across PWU risk groups. Specifically, in the very low and very high PWU groups, the indirect effect value of life satisfaction was the highest, and it significantly mediated the impact of social support on PWU. Second, in the lowest, low, and high PWU groups, the indirect effect of life satisfaction was lower, yet it still significantly mediated the relationship between social support and PWU. However, for the highest group, the aforementioned mediating pathway was completely non-significant (indirect effect = -0.01, 95% CI = [-0.02, 0.02], P  > 0.05), indicating that life satisfaction did not mediate the relationship between social support and PWU in this group. This study offers valuable insights for alleviating the adverse consequences associated with PWU, thereby fostering enhanced mental health outcomes among this demographic.

Ferroptosis is a form of regulated cell death that emerges to be relevant for therapy-resistant and dedifferentiating cancers. Although several lines of evidence suggest that ferroptosis is a type of autophagy-dependent cell death, the underlying molecular mechanisms remain unclear. Fin56, a type 3 ferroptosis inducer, triggers ferroptosis by promoting glutathione peroxidase 4 (GPX4) protein degradation via a not fully understood pathway. Here, we determined that Fin56 induces ferroptosis and autophagy in bladder cancer cells and that Fin56-triggered ferroptosis mechanistically depends on the autophagic machinery. Furthermore, we found that autophagy inhibition at different stages attenuates Fin56-induced oxidative stress and GPX4 degradation. Moreover, we investigated the effects of Fin56 in combination with Torin 2, a potent mTOR inhibitor used to activate autophagy, on cell viability. We found that Fin56 synergizes with Torin 2 in cytotoxicity against bladder cancer cells. Collectively, our findings not only support the concept that ferroptosis is a type of autophagy-dependent cell death but imply that the combined application of ferroptosis inducers and mTOR inhibitors is a promising approach to improve therapeutic options in the treatment of bladder cancer.

Nearly all eukaryotic messenger RNA precursors must undergo cleavage and polyadenylation at their 3′-end for maturation. A crucial step in this process is the recognition of the AAUAAA polyadenylation signal (PAS), and the molecular mechanism of this recognition has been a long-standing problem. Here, we report the cryo-electron microscopy structure of a quaternary complex of human CPSF-160, WDR33, CPSF-30, and an AAUAAA RNA at 3.4-Å resolution. Strikingly, the AAUAAA PAS assumes an unusual conformation that allows this short motif to be bound directly by both CPSF-30 and WDR33. The A1 and A2 bases are recognized specifically by zinc finger 2 (ZF2) of CPSF-30 and the A4 and A5 bases by ZF3. Interestingly, the U3 and A6 bases form an intramolecular Hoogsteen base pair and directly contact WDR33. CPSF-160 functions as an essential scaffold and preorganizes CPSF-30 and WDR33 for high-affinity binding to AAUAAA. Our findings provide an elegant molecular explanation for how PAS sequences are recognized for mRNA 3′-end formation.

Removal of introns from transfer RNA precursors (pre-tRNAs) occurs in all living organisms. This is a vital phase in the maturation and functionality of tRNA. Here we present a 3.2 Å-resolution cryo-EM structure of an active human tRNA splicing endonuclease complex bound to an intron-containing pre-tRNA. TSEN54, along with the unique regions of TSEN34 and TSEN2, cooperatively recognizes the mature body of pre-tRNA and guides the anticodon-intron stem to the correct position for splicing. We capture the moment when the endonucleases are poised for cleavage, illuminating the molecular mechanism for both 3′ and 5′ cleavage reactions. Two insertion loops from TSEN54 and TSEN2 cover the 3′ and 5′ splice sites, respectively, trapping the scissile phosphate in the center of the catalytic triad of residues. Our findings reveal the molecular mechanism for eukaryotic pre-tRNA recognition and cleavage, as well as the evolutionary relationship between archaeal and eukaryotic TSENs. tRNA splicing is universal. Here the authors report the structure of an active human tRNA splicing endonuclease complex bound to an intron-containing pre-tRNA, which unveils eukaryotic tRNA processing and links archaeal and eukaryotic TSEN evolution.

Global warming is widely regarded to have played a contributing role in numerous past biotic crises. Here, we show that the end-Permian mass extinction coincided with a rapid temperature rise to exceptionally high values in the Early Triassic that were inimical to life in equatorial latitudes and suppressed ecosystem recovery. This was manifested in the loss of calcareous algae, the near-absence of fish in equatorial Tethys, and the dominance of small taxa of invertebrates during the thermal maxima. High temperatures drove most Early Triassic plants and animals out of equatorial terrestrial ecosystems and probably were a major cause of the end-Smithian crisis.

OSCA/TMEM63 channels are the largest known family of mechanosensitive channels 1 – 3 , playing critical roles in plant 4 – 7 and mammalian 8 , 9 mechanotransduction. Here we determined 44 cryogenic electron microscopy structures of OSCA/TMEM63 channels in different environments to investigate the molecular basis of OSCA/TMEM63 channel mechanosensitivity. In nanodiscs, we mimicked increased membrane tension and observed a dilated pore with membrane access in one of the OSCA1.2 subunits. In liposomes, we captured the fully open structure of OSCA1.2 in the inside-in orientation, in which the pore shows a large lateral opening to the membrane. Unusually for ion channels, structural, functional and computational evidence supports the existence of a ‘proteo-lipidic pore’ in which lipids act as a wall of the ion permeation pathway. In the less tension-sensitive homologue OSCA3.1, we identified an ‘interlocking’ lipid tightly bound in the central cleft, keeping the channel closed. Mutation of the lipid-coordinating residues induced OSCA3.1 activation, revealing a conserved open conformation of OSCA channels. Our structures provide a global picture of the OSCA channel gating cycle, uncover the importance of bound lipids and show that each subunit can open independently. This expands both our understanding of channel-mediated mechanotransduction and channel pore formation, with important mechanistic implications for the TMEM16 and TMC protein families. The molecular basis of OSCA/TMEM63 channel mechanosensitivity was investigated by determining 44 cryogenic electron microscopy structures of channels in different environments, expanding understanding of channel-mediated mechanotransduction and pore formation, with implications for two protein families.