piRNA loading triggers MIWI translocation from the intermitochondrial cement to chromatoid body during mouse spermatogenesis.

The intermitochondrial cement (IMC) and chromatoid body (CB) are posited as central sites for piRNA activity in mice, with MIWI initially assembling in the IMC for piRNA processing before translocating to the CB for functional deployment. The regulatory mechanism underpinning MIWI translocation, however, has remained elusive. We unveil that piRNA loading is the trigger for MIWI translocation from the IMC to CB. Mechanistically, piRNA loading facilitates MIWI release from the IMC by weakening its ties with the mitochondria-anchored TDRKH. This, in turn, enables arginine methylation of MIWI, augmenting its binding affinity for TDRD6 and ensuring its integration within the CB. Notably, loss of piRNA-loading ability causes MIWI entrapment in the IMC and its destabilization in male germ cells, leading to defective spermatogenesis and male infertility in mice. Collectively, our findings establish the critical role of piRNA loading in MIWI translocation during spermatogenesis, offering new insights into piRNA biology in mammals.

The PIWI-specific insertion module helps load longer piRNAs for translational activation essential for male fertility.

PIWI-clade proteins harness piRNAs of 24-33 nt in length. Of great puzzles are how PIWI-clade proteins incorporate piRNAs of different sizes and whether the size matters to PIWI/piRNA function. Here we report that a PIWI-Ins module unique in PIWI-clade proteins helps define the length of piRNAs. Deletion of PIWI-Ins in Miwi shifts MIWI to load with shorter piRNAs and causes spermiogenic failure in mice, demonstrating the functional importance of this regulatory module. Mechanistically, we show that longer piRNAs provide additional complementarity to target mRNAs, thereby enhancing the assembly of the MIWI/eIF3f/HuR super-complex for translational activation. Importantly, we identify a c.1108C>T (p.R370W) mutation of HIWI (human PIWIL1) in infertile men and demonstrate in Miwi knock-in mice that this genetic mutation impairs male fertility by altering the property of PIWI-Ins in selecting longer piRNAs. These findings reveal a critical role of PIWI-Ins-ensured longer piRNAs in fine-tuning MIWI/piRNA targeting capacity, proven essential for spermatid development and male fertility.

Textbook outcomes of hepatocellular carcinoma patients with sarcopenia: A multicenter analysis.

BACKGROUND: The impact of sarcopenia on textbook outcome (TO) after hepatectomy in hepatocellular carcinoma (HCC) patients remains unclear. This study aimed to investigate the association between sarcopenia and TO, to clarify its long and short-term prognostic value, and to develop a nomogram model based on sarcopenia and TO for survival prediction. METHODS: Patients who underwent HCC resection between January 2012 and March 2017 in three large hospitals in Fujian were retrospectively recruited and divided into sarcopenia and non-sarcopenia groups based on skeletal muscle index (SMI) values. TO was defined as no 30-day morality, no 30-day readmission, negative margins, no prolonged hospital stay, and no major complications. Multivariate regression was used to screen for clinical factors associated with TO. Nomograms of overall survival (OS) and recurrence-free survival (RFS) after hepatectomy for HCC were developed. RESULTS: A total of 1172 patients were included in the study. The TO rates were 28.74% (121/421 patients) in the sarcopenia group and 43.4% (326/751 patients) in the non-sarcopenia group. The results showed that sarcopenia was an independent predictor of TO (p < 0.001), TO was an independent predictor of perioperative treatment-related sarcopenia (PTRS)(p = 0.002), and TO was an independent predictor of OS and RFS (p < 0.001). Nomogram models based on sarcopenia and TO were generated and accurately predicted OS and RFS at 1, 3, and 5 years. CONCLUSION: Both sarcopenia and TO are independent predictors of OS and RFS after HCC resection. Sarcopenia was an independent predictor of TO. Sarcopenia influenced long-term survival by affecting short-term postoperative outcomes.

Human Motion Segmentation via Velocity-Sensitive Dual-Side Auto-Encoder.

Human motion segmentation (HMS) aims to segment a long human action video into a bunch of short and meaningful action clips. Existing supervised learning approaches need a large amount of training data which may be costly in real-world scenario, while most unsupervised clustering methods cannot fully explore the temporal correlations among human motions and hard to achieve promising performances. In our paper, we design a novel unsupervised framework, called Velocity-Sensitive Dual-Side Auto-Encoder (VSDA), for HMS task. Specifically, a multi-neighbor auto-encoder (MNA) is proposed to extract informative temporal features, which fully explores the local temporal patterns of human motions. In addition, a long-short distance encoding (LSE) strategy is designed. It constrains the encoded representations of close (short-distance) frames becoming similar while the representations of far-away (long-distance) frames becoming distinctive. Similarly, this strategy is also deployed on the decoded outputs as the long-short distance decoding (LSD) module. The LSE/LSD guides the learning process explicitly and implicitly to achieve the dual-side structure. Moreover, we consider the energy variations during the human motion to propose the velocity-sensitive (VS) guidance mechanism for further model improvement. VSDA leverages the temporal characteristics of human motion and derives promising HMS performance. Comprehensive experiments on six real-world human motion datasets illustrate the effectiveness of our proposed model.

Semi-Supervised Dual Relation Learning for Multi-Label Classification.

In a real-world scenario, an object could contain multiple tags instead of a single categorical label. To this end, multi-label learning (MLL) emerged. In MLL, the feature distributions are long-tailed and the complex semantic label relation and the long-tailed training samples are the main challenges. Semi-supervised learning is a potential solution. While, existing methods are mainly designed for single class scenario while ignoring the latent label relations. In addition, they cannot well handle the distribution shift commonly existing across source and target domains. To this end, a Semi-supervised Dual Relation Learning (SDRL) framework for multi-label classification is proposed. SDRL utilizes a few labeled samples as well as large scale unlabeled samples in the training stage. It jointly explores the inter-instance feature-level relation and the intra-instance label-level relation even from the unlabeled samples. In our model, a dual-classifier structure is deployed to obtain domain invariant representations. The prediction results from the classifiers are further compared and the most confident predictions are extracted as pseudo labels. A trainable label relation tensor is designed to explicitly explore the pairwise latent label relations and refine the predicted labels. SDRL is able to effectively and efficiently explore the feature-label relation as well as the label-label relation knowledge without any extra semantic knowledge. We evaluated SDRL in general and zero-shot multi-label classification tasks and we concluded that SDRL is superior to other SOTA baselines. Furthermore, extensive ablation studies have been done which reveal the effectiveness of each component in our framework.

LARP7-Mediated U6 snRNA Modification Ensures Splicing Fidelity and Spermatogenesis in Mice.

U6 snRNA, as an essential component of the catalytic core of the pre-mRNA processing spliceosome, is heavily modified post-transcriptionally, with 2'-O-methylation being most common. The role of these modifications in pre-mRNA splicing as well as their physiological function in mammals have remained largely unclear. Here we report that the La-related protein LARP7 functions as a critical cofactor for 2'-O-methylation of U6 in mouse male germ cells. Mechanistically, LARP7 promotes U6 loading onto box C/D snoRNP, facilitating U6 2'-O-methylation by box C/D snoRNP. Importantly, ablation of LARP7 in the male germline causes defective U6 2'-O-methylation, massive alterations in pre-mRNA splicing, and spermatogenic failure in mice, which can be rescued by ectopic expression of wild-type LARP7 but not an U6-loading-deficient mutant LARP7. Our data uncover a novel role of LARP7 in regulating U6 2'-O-methylation and demonstrate the functional requirement of such modification for splicing fidelity and spermatogenesis in mice.