Emerging roles of proximal tubular endocytosis in renal fibrosis

Endocytosis is a crucial component of many pathological conditions. The proximal tubules are responsible for reabsorbing the majority of filtered water and glucose, as well as all the proteins filtered through the glomerular barrier via endocytosis, indicating an essential role in kidney diseases. Genetic mutations or acquired insults could affect the proximal tubule endocytosis processes, by disturbing or overstressing the endolysosomal system and subsequently activating different pathways, orchestrating renal fibrosis. This paper will review recent studies on proximal tubular endocytosis affected by other diseases and factors. Endocytosis plays a vital role in the development of renal fibrosis, and renal fibrosis could also, in turn, affect tubular endocytosis

Prompt Learning with Optimal Transport for Vision-Language Models

With the increasing attention to large vision-language models such as CLIP, there has been a significant amount of effort dedicated to building efficient prompts. Unlike conventional methods of only learning one single prompt, we propose to learn multiple comprehensive prompts to describe diverse characteristics of categories such as intrinsic attributes or extrinsic contexts. However, directly matching each prompt to the same visual feature is problematic, as it pushes the prompts to converge to one point. To solve this problem, we propose to apply optimal transport to match the vision and text modalities. Specifically, we first model images and the categories with visual and textual feature sets. Then, we apply a two-stage optimization strategy to learn the prompts. In the inner loop, we optimize the optimal transport distance to align visual features and prompts by the Sinkhorn algorithm, while in the outer loop, we learn the prompts by this distance from the supervised data. Extensive experiments are conducted on the few-shot recognition task and the improvement demonstrates the superiority of our method

Temporally Disentangled Representation Learning under Unknown Nonstationarity

In unsupervised causal representation learning for sequential data with time-delayed latent causal influences, strong identifiability results for the disentanglement of causally-related latent variables have been established in stationary settings by leveraging temporal structure. However, in nonstationary setting, existing work only partially addressed the problem by either utilizing observed auxiliary variables (e.g., class labels and/or domain indexes) as side information or assuming simplified latent causal dynamics. Both constrain the method to a limited range of scenarios. In this study, we further explored the Markov Assumption under time-delayed causally related process in nonstationary setting and showed that under mild conditions, the independent latent components can be recovered from their nonlinear mixture up to a permutation and a component-wise transformation, without the observation of auxiliary variables. We then introduce NCTRL, a principled estimation framework, to reconstruct time-delayed latent causal variables and identify their relations from measured sequential data only. Empirical evaluations demonstrated the reliable identification of time-delayed latent causal influences, with our methodology substantially outperforming existing baselines that fail to exploit the nonstationarity adequately and then, consequently, cannot distinguish distribution shifts.Comment: NeurIPS 202

Age-Related Loss of Innate Immune Antimicrobial Function of Dermal Fat Is Mediated by Transforming Growth Factor Beta

Dermal immature adipocytes fightagainstStaphylococcusaureusinfectionby secreting antimicrobial peptidesduring adipogenesis. Zhang et al.demonstrate that activation of the TGF-bpathway suppresses the adipogenicpotential of dermal fibroblasts andtherefore leads to an age-dependent lossof antimicrobial protection fromdermal fat. 皮下脂肪细胞作为皮肤的最后一道防线，有很重要的免疫抗菌功能，分化中脂肪细胞释放大量抗菌肽，这是一种人自源抗生素，能有效地抑制细菌生长。但这一重要的宿主天然免疫功能在发育和老化过程中如何被调控还不为人知。研究人员发现，老化过程中皮肤脂肪丢失是和真皮成纤维细胞（dermal fibroblasts）失去脂肪分化能力密切相关的。真皮成纤维细胞是皮肤深处的特化细胞，可以产生结缔组织并帮助皮肤从损伤中恢复。【Abstract】Dermal fibroblasts (dFBs) resist infection by locallydifferentiating into adipocytes and producing cathe-licidin antimicrobial peptide in response toStaphylo-coccusaureus(S.aureus). Here, we show thatneonatal skin was enriched with adipogenic dFBsand immature dermal fat that highly expressed cath-elicidin. The pool of adipogenic and antimicrobialdFBs declined after birth, leading to an age-depen-dent loss of dermal fat and a decrease in adipogene-sis and cathelidicin production in response to infec-tion. Transforming growth factor beta (TGF-b),which acted on uncommitted embryonic and adultdFBs and inhibited their adipogenic and antimicro-bial function, was identified as a key upstream regu-lator of this process. Furthermore, inhibition of theTGF-breceptor restored the adipogenic and antimi-crobial function of dFBs in culture and increasedresistance of adult mice toS.aureusinfection. Theseresults provide insight into changes that occur in theskin innate immune system between the perinataland adult periods of life.This work was supported by NIH grant R01-AR069653 to L.Z. and R.L.G. and NIH grants R01-AI083358, R01-AR052728, and U19-AI117673 to R.L.G. M.V.P. is supported by a Pew Charitable Trust grant, NIH grants U01-AR073159 and R01-AR067273, National Science Foundation (NSF) grant DMS1763272, and Simons Foundation grant 594598 (to Qing Nie). C.F.G.J. is supported by NSF-GRFP grant DGE-1321846 and MBRS-IMSD training grant GM055246. Y.Z. is supported by NIH grant R01-AI107027. 该项目研究得到了厦门大学双一流启动基金的支持

The Motion of An Inv Nodal Cilium: a Realistic Model Revealing Dynein-Driven Ciliary Motion with Microtubule Mislocalization

Background/Aims: Nodal cilia that rotate in the ventral node play an important role in establishing left-right asymmetry during embryogenesis; however, inv mutant cilia present abnormal movement and induce laterality defects. The mechanism of their motility, which is regulated by dynein activation and microtubule arrangement, has not been fully understood. This study analyzed the dynein-triggered ciliary motion in the abnormal ultrastructure of the inv mutant, aiming to quantitatively evaluate the influence of microtubule mislocalization on the movement of the cilium. Methods: We established a realistic 3-D model of an inv mutant cilium with an ultrastructure based on tomographic datasets generated by ultra-high voltage electron microscopy. The time-variant activation of the axonemal dynein force was simulated by pairs of point loads and embedded at dynein-mounted positions between adjacent microtubule doublets in this mathematical model. Utilizing the finite element method and deformable grid, the motility of the mutant cilium that is induced by various dynein activation hypotheses was investigated and compared to experimental observation. Results: The results indicate that for the inv mutant, simulations of the ciliary movement with the engagement of dyneins based on the distance-controlled pattern in the partially activation scenario are broadly consistent with the observation; the shortening of the microtubules induces smaller movement amplitudes, while the angles of the mislocalized microtubules affect the pattern of the ciliary movement, and during the ciliary movement, the microtubules swing and twist in the mutant ciliary body. Conclusion: More generally, this study implies that dynein engagement is sensitive to subtle geometric changes in the axoneme, and thus, this geometry greatly influences the integrity of a well-formed ciliary rotation